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Due to technical difficulties the medical contrast images will not be in motion, the images will appear as still pictures.
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June 24, 2008 OPTISON 3
Optison Presentation OverviewIntroductions
Larry Bell, MDGlobal Head Regulatory Affairs GE
HealthcarePre-Clinical
Morten Eriksen. M.D., Ph.D. Senior Scientist, PhysiologistGE Healthcare
ClinicalSteven B. Feinstein, M.D., F.A.C.C.Professor of MedicineDirector - Echocardiography LabRush University Medical Center Chicago, IL
June 24, 2008 OPTISON 5
Content
Chemistry, Manufacturing and Control (CMC)
Pre-Clinical data
Animal Models
June 24, 2008 OPTISON 6
Optison constituents
Structure of the Optison microsphere: Octafluoropropane encapsulated by a 15 nm thick shell of heat denatured human albumin.
Except from the gas, Optison is essentially identical to Albunex.
Optison contains:Perflutren (octafluorpropane) gas (2.8% v/v)Human albumin as shell materialHuman albumin (1%) in vehicle
June 24, 2008 OPTISON 7
Optison size distribution and lung capillaries
Size Distribution of Optison microspheres as administered compared to size distribution of lung capillaries (cumulative percentage smaller than stated size) and theoretical distribution of Optison after passage through the lungs. The number of particles from a clinical dose retained in the lungs is very small compared to the number of lung capillaries.
0
2
4
6
8
10
12
14
16
18
0 5 10 15Diameter (um)
Mil
lio
ns/m
l
0
50
100
150
Perc
en
t sm
all
er
than
giv
en
siz
e
Optison - as injected
Optison - post lung
Capillary size (cumulative)
Capillary size
Optison size
June 24, 2008 OPTISON 8
Size stability in blood plasma
0.000
0.001
0.002
0.003
0.004
0.005
0.006
0.007
0.008
1 10 100
Diameter (um)
Vo
lum
e co
nce
ntr
atio
n (
% v
/v)
3 sec
6 sec
12 sec
60 s
Volume concentration and size distribution of Optison at various time points during incubation in plasma at 37°C with 85-95% gas saturation. The data shows that Optison bubbles decrease in size.
Theory: A bubble containing Perflutren (or any other heavy gas) suspended in blood plasma might potentially increase in size by a net inward gas diffusion of N2, O2, or CO2
Optison in blood plasma
June 24, 2008 OPTISON 10
Absorption Distribution Metabolism Excretion (ADME)
• 125I-Optison microspheres are cleared from the blood pool in rats during the first few minutes following dosing.
• The liver is the major organ of uptake of albumin.
• Perflutren is cleared via exhaled air with an elimination t1/2 of 40 seconds in dogs. Almost 100% is recovered from exhaled air in 15 minutes.
June 24, 2008 OPTISON 11
General toxicology (1)
NOAEL HED Safety factor*
Single dose 20 mL/kg (rats & dogs)
10 mL/kg (monkeys)
3.2 mL/kg (rats), 11.2 (dogs)
3.2 mL/kg (monkeys)
26x (rats), 89x (dogs)
26x (monkeys)
Repeat dose
29 - 31 days
5 mL/kg/day (rats)
< 0.25 mL/kg (dog) **
0.8 mL/kg/day (rats)
-
6x (rats)
-
Repeat dose, 3 times per week for 3 weeks
5 mL/kg (rats)
20 mL/kg (dogs)
0.8 mL/kg (rats)
11.1 mL/kg (dogs)
6x (rats)
92x (dogs)
Teratology, embryonic effects
> 10 mL/kg/day (rats)
0.25 mL/kg/day (rabbits)
- -
NOAEL = No Observable Adverse Effect Level HED = Human Equivalent Dose* Relative to the highest approved human dose**not established, effects were observed at the lowest dose
June 24, 2008 OPTISON 12
General toxicology (2)
• No toxicity or local irritation after intravascular, perivascular, intramuscular, topical dermal and ocular administration of Optison.
