Conditions: Acute Ischemic Stroke
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 514
Healthy volunteers: no

Brief summary:
The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic stroke (AIS) patients treated with standard of care thrombolysis (0.9mg/kg IV rt-PA or 0.25mg/kg IV tenecteplase or TNK) within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care. Time of onset is defined as the last time the patient was last known to be well.

Detailed description:

Arms:
arm 1: 100µg/kg bolus followed by 3µg/kg per minute for 12 hours arm 2: 135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours arm 3: None

Interventions: intervention 1: Argatroban intervention 2: Eptifibatide intervention 3: Placebo
Intervention descriptions: intervention 1: Direct Thrombin Inhibitor - Argatroban is a derivative of arginine that competitively binds to the active site of thrombin thereby preventing fibrin deposition. With a half-life of 30 minutes, argatroban has an immediate anticoagulant effect after IV administration which is rapidly reversed with discontinuation of the drug. intervention 2: GP 2b/3a Receptor Inhibitor - The final step of platelet aggregation is mediated via the GP2b/3a receptor. Eptifibatide was specifically developed to ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life (\~2 hours) and rapid dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation. intervention 3: IV placebo solution

Protocol document:
Prot_000.pdf: 
MOST Stroke Trial Protocol
v6.3 2023-03-06 
 
 
 
 
 
Protocol Title 
 
Multi-arm Optimization of Stroke Thrombolysis (MOST): a single blinded, randomized controlled 
adaptive, multi-arm, adjunctive-thrombolysis efficacy trial in ischemic stroke. 
 
Study Chairs: 
Opeolu Adeoye, MD MS (Lead), Washington University in St. Louis, St. Louis, MO 
Andrew Barreto, MD MS, University of Texas, Houston, TX 
Joseph Broderick, MD, University of Cincinnati, Cincinnati, OH 
Colin Derdeyn MD, University of Iowa, Iowa City, IA 
James Grotta, MD, Memorial Hermann Hospital, Houston, TX 
 
 
 
Supported by 
 
The National Institute of Neurological  
Disorders and Stroke (NINDS) 
U01 NS100699 
 
Sponsor of IND: 
Opeolu Adeoye, MD (IND #63550) and James Grotta, MD (IND #71172) 
 
Protocol Number: 
20181464  
 
 
Protocol Version / Version Date 
Version 6.3  March 6, 2023 
 
 
 


MOST Stroke Trial Protocol
v6.3 2023-03-06 
 
 
MOST
 
 
AGREEMENT ON THE PROTOCOL 
 
 
By signing below I confirm that: 
 
 
1) I have read this protocol and it contains all necessary details for conducting this study 
 
 
AND 
 
 
2) I agree to conduct the trial in compliance with this protocol and to adhere to all regulations that govern 
the conduct of the study. 
 
 
 
         
 
 
 
      Date 
 
 
 
Printed Name 
 
 
 
Site Name 


MOST Stroke Trial Protocol
v6.3 2023-03-06 
 
 
TABLE OF CONTENTS 
 
1 
STUDY OBJECTIVES .................................................................................................................................. 2 
1.1 
Primary Objectives .................................................................................................................................................... 2 
1.2 
Secondary Objective ................................................................................................................................................. 2 
2 
BACKGROUND ............................................................................................................................................ 2 
2.1 
Rationale ................................................................................................................................................................... 2 
2.2 
Supporting Information and Prior Clinical Experience ............................................................................................. 3 
2.3 
Standard of Care Intravenous Thrombolysis  rt-PA or TNK .................................................................................. 5 
3 
STUDY DESIGN AND MANAGEMENT ........................................................................................................ 7 
3.1 
Study Design Overview ............................................................................................................................................ 7 
3.2 
Study Outcomes ........................................................................................................................................................ 8 
3.2.1 
Primary Outcomes ............................................................................................................................................. 8 
3.2.2 
Secondary Outcomes ......................................................................................................................................... 9 
3.2.3 
Clinical Outcome Assessments  Blinded Determination of Day 90 mRS ....................................................... 9 
3.3 
Imaging Acquisition and Analysis ............................................................................................................................ 9 
3.4 
Manual of Procedures ............................................................................................................................................. 10 
4 
SELECTION AND ENROLLMENT OF SUBJECTS .................................................................................... 10 
4.1 
Inclusion and Exclusion Criteria ............................................................................................................................. 10 
4.2 
Study Enrollment Procedures .................................................................................................................................. 11 
4.3 
Participating Sites .................................................................................................................................................... 11 
5 
STUDY INTERVENTIONS .......................................................................................................................... 11 
5.1 
Interventions, Administration and Duration ............................................................................................................ 11 
5.2 
Handling of Study Interventions and Blinding ........................................................................................................ 12 
5.2.1 
Blinding ........................................................................................................................................................... 12 
6 
CLINICAL AND LABORATORY EVALUATIONS ........................................................................................ 13 
6.1 
Schedule of Events .................................................................................................................................................. 13 
6.2 
Timing of Evaluations ............................................................................................................................................. 14 
6.2.1 
Pre-Intervention Evaluations ........................................................................................................................... 14 
6.2.2 
On-Study Evaluations ..................................................................................................................................... 14 
6.2.3 
Intervention Discontinuation Evaluations and Premature Withdrawals .......................................................... 14 
6.2.4 
Titration of Infusions ....................................................................................................................................... 14 
6.2.5 
Post-Intervention Evaluations ......................................................................................................................... 15 
6.2.6 
Final Evaluations and Unscheduled Visits ...................................................................................................... 15 
7 
CONCOMITANT TREATMENTS ................................................................................................................ 15 
8 
CRITERIA FOR INTERVENTION DISCONTINUATION ............................................................................. 15 
8.1 
Management of Intracranial Hemorrhage ............................................................................................................... 15 
9 
ADVERSE EVENT ASCERTAINMENT AND REPORTING ........................................................................ 16 
9.1 
Definition of Safety Outcomes ................................................................................................................................ 16 
9.2 
Reporting of Adverse Events .................................................................................................................................. 16 
9.2.1 
Definition of Relatedness ................................................................................................................................ 16 
10
STATISTICAL CONSIDERATIONS ............................................................................................................ 17 
10.1
Sample Size and Accrual ......................................................................................................................................... 17 
10.2
Data Analysis .......................................................................................................................................................... 17 
10.2.1 
Primary Efficacy Analysis .............................................................................................................................. 17 
10.2.2 
Interim Analyses ............................................................................................................................................. 18 
10.2.3 
Secondary and Exploratory Analyses .............................................................................................................. 18 
10.2.4 
Subgroup Analysis: Gender, Race, Ethnicity .................................................................................................. 18 
11
STUDY MONITORING ............................................................................................................................... 18 
11.1
Data Monitoring ...................................................................................................................................................... 18 


