University of Alberta
ASSESSMENT OF THE EFFICACY OF TOPICAL DICLOFENAC USING THE
WOMAC VA3.0 AND SF-36 AS OUTCOME MEASURES
DAVID W. GRACE O
A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Education
Department of Educational Psycholo gy
Edmonton, AIberta
Spring 1999
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ABSTRACT
In a double blind, randornized, parallel groups design clinical trial of patients with
mild to moderate osteQarthntis of the knee, a topical formulation of 2% diclofenac
(NSAID) lecithin organogel was compared with placebo gel. The WOMAC VA3.0
Osteoarthritis Index, a disease-specific outcome measure, and the SF-36, a generic health
status mesure, were used to detennine treatment efficacy. Gain score arialysis reveald
a significant Merence (ps.05) in Mprovement between diclofenac and placebo over the
treatment period on the pain subscaie of the WOMAC and the physical function
subscales of the WOMAC and SF-36. Pearson correlations were moderate to high
between the three subscales of the WOMAC and the bodily pain, physical function, and
physical role functioning subscales (0.329 to 0.618, al1 significant atps.05). The results
indicate that a topical formulation of 2% diclofenac codd be an effective alternative to
the use of oral NSAIDs in this patient population.
Acknowledgement
I wish to thank the members of my thesis cornmittee, for partïcipating in this
arduous ordeal. To Todd Rogers, my thesis advisor, words cannot express how much
your patience and encouragement has meant to me. You are an editor and teacher
without peer. Thank you for sluggin' it out with me.
1 also wish to thank my parents, Miehael and Vida, who together, made me what I
am today, for better or for wone. Now take a bow.
TABLE OF CONTENTS
Review of Placebo CoritroUed ClinicaZ Trials .............................................................. -5
Use of Topical NSATDs ................................................................................................ -9
Measuremënt Instruments ............................................................................................ 12
WOMAC VA3 . 0 OsteoartBtitis Mex .................................................................. 1 3
SF-36 Heahh Survey .............................................................................................. 14
Design ...... ..... ............. .... ............ ..., ............................................................ 1 5
Subject Selection ................................................................................................... 1 7
Subject Assignment to Treatment ............................................................................... -20
Treatments ................................................................................................................. -21
. . Study Administration ................................................................................................ -23
B Iinding Procedure ............................................................................................ -24
...................................................................................................... Study Sampling 24
........................................................................................................ Ethics ReMew 24
..................................................................................................... Adverse Events -25
................................................................................................... Smdy Documents 26
......................................................................................................... Data fntegrfty 26
Data Analyses ............................................................................................................. 27
Basef ine demographic and cluu'cd analysis ..................... ..... .............................. 2 8
Correlations among the WOMAC and SF-36 subscales at pst-trament ........... 28
O~xtcome measures anatysis .................................... .... ............................................ 29
...................................................................................... Adverse events adysis 30
RESULTS ............................. .. ............ ........... .............. -30
Withdmwak, Dropouts, and RemovaIs ..................................................................... -30
.................................................... BaseIine Demographic and Clinical Characteristics 31
Correlations Among the WOMAC and SF-36 Subscales ............................................ 32
WOMAC Gain Score Analysis .................................................................................... 32
.......................................................................................... SF-3 6 Gain Score AnaIy sis 34
..........,.,.,............................. ...*.................................................-.-... Adverse Events ,,- 36
................................................................................................................. Summq 36
TABLES & FIGURES ....................................................................................................... 39
............................................................................................................... REFERENCES -46
..................................................................... APPENDES ..... ...................,,............. 52
Appendix A
Appendix B .
Appendix C .
Appendix D .
Appencb E .
Appendix F .
Appendix G .
. WOMAC VA3 O Osteoarthritis Index ................... ..... ................. -52
........................................................................... SF-36 Health Survey -56
....................................................................... Infomed Consent Fom 59
Patient Mo1TCLatibn Sheet ......................................... ..,.... 60
......................................................... Con&mitanî Medication Record -62
.................................................................................. Ethi& ApprovaI 65
W B 5069 form-Report of an Adverse Reaction or Event Swpected
.................. .. To Drugs, Vaccines, Cosmetics, or Food Products ...... 67
Appendix K Adverse Eveats: DefinitionS. Guidelines for Classification, and
Criteria for Deteiraiinhg Relationsbip to Study Medication ............... 68
.............................................. ............... Appendix I Patient Case Repos Form .. 72
............ ................ . Appendix -3 Adverse Eveats TabIe ...... A
LIST OF TABLES
TABLE I Schedule of Chical Study .................. .... ........................................... 16
TABLE 2 Subject Drop-outs. Withdrawais. and Removds by Group ....................... 39
TABLE 3 Baseline Demographic and Ct in i~L Charactefistics by Group ................. 40
TABLE 4 WOMAC and SF-36 Subsc.de CofteIations by h u p ............................. -41
TABLE 5 WOMAC Subscale Re vs . Poa Within Group Me- and Gain
Scores by Group .............. .... ................................................................ 42
TABLE 6 SF-36 Subsixie Re vs . Post Within Group Means and Gain
Scores by Group ......................................................................................... 43
TABLE 7 Adverse Events by Gtoup .................... ... ............................................. 44
LIST OF FIGURES
FIGURE 1. WOMAC Pain Subscale 'Gain Score ..................... ..... ..CC....C~.CCC -.---.---.. -45
Assessrnent of the Efficacy of Topical Diciofenac using
the W-C VA3.0 and SF-36 as Outcome Mesures
Osteoarthritis (OA) is characterized by progressive degeneration of articular
cartilage. Epidemiological data indicate that the presence and severity of OA increases
wiîh age, although the disease may not be an inevitable result of aging (Felson, 1990;
Moskowitz, 1993; Rosenbloom, Brooks, Bellamy, and Buchanan, 1985). OA is
uncornmon in adula under the age of 40 and extremely common in those above 60.
Lifestyle, occupation and possibly genetic facton may be of etiological importance
(Felson, 1990). The relationship between risk factors and OA may differ across joints.
For iower extremity joints, obesity and injury either due to acute events or to repetitive
impact loading rnay be the most important preventable causes of the disease.
OA, also known as degenerative joint disease, has traditionally been classified into
two main subgroups: primary or idiopathic OA (occurring in the absence of any known
underlying factor) and secondary OA. In the laiter, predisposing facton include: physical
trauma, previous joint diseases, rnechanicaVanatomica anomalies, endocrine/metabolic
disorders, and neurological deficiencies (Rosenbloom et al., 1985). Whether pnmary or
secondary, the disease results in joint pain, joint stiffbess, restricted range of motion, and
joint crepitus. Joint articular cartilage and subchondral bone are the sites of these
abnoxmalities f o n d in the osteoarthritic process (Moskowitz, 1992). The disease is slow
in its evolution, and results in two primas, pathological responses. One pathological
response is the structural breakdown of cartilage leading to the development of erosions
on the cartilage surface. Contrasting with this structural loss is a second response, a joint
space narrowing due to the growth of new cartiIage and bone at the joint periphery,
resulting in osteophyte spur formation (Moskowitz, 1993).
OA often affects certain joints and spares others. Disease predeliction is for hand
joints involved in pincer grip type actions and lower weight bearing joints-joints not
designed for these tasks (Moskowitz, 1993). The interphalangeal joints of the hands
(distal and proximal), the carpometacarpal joint of the thumb, the ceMcal and lumbar
spines, the first metarsophalangeal joinf and, pxticularly the hips and hees, are primary
target areas for OA. However, OA of the h e e is of particular importance due to the
increased risk of developing co-morbidities.
Treatment of OA involves a multifaceted approach including patient education, rest,
medication, phy siotherap y, occupational therapy, and in selected patients, the use of
intra-articular steroid injections or, possibly, surgical intervention. Ho wever, the
mainstay of management is the use of oral non-steroidal anti-inflammatory drugs
(NSAIDs) (Badley, 198 1; Heynernan, 1995).
Generally, NSAIDs are weak organic acids that demonstrate a tendency to
accumulate at infiamed tissue sites. NSAIDs are thought to suppress infiammation by
reducing prostaglandin synthesis through the inhibition of cyclosxy genase. It is now
evident that the inhibition of cyclooxygenase2 (COX2), the inducible forrn of cyclo-
oxygenase, is the primary pharmacological instrument responsible for reducing
inflammation (Vane, 1994). The inhibition of its constitutive COXl is the mechanism
responsible for many of the adverse effects associated with NSAIDs (Vaile & Davis,
1998). A number of compounds, selective COX2 inhibitors, clairning greater efficacy
and an improved safety profile, are cunently in development or have recently received
reguiatory approval.
The use of oral NSAIDs is associated with a significant adverse event profile.
Many sources (Evans et al., 1995; Figueras, Capalle, Castel, and Laorie, 1994; Johnson,
Quinn, and O Day, 1995; Zimmeman, Siguencia, and Tsvang, 1995) document an
increased risk of peptic ulmtion and upper gastrointestinal tract bleeding in persons
using oral NSAIDs. The oral NSAID-related morbidity is high, primarily due to
gastrointestinal complications including ulceration and bleeding. Gastrointestinal (GI)
side effects occur in roughly 25% of those who use oral NSAIDs and treatment of these
complications has been found to add 45% to the cost of rheumatic disease care (Figueras
et al., 1994; Johnson et al., 1995). Incidences of Life-threatening gastric or duodenal
perforation and GI bleeding are 2-fold higher in elderly patients treated with oral
NSAIDs than in the younger population and the risk of fatal outcome is p a t e r in the
elderly (Davies & Anderson, 1997). OA is one of the most frequent diseases encountered
in the elderly and they cornrnonly use oral NSAIDs. Consequently, there is an additive
effect in patients with OA to present NSAIDs' side eflects: increased age and NSAID
intake (Smalley, 1995).
Efforts have been made to find solutions to the significant adverse effect profile
associated with the use oral NSAIDs. These include the development of safer anti-
inflammatory dmgs such as targeted COX2 inhibitors and modifications in the manner by
which NSAIDs are deiivered. Modifications of the oral NSAID fomdations include
buEered and sustained release products. Alternative routes of delivery include
intravenous and rectal adrninistratio~ however, these are still associated with significant
adverse events due to their reliance upon systemic h g distribution (Vaile et al., 1998).
There has also been considerable interest in the development of non-systemic routes of
NSAID delivery in recent years. These are applied topically and include sprays, plasters,
creams and gels. The rationale for using topical NSAIDs is that while there are generally
lower systemic concentrations of the h g , high concentrations can be achieved locally,
thus diminishing the risk of systernic side effects such as GI bleeding (McNeill, 1992).
Applied topically, these dmgs are formulated to penetrate the straturn comeum in
significant enough amounts to exert therapeutic activity. Reports of local enhanced
topical delivery (LETD) indicate resultant increased tissue to plasma ratios, as well as
two tissue concentration peaks. The first peak corresponds to initial local delivery and
the second peak corresponds to the dmg plasma profde (Rademacher et al., 1991; Singh
& Roberts, 1994). LETD for topical NSAIDs has been reported to occur as far as skin,
subcutaneous fatty tissue, and muscle. Topical application of NSAIDs has resulted in
measureable dmg concentrations in soft tissue compartments, enough to inhibit
inflammation. However, evidence is inconclusive regarding deeper tissues such as the
synoviurn (Grahame, 1996). Low correlations between plasma levels and therapeutic
effect, moderate to hi& correlations between plasma levels and toxicity, and moderate to
high correlations between synovial fluid levels and therapeutic effect al1 suggest that
local depots of NSAIDs may irnprove the therapeutic window for this class of agents
(Davies, 1 997).
LETD is largely dependent on the nature of dnig and vehicle, as well as skin
integrity and hydration Following topical administration of an emufsion gel or a solution
gel of diclofenac, the maximum plasma concentrations were 10% of that reached after an
intramuscular injection. The of the solution gel was almost mice that of the
emulsion gel and was reached in shorter time (Seth, 1992). A submicron erndsion
vehicle (SME) dernoIlstrateci a 40% increase in activity compared to conventional topical
formulations of diclofenac, amiutable to the dual effects of s d l e r particle size and the
penetration enhancement abiiities of phospholipids (Friedman, Schwarz, and Weisspapir,
1995). Use of phospholipid systems in topical diclofenac delivery is gaixing acceptance
due to a good tolerability profile, in addition to enhanced penetration of h g through the
strutum corneum (Friedman et al.; Kriwet & Muller-Goymann, 1995). Lecithin
organogels, which are phospholipid micro-emulsion systems, have been advocated in the
topical delivery of diclofenac, although only evidence of in vitro testing has been
available to predict percutaneous absorption (Dreher, Walde, Walther, and Wehrli, 1997;
Willimann, Walde, Luisi, Gazzaniga, and Stroppolo, 1992).