• No genotoxicity.• In-vitro human blood compatibility of
Optison without ultrasound exposure: No hemolysis.
June 24, 2008 OPTISON 13
Ultrasound related studies
• In-vivo rabbit blood compatibility of Optison with US exposure:
− No hemolysis− Reductions in WBCs comparable to latex particle
controls
• Cardiovascular effects in dogs, 0.25 mL/kg (groups of 3 animals dosed with vehicle, Optison and Optison + dipyramidole):
− No effects related to Optison at 5 min. interval measurements
• Endothelial damage studied in dogs, 0.72 mL/kg Optison and local high power ultrasound (MI = 0.8 and 1.8):
− No endothelial damage (HE staining and albumin in tissue by immunohistochemical staining) in jugular vein wall, aortic wall, myocardium and kidney compared to non-exposed control tissue.
June 24, 2008 OPTISON 14
Optison in the microcirculation
Muscle capillary intravital fluorescence microscopy studies in rat and mouse muscle with i.v. and i.a. injections of Optison:•Optison particles move with same speed as RBCs, but
adhere to inflamed endothelium without causing blockage of blood flow.[Yasu et al.]
•No alterations in arterial pressure and microvascular blood flow were observed. Large microparticles or aggregates were not seen in vessels.[Dittrich et al. 1995]
•Rat spinotrapezius muscle with arterial injections of Optison showed occasional blockage of capillaries caused by large bubbles. This was consistent with finding of prolonged contrast in dog myocardium observed after direct intracoronary injections.[Skyba et al. 1996]
Optison does not block systemic capillaries after i.v. injection
June 24, 2008 OPTISON 16
Dog modelsHemodynamic effects of particles
Anaesthetized dogs can be instrumented for simultaneous measurements of hemodynamic variables. Pressure can be measured in:
−systemic arteries −left ventricle of the heart−central veins−pulmonary artery
Blood flow in arteries and cardiac output can be measured by implanted flowmeters, ultrasound Doppler or thermodilution, and the ECG can be recorded and analyzed.
The preparations can be combined with acute disease, such as myocardial ischemia, infarction or reperfusion injury.
Direct effects of mechanical blockage of the pulmonary circulation cannot be studied in the intact animal, since the number of lung capillaries (≈ 1011) is much larger than the number of particles (≈ 108) dosed.
June 24, 2008 OPTISON 17
Pigs as experimental animals for evaluation of particle-based drugs
• Animals from the Artiodactyla order (pig, goat, sheep and cow) have intravascular pulmonary macrophages.
• These macrophages react to particles in the bloodstream by activation, phagocytosis and thromboxane A2 release.
• The resulting pulmonary vasoconstriction can be severe.
• Release of thromboxane and the pulmonary hypertension response can be abolished by indomethacine.
• Phagocytosis persists after treatment with indomethacine, causing substantial first-pass extraction of particles which adversely impacts ability to study ADME, general toxicity and efficacy.
June 24, 2008 OPTISON 18
Effect of indomethacine in pigs given Albunex.
Source: Østensen et al. 1992
0.2 mL Albunex i.v.; 27 kg pig
3.2 mL Albunex i.v. to same pig after indomethacine.
June 24, 2008 OPTISON 19
Pulmonary macrophages in different species.
Organ distribution of particles cleared from blood in different species.Source: The Pulmonary Intravascular Macrophage, ed. N.C.
Staub, 1989
Pulmonary artery pressure response to liposomes in different species.