MOST Stroke Trial Protocol
v6.3 2023-03-06 
 
 
11.2
Data Management ................................................................................................................................................... 19
11.3
Quality Assurance and Quality Control .................................................................................................................. 19 
12
HUMAN SUBJECTS ................................................................................................................................... 20 
12.1
Institutional Review Board (IRB)/Research Ethics Board (REB) and Informed Consent ...................................... 20 
12.2
Recruitment of Minorities and Women ................................................................................................................... 20 
12.3
Subject Confidentiality ............................................................................................................................................ 21 
12.4
Study Modification/Discontinuation ....................................................................................................................... 21 
13
TRIAL ADMINISTRATIVE STRUCTURE .................................................................................................... 22 
13.1
.22 
13.2
StrokeNet National Coordinating Center and National Data Management Center ................................................. 22 
13.3
Data Safety and Monitoring Board (DSMB) ........................................................................................................... 22 
13.4
Independent Medical Safety Monitor ...................................................................................................................... 23 
13.5
Endovascular Safety Monitor .................................................................................................................................. 23 
13.6
Executive Committee .............................................................................................................................................. 23 
13.7
National Institute of Neurological Disorders and Stroke (NINDS) ......................................................................... 23 
14
PUBLICATION OF RESEARCH FINDINGS ............................................................................................... 23 
 


MOST Stroke Trial Protocol
 
1 
 
v6.3 2023-03-06 
STUDY SYNOPSIS
Study Title 
Multi-arm Optimization of Stroke Thrombolysis (MOST) Stroke Trial 
Objectives 
The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 
3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two 
hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic 
stroke (AIS) patients treated with standard of care thrombolysis (0.9mg/kg IV rt-PA or 0.25mg/kg IV 
tenecteplase or TNK) within three hours of symptom onset. Patients may also receive endovascular 
thrombectomy (ET) per usual care. Time of onset is defined as the last time the patient was last known to be 
well. 
The primary safety objective of the MOST trial is to determine the safety of argatroban and eptifibatide in 
combination with IV rt-PA or TNK with or without ET per usual care, where safety is measured by 
symptomatic intracranial hemorrhage (sICH) within 36 hours from randomization. 
Design and Outcomes 
This is a three-arm, adaptive, Phase-3, single blinded, randomized controlled clinical trial at up to 110 sites in 
the United States and Canada. The first 150 subjects will be randomized 1:1:1. From 150-500 patients, 
response adaptive randomization (RAR) will favor the treatment arm showing the greatest benefit based on 
accrued data. After 500 patients, one or both intervention arms may be carried forward for fixed 
randomization versus placebo control. A maximum of 1200 patients will be enrolled. 
The primary efficacy outcome for MOST will be the 90-day mRS translated into utilities, which measure cost- 
is sICH. Secondary outcomes include a comparison between treatment groups of: the proportion of 
-hour NIHSS; proportion with 90-day mRS 
0 or 1 and 0- 2; 90-day ordinal analysis of the mRS; 90-day EQ-5D; the proportion of participants who have 
thrombectomy; the proportion of participants with parenchymal hemorrhage types 1 (PH-1) and 2 (PH-2); any 
ICH on brain imaging within 36 hours of randomization; major hemorrhage (defined as requiring >2 units 
packed red blood cells) other than intracranial hemorrhage within 7 days; 90-day all-cause mortality; 
evaluation of treatment effect in rt-PA and TNK subjects; evaluation of treatment effect in ET and non-ET 
subjects; and, evaluation of race/ethnicity and gender differences in treatment effect. 
Interventions and Duration 
After thrombolysis is started in eligible ischemic stroke patients, the patient or legally authorized representative 
(LAR) will be approached for participation in the study and consent obtained in eligible patients. Placebo, 
argatroban or eptifibatide will be started as soon as possible after consent is obtained. Participants should 
receive assigned study drug within 60 minutes of initiation of IV thrombolysis, but administration is allowed up 
to 75 minutes. A repeat NIH stroke scale will be performed at 24 (+/- 12) hours after initiation of thrombolysis. 
The primary safety outcome will be measured by any evidence of sICH within 36 hours from randomization as 
determined by a medical safety monitor and an independent neuroradiologist. Functional outcome at 90 days, 
the primary efficacy outcome, will be assessed by centralized video adjudication of interviews of the patient 
and/or LAR. 
Sample size and Power 
With a maximum N=1200, the design provides at least 80% power to detect the specified treatment effect (0.4 
utilities) when only one active arm is effective. If both treatment arms are equally effective, power is 89%. 


MOST Stroke Trial Protocol
 
 
 
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 v6.3 2023-03-06 
1
STUDY OBJECTIVES
 
1.1 Primary Objectives 
The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 
3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two 
hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic 
stroke (AIS) patients treated with standard of care 0.9mg/kg IV rt-PA or 0.25mg/kg IV TNK within three hours of 
symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care. 
 
The primary safety objective of the MOST trial is to determine the safety of argatroban and eptifibatide in 
combination with IV thrombolysis with or without ET per usual care, where safety is measured by 
symptomatic intracranial hemorrhage (sICH) within 36 hours from randomization. 
 
1.2 
Secondary Objective 
Secondary objectives include a comparison between treatment groups of: the proportion of participants with 
-hour NIHSS; proportion with 90-day mRS 0 or 1 and 0-2; 
90-day ordinal analysis of the mRS; 90-day EuroQol (EQ-5D), a self-administered questionnaire that is widely 
used to obtain utility values to derive quality-adjusted life years (QALY) for a given intervention; the proportion 
of participants who have thrombectomy; the proportion of participants with parenchymal hemorrhage types 1 
(PH-1) and 2 (PH-2); any ICH on brain imaging within 36 hours of randomization; major hemorrhage (defined as 
requiring >2 units packed red blood cells) other than intracranial hemorrhage within 7 days; 90-day all-cause 
mortality; evaluation of treatment effect in rt-PA and TNK subjects; evaluation of treatment effect in ET and non-
ET subjects; and, evaluation of race/ethnicity and gender differences in treatment effect. 
 
2
BACKGROUND 
 
2.1 
Rationale 
Intravenous (IV) thrombolysis is the only proven effective medication for the treatment of acute ischemic stroke 
(AIS). The aim of thrombolysis is recanalization and this occurs in ~50% of occluded arteries one hour after 
treatment. Arterial reocclusion occurs in 14-34% of thrombolysis treated patients within two hours and is 
associated with worse outcome. Overall, 50% of thrombolysis treated AIS patients are disabled at three months, 
likely owing to poor recanalization, reocclusion, or permanent neurological injury occurring before 
recanalization.1-7 
 
Addition of endovascular thrombectomy (ET) to thrombolysis is a recent major advance for AIS patients with 
large vessel occlusions (LVO), further supporting the impact of recanalization on outcome.8-12 However, only 46% 
of ET treated patients in published trials achieved functional independence (mRS 0-2) at 90 days13,14; 31% did 
not achieve good recanalization13,14; 25% had persistent occlusion at 24 hours8; and, only 7% of United States 
(US) hospitals perform ET.15 Thus, there is an unmet clinical need for adjunctive IV medications that could be 
administered at all hospitals (small and large) that treat patients with IV thrombolysis to augment thrombolysis 
and reperfusion. 
 