Review of Placebo Controlled Human Trials
Experience with topical NSAIDs has been gained through use in opthamology
(Koay, 1996) and acute soft tissue injuries (Campbell, & Dunn, 1994; Heyneman, 1995).
Scarce information is available on eficacy and safety in treating OA (Bakshi, Darekar,
Langdon, and Rotman, 1991; Dreiser & TisneCarnus, 1993; Rau & Hockel, 1989; Vaile
et al., 1998). Kageyama (1 987) conducted a randomized, double-blind, placebo
controlled, mdticentre study of piroxiwn gel in 246 patients with OA of the knee and
reported significantly greater improvement than placebo on a nurnber of efncacy
parameters which included spontaneous pain, tendemess, pain on movement, swelling,
and limitation of movement. In addition, patients and physicians assessed overall
improvernent (5-level scale) and response to the study dnig. It is unclear which efficacy
parameters were analyzed and what the "response to study dnig" was. Analysis of
changes in individual symptoms and quality of life measurements revealed that piroxicam
provided "signi ficantly better and more rapid improvement than placebo" (p. 1 1 5). What
these symptoms were (efficacy parameters?) and what the Quaiïty of Life (QOL)
rneasures were, is not revealed. Methods of statistical analyses are also not mentioned.
While the study seems intriguing, it was published in abstract form oniy.
Rademacher et ai. (1991) conducted a double-blind placebo controlled trial
comparing diclofenac gel to placebo gel on ten subjects with bilateral syrnptomatic
involvement (OA of both knees), spplying a different treatment to each hee. While the
primary research interest was to measure and compare dmg concentrations in synovial
fluid and plasma, h e e flexion and knee joint circumference were also measured. The
data were analyzed at pre and p s t treatment using paired t-tests. Improvement was seen
in both knees over time on both measures (w -05); however, no significant ciifferences
were found between the two treatrnents.
Sandelin et al. (1997) compared topical NSAID (eltenac), oral diclofenac, and
placebo in a randomized, double blind, multitentre study of 290 patients with OA of the
knee. The prirnary outcome rneasures, Lequesne's Index (a composite index measuring
pain and physical function) and a visual analog pain s a l e exhibited no significant
differences between either of the active treatrnents and placebo. Subgroup analysis of
patients with more severe symptoms at baseline showed statisticai significance, at pst-
treatment, between the active treatments and placebo on these measures. This was a well-
designed study, with three pardel groups, allowing sirnultaneou wmparisons of a local
(topical) and a systemic (oral) NSAID treatment with placebo. A number of reasonable
explanations for a strong placebo effect were suggested, including poor design of
outcome instrument items, making them susceptible to extreme responses. The cooiing
effect of the gel, due to its alcohol content, and local self-administration (mbbing) were
dso suggested as explanations for the placebo effect The authors suggest that, taking
into account the characteristics of 04 and the adverse events pronle of oral NSAlDs
reported in the literatwe, the NSAID gel couid be a safe alternative to oral medication,
parîjcularly in patients with more severe pain.
Moore, Tramer, Carroll, Wiffen and McQuay (1998) perfonned a quantitative meta-
analysis by which they examined the efficacy and d e t y of topical NSAIDs in acute and
chronic pain conditions (arthntis, rheumatism). niey ùicluded ail randomized clinical
trials in which pain was an outcome and compared topical NSAIDs with placebo, with
another topical NSAID, or with an oral NSAID. In the effort to locate repoits of these
clinical triais, a number of different search strategies were employed: Iibrary databases
(Medline, Embase, and the Oxford Pain Relief Database) with no restriction to English
language, and requests of phmaceutical wmpanies for unpublished reports. Abstracts
and reviews were not sought.
Al1 eligible reports were reviewed independently by each of the 5 authors to assess
adequacy of randornization and blinding, and to assess description of withdrawals. Al1
reviewers met for purposes of artairing consensus on trial quality rating. Trials described
as randomized were given one point and if the method of randomizaton was Mly
described and deemed adquate (e.g., cornputer-generated or a table of random numbers),
an additionai point was given. Inadequately randomized or non-randomized trials were
excluded fiom M e r analysis. Trials described as blinded were given one point and if
the blinding procedure was described and adequate (e.g. identicai a p e c e of
treatments), a M e r point was awarded Reports describing the reasons for and number
of withdrawals were given one point The minimum trial quality score was one and the
maximum was five.
Despite the authors' ~mprehensive efforts to review al1 eligible topical NSAID
dinical trids, and the relatively minimal standards for trial quality they set, only 12
placebo-controlled clinical trials examining treatment for chronic conditions were
retained for M e r analysis. The mean trial quality score for these 12 trials was 3.15. Of
these, only four exarnined the use of topical NSAlDs with OA subjects (two with OA of
the knee). Four of the twelve studies used diclofenac as the active treatment, of these
four, two used a plaster (patch) delivery method and two used a topical gel form of
delivery. Outcome measures for the 12 tr ials included: a 4-point pain intensity scale, a
single visual analog scale for pain, physician and patient global assessments, a 4-point
verbal pain scale, and a 5-point global rating scale.
The authors found tbat in treating chronic conditions, topicai NSAIDs performed
significantly better than placebo (p=.05) with a "number needed to treatl' mean of 3.1
(range of 2.7 to 3.8). The "number needed to treat" represents the number of subjects that
would have to be treated with a topical NSAID to achieve a successN outcorne who
would not have done so treated with placebo. Local and systemic adverse events were
rare (3.6% and OS%, respectively) and of these, only 0.5% were considered serious
enough to withdraw the subject. These incidence nites were similar to those of placebo.
While these meta-analysis results (efficacy and safety) could be viewed as biased,
owing to a publication preference for trials with positive finduigs, this quantitative review
does serve to point out the scarcity of ngorous clinical m a l s in which the efficacy and
safety of topical NSAIDs has been "scientifically" assessed Specifically, it calls attention
to the absence of published placebo controlled dinical trials for OA of the knee using a
topical diclofenac gel treatment and employing comprehensive, reliable, and valid
patientdriven outcome measurement instruments.
Use of To~icai N S m s
Topical NSAIDs have been approved for the treatment of OA in Europe and in
parts of Asia for approximately 15 years. Clearly, unpublished, proprietary clinical trial
reports for the purposes of obtauiing regulatory agency approval exist, but are
unavailable. In North America, the Health Protection Branch (HPB) in Canada, and the
Federal Drug Administration (FDA) in the U.S.A., have yet to approve a topical NSAID
for the treatment of OA. This is due, in part, to a more comprehensive set of subrnission
procedures than that required by European and Asian regulatory agencies. This increased
requirement is based upon the presence of adverse event profiles associated with this
route of delivery. Reviews of clinical trials submitted for regulatory approval have
uncovered a 1% to 2% rate of sensitization following topical application, possibly
resulting in a serious adverse reaction when a subject is exposed systemically (orally) to
the same drug or to another NSAID (Health Canada, 1998).
With other classes of drugs, alternative routes of delivery submissions required
chemistry, animal toxicology, and, in some cases, small clinical trials in humans for
purposes of determining safety (Phase 1). Due to the nature of the adverse effects profile
associated with topical NSAIDs, regulatory agencies now require phamiaceutical
companies to conduct al1 phases of investigation required for a New h g Submission
(Health Canada, 1998). This requires Phase II and III human dinical trials wsting
hundreds of millions of dollars. This may be viewed as a prohibitively expensive
procedure to undertake, when the entry of a îopical NSAID into the market would serve
to cut into the market share already held by that company's oral NSAID.
While not approved by the regulatory bodies in North Amerka, topical NSAIDs
have met with geat favor fiom physicians and patients alike. In Canada, each provincial
or territorial department of health is responsible for regdating the prescription and
compounding of pharmaceuticals (Health Canada, 1998). Daily, physicians prescribe
topical NSAIDs for the treaûnent of OA. Upon receiving a prescription, pharmacists
compound the formulation, mking the NSAID drug powder into a cream, lotion, or gel
base. In Alberta, the most popular of these topical NSAID compounds is 2% diclofenac
in PKLOJELGD. Diclofenac is a potent inhibitor of prostaglandin synthesis and exhibits
powerfùl analgesic effects. Therapeutic doses of oral diclofenac have proven to be equi-
efficacious as other comrnonly-used oral NSAIDs in the treatment of OA (Davies, 1997).
PHLOJELB is a lecithin organogel base possessing penetration enhancing qualities
manufactured by J.A.R. Pharmaceuticals Ltd. of Edmonton, Alberta, Canada. This gel
base was used for both the active cimg and placebo topical formulation. This study was
sponsored by J.A.R. Phamaceuticals Ltd., hereinafter, referred to as the sponsor.
Though the potential benefits of a topical NSAID therapy for treatment of OA are
enormous, there exists a lack of evidence for its therapeutic efficacy and safety. Reports
of clinical trials investigating topical NSAIDs are either unpublished of unacceptable
quality, or not specific to OA of the hee . This study will attempt to determine whether a
topical NSAID is an effective and d e therapeutic intervention for patients with mild to
moderate OA of the knee. Does a topical NSAID alleviate the pais stifniess, and
physical fiinctionhg impairment, symptomabic of osteoarihntis of the knee, significantiy
better than placebo?
Research Hmthesis
The one-tailed research hypothesis is as follows: Patients with mild to moderate OA
of the knee treated with topical2% diclofensc will indicate a signifiant improvement in
physical fûnctioning and the amount of pain and stifiiiess experienced and this
improvement wili be significantly greater than that indicated by patients treated with
topical placebo, as detennined by their responses to the WOMAC VA3.0 Osteoarthntis
Index and the bodily pain and physical fiuiction subscales of the SF-36 Health Survey.
The WOMAC, a disease-specific, OA treatment intervention outcome indicator,
was chosen over other outcome masures for its reliability, validity, and discriminatory
characteristics in assessing clinical efficacy in this study population.
The SF-36 is a generic quality of life measure possessing some subscdes relevant to
the evaluation of treatment efficacy. However, unlike the WOMAC subscales, the SF-36
subscales lack specificity and are susceptible to the expected demographic and clinical
characteristics of the study population: elderly and over-weight, possessing a hi& degree
of bilateral symptomatic involvement, and a hi& rate of chronic comorbidifl. Despite
this concem, significant differences in improvement between the treatment groups in
favour of topical 2% diclofenac on specific SF-36 subscales assessing bodily pain, and
physical function will serve to support the hypothesis.
The outcome measurement instruments used for the detemination of treaûnent
efficacy were the WOMAC (Western Ontario and McMaster Universities) VA3 .O
Osteoarthritis Index, developed by Beltamy, Buchanan, Goldsmith, Campbell, and Stitt
(1988) and the SF-36 (36-Item Short Form Health Survey), developed by Ware and
Sherboume (1992).
Outcome measures used to evaluate the efficacy of treatment interventions include
non-clinical measures such as cost or length of stay and clinical measures such as
mortality or functional outcornes (Wright & Young, 1997). For drug therapies, such as
topical NSAID treatments, the rnost important outcome measures for patients and
physicians are those of health-related quality of life, health status, and functional
outcornes.
Health status scales may be disease-specific or generic measures. Disease-specific
scales focus on a specific disorder, disease, or patient population and the problems
associated with it. They are genemlly considered to be more powerful ùistniments in
detecting the effects of treatment (Bombardier et al., 1995; Hawker, Melfi, Paul, Green,
and Bombardier, 1995; Martin, Engelberg, Agel, and Swiontkowski, 1997). Generic
measures, on the other han& due to their broader perspective, are better able to detect
concomitant complications in areas not spcifically related to the disease under
consideration. They also allow treatment impact to be compared across a variety of
populations and medical conditions.
WOMAC VA3.0 Osteoarthritis Index. The WOMAC (Appendix A) is a disease-
specific, multi-dimensional, self-administered, health status instrument developed
specificaily for patients with lower extremity arthritis. It is widely used to evduate the
effectiveness of operative and non-operative therapeutic interventions for the treatment of
OA. The WOMAC consists of 24 questions aggregated into 3 sepamte subscaies
measuring the foliowing dimensions using a visual analog scale (VAS): pain (5 items),
stiflhess (2 items), and physicd fûnction (17 items). There is no WOMAC cumulative
score.
The instructions for completing the WOMAC are presented to the subjects with
reference to study joint, that is, "arthritis in your knee". Item response polarity is
consistent throughout the three subscdes. The left anchor, "no", indicates an absence of
a characteritic (e-g., pain) and the right anchor, "extreme", indicates an excessive amount
of this characteristic. Subjects are instnicted to place an x on a line comecting the two
anchors, indicating the degree of pain, stiffbess or disability they had experienced in the
1 s t 48 hours. The WOMAC can be completed in about ten minutes.
Nurnerous studies report the WOMAC to be a reliable (Internal Consistency-
Cronbach's alpha range from 0.75 to 0.94 and test-re-test reliability-Inter Class
Correlations PCC] range h m 0.85 to 0.95) instrument for the assessrnent of symptoms
and physicd functioning ability in patients with OA of the knee (Bombardier et al., 1995;
Martin et al., 1997; Wright & Young, 1997). Being there is no "gold standard'' for
purposes of cornparison, a nurnber of techniques have been used to investigate the
WOMAC's criterion, content, constmct, and discriminant validity. These techniques
include examination of fiwr and ceiling effects, physician instrument ratings, and
receiver O perating characteristic curve analy sis. Without exception, the authon believe
the WOMAC to be a valid measurement instrument for use with this specific patient
population (Beaton et al.; Bombardier et al.; Martin et al.; Wright et al.).
SF-36 Health Survev. The SF-36 (Appendix B)is the most frequently used health-
status rneasure in North America It was developed to address general health concepts
not specific to any age, disease, or treatment group and to allow for cornparisons of the
relative burden of different diseases and the relative benefits of diffeirent treatments
(Ware, 1992). The SF-36 comprises of 36 questions aggregated into 8 subscales
measuring the following dimensions: general hedth perceptions (5 items), physisal
functioning (10 items), social functioning (2 items), bodily pain (2 items), general mental
health (5 items), vitality (4 items), physical role fhctioning (4 items), and emotional role
functioning (3 items). One item not included in any of the subscaies, reported health
transition, used to measure changes in health status, may be administered as a
supplemental question. For the purposes of this study, the health transition item was
included and anaiyzed as an additional subscale. The clinical investigator also chose to
rernove four of the five items comprising the general health perception subscale. The
items were deemed redundant, adding little information to the one rernaining item.
Item response choices range corn a dichotomous to a six-level response continuum.
A subscale's (physical and ernotional role hctioning) dichotomous (YesMo) items were
aggregated and qwtified, in effect creating a subscale response choice not d i k e a
multi-level response option. For example, in the case of a three-item dichotomous
response subscale, a value (one) was assigned to a "yes" response and a value (two) was
assigned to a "no" response, thus making the minimum response score on that subscale a
three, and the maximum response score, a six. Adjustments were made for differing item
and subscale response, standardin'ng them so that the larger the item and subscale
response score, the greater the respondentls bctioning, health and Mtality, and the less
pain experienced As is the case with the WOMAC, the use of a summary SF-36 score is
not recommended. It is self-administered and can be completed in approximately 10
minutes.
The SF-36 has dso k e n shown to be a reliable (subscale ICC range 0.3 1 to 0.9 1)
and valid rneasure of general health status with patients who have a variety of conditions
across a wide range of age. diseases, or treatment groups (Bombardier et al., 1995; Martin
et al., 1997; Wright et al., 1997).
Design
The study was of a double-blind, randomized, placebo-controlled parallel groups
design. The schematic of this design is:
where,
O1 - Screening Visit, O2 - Washout f eriod, O3 - Final Enrollment Visit, RA - Treatment Period (Active Dnig), Rp - Treatment Period (Placebo), and O4 - Post-Treatment Visit.
The schedule of the clinical midy as it was conducted is presented in Table 1 on page 16.
Table t
Schedule of Clinical Study
Component Screening Washout Final Enrollment Treatment Post-Treatment (Visit 1) Period (Vi si t 2) Period (Visit 3)
Number of Days 1 3-7 1 14 1 CLINICAL
Medical History X X Physical Examination X X Laboratory Tests X X Vital Signs X X X-ray Review X Adverse Events X Eligibility Review X
MEDICATIONS Acetaminophen Tablets Study Medication
DOCUMENTS & ADMINISTRATION
Informed Consent Form X Patient Information Sheet X Concomitant Medication Record Case Report Forms X X X Randomization X
OUTCOME MEASURES WOMAC X X SF-36 X X
The "independent" or predictor variable in this snidy was the OA treatment
intervention, manipulated by randornly assigning subjects to either the active h g or
placebo treatment groups. Dependent variables were the attributes measured by the three
subscales of the WOMAC (pain, stiffiiess, and physical functioning) and the 9 subscales
of the SF-36 (general health perceptions, physical fùnctioning, social fùndoning, bodily
pain, general mental health, vitality, physical role functioning, mental role functioning,
and health transition). Confounding variables uicluded weight, age, type of symptomatic
involvement, presence of chronic co-morbidity, and presence of acute intermittent illness.
These variables were controlled for by specification (exclusion cntena) in the design
phase of the study and by randomization of subjects to treatment groups.
Subiect Selection
The study subjects were recruited primarily through Dr. Kenneth Skeith's
(Clinical Lnvestigator) Rheumatology practice at the Allin Clinic and clinics at the
University of Alberta Hospital. Additional study subjects were recruited by way of
referrals fiom general practitioners and other rheumatologists in the greater Edmonton,
Alberta region. A notice of the sîudy and request for volunteers was posted in the lobby
and elevators at the Allin Clinic. Recruitment of potential study subjects (candidates)
began March 1997 and was completed October 1997.
During the Screening Visit (Visit l), each candidate was given a fidl explanation of
the study by the clinicd investigator or research nurse. When it was apparent that the
candidate understood the Mormed Consent Form (Appendk C), Patient Information
Sheet (Appendix D), and implications of participating in the study, they were asked to
sign and date the Informed Consent Fom. The candidate was provided with a copy of
the signed Monned Consent Fom and Patient Monnation Sheet At this time the
candidate was assigned a Screening ID#. They were then evaluated on their general
health status and eligibility for study entry was determined.
To be selected candidates had to satisfj the following study inclusion criteria:
at least 35 yean of age availability of subject for entire study period willingness to adhere to protocol requirements symptomatic and radiologie OA of the knee requiring daily h g therapy OA disease duration of at least 3 months clinically relevant laboratory values within f 10% of normal range.
Subjects were excluded if they possessed any one of the following exchsion criteria:
Stage 4 OA recent history (in the last two years) or presence of alcohol abuse women who are pregnant, lactating, or of childbearing potential and not using an effective form of birth control si gni ficant history of allergies corticosteroid or hyaluronic acid injections of target knee within one month prior to enrollment hypersensitivity to any NSAID local skin disease prior joint replacement surgery on target knee started physiotherapy in the preceding two weeks or anticipate starting or stopping physiotherapy during the study blood donation in previous 56 days multiple blood sampling 30 &ys prior to shidy onset subjects possessing a language or psychological barrier.
A medical histoxy, physical examination, and blood and urine sampling for
laboratory tests were then completed for those candidates who met the inclusion criteria
and did not possess any of the exclusion criteria. The medicd history consisted of an
evaluation of past or present cardio-vascdar, pulmomry, rnusculoskeletal,
gastrointestinal, genitourinary, neurological, endocrine, psychiatrie, lymphatic,
dennatologic, or immunologic disorder or disease, as well as any other medicai disorders.
The physical examination included vital signs (blood pressure, pulse rate, and respiratory
rate), height and weight, an examination of the eyes, ears, nose, throat, and an
examination of the cardio-vascular, pulmonary, muscuioskeletai, gastrointeStina1,
genitourinary, neurological, psychiatric, lymphatic, derniatologic, haematologic, and
immunologic systems. Blood and urine samples were taken for the following laboratory
tests:
Haematology: leukocytes, erythrocytes, haemoglobin, haernatocrit, platelets, lymphocytes, monocytes, neutrophils, eosinophils, and basophils. Biochernical: B.U.N., glucose, creatinine, sodium, potassium, chloride, uric acid, calcium, inorganic phosphorous, total protein, albumin, total and conjugated bilirubin, A. S.T., A. L. T., and alkaline phosphate. Urinalysis: Specific gravity, pH, W.B.C., albumin, glucose, ketone, bile, RB-C., nitrate, urobilinogen, and microscopie examination.
Baseline demographic characteristics were recorded and the candidate underwent a
series of standard baseline osteoarthntis assessments which included identification of
target knee, type of syrnptomatic involvement, presence of a chronic CO-morbidity,
presence of an acute intermittent illness, duration of OA symptoms, detemination of
ACR (Arnerican College of Rheumatology) functional grade, and determination of OA
radiographie grade. If X-rays of both knees were not current, the candidate was sent to
have them taken at this time-
Al1 snidy candidates were instnicted to discontinue their current NSAID therapy for
a washout period of between 3 and 7 days, until they met the necessary fiare critena
(persistent syrnptoms of OA requiring daily use of medication). Candidates were sent
home with a seven-day supply of acetaminophen 500mg. for pain control and a
Concomitant Medication Record (Appendix E). They were instructed to record the
fkequency and the amount of acetaminophen and other non-OA dmg treatments used
daily on this fonn.
During the Washout Period, the clinical investigator assessed the study candidate's
laboratory parameters for any abnormalities and determined whether they were clinicaily
significant. Laboratory values within IO% extendecl normal values were classified
clinically as nonnd. Those candidates with normal values or abnormal values deemed
clinically insignifiant were eligible for enrollment. Subject X-rays were also reviewed
by the clinical investigator and assigned an OA radiographie grade , if not done
previously. If the candidates had met the necessary flare criteria during the Washout
Penod, had met al1 other entry criteria, and were willing to remain in the study, their
continued participation was confimed at the Final Enrollment Visit (Visit 2). At this
visit, Concomitant Medication Records completed during the Washout Period and unused
acetaminophen tablets were collected nom the study subjects. At this time, the WOMAC
and SF-36 baseline outcome assessments were completed.
Subiect Ass iment to Treatment
Upon confirmation of eligibility, each subject was assigned a study ID# and the
corresponding medication Eighty medications were randomized (40 each for the placebo
treatment and the active dmg treatment) and numbered consecub'vely. As subjects were
enrdled they were assigned the next numbered medication, thus serving to randomly
assign each subject to either placebo or active treatment group. In order to maintain the
blind assignment, replacements were assigned the next numbered medication, not the
treatment of the subject they replaced The cornputer-generated randomization scherne
was developed using SPSS version 7.0 for Windows (SPSS Inc., 1996).
Seventy subjects were expected to complete the study. Recniitment was done on a
wntinuous bais and replacements were added until a total of 70 subjects completed the
study. Both dropsuts and withdrawn subjects were replaced. Drop-outs were classified
as those subjects who failed to complete all visits by their choice. Withbwals were
classified as those subjects withdrawn fkom the study by the dinical investigator for
protocol violations or adverse events. Subjects were discontinued and classified as
withdrawals if there was significant inter-current illness, an adverse event or surgery,
symptoms/signs indicating a possible tolric response, or a failure to comply with the
administrative requirements of the protocol. The clinical investigator was to withdraw a
subject from the study if it was determined the subject did not follow pre-study directions
regarding the use of concomitant medications, conect application of the study
medication, or if the subject was othenvise uncooperative during the study. Detailed
reasons for rernoval were recorded and every effort was made to obtain a complete
follow-up for any withdrawn patient.
Treatments
The active dmg treatment group received 2% diclofenac in PHLDJELa and the
placebo treatment group received PHLOJEL@ alone. Diclofenac is a nonsteroidal anti-
infiammatory drug (NSAID). In pharmacologie studies, diclofenac has exhibited anti-
inflarnmatory, analgesic, and antipyretic activity. As with other NSAIDs, its mode of
action is not known. Its ability to inhibit prostaglandin synthesis, however, may be
involved in its anti-inflammatory activity. PHLOJEL@ is a unique topical base
consisting of lipids and a polymer fomulated in a vehicle of water and alcohol. Its
enhanced penetration characteristics make it suited to deliver therapeutic agents to sites
within the skin or to facilitate their transport through the skin to reach other body tissues
and fluids. PHLOJEL43, with or without active drug, applied to the skin has no
discernible wanning or cooling effect There is also no discernable difference in
appearance between the two treatments.
During the Treatment Period, subjects self-administered the medication assigned to
them, either 2% diclofenac in PHLOJnd (active h g ) or placebo PHLOJELG3, three
times daily at approximately the same times each day for a period of two weeks. Dosage
arnount (2.5 gnuns) was controlled using a level scoop of medication. Subjects were
asked to apply this amount to the target knee. They were to nib the medication ont0 the
afTected area with two fingers for between 5 and 20 seconds and then wash their han&
thoroughly. The target knee was not occluded. Subjects were to maintain their usual
amount and qualiîy of physical activity and were inst~icted that application of the study
medication was to be avoided for one hour before and one hour after strenuous activity or
bathing.