Cat
Calf
Sheep
Goat
Pig
NewbornPig
Rabbit
Dog
Guinea Pig
Rat
Mouse
0 4020 60 80 100Clearanceof
Blood - BorneParticles(in % of RecoveredDose)
LungLiver/Spleen
Cat
Calf
Sheep
Goat
Pig
NewbornPig
Rabbit
Dog
Guinea Pig
Rat
Mouse
0 4020 60 80 100Clearanceof
Blood - BorneParticles(in % of RecoveredDose)
LungLiver/Spleen
10-2 10-1 1 10210
10-2 10-1 1 10210
sheepgoatcow
0
70
60
40
50
30
20
10
Pul
mon
ary
Art
eria
lPre
ssur
eCha
nge
(cm
H2O
)Pul
mon
ary
Art
eria
lPre
ssur
eCha
nge
(cm
H2O
)
0
60
40
50
30
20
10
Doses of liposomes(mol of total lipids/kg)
dogcatrat
10-2 10-1 1 10210
10-2 10-1 1 10210
sheepsheepgoatgoatcowcow
0
70
60
40
50
30
20
10
Pul
mon
ary
Art
eria
lPre
ssur
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(cm
H2O
)Pul
mon
ary
Art
eria
lPre
ssur
eCha
nge
(cm
H2O
)
0
60
40
50
30
20
10
Doses of liposomes(mol of total lipids/kg)
dogdogcatcatratrat
June 24, 2008 OPTISON 20
The pig is an inappropriate model for screening of ultrasound contrast agents• It has abundant intravascular lung macrophages,
not detected in humans, and the acute hemodynamic response to i.v. injected particles is atypical of human response.
• The response might mask other acute effects with relevance for human safety.
• The biodistribution of ultrasound contrast agents is predominantly to the lungs and the first-pass arterial concentration is reduced, this impacts the ability to study ADME, general toxicity and efficacy.
June 24, 2008 OPTISON 21
Optison / Albunex In Other Species • Albunex has been injected in dog preparations at
single doses up to 20 ml without any effects on pulmonary arterial pressure [Walker et al 1992]
• The effects of Optison on pulmonary arterial pressure in dogs is none or minimal.
• Optison does not affect pulmonary arterial pressure in man measured during CABG surgery [Erb et al 2001]
• Optison has been injected in ≈1 million doses without serious events that can be attributed to pulmonary vascular effects.Data from the pig is not a good predictor of clinical
side effects.dog models are better!
June 24, 2008 OPTISON 22
Clinical Overview
Steven B. Feinstein, M.D., F.A.C.C.
Professor of Medicine
Director of the Echocardiography Lab
Rush University Medical Center, Chicago, IL
June 24, 2008 OPTISON 23
Clinical Outline
Introduction to clinical applications
Optison NDA Clinical Safety Data
Optison Post-Marketing Surveillance
Optison Clinical Literature
Future uses of Contrast - Vascular
June 24, 2008 OPTISON 24
American Society of Echocardiography Guidelines for use of U/S contrast 2000
ASE Position PaperTask Force on Standards and Guidelines for the Use of Ultrasonic Contrast in Echocardiography: S. L. Mulvagh, MD Chair, A. N. DeMaria MD, Co chair, S. B. Feinstein MD, P. N. Burns, PhD et al., Contrast Echocardiography: Current and Future Applications, J Am Soc Echocardiogr, 2000 13(4):331-342
At present, it is the position of this guideline committee that intravenous contrast agents demonstrate substantial value in the difficult-to-image patient with comorbid conditions limiting an ultrasound evaluation of the heart. For such patients, the use of intravenous contrast agents should be encouraged as a means to provide added diagnostic information and to streamline early detection and treatment of underlying cardiac pathophysiology.
June 24, 2008 OPTISON 26
1
2
3?
4?
5?
6
3
2
11
4
5
6
Left ventricular endocardial border detection (6 apical segments as defined by the American Society of Echocardiography)
June 24, 2008 OPTISON 27
Left ventricular opacification (LVO) following intravenous injection of Optison
June 24, 2008 OPTISON 29
U/S contrast compositionProduct Shell Material Encapsulated Gas
Albunex
Protein/Albumin
Air
Optison Octafluoropropane/Perflutren
Definity
PhospholipidsSonoVue Sulphur-hexafluoride
Sonazoid Perfluorobutane
AirAlbumin
Perflutren
Optison1 mil doses, 1998-2008
Albunex~ 63,000 doses, 1994 - 1997
-Inert-Device/ISPAN -Intra-ocular use
- vaccines, blood vol. replacement- PulmoliteR _ macroaggregated albumin 150µ - 700 000 proc. p.a.