Thrombus formation and propagation are complex processes initiated by exposed collagen and/or tissue factor at 
the site of vascular injury. Recruitment and activation of platelets, platelet aggregation and cross- linking with 
fibrin(ogen) mediated by the glycoprotein (GP) 2b/3a receptor ensue, generating thrombin and fibrin. Thrombin 
further propagates platelet activation and aggregation in a positive feedback loop.16 While the fibrin component of 
a thrombus may be sensitive to thrombolysis, the aggregated platelets resist dissociation and enhance thrombin 
generation.17 Thrombolysis also stimulates platelet aggregation and thrombin generation, which may potentiate 
thrombosis and contribute to arterial reocclusion and neurological deterioration.1-3,18 Two approaches that may 
augment thrombolysis and prevent arterial reocclusion are direct thrombin inhibition with argatroban and 
inhibition of the GP2b/3a receptor with eptifibatide. 
 
Direct Thrombin Inhibition with Argatroban Augments Thrombolysis 
Argatroban is a derivative of arginine that competitively binds to the active site of thrombin thereby preventing  


MOST Stroke Trial Protocol
 
 
 
                                    3 
 v6.3 2023-03-06 
 
fibrin deposition.19 With a half-life of 30 minutes, argatroban has an immediate anticoagulant effect after IV 
administration which is rapidly reversed with discontinuation of the drug.19 In murine models of middle cerebral 
artery (MCA) occlusion, argatroban reduced the formation of microthrombi, reduced lesion volume, and, when 
combined with recombinant tissue plasminogen activator (rt-PA), reduced fibrin deposition and extended the time-
window for rt-PA.20,21 A randomized controlled trial of single agent IV argatroban within 48 hours of stroke symptom 
onset at 60mg/day for two days and 10mg twice a day for five days resulted in improved symptoms and daily 
activities in the argatroban group.22 A randomized placebo controlled safety study in 171 AIS patients found that 
high dose (100µg/kg bolus followed by 3µg/kg/minute, n=59) and low dose (100µg/kg bolus followed by 
1µg/kg/minute, n=58) argatroban were safe when started within 12 hours of symptom onset and did not increase 
sICH rates (high- dose argatroban 5.1%; low-dose argatroban 3.4%; placebo 0%).23 Based on these data, we 
conducted the Argatroban t-PA Stroke Study (ARTSS), ARTSS-2 and ARTSS-IA trials which found a favorable 
direction of effect with no safety concerns of argatroban plus rt-PA for AIS. 
 
Inhibition of the GP 2b/3a Receptor with Eptifibatide Augments Thrombolysis 
The final step of platelet aggregation is mediated via the GP2b/3a receptor.17 Murine MCA occlusion model 
studies have investigated several GP2b/3a inhibitors combined with rt-PA and found that addition of GP2b/3a 
inhibitors to rt-PA prevented microvascular platelet aggregation, increased recanalization rates compared to rt- 
PA alone (50% vs. 20%) and reduced infarct volume by 25%.24-26 Eptifibatide was specifically developed to 
ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life (~2 hours) and rapid 
dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation.17 In 
myocardial infarction, addition of eptifibatide to rt-PA increased TIMI grade 3 flow (66% vs. 39%, P=.006)27 and 
reduced coronary events without increasing the rates of bleeding complications compared to rt-PA alone.28,29 
Based on these data, we conducted the Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute 
Ischemic Stroke (CLEAR), CLEAR-Enhanced Regimen (CLEAR-ER) and CLEAR-Full Dose Regimen (CLEAR- 
FDR) trials which found a favorable direction of effect with no safety concerns. 
 
2.2 
Supporting Information and Prior Clinical Experience 
Overall, six completed Phase 2 trials suggest the combination therapies are safe at the doses proposed. The 
studies were underpowered to demonstrate efficacy, but our analyses suggest a direction of effect in favor of 
the combination therapies.30-35 We propose to study this definitively in the MOST trial. 
 
Table 1 
Design and Sample Size of Six Completed Phase 2 Trials
ARTSS
ARTSS-2
ARTSS-IA
CLEAR
CLEAR-ER
CLEAR-FDR
Intervention 
0.9mg/kg rt-PA + 
low dose 
argatroban 
0.9mg/kg rt-PA + 
low or high dose 
argatroban 
0.9mg/kg rt-PA + 
high dose 
argatroban 
0.3mg/kg and 
0.45mg/kg rt-PA 
+ eptifibatide 
0.6mg/kg rt-PA + 
eptifibatide 
0.9mg/kg rt-PA 
+ eptifibatide 
Study Size 
 
n=65, single arm 
 
n=90, 3-arms 
 
n=10, single arm 
n=94, 69 
combination, 25 
rt-PA 
n=126, 101 
combination, 25 rt-
PA 
n=27, single 
arm 
Randomized
No 
Yes 
No 
Yes 
Yes 
No 
 
The ARTSS Trial  Low Dose Argatroban + Standard rt-PA is Safe and Promising 
This single arm study of 65 patients combined standard dose rt-PA with 100µg/kg bolus of argatroban followed 
by a 48-hour infusion targeting a partial thromboplastin time (PTT) of 1.75 x baseline. The mean ± SD age for 
ARTSS patients was 63 ± 14 years and the median (range) NIH stroke scale score (NIHSS) was 13 (3-25). 
The endpoints were sICH and recanalization rates. sICH rate was 4.6% and 78% achieved partial or complete 
recanalization at 24 hours.30 Ultra-early recanalization at 2-hours post rt-PA was measured using validated and 
centrally adjudicated transcranial Doppler (TCD) ultrasound waveforms.36 Although this was a single-arm study, 
eligibility criteria and outcome variables were a priori chosen to closely match the CLOTBUST study18 that 
included a control arm (rt-PA alone) to allow comparison of 2-hour recanalization. Complete recanalization at 2 
hours occurred in 30% of argatroban + rt-PA patients compared to 13% rt-PA alone. 
 
The ARTSS-2 Trial  Higher Dose Argatroban + Standard IV rt-PA is Safe and Promising 
This Phase 2 randomized controlled clinical trial was designed to estimate overall treatment benefit among 
stroke patients treated with rt-PA who are randomized to either low dose argatroban (100µg/kg bolus, followed  
 