Subjects were given a supply of acetaminophen 500 mg tablets at the Screenùig
Visit p is i t 1 ) for use during the Washout Period and at the Final Enrollment Visit (Visit
2) for use during the Treatment Period. They were instructed to use no more than eight
500 mg tablets per &y for wntrol of pain. No other concomitant medication for ~eating
OA (for example, cortisones, NSAIDs, and pain killers) was allowed Each subject was
questioned specifidy regarding adherence to these restrictions during the Final
Enrollment Visit and Post-Treatment Visit. If they admitted prohibited dnig ingestion,
the clinicai investigator decided whether the subject wss permitted to rernain in the study,
depending on the amount or type of h g used and whether this would have an effect
upon the subjectrs responses on the WOMAC or SF-36. The drug and dosage was noted
and reported. Subjects were asked to record the fiequency of usage and the amount of,
assigned study medication, acetaminophen, and other non-OA dnig treatments used daily
on the Concomitant Medication Record
At the Post-Treatment Visit (Visit 3), Concomitant Medication Records
completed during the Treatment Penod, unused shidy medication, and unused
acetarninophen tablets were coiiected fiom the subjects. During this visit, the series of
clinical assessments that were administered during the Final Enroiiment Visit (Visit 2)
were completed (see page 18). The second set of WOMAC and SF-36 outcome
instruments were completed by subjects at this time. Blood and urine samples were
collected for the haematology, biochemical and urinalysis laboratory tests. Upon receipt
of the laboratory results, the clinical investigator assessed each abnormal laboratory value
outside off 10% of n o d values and determined whether it was clinically significant
and treatment related. Laboratory values within 10% extended n o m 1 values were not
assessed as they were assumed to be clinically normal. Treatment related abnormal
laboratory values were reported as an adverse event.
Study Administration
Drug Accountabilitv. AR inventory record of study dntgs dispensed and retumed
was maintained. Study medication and concomitant medication (acetarninophen) for the
purpose of pain control, was provided to study subjects in both treatment groups.
Blindinn Procedure. Neither the clinical investigator nor the research nune in
charge of the clinical aspects of the study, in +cular of the adverse events, was
infonned of which study medication (placebo or active h g ) the study subjects were
given. The subjects were dso unaware of which study medication they were given. The
employees of J.A.R Pharmaceuticals Ltd, responsible for the manufâcture, packaging,
and labeling of study rnedications, and data input personnel were unaware of the blinding
code. Upon coding the medication containers, the principal investigator sealed the
randomization scheme in an envelope to be opened after al1 data had been entered into
study database or, in the case d a serious adverse event, it was deemed necessary by the
clinical investigator to detemine a subject's medication
Studv Samplina. No more than 60ml of blood was dram fiom each subject over
the duration of the study. Blood and urine samples were collected for laboratory testing
during the Screening Visit (Visit 1) and Post-Treatment Visit (Visit 3). These were
collected and processed by the Dynacare Kasper Medical Laboratory staff on-site at the
Allin C h i c and sent to their central facility for analysis.
Ethics Review. An Application for Ethics Review, the Study Protocol, an Informed
Consent Form, and a Patient Information Sheet were submitted to the Institutional
Review Board (Caritas Research Steering Cornmittee) for ethics approval. Verbal
approval to conduct the shidy was given pending the incorporation of suggested minor
amendments to these documents. These changes were made, reviewed, and written ethics
approval was received prior to initiation of the study (Appendix F). Guidelines as drawn
up by the Institutional Review Board were followed with regard to the ethical treatment
of human subjects in the study.
Adverse Events. C l in id adverse events or serious adverse events were
subjective or objective signs or symptoms of illness that appeared during the course of
the study regardless of whether they had a causal relationship to study medication. This
included al1 events both expected (known p h a d o g i c response) and unexpected or
mwanted. Moreover, dl events that occurred in relation to the clinicai study after the
last drug administration were estimated as an Adverse Event or Serious Adverse Event.
It was the clhical investigator's responsibility to record and report d l adverse
events occming during the study (including al1 deviations of Iaborato~y values from
normal ranges), regardless of their relationship to the study medication. If judged
necessary by the clinical investigator, an adverse event was recorded on the HPB 5069
form - Report of an Adverse Reaction or Event Suspected Due to Drugs, Vaccines,
Cosmetics, or Food Products (Appendix G).
Information about a serious adverse event was recorded on the HPB 5069 form and
was reported to the Sponsor within one working day. This report was to contain a
detailed description of the observed symptorns and the contra-active therapy prescribed.
The clinical investigator was to judge the possible causal relationship between the event
and the study dmg. The cl inid investigator was to arrange additional examinations at
his own discretion to clarify if the event was connected with the study medication and to
decide whether or not a specialist should be consdted Al1 adverse events, serious or not,
were followed up and reported regularly to the Sponsor until an outcorne was known.
The Sponsor or its representative was responsible for notification to regdatory agencies.
Definitions of adverse and serious adverse events, guidelines for classification of adverse
events, cnteria for determining the relationship of sny adverse event to study medication,
and requirements for adverse events documentation are fond in Appendix H.
Studv Documents. Study documents were designed to fulfill regdatory
requirements (Study Protocol, Clinical Trial Document Amendment Form, Informed
Consent Fom and an Adverse Events Table), and to facilitate subject, clinical
investigator, and research nurse protocol cornpliance (Patient Information Sheet,
Concomitant Medication Record, Schedule of Clinicd Study Fable II and Patient Case
Report Forrn [Appendix I]). Other documents, developed by outside agencies, were also
used. These included the Caritas Steering Cornmittee Application for Ethics Review, the
HPB 5069 form (Report of an Adverse Reaction or Event Suspected Due to Dnigs,
Vaccines, Cosmetics or Food Products), and the two subject-administered outcome
measurement instruments-the WOMAC VA3.0 Osteoarthritis Index and the SF-36 Health
Survey.
A Concomitant Medication Record was aven to study subjects at Screening
(Visit 1), to be completed during the washout period, and at Final Enrollment (Visit 2), to
be completed during the two-week treatment period. Subjects were instmcted to record
the type, dosage amount and fkquency of al1 medications used during the two periods,
including al1 prescription, "over-the-counter" and study medications. The purpose of this
was twofold This "self-record document served not only to alert the clinical
investigator to possible protocol violations (restncted drugs), but, also to increase the
likelihood of regular application of study medication.
Data IntemiW. Patient Case Report Forms (CWs) were designed to serve as
source documents (patient charts) and to facilitate the chronological, by visit, collection
of study data. Demographic and clinical data were collected in order as ourlined in the
CRF. Queries and checklists ensured that few steps were missed and al1 data was
collected as required. Pocket pages held subject x-rays, laboratory results, Adverse
Events Table (Appendix J), completed Concomitant Medication Records, and completed
outcome rneasurement instruments (WOMAC and SF-36). The clinical investigator and
research nurse were queried as to the nature of rnissing data. Where possible, data was
recovered fiom patient charts.
All information pertinent to the analyses of safety and efficacy was coded and
entered into an SPSS database (SPSS Inc., 1996). The entered data was checked for
accuracy by two people and then locked, awaiting the entry of the treatment variable and
subsequent data analysis. Disagreement between the two checkers was resolved through
a mutual review of the midy document in question.
Data Analvses
Al1 statistical tests were nin with alpha set at .05. This was done in consideration
of the conventions existing in the phamaceutical industry. It codd be argued, however,
that due to the subjective nature of responses to the WOMAC and SF-36, a lower
probability value should be employed. More research has to be done on the use of these
outcome rneasures for making decisions regarding the health of patients. It is a relatively
recent concern for the pharmaceutical industry and its regulatory bodies. While the
research hypothesis was one-tailed, two-tailed significance tests were usecl, to provide
protection against excessive Type 1 error.
Al1 sample distributions were assumed to be normal for this population. Levene's
test for equality of variance between groups was conducteci for al1 pararnetric tests.
Statistical analyses were conducted using SPSS version 7.0 for Windows (SPSS Inc.,
1996).
Baseline demomvhic and clinical analvsis. Demographic and clinical
characteristics can be grouped into three categories of variables as follows. Gender,
target knee, type of symptomatic involvement, presence of chronic co-morbidity, and
presence of acute intermittent illness are all categorical, nominal variables. With the
exception of type of symptomatic involvernent they are also dichotomous. ACR @e is
a categorical, ordinal variable. The rernaining demographic and clinical variables. age,
height, weight and duration of OA are continuous or ordered discrete, in that they are
measured on a ranked spectlum possessing quantifiable intervals.
Descriptive statistics, fiequencies and tests for detemiining significant differences
between treatment groups were conducted for each variable at baseline (pre-treatment).
AI1 nominal or ordinal demographic and clinical variables were analyzed for differences
between treatment groups at baseline using Chi-square tests for independence for gender,
target knee selection, presence of chronic co-morbidity, presence of acute intermittent
illness, symptomatic involvement, and ACR grade. Independent samples
t-tests (Bolton, 1997, chap. 5) were used to determine if significant differences existed
between treatment groups at baseline on the following ratio variables: age, height,
weight, and duration of OA.
Correlations arnona the WOMAC and SF-36 subscales at mst-treatment.
Bivariate correlations arnong the subscaies of the WOMAC and the SF-36 were
calculated using the subscale's pst-treatment score aggregated over both treatment
groups. This was done to detennine if a significant relationship existed among subscales,
giving an indication of whether or not they are mewuring s i d a r characteristics of health
status. Pearson's correlation coefficients were wmputed, an appropriate statisticd
procedure to use for quantitative, normalIy distriiuted variables. As mentioned above,
two-tailed tests of signîficance were used for the statistical nnalysis.
Outcome measures analvsis. Though the WOMAC and SF-36 subscales are
comprised of items possessing ordinal scale charsicteristics, there is ample evidence
supporthg the use of parametric statistical tests for analyses. Bolton (1997) States "the
use of parametnc methods to analyze rating s a l e data is considered to be acceptable by
many statisticians, including members of the Federal Dmg Administrationn (p. 540). The
WOMAC consists of three discrete subscaies or variables, however, owhg to the large
number of possible item response values dong a continuum (Visual W o g Scale) and
their ordered nature, they closely resemble continuous, ratio variables and were analyzed
as such.
The SF-36 measmernent instrument consists of nine subscales, twi, of which consist
of one categorical, ordinal variable (general health and change in health), and two of
which con& of multiple dichotomous response items @hysical and emotional role
functioning) that were wnsolidated to produce an ordinal variable. The rernaining five
subscales are classified as ordinal variables. The SF-36 is a robust instrument, in that it
works wel1 with the various populations fhm which its sarnples are ciram and its design
generally precludes the hannful eff- of gross systematic errors or outliers. Thus, the
nine subscales or variables were statistically analyzed using parametric methods.
Analysis of gain scores was w d to determine whether there was a significant
difference in the average score gain of the two treatments on the WOMAC and SF-36
subscales. This is an appropriate statistcai method to ernploy when the study subjects
are drawn randomly nom &&ed populations and if the pwpose of the study is to
compare these subjects with respect to average gain, trend, or other intrasubject contras
(Bock, 1975, chap. 7). The difference in scores fiom basehe to pst-treatment for each
subject was calculateci and the goup mean ofthese changes was then compared between
treatments using an independent samples t-test.
Adverse events andvsis. Adverse events were caîegorized by type and severity.
The andysis was conducteci with alI landomized subjects (74). A wunt and incidence
nite (%) for each category by treatment group were calculated. These included percent
within event, percent within miment, and percent of total number of subjects
randomized,
Results & Discussion
Withdrawals. Dropouts. and Removals
There were 88 candidates screened for the clinicd trial (Table 2). Of this number,
12 candidates did not meet the specified entry criteria Seven did not meet the n m
OA inclusion criteria, 4 did not want to fu1611 the stated study obligations or were
unavailable for the length of the study, and one was unable to dEciently understand the
English language. Two candidates met the enfq cnteria but did not wish to continue
&er the washout period (withdrawals). Hence, 74 subjects remained and were
randornimi Of these, two subjects (boa placebo) did not complete dl visits (drop-outs),
one subject (placebo) was withdrawn fiom the study due to a protocol violation (appiied
medication to the wrong location), and one subject (active dmg) was withdrawn fiom the
study d e r 5 days of treatment due to a skin rash. The final sample sizes (those
completing the clinical trial) were 33 placebo and 37 active drug.
One subject (active dmg) failed to cornplete the WOMAC at the Final Enrollment
Visit (Visit 2) and three subjects (one placebo and two active cimg) failed to complete the
WOMAC at the Post-Treatment Visit (Visit 3). After the removal of these 4 cases, 32
cases in the placebo treatment group and 34 cases in the active dnig treatment group were
included in the statistical analyses of demographic and clinical characteristics and
outcome measures (WOMAC and SF-36).
Baseline Demomphic and Clinical Characteristics
Baseline demographic and clinical characteristics are given in Table 3. There were
no significant differences between treatment groups on baseline characteristics of age,
gender, height, weight, type of symptomatic involvement, presence of chronic co-
morbidities and acute intermittent illnesses, target knee selection, ACR grade, and
duration of OA.
Bilateral symptomatic involvement (OA of both knees) was present in 77% of
subjects and chronic CO-morbidities were experienced by 50% of subjects. Mean age of
the subjects was over 6 1 years. Obesity was characteristic of the population sarnple,
subjects weighing, on average, over 87 kilograms. While these results may seem
extreme, they are characteristic of patients suffering fiom OA of the lower extremities. It
is evident that the sample of subjects for this shidy was representative of the target
population of concern.
Correlations Amonn the WOMAC and SF-36 Subscaies
Pearson's comelations were very high (significant at theps .O1 level) for d l three
WOMAC subscales with each another (Table 4). These co~elations mged fiom 0.715
to 0.867. SF-36 bodily pain, physical fünction, and physical d e function subscales were
moderately to highiy correlated with the three WOMAC subscales (range -0.329 to
-0.6 1 8). Negative correlations are due to the opposite polarities of the WOMAC and the
adjusted SF-36. These correlations were al1 significant atpi .O 1. The rernauiing SF-36
subscales exhibited much lower correlations with the WOMAC subscales (range -0.0 16
to -0.2821, none significant at ps .O 1. This concun with findings reported in the
literature (Wright, 1997; Martin, 1997). With reference to the WOMAC, the highly
correlated SF-36 subscales are likely rneasuring similar constructs and these constructs
are dissimiliar to those being measured by the remaining SF-36 subscales.
WOMAC Gain Score Analvsis
As hypothesized, there was a ~ i ~ f i c a n t difference in gain scores between
treatment groups on the pain and physical fûnction subscales of the WOMAC (Table 5).
Subjects in the active treatment group experienced a significantly greater degree of pain
relief and physical firnctioning ability than did those subjects in the placebo group over
the period of treatment. Repeated measures analysis produced identical resdts.
Figure 1 presents a graphical representation of this significant difference in
improvement between the treatment groups as measured by the pain subscale (the same
scenario applies to the physicd fiinction subscale). At baseline (pre-treatment), the
placebo group experienced less pain than the active treatment group, though not
significantly so. At pst-treatrnent, the active group experienced less pain than the
placebo treatment group. This difference between the treatment groups was also not
signifieant. Only the active group experienced a significant decrease in pain over the
treatment p e n d (on dl WOMAC subscales). Gain score analysis allowed for
quantification of this improvement within each group by subtracting the subjectfs pre-
treatment response score fiom their pst-treatment response score. The group mean of
these differences were calculated and an independent groups t-test was used to compare
the difference means.
n ie diflerence between pre and post within the active group was significant on d l
three subscales. However, while the active group experienced a significant decrease in
stifhess over the course of the study, this decrease was not significantly different than
the decrease in stiffness experienced by the placebo group. A possible explanation for
this is that the stiffhess subscale consists of only two items and may not be of sufficient
sensitivity to discnminate between the two groups. For the same reason, it may be more
sensitive to outliers or extreme respowes than the other two scales.
Stiffhess in OA patients is generalIy most severe upon arising in the morning. It
may not be as great a concem later in the &y as the joints are being worked. One of the
items in the sti&ess scale refers to stiffiiess in the am. and the other refers to stiffhess
later in the &y. Significant differences in responses to the stifiess subscale a.m. item
rnay be mitigated by a more balanced, by group, p.m. item response when item responses
are combined inio subscale scores. A combined group analysis of the two items (using a
paired t-test) revealed no significant differences on the responses to the two items at pre
and pst-treatment. An additional theory, somewhat contradictory to the one presented
above, is as follows: is it possible that experiencing less pain is associated with greater
mobility and physical functioning, resdting in increased knee flexion and usage, and that
this, in tum, leads to knee fatigue and sîiffhess. This was not testable as it invoIves a
comprehensive examination of the stiffhess domain's utility as an important outcome
measure when the primary outcome of interest for a -ment intemention is pain
reduction.
SF-36 Gain Score Analvsis
SF-36 subscaie pre vs. pst within group means and gain scores by group are given
in Table 6. There was no significant ciifference behveen pre and pst-treatments
observed on any of the subscales for the placebo group. n i e active group improved
significantly on the bodily pain, change in health, physical function, and physical role
functioning role subscales. Gain swre analysis found the magnitude of gain from pre to
pst-treatment was significantly greater for the active treatment group than for the
placebo group on the physical fimction and the change in health subscales. On the SF-36,
the physical function subscale has the greatest number of items (IO), dl but one of them
dealing with an activity that requires strenuous movement of the knee or walking. II is
also highly correlatesi with the physical function subscale of the WOMAC. This subscale
looks to be the most sensitive of the SF-36 subscales to an improvement in OA of the
knee due to the number and content of response items.
Hypothesized, a priori, to be an outcome measure supporthg our research
hypothesis, the bodily pain subscale failed to indicate a significant ciifference between
treatment groups in the magnitude of pain relief experienced from pre to pst. M y the
active group experienceed a significant degree of pain relief over tirne. Post-shidy review
of the two bodily pain subscale items fin& overly general references to pain. The items
were not designed to detect disease-specific improvement, nor do the situations presented
involve activities utilin'ng the knees.
The change in healîh scde consists of only one question having five possible
responses, ranging fiom "Much better now than one week ago" to "Much worse now than
one week ago". It queries: Comoared to one week ago, how would you rate your health
in general now? The question asks for a description of generai health, orienting the
subject to make a cornparison to a previous point in time or examine improvement. As
patients were asked this question at baseline (after a 3-7 &y washout), after they had
experienced the "flare" criteria, it is not surprishg they would feel worse than a week
before, when they were stilf on a treatment for OA. The subjects were then asked this
question after they had been on two weeks of study treatment. Those in the placebo
group had been without medication for 3 weeks, while those in the active group had been
on active h g therapy for two weeks. In effecî, the design of the question and this study
serve to exaggerate and moderate the item responses for the active and placebo treatment
groups, respectively. This wouid explain the significant ciifference in gain over treatment
period the active group experienced venus the placebo group.
With the exception of, general health and physical function, d l SF-36 subscales are
composed of items that include a modifjmg phrase, "during the past week", similar to
that of the change in health subscale. The problems with analysis of these suka les are
as presented in the above discussion of the change in health subscale. This confounding
"time element" instrument design characteristic was not forseen during selection of
outcome measurement instruments, nor during the study design phase.
Adverse Events
Al1 subjects randomized (36 placebo and 38 active) were included in the analysis of
safety (Table 7). The active group expenenced six adverse events (four rash, one nausea
and cramps, and one case of hirsutism) and the placebo group, nine adverse events (five
rash, two nausea, one numbness and one cornplaint of pniritis). Al1 adverse events in
both groups were mild in severity and did not require immediate treatment. The nine
"rash" and one p ~ t i s events were detennined by the clinical investigator to be of
"possible" relationship to study medication (active or placebo). Al1 other events were
deemed "not related" to study medications (see Appendix H for explanation). 16% of the
active treatmea group and 25% of the placebo treatment group expenenced some type of
adverse event. While these rates are hi&, the fact that the placebo group had a higher
incidence rate or one at dl, leads one to speculate that a number of "rash" events may
have been caused by the gel and not the dmg. One subject in the active drug treatment
group reporting a rash wss withdrawn fiom the study by the clinical investigator. Al1
other subjects completed the study. Al1 subjects experiencing adverse events had their
symptoms disappear, either during the study, or shortIy afier study completion.
Summarv
Physicians and patients express concem with the intake of oral medications,
particularly when the area exhibiting p i n can be localized. OA of the h e e has been
treated by a number of methods and interest continues to be generated among physicians
and patients for topicid treatments. A significant difference was found between the active
and placebo treatment groups in the magnitude of change on the WOMAC mesures over
the course of treatment. Although both groups improved, it is clear that the active
treatment contributed to a more positive change in patient pain and physicai functioning.
This disease-specific instrument (WOMAC) was designed to detect irnprovement due a
specific intervention. In this study, usefulness of the intervention for a patient's pain and
physicd funaionhg due to a phcular disease (OA of knee), is confimed. Iack of
significant findings on most subscaies in the generic measure (SF-36), as measured by
subject's responses to subscale items, reveal that these elderly subjects continue to
experience major disabilities due to other CO-rnorbidities and symptomatic involvement,
suggesting that addressing one condition (OA of the knee) may not significantly improve
overall functioning.
Use of the WOMAC as a criterion of treatment success or failure in OA may be of
value relative to the recent trend of the regulatory agencies to increase the emphasis
placed upon direct patient impressions (Health Canada, 1998). The direct recording on
rating scales of cornfort, flexibility, and pain rneasures encourage the patient to become
more conscious of the health domains being measured and the treatment process itself
More research needs to be done, exarnining the validity, reliability, and responsiveness of
outcome measurement instruments, both generic and disease-specific, for use with
specific patient populations. This is of particular importance, if these measures are to be
used as the pnmary indicators of treatment efficacy in human ciinical trials for the
purpose of new drug submissions to regulatory agencies.
Future studies regarding topical delivery of diclofenac should compare it to other
topical formulations, evduate chronic usage, and examine optimal dosage range and
intervals. EEcacy of topical diclofenac for the treatment of acute tissue and joint trauma,
such as sports-related injuries, is another possible area of research. From results of this
double-blindeci, placebo-controlled, randomized study, topical diclofenac delivery
appean to have therapeutic value in treatment of OA of the h e e as detennined by a
disease-specific, patient-driven, subjective m e a s u r d e WOMAC Osteoarthritis Index.
Table 2
Subiect Dromuts, Withdrawals and Removals bv gr ou^ -
Reasons Placebo Active N n II
Screening (Visit 1) Did not meet necessary OA inclusion criteria Did not want or were unable to fiilfiIl study obligations UnabIe to sufficientiy understand English
Total 76 Washout Period 76
Did not wish to continue &er washout period
Total 74 Final Enroilment (Visit 2) 36 38 74
Randomization
Total 36 38 74 Treatment Period 36 38 74
Withdrawn from study by clinical investigator due to rash -1" -1
Total 36 37 73 Poçt-treatrnent (Visit 3) 36 37 73 Did not r e m for Post-Treatment Visit (Visit 3) -2d -2 Removed fiom study due to protocol violation -lw - i
Totd 33 37 70 Statistical Analyses of Eflicacy 33 37 70 Failed to complete WOMAC at Finai Enrollment (Visit 2) -1' - 1 Failed to complete WOMAC at Post-Treatment (Visit 3) -1' -2' -3
Total 32 34 66 Note. Adverse events analysis conducted with al1 randornized subjects. WIndicates withdrawals. d~ndicates &op-outs. 'Indicates removals.
Table 3
BaseIine Demogra~hic and Clinlcal Characteristics by gr ou^
Variable Placebo Active Test n n 2
Gender Female 20
Male 12 14 .O9 Target Knee
Left 13 13 Right 19 20 .O 1
Symptomatic Involvement Bilateral 26 25
Unilateral Left 2 3 Unilateral Right 4 6 .56
Chronic Co-morbidiîy Absent 14 18 Present 17 15 -56
Acute Intermittent Illness Absent 28 31 Present 4 2 .80
ACR Grade f O I 2 10 6 3 19 22 4 3 3 2.22
x t sD, (n) x rt SD, (n) t
Age 63.94 + 10.79, (32) 58.62 f 14.19, (34) 1-71 Height (cm) 164.33 f 8.74, (32) 165.78 t 10.64, (34) œ.60 Weight (kg) 85.53 f 17.27, (32) 89.75 f 22.27, (34) 0.86 Duration of OA (months) 143.32 + 153.14, (31) 127.56 f 179.87, (34) 3 8
Table 4
WOMAC and SF-36 Subscale Correlations at Post-Treatment
Subs~alc WOMAC WOMAC WOMAC SF-36 SF-36 SF-36 SF-36 SF-36 SF-36 SF-36 SF-36 SF-36 Emotional Physical
Physical Bodily Change Physical Rolc Gcncral Mental Role Social Pain Stifliicss Furiction Pain in llcallh Funciion Function Hcalh Hcalih Function Functicm Vitalily
WOMAC S(iflms WOMAC Physical Function SF-36 Wily Pain SF-36 Changc in Hcalîh SF-36 Physical Funciion SF-36 Emotional Rolc Function SF-36 Gcneral
SF-36 Mental Health SF-36 Physical Role Funclion SF-36 Social Funcîiori SF-36 Viîalily
Table 5
WOMAC Subscale Pre vs. Post Within Group Means and Gain Scores bv gr ou^
Subscaie Placebo Active Gain 11 X k S D n XISD t
Pain f re-Treatment 32 4.M t 1.83 34 4.47 + 1.75
Post-Treatment 32 3.43 f 1-96 34 2.82 f 1.83 Gain Score 32 -.61 f2.18 34 -1.65 ,+ 1.52 2.27*
Physical Function Pre-Treatment 32 4.15 +, 1.83 34 4.64 + 1.65
Post-Treatment 32 3.70 f 2.02 34 3.442 1-81 Gain Score 32 -.45 + 1.61 34 -1.20 + 1.34 2.07*
Stifhess Pre-Treatrnent 32 4.86 I 2.08 34 4.91 f 1.86
Post-Treatment 32 4.61 + 2.46 34 4.05 i 2.2 1 Gain Score 32 -.25 f 1.88 34 9-86 + 2.01 1.26
* p 5 -05.