June 24, 2008 OPTISON 30
Overview of Clinical Investigations (1995-1996)
Study No.
Study Description Dose
Individual/accumulated
No. subjec
ts
FS-1000 Safety, dose-ranging, preliminary efficacy 0.5 40.0 mL
44.0 mL
40
FS-1250 Safety: Evaluate immunologic response to re-challenge – 1 year later (Patients from FS-1000)
20.0 mL
0.02 mL *
5
FS-1500 Mass Balance: Measure PFP in blood and expired air as a measure of clearance; half-life;
recovery in expired air
20.0 mL 10
FS-6000 Single Blind Safety and immunological response in healthy volunteers and in subjects with cardiac, hepatic and respiratory diseases.
Comparison to 1% HSA
20.0 mL 50
FS-3000 Comparative: Evaluate safety and efficacy for endocardial border delineation and left
ventricular chamber opacification vs. Albunex and enhancement of Doppler signals vs.
baseline, non-contrast signal
0.2 5.0 mL
8.7 mL
101
FS-3500 Comparative: Evaluate safety and efficacy for endocardial border delineation and left
ventricular chamber opacification vs. Albunex and enhancement of Doppler signals vs.
baseline, non-contrast signal
0.2 5.0 mL
8.7 mL
102
* Intra-dermal injection
June 24, 2008 OPTISON 31
Clinical Safety Parameters – all studies
Criteria FS-1000*(n=40)
F5-1500*(n=10)
FS-6000**(n=50)
FS-1250*(n=5)
FS-3000/FS-3500
***(n=203)
12-lead ECG X X X X X
Physical examination
X X X X X
Neurological examination
X
Spirometry X X
Vital Signs X X X X X
O2 Saturation X X X X X
Chemistry Panel X X X X X*Baseline, 2h, 24h** Baseline, 2h, 48h *** Baseline, 30 min, 48h (up to 10 days) Vital signs 5 to 20 min intervals. Min 48h and max 10 days between each test agentsO2 sat at -2, 2, 4, 6, 8, 10, 20 and 40 min
June 24, 2008 OPTISON 32
Clinical SafetyThere were no safety concerns based on physical & neurological exams, spirometry & chemistry
CriteriaPhysical examinationNeurological examinationSpirometryChemistry Panel
No clinically significant changes after Optison, or between Optison and Albunex or 1% HSA
Demo
PFP
June 24, 2008 OPTISON 33
Clinical ECGsThere were no changes in 12 lead ECG
Protocol
Results
FS- 1000
No changes
FS- 1500
3 subjects with minor rhythm changes
FS- 6000
No changes
FS- 1250
1 subject had irregularities at baseline which reverted to NSR
FS- 3000
No changes
FS- 3500
No changes
No clinically significant changes after Optison, or between Optison and Albunex or 1% HSA
June 24, 2008 OPTISON 34
Clinical Vital SignsBased on body temperature, heart rate, respiratory rate & BP
• No changes for FS-1000, FS-1250, FS-6000, FS- 3000 and FS-3500
• FS-1500 (PK study, N=10) Individual changes:– One patient elevated respiration rate of 22
breaths/min– One patient had increase in HR and multiple AEs –
uncertain relationship
June 24, 2008 OPTISON 35
Clinical Oxygen Saturation for OptisonProtocol Results
FS- 1000
Statistically, but no clinically significant changes
(at 6 min one patient tried to minimize breathing & coughed: O2 Sat. changed from 96 to 87% but recovered to 96% at 8 min)
FS- 1500
No changes
FS- 6000
No changes –vol 20mL - 1 liver (HPS) subj. remained stable at 76%
FS- 1250
No changes
One lung patient declined 8.25% after 1% HSA at 10 min.
FS- 3000
3,636 oxygen measurements, 13 measurements changed (0.4%) in 5 patients.
FS- 3500
3,672 oxygen measurements, 7 measurements changed (0.2%) in 4 patients .
