Title: A randomised parallel group double blind placebo-controlled dose ranging Trial of low dose adjunctive alTeplase during priMary PCI (T-TIME).
Funder: Chief Scientist Office (Scotland)

Abstract: STEMI causes heart failure and premature death. Whilst primary PCI to open the blocked coronary artery saves lives 40-50% of STEMI patients have microvascular obstruction (MVO). Fibrin-rich microthrombi and microvascular injury cause MVO which is delineated by magnetic resonance imaging (MRI). MVO is prognostically important since it is an independent predictor of heart failure and reduced survival so increasing the public health burden of MI. There are no evidence-based treatments for MVO. Our proposal is novel and unique since it is the first in primary PCI to target fibrin with direct lysis of fibrin-rich microthrombi in the culprit artery. AIM: To evaluate if low dose intracoronary fibrinolysis given initially after mechanical reperfusion can reduce MVO and improve clinically-important surrogate measures of cardiac outcome. Full dose I.V. alteplase (100 mg) is an effective fibrinolytic but confers a dose-related risk of bleeding and as a stand-alone therapy is inferior to primary PCI (standard care). OBJECTIVE: To evaluate the efficacy mechanisms and safety of reduced dose intracoronary alteplase when given during primary PCI in high-risk STEMI patients. The circulating half life of alteplase is 5 min but its ‘deep tissue’ beta half life is ~40 min (local delivery avoids hepatic first-pass clearance). Therefore we will conduct a placebo-controlled dose-ranging trial of very low (1/10th; 10 mg) or low (1/5th; 20 mg) dose intra-coronary alteplase given after mechanical reperfusion at the start of PCI in 618 patients (206/group).HYPOTHESES: Local intracoronary delivery of alteplase upstream of the culprit lesion will lyse persistent & de novo fibrin-rich thrombus and so reduce and prevent MVO. Low dose alteplase will be safe. PLAN: A randomised parallel group double blind placebo-controlled dose ranging Phase II trial of intracoronary alteplase in 618 STEMI patients with an occluded artery (a marker of increased risk) treated 6 hrs from symptom onset. T-TIME will take place simultaneously in 8 UK hospitals (~80 patients/site; Site Feasibility Assessments done). Recruitment/consent will be lead by the Consultant Cardiologist. SAFETY early efficacy of reperfusion surrogate outcome measures will be prospectively evaluated and a health economic evaluation will also be performed. STUDY DRUGS: Alteplase and identical placebo will be given in a double-blind manner by slow manual infusion using a flushed aspiration catheter. The trial will include 3 groups (pre-prepared packs): (1) placebo (2) alteplase 10 mg (3) alteplase 20 mg at the start of PCI only. The Primary Efficacy Outcome is extent of late MVO (% of LV mass) 2 days post-MI which is prognostically-validated surrogate outcome. MVO is defined as a dark zone of persistent hypoenhancement with signal intensity >2SDs lower than the bright hyperenhanced myocardium with late gadolinium MRI. Secondary measures of alteplase effect will be studied: Acute: ECG (residual ST elevation) angiographic blush grade TIMI frame count thrombus score (change in thrombus score post- vs. pre-study drug); 2 days: MRI (MVO on first pass contrast MRI myocardial salvage infarct size LV function & volumes); 3 months: MRI NT-BNP. Blood will be collected in the first 24h post-MI for coagulation markers of alteplase mechanisms & safety. The cardiologists will complete a questionnaire for feasibility and safety of study drug administration. Health outcomes (death bleeding stroke MI and heart failure) for safety will be prospectively collected (mean Fup 15 months). Quality of life (EQ-5D; SF-36) at baseline 3 & 12 months will be assessed and a health economic evaluation will be done. SAMPLE SIZE: n= 618 patients will be recruited (206 subjects / group): 1. Placebo; 2. Alteplase 10 mg; 3. Alteplase 20 mg. With a minimum of 186 patients in each group there would be 80% and 90% power at a 5% level of significance to detect between-group mean differences of 1.49% or 1.72% respectively assuming mean (SD) of 3.2 (5.1)% for the extent of late MVO in the comparator group. All of the data will be used and both high- and low-dose alteplase groups will be compared with placebo. A minimum of 558 patients with follow-up for Late MVO will be needed. 618 (n=206/group) patients will be recruited to allow for deaths and incomplete data (i.e. MRI claustrophobia). A sensitivity analysis will be performed imputing worst outcomes for deaths. The sample size will be sufficiently large to address feasibility safety and potential efficacy (with prognostically important surrogate markers). All these parameters will be evaluated to form an overall strategic view in order to select one dose for a future Phase III trial. ANALYSIS PLAN: Core laboratory analyses in Glasgow (ECG angiogram MRI). Secondary analysis will include comparison of the two alteplase doses on the binary MVO outcome. In addition a dose response relationship will be investigated using a trend test across doses. MVO will also be analysed as a continuous outcome using a Wilcoxon rank-sum test adjusting for ties. For continuous MRI outcomes ANCOVA analyses will adjust for size of the area-at-risk 2 days post-MI. Enrolment follow-up and analyses of all data for the primary surrogate outcome (day 2 MRI) will be completed within 4 years. After approximately 40% of patients have been randomised and followed-up for 3 months there will be a futility analysis in addition to the IDMC safety analysis (10% of patients). Our multidisciplinary team has expertise in cardiology fibrinolysis and trials. Trial coordination will be lead by the NIHR-registered Trials Unit the Trial Steering Committee (with patient advocate) IDMC and Clinical Event Committee. Full ethics approval has now been obtained (REF 13/WS/0119; Aug 2013). Site Feasibility Assessments have been performed and a Deliverability Plan has been set with the Sponsor. Recruitment =40 patients/year for 24 months; Trial duration 33 months. CONCLUSION: T-TIME will provide new knowledge on MVO and its treatment. Low-dose alteplase is widely used in the NHS. If efficacy and safety are confirmed T-TIME will support a Phase III trial for cost-effectiveness in the NHS.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR