Trial design: i-Base training London - September 2007

Trial design: how do we know what is real?

African Eye Trust Treatment Advocate Training

20 September 2007

Simon Collins

www.i-Base.info

Trial design: i-Base training London - September 2007

i) something about HIV that you know for sure (a fact)

ii) something about HIV that you are not sure of (an uncertainty)

Two examples

Trial design: i-Base training London - September 2007

i) List why you think the fact is true

ii) List why you are uncertain about the second point

Why?

Trial design: i-Base training London - September 2007

As advocates we need to know how reliable anything we say is. • What evidence is there? • What facts have been proven? • What are the conditions for that evidence? • And what don’t we know?

Trust vs proof

Trial design: i-Base training London - September 2007

Discussion on the UK-CAB list about a microbicide trial where everyone in the study was given condoms, prevention advice, and either a microbicide or placebo• How would you know if the microbicide worked?• Was scientific explanation difficult to follow?

Recent example

Trial design: i-Base training London - September 2007

• Observed evidence - from which we can come up with ideas or hypotheses (eg HIV prevalence)

• Proven evidence - where a hypothesis has been tested and specific results have been seen(eg - could HIV be a virus)

Types of evidence

Trial design: i-Base training London - September 2007

Discussion on the CAB list about how certain we are that HIV is a sexually transmitted virusIs HIV an infection? Does it exist?History of HIV• Case studies• Epidemiological studies• Cohort studies

Recent example

Trial design: i-Base training London - September 2007

NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org

ROLE OF VIRAL LOAD IN BOTH TRANSFUSION- AND HETEROSEXUAL-TRANSMISSION OF HIV-1 INFECTION.

BACKGROUND: In the TSS, 90% of recipients of components from HIV-1 positive donors became infected. In contrast, 32% of long-term heterosexual partners of the recipients became infected. We examined the importance of plasma viral load in these two contexts representing very different mechanisms and probabilities of transmission.

METHODS: Donors' sera stored at donation and recipients' sera collected throughout the period of possible transmission to their partners were evaluated for quantitative HIV-1 RNA using the Amplicor HIV Monitor Assay™ (Roche Molecular Systems, Inc.).

RESULTS: Mean RNA levels for transmitting and non-transmitting donors were 3.4 and 3.0 logl0 copies/m L (p= 0.0l). Levels for sexually transmitting and non-transmitting recipients were 4.3 and 3.6 logl0 copies/mL (P= 0.05).

CONCLUSION: Viral load appears to be the identifiably important determinant for both transfusion- and heterosexual-transmission of HIV-1 infection. (Supported by NHLBI Contracts NOl-HB-4-7002,4-7003, and 9-7074.)

3rd CROI - 1996 Abst 31

Trial design: i-Base training London - September 2007

NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org

HETEROSEXUAL TRANSMISSION OF HIV-1 FROM TRANSFUSION RECIPIENTS.

INTRODUCTION: HIV-1 infected transfusion recipients (recips) are useful for studying heterosexual HIV-1 transmission, as the duration of infection is known and confounding risk behaviors are rare.

METHODS: The Roche HIV-1 Monitor Assay was used to quantitate HIV-1 RNA in frozen sera from a cohort of 45 heterosexually active HIV-1 (+) transfusion recips (31 m, 14 f), of whom 6 males transmitted HIV-1 to female sexual partners (J AIDS 1994; 7:705-1 0).

RESULTS: HIV-1 RNA levels were similar in male and female recips (mean copies/mL: 25,642 vs 26,124, respectively). The table compares HIV-1 RNA load in male transmitters (TR) and non-transmitters (NGR): (table: see text).

N HIV-1 RNA load (copies/mL)range median mean S.D.

TR 6 7,700-143,000 43,400 64,645 57,064NTR 25 200-181,000 5,760 16,289 35,847

CONCLUSIONS: The low rate of female to male HIV-1 transmission is probably due to physiological rather than virological factors. There is a strong association between viral load and heterosexual transmission from male to female. Therapies that reduce viral load may reduce the rate of heterosexual spread of the epidemic.