No clinically significant changes after Optison, or between Optison and Albunex or 1% HSA
1000&
6000
June 24, 2008 OPTISON 36
Transient changes ( ) in Oxygen Saturation Protocol
Agent Patient # with decreased Oxygen Saturation
Patient # with increased Oxygen Saturation
Comments
FS- 3000
Optison
3117 COPD, MI, HTN, smoker
3121 275 lbs, DM, MI, nicotine and alcohol use
3416 Nicotine and alcohol use, valve dx, HTN, MI
3113 228 lbs, pleural effusion
Albunex
3118
FS- 3500
Optison
5319 COPD, pneumonia
5111 221 lbs, sleep apnea, DM
5305 83 years of age
5410 Chronic bronchitis, pneumonia, CAD
3000&
3500
• None of the changes were symptomatic• Change defined as > 7.5% from baseline• All changes were transient in nature• Changes are considered random fluctuations, or related to undiagnosed OSA or variability of oxygen saturation measurements in subjects required to rest in supine position for over 2 hours.
June 24, 2008 OPTISON 37
Clinical Immunological Responses: NoneProtocol
# Subjects Optison
# Subjects1% HSA
Intra-dermal & i.V. inj.
Blood samples
Blood analysis - ELISA
Cytokines & complement activation
FS- 1000
16 X -24 h, -1h
2h
1,2,3 wk
IgG, IgA, IgM, IgD & IgE
-
FS- 1250
5* (from FS-
1000)
X Interleukin-1 alpha, interleukin-2, TNF-α. iC3b & SC56-9
FS- 6000
25 25 X
FS- 1000 FS- 1250 FS- 6000No immunological response
1 subject: mild skin reaction after intra-dermal inj., and did not receive i.v. inj. None of the subjects developed antibodies to Optison or had any cytokine release or complement activation.
1 subject had total CPK at 2h of 157 U/L (Normals 26-140 U/L). Returned to normal within 24h. Subject had several AEs – all resolved. No other responses.
No specific antibodies to Optison. No significant increases above normal ranges of cytokine release or complement activation* Intra-dermal approx 1 year after first i.v.
inj.
June 24, 2008 OPTISON 38
Optison NDA includes adverse events only
Adverse Events: Any event happening within the study period,- temporally related but not necessarily casual related
Adverse Reactions: Reactions (events) within the study period with a causal or unknown relationships to the product
June 24, 2008 OPTISON 39
All AEs were mild/moderate, transient and frequently unrelated to OptisonAdverse Events in All Participants Exposed to Optison
Body System Phase III Trials All Trials (Ph. I, II & III)
N= 199 N= 279
No. % No. %Body as a whole 13/199 6.5 47/279 16.8
Cardiovascular System 8/173 4.6 11/182 6.0
Digestive System 6/70 8.6 14/85 16.5
Endocrine System 3/73 4.1 3/77 3.9
Hemic and Lymphatic System
1/17 5.9 2/20 10.0
Musculoskeletal System 5/55 7.3 15/78 19.2
Nervous System 4/34 11.8 6/39 15.4
Respiratory System 8/79 10.1 14/92 15.2
Skin and Appendages 3/30 10.0 7/36 19.4
Special Senses 4/50 8.0 19/72 26.4
Urogenital System 2/56 3.6 9/74 12.2
One patient can have multiple events and are recorded as such
June 24, 2008 OPTISON 40
AEs in patient with impaired cardiac function is lower than for not impaired patientsAdverse Events in Patients with Impaired Functions Exposed to
Optison
Body System
Phase III Trials All Trials (Ph. I, II & III)Impaired Not Impaired Impaired Not Impaired
No. % No. % No. % No. %
CARDIAC IMPAIRMENT