MOST Stroke Trial Protocol
4
v6.3 2023-03-06
Figure 2 
mRS
by 1µg/kg/minute IV infusion for 48 hours), high dose argatroban (100µg/kg bolus, followed by 3µg/kg/minute IV 
infusion for 48 hours) or rt-PA alone. ARTSS-2 enrolled 90 patients at seven US and seven United Kingdom 
(UK) centers. Characteristics of enrolled patients are shown in Table 2. More argatroban patients reached mRS 
of 0-1 at 90 days as shown in Figure 1a and a trend in favor of improved outcomes in the high dose argatroban 
arm is shown in Figure 1b along with similar sICH.31 Relative risks were adjusted for clinical site, terminal ICA 
occlusion, and Hemorrhage After Thrombolysis (HAT) score37 which includes NIHSS, glucose and CT 
hypodensity. The equivalent difference in the utility score in favor of the high dose argatroban combination arm 
would be 1.0 (-0.9, 2.8).
Table 2 - ARTSS-2 Patient Characteristics
IV rt-PA Alone
N=29
Low Dose Argatroban
N=30
High Dose Argatroban
N=31
Age in years, mean ± SD
68.9 ± 15.4
70.9 ± 15.1
67.1 ± 13.4
Stroke Onset to IV rt-PA bolus, minutes, mean±SD
110.8 ± 44.7
132.3 ± 51.8
115.6 ± 46.2
Baseline NIHSS, (median, range)
15 (4-26)
16 (2-29)
13 (3-33)
ASPECTS score, (median, IQR)
10 (8, 10)
8 (6, 10)
9 (8, 10)
Figure 1a 
ARTSS-2 distribution of 90-day mRS
Figure 1b 
ARTSS-2 adjusted RR for sICH
The ARTSS-IA Trial 
rt-PA + Argatroban + ET is Safe
This proof-of-concept, single-arm, feasibility and safety study (ARTSS-IA; NCT02448069) assessed the MOST 
high dose argatroban regimen in AIS patients who receive IV rt-PA and ET. Ten patients were enrolled.
Median age was 68 years (range 52-92) and median NIHSS was 19.5. All 10 patients received 12 hours of 
argatroban infusion and none suffered sICH or procedural complications. Study procedures did not prolong ET 
time metrics (i.e., imaging to groin-puncture) compared with non-ARTSS-IA ET cases.32
The CLEAR Trial 
Half Dose rt-PA + Eptifibatide is Safe
This randomized dose escalation study showed that eptifibatide (75µg/kg bolus followed by 0.75µg/kg/min 
infusion for 2 hours) could be safely combined with 0.3mg/kg or 0.45mg/kg of rt-PA administered within three 
hours of symptom onset in AIS. sICH rate was 1% with no signal of efficacy as compared to IV rt-PA alone.33
The CLEAR-ER Trial 
0.6mg/kg rt-PA + Eptifibatide is Safe and Promising
CLEAR-ER randomized 126 AIS patients treated with rt-PA within three hours to 0.6mg/kg rt-PA plus 
eptifibatide (135µg/kg bolus and a 2-hour infusion at 0.75µg/kg/min) (n=101) vs standard rt-PA (0.9mg/kg) 
(n=25). Combination arm patients were non-significantly younger (72 vs 76 year, P=0.63), had lower NIHSS (12 
vs 17, P=0.11) and had shorter times to IV rt-PA (113 vs 129 minutes, P=0.69). The age, NIHSS and time- to-IV 
rt-PA adjusted odds ratio was 1.38 (95% confidence interval (CI), 0.51-3.76; P=0.52) in favor of rt-PA
+eptifibatide.34 The sICH rate was 2%.34
Due to imbalances in the treatment and control arms of CLEAR-
     
ER, we also matched 85 CLEAR-ER to 169 contemporaneous IMS
III/ALIAS rt-PA only subjects using a propensity score matching approach.38
                
The primary outcome was 90-day severity-adjusted mRS
dichotomization based on baseline NIHSS.39 Median age in CLEAR-ER
and control subjects was 68 years; median NIHSS in the CLEAR-ER
subjects was 11 and in control subjects 12. At 90 days, 45% of CLEAR-ER
         


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                                    5 
 v6.3 2023-03-06 
subjects had favorable outcomes vs 36% in controls (unadjusted RR 1.24, 95% CI 0.91-1.69, p=0.18) (Figure 2). 
Secondary outcomes were 52% vs 34% excellent outcomes (mRS 0-1) (RR 1.51, 1.13-2.02, p=0.007); 60% 
vs 53% favorable outcome (mRS 0-2) (RR 1.13, 0.90-1.41, p=0.31); and ordinal Cochran-Mantel-Haenszel 
p=0.10.38 The equivalent difference in the utility score in favor of the eptifibatide combination would be 0.43 (- 
0.37, 1.24). 
 
The CLEAR-FDR Trial  Standard rt-PA + Eptifibatide is Safe and Promising 
This was a single arm safety study of standard dose (0.9mg/kg) rt-PA plus eptifibatide. The primary goal was to 
ensure with high probability (defined as 80%) that the rate of sICH does not exceed 8%, the expected sICH 
rate based on patients from the NINDS trial who meet inclusion/exclusion criteria for the CLEAR trials. The 
stopping rule for the CLEAR-FDR trial was 3 sICH cases within the first 19 patients enrolled or 4 out of 29 
patients enrolled. With a sample size of 30, a two-sided 95% confidence interval for a rate of 8% would be 0% 
to 18%. Twenty seven AIS patients were enrolled. Median age was 73 years (range 34-85) and median NIHSS 
was 12 (range 6-26). One sICH (3.7%, 95%CI 0.7%-18%) occurred.35 We found comparable safety of full dose 
rt-PA plus eptifibatide with historical rates of sICH with rt-PA alone. 
 
We also performed propensity score matching of 18 CLEAR-FDR subjects and 52 rt-PA only subjects from 
both IMS III and ALIAS. All subjects had a baseline mRS of 0 or 1. At 90 days, CLEAR-FDR subjects had a 
nonsignificant greater proportion of patients with a favorable primary outcome (61% versus 38%; RR 1.59; 
95% CI 0.96-2.63; P=0.10). Secondary outcomes also favored CLEAR FDR subjects: mRS 0-1 67% versus 
38% (RR 1.73, 95% CI 1.08-2.79; P=0.04); mRS 0-2 67% versus 58% (RR 1.16, 95% CI 0.77-1.73; P=0.50); 
and ordinal Cochran-Mantel-Haenszel, P=0.13. The equivalent difference in the utility score in favor of the 
eptifibatide combination would be 1.14 (-0.55, 2.83). 
 
2.3 Standard of Care Intravenous Thrombolysis  rt-PA or TNK 
Treatment with IV rt-PA is an FDA approved medication for AIS. Emerging data on tenecteplase (TNK) 
has led to its adoption as standard practice globally and in the United States. rt-PA is administered as a 
bolus followed by an hour infusion while TNK, a variant of rt-PA, is a single bolus. rt-PA is cleared from 
the plasma with an initial half-life of 5 minutes, while the terminal half-life is 72 minutes. TNK is cleared 
from plasma with an initial half-life of 20 to 24 minutes, while the terminal half-life is 90 to 130 minutes.40 
 
A meta-analysis of five randomized trials involving 1,585 patients demonstrated non-inferiority of TNK to 
rt-PA.41 The American Stroke Association treatment guidelines indicate it may be reasonable to use TNK 
0.25mg/kg as an alternative to alteplase in cases of patients with large vessel occlusion and more severe 
strokes undergoing thrombectomy (AHA Class 2b, Level of Evidence B-R).42 Several large academic 
centers in the United States have switched to TNK as standard of care instead of rt-PA in all AIS 
patients.43 Additionally, the Canadian Alteplase compared to Tenecteplase (AcT) trial involving 1600 
patients demonstrated non-inferiority of TNK to rt-PA establishing it as a reasonable alternative and 
providing further rationale for global thrombolytic standards.44 Thus, for the MOST trial, 0.25mg/kg TNK or 
0.9mg/kg rt-PA within three hours of AIS symptom onset will be allowed as standard of care thrombolysis 
per local practice at performance sites. 
 
TNK is Non-inferior with Similar Safety as rt-PA in AIS 
Forest plots from the meta-analysis by Burgos and Saver41 below indicate non-inferiority/no difference in 
functional outcomes, symptomatic intracranial hemorrhage or mortality between rt-PA and TNK.  
 
 
 
 
 


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                                    6 
 v6.3 2023-03-06 
Figure 3 
Comparison of Functional Independence
 
Forest Plot comparing Tenecteplase vs Alteplase, for functional independence (mRS 0-2), in trials with no or uncommon (0-10%) use 
of concomitant endovascular thrombectomy (EVT), intermediate levels (11-99%) of concomitant EVT, or planned EVT for all patients. 
There was no evidence of heterogeneity across subgroups, p(interaction) = 0.47, I2=0%. 
Figure 4  Comparison of Symptomatic Intracranial Hemorrhage 
 
Forest plot comparing Tenecteplase by dose subgroups vs Alteplase, for the safety endpoint Symptomatic ICH. Overall, the risk 
difference point estimate favored TNK over ALT: 0% (95% CI -1% to 2%). The lower 95%CI bound of -1% fell on the margin. The 
dashed blue line indicates the -1% non-inferiority margin.  


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Figure 5 
Comparison of Mortality
 
Forest plot comparing Tenecteplase by dose subgroups vs Alteplase, for safety endpoint death. The risk difference point estimates did 
not favor TNK: 0% (95% CI -3% to 2%). The lower 95%CI bound of -3% did not fall within the stringent margin of -1%. Dashed blue line 
indicates the -1% non-inferiority margin. 
Safety of Combining TNK with Argatroban or Eptifibatide in AIS 
The existing preliminary data and Phase II trials support safety of the combination of rt-PA with the study 
interventions. Given the similarity in the safety profile of TNK and rt-PA in AIS, we do not expect safety 
concerns by combining TNK with argatroban or eptifibatide. However, there is limited data available. The 
safety plan for MOST allows controlled monitoring of subjects after every 30 enrollments. Specifically, 
within the TNK and rt-TPA subgroups, sICH rates by treatment group will be reported to the DSMB. The 
probability that observed sICH rates are higher than the expected 3% in any given combination arm will 
be estimated and DSMB recommendations will be followed. A 95% probability that the rate in an 
intervention arm or subgroup exceeds an expected rate triggers DSMB review. After review of data from 
every 30 enrollments, the DSMB may request a detailed review at lower probability at its discretion. 
Details of safety monitoring are described in the Safety Monitoring Plan with the oversight of the DSMB. 
 
3
STUDY DESIGN AND MANAGEMENT 
 
3.1 
Study Design Overview 
The MOST trial is a multi-arm, adaptive, single blinded, randomized controlled Phase 3 clinical trial conducted 
at up to 110 sites to determine whether argatroban and/or eptifibatide is superior to placebo in improving 90-
day modified Rankin scores (mRS) in acute ischemic stroke (AIS) patients treated with IV rt-PA (0.9mg/kg) or 
TNK (0.25mg/kg) within three hours of symptom onset. We will also assess the safety of the combination 
therapies. A schematic of study activities is illustrated below. 
 
Study Arms: 
1.
argatroban (100µg/kg bolus and a 12-hour infusion at 3µg/kg/min) 
2.
eptifibatide (135µg/kg bolus and a 2-hour infusion at 0.75µg/kg/min) 
3.
placebo 


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We will enroll a maximum of 1200 subjects. The first 
150 subjects will be randomized in a 1:1:1 ratio to 
either argatroban, eptifibatide, or placebo. From the 
150th to the 500th subject enrollment, response 
adaptive randomization (RAR) will favor the active 
arm showing the greatest benefit based on accrued 
data. After 500 subjects, one or both intervention 
arms may be carried forward for fixed randomization 
versus placebo. When N=500, one (or both) arm(s)
may be stopped for futility if there is <20% chance of demonstrating benefit in either intervention (argatroban or 
eptifibatide) if the trial were to continue. Next, one (or both) arm(s) may be stopped for futility when N=700 or 
N=900, if there is <5% chance of demonstrating benefit in either intervention if the trial were to continue. One 
(or both) arm(s) may be stopped early for efficacy after 700 or 900 subjects if an arm has an expected success 
predictive probability of demons
We will also assess the safety of argatroban and eptifibatide in combination with IV thrombolysis and ET. The 
National Data Management Center (NDMC) will generate periodic DSMB reports throughout the trial. The 
stud
determine if a hemorrhage is symptomatic. We expect 30% of enrolled subjects will receive ET.9,11 The 
endovascular safety monitor will review all ET cases for safety particular to ET.
3.2
Study Outcomes
3.2.1
Primary Outcomes
Primary Efficacy Outcome
The primary outcome measure for the MOST trial will be the 90-day mRS scores translated to patient-centered 
utilities.45,46 The utility values assigned to each mRS score are shown below in Table 3 and the comparisons of 
the utility values to observed treatment effects in pivotal stroke trials are shown in Table 4.
Table 3 
Utility Scores for Each mRS Score
mRS Score
0
1
2
3
4
5
6
Rivero-Arias et al utility scores.44
10
8.7
7.3
6.0
2.8
-0.1
0
Hong & Saver utility scores45
10
9.5
7.9
6.7
3.5
0.1
0
MOST Trial utility scores
10
9.1
7.6
6.5
3.3
0
0
Table 4 
Effect Size Using Ordinal or Dichotomized and Utility-Weight Analysis of the Modified Rankin Scale
Proportion of mRS
Utility-Weighted mRS
Trial
Odds Ratio (95% 
CI)
% 0-1 (0-2)
Control
% 0-1 (0-2)
Treatment
Mean 
Utility
Control
Mean Utility 
Treatment
Delta Utility 
Means
95% CI
NINDS TPA
Trials^
1.7 (1.1-2.6)
26.6 (38.5)
42.0 (49.4)
5.01
5.90
0.89
0.31 
1.49
MR CLEAN#
1.67 (1.21-2.30)
6.0 (19.1)
11.6 (32.6)
3.62
4.62
1.00
0.43 
1.57
IMS 3^
1.08 (0.77-1.52)
8.9 (38.7)
12.8 (40.8)
5.05
5.41
0.36
-0.24 - 0.97
IST 3^
1.27 (1.10-1.47)
21.0 (35.0)
24.0 (37.0)
4.18
4.48
0.30
0.01 - 0.58
ECASS 3^
1.28 (1.00-1.65)
45.2 (61.6)
52.4 (66.5)
6.74
7.00
0.26
-0.18 - 0.70
^ dichotomized analysis; # ordinal analysis
Primary Safety Outcome
The primary safety outcome will be the sICH rate defined as a type 2 parenchymal hemorrhage (PH2) or a 
hours of randomization.47
PH-2 refers to the following classification of ICH after ischemic stroke as proposed by Berger et al.48:
Figure 6 
MOST Trial Schematic


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Table 5  Classification of Hemorrhage 
Type
Description
Hemorrhagic Infarct Type 1
Small petechiae along margin of the infarct
Hemorrhagic Infarct Type 2 
More confluent petechiae within the infarcted area but without 
space-occupying effect 
Parenchymal Hematoma Type 1 
Hematoma in < 30% of the infarcted area with some slight space 
occupying effect 
 
Parenchymal Hematoma  Type 2 
Dense hematoma > 30% total of the infarcted area with 
substantial space-occupying effect or any hemorrhagic area 
outside the infarcted area 
 
3.2.2 Secondary Outcomes 
Secondary Efficacy Outcomes 
outcome)49; change from baseline to 24-hour NIHSS48; proportion with 90-day mRS 0 or 1 and 0-2; 90-day 
ordinal analysis of the mRS50; 90-day EQ-5D51; the proportion of participants who have thrombectomy. 
 
