Download clinical study summary - Reliance Life Sciences

Reliance Life Sciences conducted a study on R-TPR-004 (Reteplase- Recombinant Plasminogen
Activator) in subjects with ST segment elevation Myocardial Infarction (STEMI) in 2009.
BACKGROUND
tPA is a secreted serine protease which converts the proenzyme plasminogen to plasmin, a
thrombolytic enzyme. Plasminogen is synthesized as a single chain which is cleaved by the enzyme
into the two chain disulfide linked plasmin. This enzyme plays a role in cell migration and tissue
remodeling. Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive
bleeding; decreased activity leads to hypofibrinolysis which can result in thrombosis or embolism.
Reteplase is a non-glycosylated deletion mutein of tPA, containing the kringle 2 and the protease
domains of human tPA.
Reteplase is administered intravenously and is cleared from plasma at a rate of 250-450 mL/min by
the liver and kidneys. It is also cleared from circulation by 21-antitrypsin. The
terminal half-life is approximately 170 min. Potency is expressed in units (U) using a reference
standard which is specific for Reteplase and is not comparable with units used for other thrombolytic
agents.
Reteplase is a sterile, white, lyophilized powder for IV bolus injection after reconstitution with sterile
WFI.
STUDY DESIGN
RLS conducted the study across 19 hospital sites in India.
This study was a prospective, open-label, single-arm, multicentric trial. Subjects with STEMI admitted
to a hospital intensive care unit within 6 hours of onset of symptoms and meeting all eligibility criteria,
were enrolled in the study. Subjects were followed at 30 min, 60 min, 90 min, 120 min, 6 hr, 8 hr, 12
hr, 16 hr, 24 hr, 48 hr, and pre-discharge and at the day 30 post treatment. ECG, hemogram,
biochemistry, cardiac enzymes and echocardiography were performed as per the study schedule at
various intervals. The primary objective was all cause mortality rate at 30 days post dosing, to be
compared against the published data for the innovator product to establish biosimilarity. Each subject
received a total dose of 20 units of R-TPR-004 within 6 hours after the onset of AMI symptoms. The
dose was given as two 10 unit IV injections each over 2 minutes, no more than 30 minutes apart.
Patients at each site were enrolled only after receiving approval from the respective Ethics committee.
All patients were required to give written informed consent prior to enrolment in the study.
Secondary objectives included the evaluation of the resolution of elevated ST segment at the 90th
minute post dosing, rates of myocardial re-infarction(s) occurring within 30 days of post dosing, rates
of heart failure occurring within 30 days of post dosing, changes in left ventricular ejection fraction
occurring within 30 days of post dosing, events of ventricular tachyarrhythmia occurring within 30 days
of post dosing, and the need for emergent or planned recanalisation procedures (PTCA, stent and or
CABG) occurring within 30 days of post dosing as well as safety evaluations.
Male and female subjects in the range of 18 to 75 years of age presenting with chest pain and/or
equivalent symptoms and diagnosis of AMI along with specific 12 lead ECG changes such as ST
elevation of ≥ 0.1 mV in two or more limb leads or ST elevation of ≥ 0.2 mV in two or more
contiguous precordial leads were included. Subjects with LBBB, internal active bleeding, AMI
secondary to occlusion of one lesion treated previously with a percutaneous coronary intervention,
suspicion of aortic dissection, clinical pericarditis including pericarditis after this episode of AMI,
history of contraindication to thrombolytics, or hemorrhagic diathesis, previous CVA, TIA of any
kind, intracranial tumor, arteriovenous
malformation, cerebral aneurysm, major surgery,
parenchymal biopsy, ocular surgery or severe traumatism within 6 weeks prior to screening for
study were excluded. Patients with unexplained puncture in a non compressible vascular location
in the last 24 hours, arterial hypertension of systolic BP > 200 mm Hg and diastolic BP > 110 mm
Hg at entry which did not respond rapidly to treatment, cardiogenic shock, administration of
Reteplase in the last 14 days or of any glycoprotein IIa/IIIb inhibitor in the 24 hrs prior to screening
for study were excluded. Subjects on oral anticoagulant treatment were also excluded.