Body as a whole 1/34 2.9 12/165 7.3 1/34 2.9 46/245 18.8
Cardiovascular System 1/32 3.1 7/141 5.0 1/32 3.1 10/150 6.7
Digestive System 0/15 0.0 6/55 10.9 0/15 0.0 14/70 20.0
Endocrine System 1/16 6.3 2/57 3.5 1/16 6.3 2/61 3.3
Hemic and Lymphatic System
0/6 0.0 1/11 9.1 0/6 0.0 2/14 14.3
Musculoskeletal System 0/13 0.0 4/42 9.5 0/13 0.0 15/65 23.1
Nervous System 0/8 0.0 4/26 15.4 0/8 0.0 6/31 19.4
Respiratory System 1/30 3.3 7/49 14.3 1/30 3.3 13/62 21.0
Skin and Appendages 0/5 0.0 3/25 12.0 0/5 0.0 7/31 22.6
Special Senses 1/11 0.0 4/39 10.3 0/11 0.0 19/61 31.1
Urogenital System 0/10 0.0 2/46 4.3 0/10 0.0 9/64 14.1Significant cardiac disease as documented by medical history; EF< 40%:
June 24, 2008 OPTISON 41
AEs in patient with impaired pulmonary function are lower or same level as for not impaired patients
Adverse Events in Patients with Impaired Functions Exposed to Optison
Body System
Phase III Trials All Trials (Ph. I, II & III)Impaired Not Impaired Impaired Not Impaired
No. % No. % No. % No. %
PULMONARY IMPAIRMENT
Body as a whole 2/47 4.3 11/152 7.2 5/53 9.4 42/226 18.6
Cardiovascular System 2/47 4.3 6/126 4.8 2/49 4.1 9/133 6.8
Digestive System 1/17 5.9 5/53 9.4 3/19 15.8 11/66 16.7
Endocrine System 2/22 9.1 1/51 2.0 2/24 8.3 1/53 1.9
Hemic and Lymphatic System
N/A N/A 1/17 5.9 0/1 0.0 2/19 10.5
Musculoskeletal System 0/10 0.0 4/45 8.9 3/15 20.0 12/63 19.0
Nervous System 1/9 11.1 3/25 12.0 1/10 10.0 5/29 17.2
Respiratory System 2/21 9.5 6/58 10.3 5/27 18.5 9/65 13.8
Skin and Appendages 0/8 0.0 3/22 13.6 0/10 0.0 7/26 26.9
Special Senses 0/10 0.0 4/40 10.0 3/13 23.1 16/59 27.1
Urogenital System 0/13 0.0 2/43 4.7 2/18 11.1 7/56 12.5Respiratory diseases – COPD, emphysema, pulmonary hypertension, bronchiectasis
June 24, 2008 OPTISON 43
Spontaneously Serious Adverse Reports 1998 – 200812 reports in 10 years with ~1million doses administered < 0.001%
Patient no.
Event Comments Cause*
0206s-000225 Jan’ 01
Chest pain with abnormal ECG
1h post Optison Unknown
0206s-00038 Feb’01
Decreased HR 175 71 bpm. Chest pain. Abnormal ECG
Dobutamine peak dose 40 mg/kg. Possible paradoxical response to dobutamine? (8% occurrence –JACC 1997,29(5):994. Responded to atropine.
Unknown
0207s-000912 Aug’98
Convulsion. ER visit for chest pain and ventricular tachycardia; status post cardioversion. Recovered.
Unknown
0207s-001024 Feb’00
Bradycardia Treated with fluids, 1mg atropine. Continued stress test without symptoms.
Unknown
0207s-001113 Apr’00
ECG change Reporting physician felt the recorded EKG changes were not symptomatic or caused by Optison
Unrelated
0507s 00526 July ‘05
Pericardial rupture post MI, death
Angina x 1 week. Admitted with acute inferior MI. Two days later Dobuamine stress echo.
Unrelated*Defined by the reporter of event
Optison 1998-2005, 2007 to present
June 24, 2008 OPTISON 44
Spontaneously Serious Adverse Reports 1998 – 200812 reports in 10 years total administered doses~1 mill ~0.001%
Patient no.
Event Comments Cause*
0206s-0001 19 June’02
Anaphylactic shock. Hypoxia. Chest pain
Hypotension, nausea began within 5 min Related
0402s-000217 Fed’04
Anaphylactic reaction Multiple allergies. Previous blood transfusion without reactions. Possibly related?