Secondary Safety Outcomes 
These will include the proportion of participants with parenchymal hemorrhage types 1 (PH-1) and 2 (PH-2); 
any ICH on brain imaging within 36 hours of randomization; major hemorrhage (defined as requiring >2 units 
packed red blood cells) other than intracranial hemorrhage within 7 days; and, 90-day all-cause mortality. 
 
3.2.3 Clinical Outcome Assessments  Blinded Determination of Day 90 mRS 
Given the single blinded design, a blinded central assessor will determine the primary outcome in MOST. 
The clinical evaluation outcomes of interest for the MOST trial include the 24-hour NIHSS, the Day 30 and Day 
90 mRS and the Day 90 EQ-5D.51 All assessments will be conducted by certified study personnel. An individual 
who is blinded to treatment assignment should assess the 24-hour NIHSS. The Day 30 mRS evaluation will 
occur in-person or via telephone call with the subject and/or proxy (if the subject is unable). The telephone mRS 
has been shown to have good agreement with face-to-face mRS (weighted kappa 0.82, 95% CI 0.77-0.88).52,53 
The Day 90 mRS should be conducted by video recorded face-to-face interviews. If this is not possible, a 
recorded remote assessment by video or telephone will be used. The Day 30 and Day 90 mRS score will be 
assigned by local study personnel. A blinded central assessor will assign Day 90 mRS from video recordings 
performed by local personnel. The central mRS assignment will be used for the primary outcome assessment. 
Central mRS assessments will be recorded on videos which will be uploaded to a secure server where they will 
be checked, stored and distributed for independent scoring by expert raters, with committee discussion as 
appropriate. 
 
3.3 
Imaging Acquisition and Analysis 
Imaging protocols: Heterogeneity of varying scanner capabilities and changing scanners at the participating 
sites is expected in multicenter imaging trials. Hence, absolute standardization is difficult. The imaging obtained 
will be standard of care and require that the imaging protocols at the enrolling sites are based on the Stroke 
Imaging Research (STIR) consortium recommendations, which have been designed to accommodate different 
makes of scanners.54 This will increase the homogeneity of the imaging studies obtained at the different sites, 
and the central review will further ensure that the imaging biomarkers used in this study are comparable from 
site to site. 
 
Imaging analysis: To protect confidentiality and prevent bias, all imaging data will be transmitted via a secure 
platform to the study neuroradiologist for central interpretation of: (1) Baseline non-contrast CT- Acute ischemia 
defined by ASPECTS score, (2) Baseline vascular imaging CTA/MRA- LVO (defined as intracranial ICA, MCA-
M1 or basilar occlusion) and (3) 12-36 hour follow up noncontrast CT or MRI- safety monitoring for presence of 
hemorrhage and grading of hemorrhagic transformation. 
 
Data collected include the baseline ASPECT score for all randomized subjects, the presence of LVO (yes or no) 
at baseline for patients undergoing ET, and presence of ICH, PH-1, and PH-2 on the 12-36 hour CT or MRI for all 
randomized subjects. These imaging data will be determined by the central imaging readers. 


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Of primary interest is the proportion of PH-2 ICH as this is used to define the primary safety outcome which will 
be adjusted for by the baseline ASPECTS score. At the end of the trial, the proportion of subjects with any ICH 
and the proportion who develop PH-1 and PH2 will be reported by treatment group. Other imaging data (e.g., M2 
occlusions or collateral scores) will be noted and included in exploratory analyses separate from the aims of the 
present proposal. 
 
3.4 
Manual of Procedures 
The Manual of Procedures will be a document containing detailed instructions on the recruitment process, 
study procedures and data collection. The document should be used by the clinical sites for day to day 
operations. Revisions to the manual will be made as necessary. 
 
4
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
1.
Acute ischemic stroke patients 
2.
Treated with 0.9mg/kg IV rt-PA or 0.25mg/kg IV TNK within 3 hours of stroke onset or time last known well 
3.
 18 
4.
 thrombolysis 
5.
Able to receive assigned study drug within 60 minutes but no later than 75 minutes of initiation of IV 
thrombolysis  
Exclusion Criteria: 
1.
Known allergy or hypersensitivity to argatroban or eptifibatide 
2.
Previous stroke in the past 90 days 
3.
Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous 
malformation 
4.
Clinical presentation suggested a subarachnoid hemorrhage, even if initial CT scan was  normal 
5.
Any surgery, or a biopsy of parenchymal organ in the past 30 days 
6.
Trauma with internal injuries or ulcerative wounds in the past 30 days 
7.
Severe head trauma in the past 90 days 
8.
Systolic blood pressure persistently >180mmHg post-IV thrombolysis despite antihypertensive intervention 
9.
Diastolic blood pressure persistently >105mmHg post-IV thrombolysis despite antihypertensive intervention 
10. Serious systemic hemorrhage in the past 30 days 
11. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, 
hereditary fructose intolerance or oral anticoagulant therapy with INR >1.5 
12. Positive urine or serum pregnancy test for women of child bearing potential 
13. Glucose <50 or >400 mg/dl (<2.8mmol/L or >22.2 mmol/L) 
14. Platelets <100,000/mm3 
15. Hematocrit <25 % 
16. Elevated pre-thrombolysis PTT above laboratory upper limit of normal 
17. Creatinine > 4 mg/dl (>354 µmol/L) 
18. Ongoing renal dialysis, regardless of creatinine 
19. Received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) in full dose 
within the previous 24 hours 
20. Abnormal PTT within 48 hours prior to randomization after receiving heparin or a direct thrombin 
inhibitor (such as bivalirudin, argatroban, dabigatran or lepirudin) 
21. Received Factor Xa inhibitors (such as Fondaparinaux, apixaban or rivaroxaban) within the past 48 
hours 
22. Received glycoprotein IIb/IIIa inhibitors within the past 14 days 
23. Pre-existing neurological or psychiatric disease which confounded the neurological or functional 
evaluations e.g., baseline modified Rankin score >3 
24. Other serious, advanced, or terminal illness or any other condition that the investigator felt would pose a  


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significant hazard to the patient if rt-PA, TNK, eptifibatide or argatroban therapy wasinitiated
a. Example:  known cirrhosis or clinically significant hepatic disease 
25. Current participation in another research drug treatment or interventional device trial - Subjects 
could not start another experimental agent until after 90 days 
26. Informed consent from the patient or the legally authorized representative was not or could not be 
obtained 
27. High density lesion consistent with hemorrhage of any degree 
28. Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT 
Scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for 
treatment 
 
4.2 
Study Enrollment Procedures 
At the enrolling center, thrombolysis patients will be screened by the treating Stroke Team physician based on 
the inclusion and exclusion criteria for the study. Subjects for the MOST trial will be recruited from all patients 
with suspected AIS admitted to participating hospitals. Given that time to treatment is critical for optimal 
outcomes, IV thrombolysis and ET will be planned and administered per usual care. Those not meeting eligibility 
criteria will continue to be treated per usual care and will not be enrolled in the trial. Those who meet inclusion 
and exclusion criteria will be approached for possible consent and enrollment. This must be done quickly as the 
patient should be consented and study drug started within 60 minutes of thrombolysis initiation without 
interfering with plans for ET if indicated. Study drug administration up to 75 minutes of thrombolysis is allowable. 
Telemedicine and other remote procedures may be used for informed consent per approval by the United 
States Central Institutional Review Board or the Canada Research Ethics Boards. 
 