SF-36 Subscale Pre vs. Post Within Groun Means and Gain Scores bv Grom
Subscde Placebo Active Gain
Bodily Pain PreTreatment 32 2.86 + -61 33 2.76 f -81 Post-Treatment 32 3.00 i .71 33 3.02 f -85
Gain Score 32 -14 5.59 33 .26 f: .66 0.75 Change in Health
Pre-Tmtment 32 2.97 f -54 3 1 2.77 I -62 Post-Treatment 32 3.16 f .63 31 3.39 f .67
GainScore 32 .19 f -69 31 .61 $ .92 -2.08* Emotional RoIe Functioning
PreTreatment 31 5.48 I.96 32 5.03 f: 1.33 Post-Treatment 3 1 5.45 f .96 32 5.03 f 1.28
Gain Score 31 -.O3 f .75 32 0.00 f 1.14 -.13 GeneraI H d t h
Pre-Treatment 32 3.25 f .88 31 3 .O6 f 1-00 Post-Treatment 32 3.28 * .96 31 3.16 f -97
Gain Score 32 .O3 I -40 31 -10 f -47 -.59 Mental Health
ReTreatment 3 1 4.94 I .84 32 4.70 i .79 Post-Treatment 3 1 5.07 * .67 32 4.68 f .98
Gain Score 31 .12f -67 32 0.02 f .72 -8 1 PhysicaI Function
Pre-Treatment 32 1.97 f .40 34 1.68 i -35 Post-Treabnent 32 1.98 f -46 34 1.83 f -41
Gain Score 32 0.00 f . l8 34 .I5 f .30 -2.33* Phy sical Role Functioning
Pre-Treatment 28 5.57 f 1.67 32 5.22 f 1.48 Post-Treatment 28 5.79 f 1.69 32 5.75 f 1.63
Gain Score 28 .21 i: 1.13 32 -53 f 1.22 -1.04 Social Functioning -
PreTrtatment 32 4.28 f -75 33 3.77 f -88 Post-Treatment 3 2 4.34 f .62 33 3.94 f .96
Gain Score 32 .O6 f .58 33 17 f .79 9.6 1 Vitality
Pre-Treatment 31 3.46 f 1.11 32 3.44 f 1.01 Post-Treatment 3 1 3.56 f .96 32 3.55 * .95
Table 7
Adverse Events bv gr ou^
Severity/Event Placebo Active Total
No Event Count % within event % within treatment % of Total
Count % within event % within treatment % of Total
MildMausea & Cramps Count % within event % within treatment % of Total
Count % within event % within treatment % of Total
Mi WHirsutism Count % within event % within treatment % of Total
Count % within event % within treatxnent % of Total
Count % within event % within treatment % of Total
Total Count
Figure 1
WOMAC Pain Subscale Gain Score
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Appendix A
WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0
INSTFtUCTiONS 70 PATIENTS
In Sections A, 8 and C questions will be asked in the following format and you should give your answers by putt ing an "X" o n the horizontal tine.
NOTE: 1. I f you put your "X" at the left end o f the line, Le.
then you are indicating that you have no pain.
2. If you put your " X " at the right end of rhe Iine, i.e.
then your are indicating that your pain is extreme.
3. Please note: al that the further to the right you place your "X" the more pain you are
experiencing . b) that the further to the left you place your "X" the fess pain you are
experiencing . cl please do not place your "Xn outside the end markers.
You will be asked to indicate on this type of scale the amount of pain, stiffness or disability you have experienced the fast 48 hours.
Remember the further you place your "X" to the right, the more pain, stiffness or disability you are indicating that you experienced. Finaliy, ptease note that you are to complete the questionnaire with respect t o your study jointW. You should think about your study joint(s) when answering the questionnnaire, i.e., you should indicate the severity of your pain, stiffness and physical disability that you feel is caused by arthritis in your study joint(s). Your study jo in tk) has been identified for you by your health care professional. If you are unsure which jointIs) is your study joint, please ask before completing the questionnaire.
WOMAC OSTEOARTHRlf lS INDEX VERSION VA3.0
INSTRUCTIONS: Tho followfng questions concorn tfir mount o f pah you have *
e x p u i n c d due to wzW& th yow hw, Foi rrch aininion, ploato antor th@ imount of pain sxperisncrd in th. lut 48 houtt. (Plrue muk your rnman wfth .n 'X'.)
QUESTION: How much pain do y u hava?
1. Wdüng on a fht surface. rr j r i . i u - 1 I -
2. Going up or down mirs. 1 JLir.rw - 1 I ri*
3. At night white in bsd.
4. Sining or lying.
INSTRUCTiONS: Tb@ following questions concern the amount o f jdk2 stMJess h o t pnn) you h.ve .xpmU18ncd br the Irst 48 hou= in your knm. Stiffness b a sensation of rrsviction or slowness in the rase with which you move your joints. (Floua muk your inswers with in 'X'.)
6. How revera is your Iaffness aftw fint awikrning in the morningl
7. How revue is your stiffneit rftsr ritting, lying or resting 1at.r in th. . dry?
Section C
INSTRUCTlONS: The following questions concern y o w physicrl fvncriun. By this we rnein your wbfity ta moue rroundmd ?O look 8ft.r youneif. For mach of the following acrivities. pleasa indicrte the degtae of difficulry you have experienced in the Iasr 48 hours dur to arthritis in your knee. (PImue mark your answen wi2h an 'X ' . )
QUESnON: Whn degr- of dïfficufty did you have with ...
8. Oescending mirs. * I lem-.
hn I I m
9. Ascending stairs.
10. Rising from sirting.
1 1. Standing.
12. Bending to flooc. I Jtrrnrw
h m I I - 13. Walking on a flat surface.
14. Gening inlout of car.
15. Coing shopping.
16. Putting on socks1stockings. NO I J t m n e
P m 1 t
17. Rising from bed.
18. Taking off sockslstockings.
19. Lying in bed. ' h l JEiom r- I 1 -
20. Getting iniout of bath.
24. Light domestic dulies. i o : IaawWna - 1 1 -
PARIS SECTOGRAM:
Pain (degrtes) Stiffners (degrces) Physicrl Function (degrtes1 Total (degrees)
Appendix B
This sunrey must br cornpleted by the pitirnt and chrckrd for completion by site pwsonnel.
INSTRUCTIONS: This survey asks for your views about your health. This information will help keep track of how you feel and how well you are able to do your usual anivities.
Answer every question by marlu'ng the answer as indicsred. If you are unsure about how to answer a question, please give the best answer you c m .
1. ln general, would you say your health is: . . . . . . . . . . . . . . . . . . . . . Excsllam . . . . . . . . . . . . . . . . . . . . . . . . Vew Good . . . . . - . . . . . . . . . . . . . . . . . Good ........................... Fair . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poor ...........................
2. Combared to one week cao, how wouid you rate your health in general m? kircle one1
Much botter now than one week ego . . . . . 1
Somewhat bener now than one week ago . . 2
About the same as one week ago . . . . . . . 3
Somewhat worse now than one week ego . 4
Much worse now than one week ago . . . . . 5
3. The following items are about acinviues you rnight do during a typical day. Does your health now limit you in these activities? If so, how m u a ?
(circle one nurnber on each Iinel r
A C T l v m ~
a. Vigerow m e s such u running. Sbm h a w objrnt. prninprtinq in mmnvovs swru
h. Modarna uthider ruch as rnovirq J nMe. purmng r vacuum chiner. badinp. or pleying gow
c. Lifting or arrving pcar ies
d. Ctimbiq srvad ffights of stairs
e. Climbing OM nigm of mira
1. Bending. krtaeling. or mooping
p. Wmikùigrnored>in~mih
h. Wiiking sevard bloeirr
i. Wallcing M. Mo&
1. Bir)ung or drcssinq yoursdf
Y*.. Umt.d A Lat
1
1
1
1
1
1
1
1
1
1
ras. umh.d A M.
2
2
No. N o t Umited
At Au
3
3
2
2
3
3
2
2
2
2
2
2
3
3
3
3
3
3
4. Ouring the p s t week, have you had any of rhs following problems with your work or other regolar daily aciivities 4s a rcsuit of vour ~hvsicaf health? s
(Ùrcla one nurnber on erch linel
I YES I NO 1 1 a. tut down on tfu .mount of dm. yau rprnt on work or olhrt 1 I 2 t
5. During rhe pst week, have you hrd any of tfie following problamt with your work or other regular daily activities p s a result of anv emotional ~roblemp (such as fading depressad or anxious)?
(arcle one nurnber on each fine}
l YES NO
6. During the past week, to what exrent has your physical health or ernotional problems interfered with your normal soaal activibes with family, friands, neighbors or groups?
........................ Not at ai1 1
Moderately ....................... 3
Quite a bit ....................... 4
7. How much bodiiv pain have you had during the p a s week? (circle one]
None ........................... 1
........................ Very miId 2
Mild ........................... 3
Moderate ........................ 4
Sevtre .......................... 5
...................... Vcry Severe 6
SF-36 HEALTH SURVEY (contedl
8. During the past week, how much did g~&! interfaru m'th your normal work (including both wotk autside the homa and housework)?
(circle one1
Not at aIl . . . . . . . . . - . . . . . . . . . . . . . . 1
A linlr bit . . . . . . . . . . . . . . . . . . . . . . . . 2
Moderrtely . . . . . . . . . . . . . . . . . . . . . . . 3
Quite 8 bit . . . . . . . . . . . . , . . . . . . . . . 4
Exuemely ........................ 5
9. These questions are about how you ftef and how things hava been with you week. For each question, please give the one answer that cornes ciosest to the way you have k e n feeling. How much o f the time during jhe bast week -
10. During the pest week, how much of the time has your phvsical health or emotional broblems interfered with your social acrivities ilike visiting wkh friends, relatives, etc.)?
(circle one number on each l in4
icircIe one)
AEI of t)W f i e
AI1 of the time . . . , . . . . . . . . . . . . . . . . . 1
Most of the ame . . . . . . . . . . . . . . . . . . . 2
Mort ot th. Tune
Some of the time . . . . . . . . . . . . . . . . . . . 3
A little of the time . . . . . . . . . . . . . . . . . . 4
A Gooù Bk of dia
T i n v
r. Oîd you feel Ml of pep?
b. Havi you been r vrry n e i ~ u r parron?
c. HIW yau Iek CO down in tk dumm thrt nothing muld cheer you up?
d. Have wu felt calm and pracrfut7
r. O i mu havm i bt of rnirgv?
1. Have vou fek downhemed and blif.!
g. Oid v u fed wom out?
h. Hrwi vou besn r hippy prrson?
i. Di8 WU fei l t h d ?
None of the time . . . . . . . . . . . . . . . . . . . 5
3
3
Sonw of th Tune
1 2
1 2
4
0
1
A Unk o f t h . T i
2
None of the
5
5
3 4
3 4 r
3 4
3 4
3 4
6
6
5
5
5
5
5
5
5
1 2
3
3
6
6
6
6
6
6
6
1
1
1
1
1
4
d
1
2
2
2
2
2
Infonned Consent Form
PHARMACEUTICALS LTD.
INFORMED CONSENT F O M
Inwrtigrton: Dr. Kenmeth J. SlIritù, phone nmber 482-7551 Dr. J-cr A. -ers, phone nmmkr 4-78
Patient Ixifonnation Sheet
PHARMACELJTICALS LTD.
PATIENT INFORMATION S m
In the pmsmt study, you wi be tFeabsd with -2% diidolbm in PHLdJUn or PHLoJElm as pkabo (an ineetive substmœ). FIowwer, the study is dw#e-bb'nd; tbat is, neitheryou müw p h l a i a a n w J I k n o w w n i c h o f ~ 2 ~ y o u a r s rweking. T b d ~ o f t h e t r s a t m d n t w ü l & e 2 ~ .
TheshidyriequimadotsIof3viriQ One@--n~visit)ispnortostMingto ensurs thatyouro&amrtMbis ~ a n d t t i a t y o u am &hmvbewidl. Thiswin invoive takingabicmâswnpk. I n t h i s v i s i t n i s w i l l . 6 ( y w r t o s t o p u u r i g a n y o n l ~ d w -
AtttmnoxtVSbif, t h e t o p i c a l m e d i a W n w ü h e ~ a n d a d i n ~ ~ w i l l be mada of the ocüvity ofyowarthntis. You wilf a b b@ mkedbofll out two 8hod questionnaires~wiUtelfwihawmuchyoura~istrwblaigyw. Ywwüiberuquimd togiveanooiersampleof~.
T w weeks after this pu will have the third visit and you will be assesad using the same procedures as the sacond via A lest biood $ample will be drawn at the tirne of the third visit to measure the ievd of dfug in your systern,
Each W will take 1 h r of your time. The total amount of Wood d m from you wiü bs no mm than 4 Wapoms.
Voluntrry Participmdori: Participation in ais study is voiuntary and a refusai to partia'pate will not o t h e w h
affect your Mure mediil mm. F d frse to disculis your participation with y w r fmily and/or primary cars physiâan pdor ta mrdling in this dudy. In addition, you may withdraw at any tim you wish, and equaily, the physician mey requin you to d i n u e if he is canoemed about a possible side effed You may ba asked to anplet8 s post-study examinatioci which indudes: a ml assesment end biood and urine sampies simifar to those taken during the screening visa By agreeing to partiapats in the study, you will aiso agrw to not increase or aiter any of your msdicatioris withaut disaissirtg it with the study investigatorç.
Confidenüality: The records cd this study will be mfidential, and no mentiori will be made of p u r
name in m y reporl; however, J A R Phamaoeuticals Ltd., the Canadian Heatth Pratedion Branch or ooier international mgubbry -85 have the rigM to inspect your study m o r d s (relating to this study only). fil study mords wiB be stomd at JAR. Pharmaœukals Ltd. for a psriod of fiReen ysers.
Please feel fme to ask questions about any aspect of this research, thii infomration shest, or your rights as a study participant, dthar now or in the Mure and you cen dimct p u r questions to Dr. Kerinsth Skeith et 482-7551.
if you bave futther cmcems abouî any aspect of this study, you mey eontad ihe Patient Coriœrns of the Capital Heatth Auttronty at 47-92. This omcb has no affiliation with !he study invwgatom.
JAR-97-0202b
Patient Sludy ID # - - - J.A.R. PharmaceuOcals Ltd. Weeù 2
Patient lnitlals
CONCOMITANT MEDlCAïlON RECORD
Week 2 to (monthlddlyy) (monthlddlyy)
Please fiil out this fwm as wxwmtety as possible. It is very important that you nmfd any and dl medications that you use for the time of the study. This witl give the investigators the information lhey need to detemine the safety and effediveness of the dru0 (gel) lhat is being studied.
Acetarninophen Acetaminophen Acetam i nophen AcetaminoQhen Aœtaminophen
Aœtaminophen Acetaminophen
PHLOJEL " PHLOJEL PHLOJEL
Other (Specify)
DAY 1 -
Dose Time
- DAY 2
Dose
DAY 3 @w
Time Dose Dose
L
Time T i m
MY&
Dose
DAY 6
Time Dose
DAY 7
The Dose Time
JAR-97-0202b
Patient Study ID #
J.A.R. Pharmaceuücals Md. Week 3
Patient lnitials -
CONCOMITANT MEDICATION RECORD
Week 3 to (mon thlddlyy ) (mthidd(W)
Pkase fil1 out this f m as accuratdy es possible. It 1s very important that you record any and al1 medlcatbns that you use for the time of the study. This will give the investigatws the information they need to detemine Vie safety and effectiv- of the drug (gei) that is being studied.
Appendix F
Ethics Approvd
I l CARITAS HEAi Yh GROUP
March 1 9, 1997
Dr, James A Rogers JAR Pharmaceuticals Ltd. Box 60052, University of Alberta Postal Outlet Edmonton, Alberta T6G 2S4
f [ Dear Dr. Rogers:
Re: A Double-Blind, RandomIted, PIacebo-ControlIed Clinicai Tdal of Topical Diclofenac in Pafients with Osteoattttrfti.~ of the Knee Amendment #i - March 7,1997
Thank you for presenting this study at the March 7, 1997 meeting of the Caritas Research Steering Cornmittee, and for subrnitting Amendment #t to the P ~ ~ O C O I , dated Mar& 7,1997.
Amendment #1 makes a change in the dose and application instructions to more dosely nfled the common application pradiœs and dose amount curretntly employed by patients in Alberta using topical diclofenac This change is acceptable to the Cornmittee.
Amendment #l also makes the following changes requested by the Cornmittee: 1. A font change to improve readability. in consideration that many participants will
be elderiy; 2. The sentence with regard to exclusion of individwfs of childbeanng potential
has been underlined for emphasis; 3. The height and weight restridions have b e n removed; 4. The reference to the Cornplaints Onice of the Capital Health Authority has b e n
changed to Brenda Waye, Caritas Corporate Manager.
Wth these changes, the Protocol as amended and the InfonaüonlConsent F o m have the appmval of the Caritas Research Steenng Committee from an ethical and scientific viewpoint
.... 2
Mrmbers Edmonton Gcnml Site Misericordia Cmmanity Health Cmm Crcy Nuns Community Hmllh Cenln?
We w I d a-ate a report to out Committee on completion of ais projed. It would aIso be appreeiated if credit would be given to Caritas and its Research Steering Cornmittee in publications where appropriate.
if you have any questions, phase do not hesitate to mtad me. I c m be paged at the Grey N w s Community Hospital and Health Centre, or you may have a message with the cornmittee secretary, Ms. Peggy Morton, et 930-5924 or fax 930-5961.
Chair, Caritas Research Stearing Cornmittee k
f t
~llwpdo~1\rosearchMclofenac.m24 CRSC Fife
Amendment #l incorporates al1 the changes rsquested by the Cornmittee as follove:
Appendut G
HPB 5069 form-Report of an Adverse Reaction or Event Suspected
To Drugs, Vaccines, Cosmetics, or Fmd Products
Appendix H
Adverse Events: Definitions, Guidelines for Classification, and
Ciiteria for Determining Relationshîp to Study Medication
Definitions
Clinical adverse events or senous adverse events are illness subjective or objective signs
or symptoms that have appearrd during the course of a study indtptndently of a causai
relationship to study medication. This includcs al1 events both cxpcctcd (known
phannacologic responsc) and uncxpccted or unwanttd occUrriLlg during the course of the
study. Moreover, al1 events that occur in relation to a clinical study afbr the last drug
administration have to be estimated as an Adverse Event or Senous Adverse Event.
AdVmmehnnCI Event reiated or non-related to study medications
Intercurrent illnesses
Important abnormal labomtory values, as well as significant shifts fiom basdine within
the range of normai, which the Cliaical Investigator considers to be clinidly important
ri^ Advaru hrrnb Overdose
Resuits in in-patient hospiidization
Life-threatening
Fatal
Cancer
Permanently Disabling
Classification of Adverse Events
Al1 adverse events will be recordeci on an adverse event information shed and
Causing no limitations of usual activities; the subject may experience slight discornfort.
Causing some limitation of usual activities; the subject may experience annoying
discornfort.
Causing inability to carry out usual activities; the subject may experience intolerable
discornfort or pain.
CausalitylDrug-Related Assessrnent
The ClinicaI Investigator will detennine the relationship of any adverse evmt to
study medication according to the following cnteria:
Definite
A reaction that foIlows a misonable tempord sequmce fiom administration of the dmg;
that foIIows a known or cxpcctcd responst pattern to the suspected drug; that is
confrrmed by improvement of stopping the dnig and by tht mppearance of the reaction
of repeated exposure and that muld not be explaincd by other known b n .
Probable
A reaction that follows a reasonable temporal squence fiom administration of the dmg,
that follows a known or t-ed response pattern to the suspccted d g ; that is
confimeci by improvement of stopping the h g and that couid be txplained by the
administration of the cimg.
Possible
A reaction that fol1ows a reasonable temporal sequence h m adminisiration of the dmg;
that follows a known or expectcd response pattern to the dnig, but that could rcadily have
been produced by a number of other hctors.
Unli k e I ~
A reaction that follows a rcasonable temporal sequcnce h m administration of the drug
but that couid probably not be explained by the administration of the cimg.
Nat related
Registration Procedure of Adverse Events
It is the Clinid Investigator's rcsponsibility to record and report dl adverse
events which occur during the study (including ail deviations of laboratory values h m
normal ranges). regardless of thcir rclationship to the study medication Xfjudged
necesmy by the ClUiicd Investigator, an adverse event will be recorded on the HPB
5069 fonn, Report of an Adverse Reaction or Event Suspectcd Due to Drugs, Vaccines,
Cosmetics or Food Products.
Information about serious adverse event will be recorded on the HPB 5069 form and will
k reported to the Sponsor within one worlcing day. Thû report will contain a &tailcd
description of the obsemd symptoms and the contra-active thmpy. The Clinical
Investigator wiU judge the possible causal rclationship bmvan the event and the study
d w -
The CIinical hvestigator will arrange additional examinations at his own discretion to
clarify if the event is connected with the study medication and wiii consuIt a speciaiist if
necessary. Al1 adverse events, senous or not, will be followed up and reported regularly
to the Sponsor until an outcome is known.
The Sponsor or its representative will be responsible for notification to regdatory
agencies.
Any event that does not mect the above criteria; therc is sufficient information that
etiology of the event is in no sequence to the study dmg.
No! ~ossible to i u d ~ e
A judgment of the relation to stuciy h g is not possibIe.
Adverse Events Documentation
The recording of every single Adverse Event and /or Serious Adverse Event has
to meet special requirements:
detailed subject &ta
exact documentation of the evcnt
exact description of temporal sequence folIowing drug administration
documentation of duration and severity
documentation of the rcsuits of diagnostic and therapwtic m m m e n t s
resuiîs of a repeated exposure (re-challenge) if possible
details to the development and outcorne including medical judgment
as much data as possible have to be obtained *ch are important for judgment
concemïng the relationship of the adverse event to study dmg
critical examination of the ~Iationship to study dmg
hl1 adverse events will follow this scheme when spontaneously reported by the subject,
obscrved by the Ciinical Invesigator or elicited by g e n d qutstioning.
Patient Case Report Form
SCREENING IW PAli ENT t NITIALS
PAtlENT CASE REPORT FORM
CCINICAL SCREENING (VISIT 1)
08mognphic Data
Date: Scmning IWY: Gender: Race: (monthlddlyy)
Initiais: Age: 008: (mont hlddlyy)
Phone #: H) w) m p a t i o n :
Pnrnary Physician: Phone #:
Next of Kin: Phone #:
J A R PHARMACEUTICALS LTD. PAGE 1 OF 13
RESEARCH PROTOCOL JAR-97-02026
SCREENING ID# PATiENf INlnALS
Medical Historv
Osteoarthritis of the knee: Yes No If Yes, date of diagnosis:
Corticosteroid or hyalwanic acid injections of the target knee in the last one month:
Yes NO If Yes, give date:
Prior total joint replacement surgery on target knss:
Yss No If Yes, give date:
Have you started physiotherapy in the last two weeks?
Yes No if Yes, give date:
Do you anticipate starb'ng or stopping physiotherapy during the duration of the study'?
Yes No
Alcohol History (iist # of drinks / day. wk or mo):
Dmg Dependency, Psychological Disease:
Cardiovascular Disease:
Gastrointestinal Disorclers:
Musculoskeletal:
Neurological:
Lyrnphatic:
Dermatologie:
Immunotogic:
Haematological Disease:
Diabetes:
Glaucoma:
Genitourinary
Endocrine:
Pufmonary (asthma, brondiitis):
Allergies:
AIlergy to NSAiD's or similar dnigs:
Signifiant ltlness in past 30 days:
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
J A R PHARMACEUTlCALS LTD. PAGE 3 OF 13
RESEARCH PROTOCOL JAR19742028
SCREENING ID# PATIENT INlTfALS
Tie: A Double-Blind, Randomized Placebo-Conadled Clinical Trial O1 Topid
Didofenac In Patients Wrth Osteoarthritis Of The Knee.