Unknown
0207s-00276 Aug’99
Urticaria, facial edema Patient on ACE-inhibitor (Lisinopril). Treated with anti-histamins and steroids
Unknown
0206s-0006 8 Feb’01
Shortness of breath. Baseline hypoxia with Ox sat ~70% post 10 days C-section.
30 y old, 388lbs (176 kg)
Heparin used and patient recovered
Unknown
0402s-000325 Feb’04
Hypoxia Hypoventilation prior to Optison and 1 day post-op CABG
Unrelated
0508s-0006
31 Aug’05
Dyspnea exacerbation Multiple co-morbidities and multiple drug sensitivities. Underwent dobutamine stress echo resulted in increased shortness of breath
Unknown
*Defined by the reporter of event
June 24, 2008 OPTISON 45
One reported death unrelated to Optison * July 18, 2005, Acute inferior MI (1 week of
angina) July 21, 2005, low dose dobutamine stress
echo (10mcg/kg/min) Approximately 1 h later, found
unresponsive in electromechanical dissociation (EMD)
CPR unsuccessful, urgent 2-D echo, new pericardial effusion noted
Diagnosis: Post MI myocardial rupture* Occurred in the United Kingdom
June 24, 2008 OPTISON 46
“In conclusion, it appears from the report of Dr. Hillis that is highly
likely that the death of this unfortunate patient occurred as a
result of spontaneous cardiac rupture and is not likely to be
related to the procedures that were carried out prior to the incident.”
Dr. Roxy SeniorConsultant Cardiologist
June 24, 2008 OPTISON 48
Review of clinical literature 1998-2008
• 975 ICU patients: chest pain & no ST-elevation
• 3 ml Optison
• No AEs related to Optison. No serious cardiopulmonary reactions or deaths
• 105 patients with continuous ECG, O2 Sat. & hemodynamic measurements
• No significant changes after Optison
Variable Pre-Optison
Post-Optison
P-value
Heart rate 72±14 72±14 0.62
sDB 135±27 133±28 0.35
dBP 72±15 76±16 0.66
O2 Sat 97±2 98±2 0.3
PR Interval 165±26 167±25 0.41
QRS interval
98±22 99±23 0.56
QT interval 403±53 407±43 0.20
QTc interval
434±64 437±33 0.79
56 clinical studies: ~9250 patients received Optison
Patient population: 8670 cardiac ( incl. 2159 ICU patients) & 578 non-cardiac
No concerns about Optison AEs or changes in any safety parameters
Tong 2005/Wei 2008*: ICU patients with chest pain and non-diagnostic ECG
* Report on safety data not previously published
June 24, 2008 OPTISON 49
Erb et al, JASE 2001, vol 14: 595-600Intraoperative Contrast Echocardiography with IV Optison Does Not Cause Hemodynamic Changes During Cardiac Surgery
• 35 heart surgery patients (CABG, ASA class IV), received 97 total injections of 0.3ml bolus doses of Optison delivered via a central venous catheter
•No statistically significant differences in ST-segment changes, HR, arterial and central venous pressure, peripheral O2 saturation, cardiac index, LVEF and regional wall motion were seen 5 and 10 min after Optison in all patients undergoing concurrent use of anesthetics, high oxygen content and positive end expiratory pressure (PEEP).
Sub-groups Time of measurements
PAs mmHg
PAd mmHg
CO2 comments
97 injections
(n=35 patients, ASA class
IV**)