A consent process must be executed for all subjects entered in the trial. Obtunded patients are not automatically 
excluded from the study. If neither the subject nor the LAR (i.e., the individual legally empowered in the state 
where the consent is obtained) can provide consent, entry into the study will not proceed. 
 
Once a subject has been deemed eligible and consent has been obtained, they may be randomized. 
evaluates the treatment arm distribution and generates a randomization number based on the randomization 
scheme. The randomization number corresponds to one of the study drug kits in inventory at the clinical site. A 
web-based central randomization system will be developed by the NDMC and implemented through the 
 
 
A screen failure log will be maintained by study site documenting reasons for trial ineligibility. 
 
4.3 Participating Sites 
Participating sites for MOST will be comprised of up to 110 enrolling sites in the United States and Canada. 
 
5
STUDY INTERVENTIONS 
 
5.1 Interventions, Administration and Duration 
The study intervention will be one time administration of argatroban (100µg/kg bolus followed by 3µg/kg per 
minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) or 
placebo. We anticipate subjects will be treated in the emergency department (ED) after presentation with AIS. 
Argatroban, eptifibatide, or placebo will be administered within 75 minutes of initiation of thrombolysis. All study 
medications must be stopped at 12 hours from the initial bolus of study medication regardless of interruptions to 
the infusion. Participants will be monitored closely in the intensive care unit (ICU) and monitored for neurological 
deterioration secondary to sICH. In-hospital clinical care, including indications for ET, will be per American 
Stroke Association (ASA) or Canadian Stroke Best Practice Recommendations (CSBPR) treatment 
guidelines.55,56 
 
 
 


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5.2 Handling of Study Interventions and Blinding
Commercially available argatroban and eptifibatide will be procured by the NIH StrokeNet Central Pharmacy. 
The Central Pharmacy will assemble the commercially available product into study drug kits and ship to Clinical 
Performing Sites in the United States for study use.  
The Research Pharmacy at the University of Calgary will assemble commercially available argatroban and 
eptifibatide into study drug kits and ship to Clinical Performing Sites in Canada for study use.  
 
5.2.1 Blinding 
Argatroban and placebo subjects will initially receive a bolus followed by a 12-hour infusion. Eptifibatide arm 
subjects will receive a bolus followed by a 2-hour infusion. A 10-hour saline infusion will be administered after 
the 2-hour eptifibatide infusion to maintain the single blind. Investigators are unblinded to treatment arms, but 
subjects and LARs are blinded throughout the duration of the trial.  
The two primary concerns of lack of blinding are: 1) knowledge of the treatment arm could bias endpoint 
assessments of safety (sICH) or efficacy (mRS at 90 days); and, 2) knowledge of an active treatment could 
influence the decision of investigators to proceed with ET in some participants, although we believe this is 
unlikely. Centralized blinded adjudication of sICH, and centralized blinded 90-day mRS assessments will mitigate 
the first concern, and requiring a clinical decision regarding a plan to proceed to ET prior to randomization will 
mitigate the second concern. A schematic of the blinding process for MOST is shown in Figure 7.  
 
 
 
Once a patient is randomized, the study team member will retrieve the study drug kit from site inventory 
labeled with the randomization number assigned by WebDCUTM. The study kit will contain saline placebo, 
argatroban or eptifibatide sufficient for administration to the maximum dosing weight of 100kg.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 7
Schematic of study treatment administration. 


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6
CLINICAL AND LABORATORY EVALUATIONS
 
6.1 
Schedule of Events 
 
Table 6 Schedule of Events
Time 
 
Baseline 
2 hour (+/- 30 
min ) 
(after start of 
study drug) 
 
6 hour 
(+/- 30 min ) 
24
hours 
(+/- 12 
hrs) 
Day  
3/Discharge* 
(+/- 24hrs) 
 
Day 30 
(+/- 7 
days) 
Day 90 
(+/- 14 
days) 
Inclusion Exclusion Criteria 
X 
 
 
 
 
 
 
Subject Enrollment 
X 
 
 
 
 
 
 
Informed Consent/ 
Randomization 
X 
 
 
 
 
 
 
History & Physical# 
X 
 
 
 
 
 
 
NIH Stroke Scale 
X 
 
 
X 
 
 
 
Modified Rankin Score 
X 
 
 
 
 
X 
X 
EQ-5D
 
 
 
 
 
 
X 
CT/MRI scan (SOC#) 
X 
 
 
X 
 
 
 
CTA/MRA (if SOC) 
X 
 
 
 
 
 
 
CBC with platelets# 
X 
 
 
 
 
 
 
Glucose, electrolytes, 
BUN/creatinine, PT# 
X 
 
 
 
 
 
 
aPTT 
X# 
X$ 
X$ 
 
 
 
 
Dosing Titration$  
 
X 
X 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X^ 
X^ 
End of Study 
 
 
 
 
 
 
X 
#Standard of care     *whichever comes first      ^serious AEs only     $argatroban arm only     
 protocol


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                                    14 
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6.2
Timing of Evaluations
 
6.2.1 Pre-Intervention Evaluations 
These evaluations occur prior to the subject receiving any study interventions. 
 
Screening 
A history, physical examination, and NIH stroke scale will be performed by the Stroke Team physician, and 
intravenous thrombolysis will be started per usual care in eligible patients. Thrombolysis is to be started as 
soon as possible in the ED, and delays in initiating therapy are to be avoided. For patients eligible for ET, 
rapid transport to ET should be initiated and facilitated prior to engaging in discussions regarding the study. 
 
Entry/Baseline 
If thrombolysis is started within 3 hours from symptom onset, the patient will be evaluated for eligibility for the 
trial. Informed consent will be obtained from the patient (if able) or LAR. A baseline modified Rankin score 
-event). Baseline 
usual care imaging and lab data points that will be collected include the CT/CTA findings, complete blood 
count results, glucose and electrolyte panel with BUN/creatinine, coagulation parameters (including pre-
thrombolysis PT/PTT/INR) and urine pregnancy tests in women of child-bearing age. 
 
6.2.2 On-Study Evaluations 
The NIH stroke scale score will be performed on every subject immediately prior to initiation of intravenous 
thrombolysis therapy and at 24 hours post initiation of study drug. The NIHSS will be done by an NIHSS 
certified investigator. A non-contrast head CT or magnetic resonance imaging (MRI) of the brain (per usual 
care) will be performed at baseline and within 36 hours of randomization.  An aPTT will be assessed at 2 
hours and 6 hours, according to the WebDCUTM generated instructions, in argatroban arm subjects. All 
adverse events will be reported from randomization through Day 3 or Discharge, whichever comes first.  After 
Day 3/Discharge, only serious AEs and safety outcomes will be reported. At Day 30 and Day 90, the modified 
Rankin score will be collected. The EQ-5D will be collected at Day 90. 
 