PATtENT CASE REPORT FORM
R E G U W R Y
Has the study b e n explained to çhe patient and hislher quesiions a r w e ~ ? Yea No
Has the patient read and understood the Patient Information Sheet? Yes No Has the patient read and understood the lnformed Corisent Fom? Yes No Has the patier?t signed and dated the Informeci Consent F m ? Yes No Has the witness signed and dated the patient's Informeci Consent Fom? Yes No
CUNICAL SCREENING (VISIT 1)
Demographic Data
Date: Screening 10#:
Age: Race:
Medical Hbtory 1 Phyrical Examination
ts the patient available br the entire study period? Yes No
Is the patient pregnant? Yes No N A
Is the patient presently breastfeeding? Yes No N/A
Is the patient presentiy able to bear children? Yes No NIA
If Yes, 1s the patient using an e M v e form of birth control?
y= ( s r n t u p e No
Note: Measurements of wt and ht done without shoes
Wt: Ib. = kg. Ht: in. = cm. BP (After 5 min of rest): Ami used for BP: TPR: Time of vital signs:
Nu rse/P h ysician signature:
J.AR PHARMACEüllCALS Lm. PAGE 2 OF 13 JAR-9102028
RESEARCH PROTOCOL JAR-9742028
Condition Stilf Present
Yes No
Yes No
Blood donation I Multiple samples in past 56 days: (circle) Yes No
If Yes, give date: History of fainting upon blood sampling: Yes No
Has the patient had x-rays taken of himer knee recently? Yes No
If Yes, give date and have the x-rays sent to the dinic to be reviewed during
Current Medications
ldentify the medications the patient is cumntly taking for osteoarthritis or for eny other conditions. List by name, daily dose and the condition for w h i i the patient takes them.
washout Date:
If No, send the patient for x-rays of both the right and ieft knees.
NursefPhysician signature:
Send the patient to the physician with hisfher signed lnfomred Consent Form.
Condition forwhich medication is takm
A
N a m of medication
PAGE 4 OF 13
Oaily Dose
RESEARCH PROTOCOL JAR4742026
SCREENING IW PATIENT INlTlALS
Generai Appearanœ:
Dematolog ic:
E y es:
Gastrointestinal:
Genitourinary:
Musculoskeietal:
Lymphatic:
Neurological:
Endocrine:
Haematologic:
ImmunoIogic:
Disease duration of symptorns in knees: Radiographie Grade: Left Knee: Grade l a Grade Il Grade Ill Grade IV
Right Knee: Grade l Grade 11 0 Grade Ill Grade N
Does this patient have unilateral or bitateraI symptomatic involvement (Check One):
Unilateral Left: Unilateral Right: a Bilateral:
ACR Funcüonal Grade: Grade l Grade Il Grade Ill Grade I V ~
Chronic mmorbidity: Absent Prasent ( S m )
Acute Intemittent Illness: Absent Present (Specify) -
Identification of Target Knee: Right [7 ~eftn Has Informeci Consent Form been signed by physician? Yes No
Physician's Signature: Date:
JAR PHARMACEUTICALS LTD. PAGE 5OF13
RESEARCH PROTOCOL JAR-97-02OZB
PATIENT INITIAiS
Has patient been instructed to haR the use of wrrent thetepies for OA?
Has patient been instructed in the use of acstaminophen for pain control?
Has patient k e n instructed how to fiIl out Concomitant Medication Record?
Has patient been provided with a: a) Copy of signed Informed Consent Fom and Patient Information Shæt?
b) One week supply of aceteminophen (identifid with screening ID #)?
c) Concomitant Medication Record (iintified with scmening 10 #)?
Has patient booked an appointment for Visit 23
Has patient been instnicted to return:
a) Unused acetaminophen on VÏsit 23
b) Concomitant Medication Record on Wsit 23
Yes
Yes
Yes
Yes
Yes Yes
Yes
Yes
Yes
Laborsitorv Has patient's laboratory requisition b e n completed? Yes No
Has patient been sent to lab for blood /urine sampling (lab tests)? Yes No
Record patient's laboratory identification number:
Washout Period
Note: Insert photocopies of laboratory resuits and x-mys in following pocket page.
Have the leboratory reports and x-rays been reviwd? Yes No
List any significant findings and adion taken:
-
Physician's Signature: Date:
J A R PHARMACEüTiCAlS LTD. PAGE 6 OF 13
RESEARCH PROTOCOL JAR4742028
SCREENING I û # PATIENT
PATIENT EUGlBlLIN RECORD (SCREENING TO WSIT 2)
Were there any findings in the dinical screening which predudes patient from continuing
in the study? Yes No
Did the laboratory resub indicate any reasan(s) for which the patient should be
excluded from the study? Yes No
List any significant change in the patient's general heaith status since the last visit?
Do any of the above changes predude patient from wntinuing in the study? Yes No
Have any prohibited concomitant medications been taken since Visit 13 Yes No
Sm-fy : Is the patient ineligible or unwilling to continue in the study? Yes No
If any of the above answers are Yes, please complete the folfowing section:
Date of Termination: (montNddlyy)
Reason for Termination:
Patient Wrthdrawal
Significant Intercurrent Illness, Surgery
Protocol Violation
Adverse Events (please complete adverse event table - page 13)
Other (please specify)
- - - - - - - - .
Clinical Investigatots Signature: Date:
J A R PHARMACEUTICALS LTD. PAGE 7 OF f 3
RESEARCH PROTOCOL JAR-9742028
lnsert Concomitant Medication Reaxd from week 1 into the pocket page et the end of this Case Report Form.
FINAL ENROLMENT VISIT (VISIT 2) Date: (monttùddtyy)
Has patient expenenced the necesswy OA flare aiteria? Yes No
If No, patient is not eligible to participate in this study at this time. Patient may
retum after OA flem criteria has been met. Did patient return acetaminophen and Concomitant Medication Record? Yes No
Has patient been assigned a study ID#? Yes No
Patient Global Assessrnent of Musculoskeietal Condition Haw would you dassify how your OA of the knee has been in the last wsek? (cirde):
a) No problem b) Mifd c) Moderate d) Severe
Physician GIoba! Asseasment of Mwculoskeletaf Condition Your overall assessrnent of the patient's OA of the knee is one of the following (circie):
a) No problem b) Mild c) Moderate d) Severn
Have the foflowing been checked fbr corresponding Study 10 # and VbiWeek #?
WOMAC Osteoarthntis Index Version VA3.0 Yes No
SF-36 Heaith Survey Yes No
Concomitant Medication Record Yes No
Study Medication Pots Yes No
Amtaminophen Pi11 Mals Yes No
For the following measurements, use the check boxes to indicate completion:
Physician Global Assessrnent of Musailoskeletal Cond'rtion
Knee Range Of Movement (final page of WOMAC)
Patient GMI Assessrnent of ~usarioskelstai ~ o ~ i
WOMAC Osteoarthritis lndex Version VA3.0
SF-36 Health Survey
J A R PHARMACEUTlCALS Lm. PAGE 8 OF13
RESEARCH PROTOCOL JAR-974202B
SCREENING IW STUOY tb # PATIENT INIRALS
Has patient been instnrcted in the use of the PHLOJEL IY medication? Yes No
Has patient been instnicted in the um of acetaminop hen for pain confrol? Yes No Has patient been instructed how to fiIl out Concomitant Medication Record? Yes No
Has patient been provided with a: a) Two week suppiy of acetaminophen (identifieci with Study ID # & Week #)? Yes No
b) Two weetk supply of PHLOJEL medication? Yes No
c) Concomitant Medication Record (identified with Study ID # & Week #)? Yes No
iias patient booked an appointment for ViR 31
Has patient been instmcted to retum:
a) Unused aœtaminophen on Visit 31
b) Unused PHLOJELw medication on Visit 33
c) Concomitant Medication Record on Visit 31
Yes No
Yes No Yes No
Yes No
La boratory
Has patient's labofatory requisition been completed? Yes No
Has patient been sent to lab for blood sampling(phamacokinetics)? Yes No
Record patient's laboratory identificatjon number.
NursefP hysician's Signature: Date:
TREATMENT PERIOD
Has patient been contacted and questioned regarding hidher health status? Yes No
Has patient been reminded to return the fdlowing on Visa 3:
a) Unused aœtaminophen? Yes No
b) Unused PHLOJELTY medication? Yes No
c) Concomitant Medication Record (Weeks 2 and 3)? Yes No
JAR PWMACEUTICALS Lm. PAGE 9 OF 13
RESEARCH PROTOCOL JAR4742028
SCREENING ID# SWDY ID # PARENT INtlïALS
PATIENT ELlGlBlLlTY RECORD (VISIT 2 1 O VISlT 3)
List any significant change in the patient's general health status sinœ the Iast visit?
Do any of the above changes predude patient h m continuing in the study? Yes No
Have any prohibited concomitant medpcations been taken since Visit 23 Yes No Specify:
Did the patient deviate ffom hisfhsr n o m l levd of actMty since Visit 21 Yes No
sww Did the patient receive any additional medical treatment since Msit 23 Yes No
Spedfy: Did the patient deviate from the instructions mgarding the application of PHLOJELTY
medication (dosage and frsquency)? Yes No
specify: Is the patient ineligible or unwilling to continue in the study? Yes No
If any of the a bove answers are Yes, please complete the foJlowing section:
Date of Temination: (month/dd/yy)
Reason for Termination:
Patient Withdrawal
Signifiant Intercurrent lllness, Surgery
Protml Violation
Adverse Events (please complete adverse event table - page 13)
Other (please specify)
JAR PHARMACEUtlCAlS LTD. PAGE IOOF13
RESEARCH PROTOCOL JAR-974202B
SCREENING IW STlJDY ID # PATIENT lNllïALS
Çlinical Investigator's Generaf CamrrlgafS
Clinical Investigator's Signature: Date:
POST-TREATMENT ViSlt (VISIT 3) Date: (month/dd/yy)
Did patient retum the:
a) Unused acetarninophen? Yes No
b) Concomitant Medication Record (Weeks 2 and 3)? Yes No
c) Unused PHLOJELn" medication? Yes No
Insert Concomitant Medication Record fmn weeks 2 and 3 into aie m e t page at the end of this Case Report Form.
Patient Global Assessrnent of Musculoskeletal Condition How would you classify how your OA of the knee has been in the last week? (circle):
a) No problem b) Mild c) Moderate d) Severe
Physician Global Assessrnent of Musculoskeletal Condition Your overall assessrnent of tf~e patient's OA of the knee is one of the following (circle):
a) No pmblem b) MiId c) Moderate d) Severe
Have the following been checked for the corresponding Study ID# and VisitMI-k W7
WOMAC Osteoarthritis Index Version VA3.0 Yes No
Physician Global Assessment of Musafkskeletal Condition Yes No
Paüent Global Assessrnent of Musculoskeletal Condition Yes No
SF36 Hskh Survey Yes No
JAR PHARMACEUTICALS Lm. PAGE $1 OF 13
RESEARCH PROTOCOL JAR-974202B
SCREENING ID# STUOY ID # PATIENT INlTIALS
For the following measumments, use the check boxes to indicate completion:
[7 PhysPan G-1 Assessrnent of MuscubskekM Condition
O Knee Range Of Movement (final page of WOMAC)
O Patient ~ i o ~ v of ~u#riio~ke~eta~ ~ond'nion
O WOMAC Osteoarlhritis Index Version VA3.0
Has patient's laboratory requisition been completed? Yes No
Has patient been sent for blood and urine sarnpling? (phannacokinetic & iab) Yes No
Record patient's laboratory identification nurnber:
Note: lnsert photocopies of laboratory results in following -et page.
Nurse/Physicianls Signature: Date:
J A R PHARMACEUVCALS LTD. PAGE 12 OF f 3
RESEARCH PROTOCOL JAR-9792028
SCREENING lû# STUDY ID # PATIENT 1NIiIALS
ADVERSE EVENTS: O NONE
ADVERSE EVENT S TABLE
Are any symptans eonsidered to be serious adverse events: Yes No NIA
If Yas, please cornpiete an HP0 fom (Report fonn for A€ or event suspeded due to lhga, Vacdnes, Cosmetics or food
Produds) wrd indude it in the CRF. Report to J.A.R. Phannaceuticals Ltd. Immedieteiy.
Action Taken 1 = None 2= Dnig 3= Other
Symptorns
JAR PHARMACEUTlCALS LTD. PAGE 130F 13
Start (date and time)
Omg ReiaLion O= U n k m l= Not Related 2= Unl'ikeiy 3= Possible 4= Probable 5= Definite
End (date and time)
Inteiwity 1= Mild 2= Moderate 3= Severn
![Shostak Unit 4 Picture Associations. Arduous[Arduous] Lifting the heavy boxes during the move was arduous work. Definition: (adj.) hard to do.](https://static.documents.pub/doc/80x56/551446c05503462d4e8b4c11/shostak-unit-4-picture-associations-arduousarduous-lifting-the-heavy-boxes-during-the-move-was-arduous-work-definition-adj-hard-to-do.jpg)