3rd CROI, Abs 258

Trial design: i-Base training London - September 2007

• experimental vs

observational

• cross-sectional vs

longitudinal

• prospective vs

retrospective

Different types of trial

Trial design: i-Base training London - September 2007

•• Randomised controlled trial (RCT) - Randomised controlled trial (RCT) - gold standard = prospective, randomised,

double- blinded, placebo-controled study’ - explain

•• Cohort studyCohort study

•• Case-control studyCase-control study

•• Cross-sectional studyCross-sectional study

•• Case series/case note reviewCase series/case note review

•• Literature review/systematic reviewLiterature review/systematic review

•• Meta-analysisMeta-analysis

Different types of studies

Trial design: i-Base training London - September 2007

• Randomisation• Blinding and double-blinding• Placebo, control• Study size and population (baseline)• Standard of care• Ethics• Informed consent

Key concepts

Trial design: i-Base training London - September 2007

Randomisation

• Selecting people for any group or event by chance - like throwing a dice or tossing a coin - other examples - good and bad?

• Not haphazard allocation

• Not being able to predict the allocation of each participant

Trial design: i-Base training London - September 2007

Randomisation

• To ensure that there is a balance at the start between the groups being studied and there are no systematic differences (in known and unknown variables)

• Provides a sound basis for statistical evaluation of data.

• To ensure that any difference in outcome between the different groups is due to differences in treatment or other intervention

Trial design: i-Base training London - September 2007

Blinding

• Not being able to predict the allocation of each participant

• A participant not knowing the treatment arm

• Double-blinding - neither the participant nor the doctor know the treatment arm

Trial design: i-Base training London - September 2007

Placebo

• Dummy pill that looks, tastes, smells and feels like the drug being studied (impossible to make a ritonavir liquid placebo that wasn’t toxic)

• Placebo trials often involve patients taking more pills

Trial design: i-Base training London - September 2007

Control

• A treatment arm that acts as a comparison to an intervention

• Usually this should be standard of care - examples?

Examples : Prevention and treatment trials

Trial design: i-Base training London - September 2007

Study size and population

• How does the size of a study affect the results?

• How does it affect interpretation?

• Who is being studied?

• What else could be going on?

Trial design: i-Base training London - September 2007

NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org

SAFETY PROFILE OF LAMIVUDINE (3TC) IN PATIENTS WITH ADVANCED HIV-INFECTION.

3TC is a new reverse transcriptase inhibitor which appears promising for the treatment of HIV infection. One of its main advantages is the lack of side-effects compared to other nucleoside analogues. However, there is little data on its tolerance in the advanced stages of HIV infection. 36 patients with advanced HIV infection were enrolled in a compassionate protocol at one centre. There were 32 males and 4 females with a mean age of 39.6 + 9.2 years (range 18 - 55 years). The mean CD4 count at onset of therapy was 80+/-68 cells/microliter. 15 patients received 3TC as a single antiretroviral agent, and 21 patients received combination with AZT, ddI or ddC.

7 patients (19.4%) discontinued 3TC because of side-effects, and 17 patients (47.2%) reported some side-effects. Side-effects attributed to 3TC was more common in patients receiving single antiretroviral agent, 12 (80%) vs those receiving combination therapy, 5 (25%). Mean number of medications received by patients with side effects (4.3) was similar to those with out adverse events (4.5).

The most frequent side effects were hair loss 5 (13.9%), neuritis 5 (13.9%), anaemia 4 (11.1%), leucopenia 4 (11.1%) with 2 severe neutropenia (less than 500 cell), nausea and vomiting 3 (8.3%). 3TC is less well tolerated in advanced HIV disease, compared to reports in earlier stages of the disease, and can cause serious side effects.

3rd CROI, Abs 134

Trial design: i-Base training London - September 2007

NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org

PLASMA HIV RNA LEVELS DURING STAVUDINE (D4T) THERAPY OF PATIENTS WITH ADVANCED AIDS

OBJECTIVE: This is an interim report on the effect of d4T therapy on plasma viremia in patients intolerant to other antiretroviral therapies or have experienced a significant clinical or immunologic deterioration while receiving these therapies.

METHODS: Advanced AIDS patients enrolled in a d4T compassionate use study (Named Patient Program) were evaluated at O (pretreatment), 1 and 3 months for changes in plasma viral load (HIV RNA PCR, Roche Amplicor HIV Monitor Kit). All patients had a history of long-term antiretroviral therapy (ZDV, DDI, or DDC). Subjects received one of three doses (40, 30 or 20 mg d4T, b.i.d.) depending on weight and contraindications.