Patient Disposition
Figure 1: Patient Disposition
Screening visit (-6 to 0 hr)
N = 83 patients
Enrolled (0 min)
N = 80
Discontinued
N = 9 (11.25%)
Withdrawal of consent: 1 (1.25%)
Screen Failure
N = 03
Completed
N = 71 (88.75%)
ST elevation less <0.1 mv in
two more limb leads: (2)
Lost to follow-up: 1 (1.25%)
Death: 5 (6.25%)
Other: 2 (2.50%)
Any other condition which
investigator feels would pose
significant hazards to subject if
IP administered: (1)
RESULTS
Primary Efficacy
There were 5 (6.25%) deaths (95% CI: 01 – 12) reported in the study at 30 days post dosing, which is
within acceptable limit (assumed upper 95% CI ≤13). The study demonstrated that R-TPR-004 has
significantly reduced mortality which is comparable to earlier studies with Reteplase (GUSTO-III –
7.47%, ASSET – 7.20%, INJECT – 9.02%).
Summary of mortality by cause
Cause of Death
Reteplase (N=80)
Acute Extensive Myocardial Infarction With Cardiac Failure
1(1.25%)
Acute Left Ventricular Failure & Acute Renal Failure
1(1.25%)
Cardiac Arrest
1(1.25%)
Cardio Respiratory Arrest
1(1.25%)
Ventricular Tachycardia & Fibrillation Leading To Cardiac Arrest
1(1.25%)
Secondary Efficacy
1. Forty-one (51.25%, 95% CI: 40 to 60) patients achieved 50% lowering of ST segment level at 90th
minute post dosing.
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Figure 2 – Mean ST segment Elevation
2. Frequency of myocardial re-infarction was 3.75% with R-TPR-004 which is equivalent or less than
other studies with reteplase (GUSTO-III – 4.20%, ASSET – 3.90%, INJECT – 5.00%).
3. Cardiac Failure was observed only in 2.50% patients as compared to >17.00% reported in earlier
studies.
4. Mean Left Ventricular Ejection Fraction significantly (p = 0.0002) increased from baseline (44.3%)
to end to study (48.79%).
5. Overall incidence of cardiac arrhythmia post-dosing was 5.00%. Ventricular tachycardia and
ventricular fibrillation contributed 3.75% and 1.25% respectively.
6. 2.50% patients required emergent recanalization procedure (PTCA) in the study.
R-TPR-004 has demonstrated efficacy by reducing mortality in patients with STEMI. As compared to
other studies, R-TPR-004 also decreased the frequency of re-infarction, cardiac failure, cardiac
arrhythmia and need for recanalization procedure. There was also significant increase in LVEF and
50% lowering of ST segment in >50% of patients at 90 th minute post dosing.
Safety Results
20 IU of R-TPR-004 was administered with in 6 hours of myocardial infarction. There were 64 (80%)
patients with at least one adverse event, of which 18 (22.50%) patients had at least one adverse
event related to study drug. Most common adverse events were bradycardia, coronary artery disease,
constipation, vomiting, chest pain, pain at drug administration site, pyrexia, headache, cough,
hypertension and hypotension.
1. Most frequent adverse event related to R-TPR-004 therapy was serious and non-serious bleeding
that occurred in 7.50% patients in the study which is comparable with earlier reported studies
(GUSTO-III – 7.85%, ASSET – 11.66%, INJECT – 15.00%).
2. 2.50% patient required blood transfusion during study period which is comparable with earlier
reported study (INJECT- 2.20%)
3. 7.50% patients experienced pain at study drug administration site.
4. There were 11 SAEs including 5 deaths. Only one SAE (melena) was ‘probably’ related to study
drug.
5. There were no stroke events reported during study period as compared to incidence in other
reported studies (GUSTO-III – 1.64%, ASSET – 1.10%, INJECT – 1.23%).
6. Statistically significant fall was observed in platelet count (p<0.0001) post-dosing which was
clinically non-significant.
7. Rise in cardiac enzymes level was seen up to 8-hour post dosing and then declined persistently
which was consistent with MI throughout the study.
8. Coagulation profile of patients remained under control throughout the study.
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9. Hypotension was reported in 12.50% patients which is comparable with other reported studies
(GUSTO-III – 20.60%, INJECT – 15.50%).
10. Other important cardiac events reported were pericarditis (2.50%), bradycardia (8.75%), cyanosis
(1.25%), hypertension (10.00%) and thrombosis 2.50%)
R-TPR-004 therapy was safe and easy in administration. The frequency of bleeding events, strokes,
hypotension and arrhythmias were less with R-TPR-004 therapy when compared to reported studies
of Reteplase. None of the 5 deaths, reported were related to R-TPR-004 therapy.
Conclusion
Overall, study demonstrated that R-TPR-004 was efficacious to reduce mortality in patients with
STEMI. It also reduced the disease related cardiac complications, which are comparable with other
Reteplase studies. The overall safety profile is comparable with that reported in other studies of
Reteplase.
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