5 min vs baseline 1.3 ± 2.4 0.6 ± 2.4 0.2 ± 2.3 NS
10 min vs baseline
0.7 ± 5.0 0.9 ± 3.0 -0.5 ± 2.0
NS
** Patients have severe systemic disease that limits activity and is a constant threat to life.
June 24, 2008 OPTISON 50
Herzog, JAMA 2008, vol 299; 2023-2025 Incidence of adverse events associated with use of perflutren contrast agents for echocardiography• 112 776 Echo studies from Hennepin County Medical Center, Minneapolis, Minnesota
• 16 025 received ultrasound contrast Optison: 3051 patients (Feb1998 – Feb 2002) Definity: 12 974 patients (Feb 2002 – Oct 2007)
• All patients receiving contrast were routinely observed for at least 30 min
• Patient groups were similar
• Methods of identifying adverse events were comparable
• No adverse events after Optison
• 20 Adverse events after Definity of which 4 were serious:
- 65% had history of allergy- 65% were women- Causal relationship uncertain
Patient population Definityn=1297481%
Optisonn=305119%
Indication for resting echo:
LV function
WM abnormalities
Right heart function/ pulmonary hypertension
Valvular disease
10764
2522
1768
1304
2447
558
377
334
ICU patients 2431 520
Estimated Pulmonary artery pressure > 35 mmHg
1882 440
Overall rate of Adverse Events was low
June 24, 2008 OPTISON 52
• More than 79 million American adults have CVD
• 1.2 million Heart Attacks
• 700,000 strokes
• 240,000 TIAs
• CVD is no 1 reason in hospital discharges
Anterior difficult w/o contrast
Anterior walls w/ contrast
*Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007
Need for improved management and non-invasive diagnosis of cardiovascular disease
June 24, 2008 OPTISON 53
Nearly 1/3 of Americans (73 Million) have diabetes or are at risk• 58 million people die each year from CV disease
• DM and HTN are the primary predisposing factors
• Over 90% of type II DM is linked with excessive weight
• 147 million people have impaired glucose tolerance and will increase to 420 million by year 2025; most notably in developing countries 84M to 228M
• > 65 years of age = 15.8% with diabetes
• USA Prevalence of diabetes = 9.3% (6.5% diagnosed and 2.8 undiagnosed)
• USA = 26% of the population have impaired fasting glucose
N Engl J Med. 2007 Jan 18;356(3):213-5
June 24, 2008 OPTISON 54
Future use of vascular U/S contrast could play a significant role in CVD management1. Enhancement of the carotid
artery luminal morphologyin patients with known or suspected carotid artery stenosis
2. Improved resolution of c-IMT for CV risk assessment in patients with riskfactors…monitoring of treatment
3. Identification of arterial wall neo-vascularization (vasa vasorum) in patientswith known stenosis
Anterior difficult w/o contrast
Anterior walls w/ contrast
June 24, 2008 OPTISON 57
Identification of arterial wall neo-vascularization (vasa vasorum)
Courtesy:Hans-Peter Weskott, Hannover, Germany
June 24, 2008 OPTISON 58
U/S contrast expected to be safe and effective in subjects at risk of vascular diseaseDose of U/S contrast: Same range as approved indication
MI carotid imaging: 0.06 – 0.40
Safety parameters: Vitals, O2 saturation, 12-lead ECG, AEs
Study population:
Phase 2: Subjects with known or suspected carotid artery disease
Stable cerebrovascular and cardiovascular disease
Phase 3/clin.practice:Include more unstable patients representing patients in clinical practice (dependent on phase 2)
June 24, 2008 OPTISON 59
Summary: Optison has an excellent safety profileBased on pre-clinical, clinical and post-marketing experience• Pre-clinical studies indicate Optison is safe
- The pig is an inappropriate model for safety of ultrasound contrast agents and the canine may be a more appropriate model
•Clinical NDA studies show no serious safety concerns -Extensive safety monitoring (ECG, vital signs, O2 saturations,
immunological, cytokine, complement) revealed no significant findings
• Post-marketing experience in ~1 million patients: excellent safety profile
- 45 post marketing non-serious reports- 12 SAE’s- One reported death; follow up information revealed death by cardiac
rupture unrelated to Optison usage (adjudicated by Dr. Roxy Senior, external reviewer)
• Literature survey patients no safety concerns- ~60 studies and > 9200 Optison patients including > 2100 ICU patients
- Erb et al 2001: No pulmonary artery pressure changes in critically ill ventilated patents with catheters in place receiving Optison bolus injection
- Herzog 2008 (N=16,025): No Optison adverse events in 3051 patients