RESULTS: To date, 23 HIV-infected patients (CDC stage B2-C3) who had specimens available at O and 1 month have been evaluated. Pretreatment viral loads ranged from 2,875,000 to 2,300 HIV RNA copies/ml with a median of 200,485. After one month of d4T therapy, the median viral load decreased by 0.2 logs (P= 0.03, Wilcoxon signed rank test). There was no significant difference in median plasma viral loads between the pretreatment and 3 month time points (N=13, -0.16 log, P= 0.152).

CONCLUSION: One month of d4T therapy produced a small but significant reduction in the plasma HIV-1 RNA load in our patients with advanced HIV disease..

3rd CROI, Abs 136

Trial design: i-Base training London - September 2007

NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org

VIROLOGICAL EFFICACY OF STAVUDINE VS PLACEBO IN EARLY HIV INFECTION.

OBJECTIVE: To compare the virological efficacy of two dose levels of stavudine with placebo in asymptomatic HIV infected subjects (CD4 : 350-750 cells/mm©¯).

METHODS: Sixty six subjects were included on the basis of positive HIV PBMCs culture and assigned randomly to either 80 mg (N=22) or 40 mg (N=22) of stavudine or to placebo (N=22). Virological evaluation (virus isolation, quantitative cell viremia, plasma RNA quantitation (NASBA), ICD p24) was performed at Day -35, Day 0 and monthly for the first three months (Ml, M2, M3).

RESULTS: Baseline (mean of cell viremias : 8.3 NIU/106 cells and mean of plasma RNA viremia: 14732 copies/ml). A trend to the decrease of isolation rate was observed in the two stavudine groups as compared to placebo group but this decrease was not significant. Cell viremia titers exhibited significant decreases in the 80 mg group : 0.6 log at Ml, 1.0 log at M2 and M3 (p < 0.01 in the three cases). In the 40 mg group, viremia titer decreases were less marked (0.5 log at Ml and M2, 0.7 log at M3) but still significant (p < 0.01 in the three cases). No significant change was observed in placebo group. Partial results of plasma RNA viremia exhibited significant decreases under therapy : 0,6 log at Ml and M3 in the 80 mg group, 0,4 log at Ml and M3 in the 40 mg group. No significant change of plasma RNA viremia was observed in placebo group.

CONCLUSION: A dose-dependent efficacy of stavudine was observed as compared to placebo in asymptomatic subjects with high CD4 cell count. The analysis of cell culture and plasma RNA viremias provided concordant significant results. Implications for the design of future virological evaluations will be discussed.

3rd CROI, Abs 142

Trial design: i-Base training London - September 2007

Example

• How do you understand these examples of early studies of 3TC and d4T

• Important to know history of drugs

• If the drug name was not included - could you have guessed the study was talking about 3TC

• Risk of relying on results of small studies with many confounding factors (ie advanced HIV)

Trial design: i-Base training London - September 2007

Standard of care

• Should be common sense - the best current treatment

• Standard of care should be given to every person in a study as a minimum treatment

• It is unethical to pretend that current knowledge doesn’t exist

Trial design: i-Base training London - September 2007

Ethics

•Only randomise if there is uncertainty

•Good ethics is good science

•Bad ethics is bad science

Trial design: i-Base training London - September 2007

Ethics

Is it always ethical to have controls?

OR

Is it ever ethical not to have controls?

Trial design: i-Base training London - September 2007

Informed consent

• Written and verbal information to ensure that someone who joins a study understands the potential risks and benefits

• That they understand what is required by joining the study

• That they should be free to leave the study at any time without it jeopardising their healthcare

• That they acknowledge and agree to these terms

Trial design: i-Base training London - September 2007

Exercise

• Decide a hypothesis or idea• Design a study to test the hypothesis• Study size? - big event or small event?• What are the benefits of the study• What are the weaknesses of the study

Trial design: i-Base training London - September 2007

Thank you…

www.i-Base.info

simon.collins@i-Base.org.uk

Some of these slides were adapted from a presentation given by Tim Peto to the first UK-CAB

meeting in May 2002. Available online: www.ukcab.net