6.2.3 Intervention Discontinuation Evaluations and Premature Withdrawals 
Per standard of care after treatment with thrombolysis, the infusion should be discontinued and a repeat 
head CT performed if the participant develops sudden neurological worsening or severe headache during 
treatment. If ICH is detected on CT, reversal agents including prothrombin complex concentrate (PCC), 
cryoprecipitate, platelets and fresh frozen plasma should be administered. A neurosurgery consultation 
should be obtained. Guidance for management of ICH is provided in section 8.1. 
 
6.2.4 Titration of Infusions 
Argatroban requires titration to target aPTT at 2 and 6 hours after initiation, according to the WebDCUTM 
generated instructions. For argatroban arm subjects, clinical personnel will titrate the study drug infusion 
per protocol. 
 
 
 
 
 
Figure 8  Protocol for aPTT Titration  


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a 2-hour infusion, the infusion from 2-12 hours will be increased from 3µg/kg/min to 3.5µg/kg/min, or 18 mL/hr 
to 21 mL/hr, of 1mg/mL argatroban. 
 
6.2.5 Post-Intervention Evaluations 
Per standard of care, the subject will be admitted to the ICU and neurological assessments performed hourly 
for 24 hours. Clinical care and use of ET will be per American Stroke Association (ASA) or Canadian Stroke 
Best Practice Recommendations (CSBPR) guidelines.55,57,56 
 
6.2.6 Final Evaluations and Unscheduled Visits 
In-hospital assessments will occur daily for 3 days or until Discharge, whichever comes first. The Day-30 
visit will be completed over the phone or in-person. The final assessment will occur at Day 90. Every effort 
should be made to conduct this visit in-person. The mRS interview should be video recorded. 
 
7
CONCOMITANT TREATMENTS 
Concomitant use of antiplatelet or anticoagulant medications is prohibited in the first 24 hours after initiation 
of thrombolysis unless a safety scan shows it is safe to administer in an effort to avoid common deviations. 
Thereafter, antiplatelet agents may be initiated per usual care. Anticoagulant medications are discouraged 
per ASA and CSBPR guidelines,55,58 except for venothromboembolism prophylaxis. In the event that systemic 
anticoagulation is thought clinically necessary, the route, frequency, dose and duration must be documented. 
Endovascular thrombectomy may occur per usual care. For ET patients, heparin may be used for line flushes 
only but no systemic antithrombotic agents are permitted. 
 
8
CRITERIA FOR INTERVENTION DISCONTINUATION 
The most likely reasons for discontinuing the intervention after enrollment are acute neurological deterioration 
possibly secondary to sICH during the infusion, and refractory hypertension (blood pressure cannot be 
maintained below 180/105mmHg despite a continuous infusion medication). In both cases, the rt-PA and/or 
study drug are to be stopped immediately. The subject should continue to be followed and data collected per 
the study protocol. 
 
8.1 
Management of Intracranial Hemorrhage 
Reversal of Intracranial Hemorrhage 
Reversal of intracranial hemorrhage is key for all treatment arms since IV thrombolysis will be administered to 
all enrolled subjects. However, the overall goal of stopping bleeding remains the same and thus the reversal 
approach is similar for all three treatment arms (see below). 
 
Management of intracranial hemorrhage 
Intracranial hemorrhage should be suspected if there is any acute neurological deterioration (new headache, 
acute hypertension, seizure, or nausea and vomiting) or acute increase in BP. 
 
If ICH is suspected: 
 
Discontinue rt-PA and/or study drug infusion until ICH is ruled out 
 
Immediately perform CT scan 
 
Draw coagulation tests that may include INR, PT, aPTT, platelet count, fibrinogen, thromboelastography 
(TEG) and type and screen 
 
If ICH is not present, re-start the rt-PA and/or study drug infusion at the discretion of the investigator 
If ICH present: 
 
Administer thrombolysis reversal agents per local protocol  
 
Consider emergent neurosurgical consultation 
 
amily or next-of-kin 


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For patients who received eptifibatide:
 
Consider DDAVP infusion (0.3mcg/kg IV x 1at the discretion of investigator); and/or 
 
Consider a transfusion of platelet concentrates (based on absolute low platelet count <100k or reduced 
maximum amplitude [MA] value on TEG) per local protocol or Cryoprecipitate (if prolonged K-value on 
TEG) in case of major or life-threatening bleeding or urgent need for normalization of platelet function in 
case of surgery 
 
9
ADVERSE EVENT ASCERTAINMENT AND REPORTING 
 
9.1 
Definition of Safety Outcomes 
The following are safety outcomes of the study: 
 
sICH within 36 hours from randomization 
 
Proportion of participants with parenchymal hemorrhage types 1 (PH-1) and 2 (PH-2) within 36 hours of 
randomization 
 
Any ICH on brain imaging within 36 hours of randomization 
 
Major hemorrhage (requiring >2 units of packed red cells) other than intracranial hemorrhage within 
seven days of randomization  
 
All-cause mortality within 90 days of randomization  
 
Symptomatic Intracerebral Hemorrhage: A type 2 parenchymal hemorrhage (PH-2) or remote parenchymal 
hemorrhage associated with a four or more point increase in the NIHSS score from baseline to subsequent CT 
scan at the time of worsening, per SITS-MOST definition.47 Hemorrhage classification will be based on central 
neuroradiologist review and the final judgment regarding whether the hemorrhage is symptomatic will be made 
by the independent safety monitor. 
 
9.2 
Reporting of Adverse Events 
All adverse events (AEs), all Serious AEs, and all safety outcomes will be reported from randomization 
through Day 3 or Discharge, whichever comes first. After Day 3/Discharge, all serious AEs and all safety 
outcomes will be reported. For each reportable AE, an AE case report form (CRF) will be submitted in 
WebDCUTM capturing the details of the event including date of onset, severity, duration, and relationship to the 
treatment. For serious AEs, additional information, including narrative summaries will be submitted.  
Non-serious events are reported in WebDCUTM within 5 days of the site PI and primary study coordinator
awareness of the event, and serious adverse events are reported within 24 hours of the site PI and primary 
study coordinator
 Sites are responsible for updating AE reports with new 
information as it becomes available (e.g., date of resolution, action taken). All serious AEs must be followed 
for the duration of the study follow-up or until resolution, whichever comes first. Upon completion of the study 
protocol by the 
information regarding each AE must be completed, if not done earlier. 
 
If an event is determined to be unexpected (not previously observed), related to trial participation (study drug) 
and meets FDA and/or Health Canada criteria as a serious event, an expedited safety report will be submitted 
to the FDA in accordance with CFR 312.32 and to Health Canada in accordance with C.05.014. 
 
9.2.1 Definition of Relatedness 
Details will be provided in the MOP. For each Adverse Event, the relationship to the study treatment 
(relatedness) must be recorded as one of the choices on the following scale: 
 
Not Related 
 
Unlikely 
 


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Reasonable possibility
Definitely
10
STATISTICAL CONSIDERATIONS
This section is an overview of the statistical considerations. Complete details can be found in the Statistical 
Analysis Plan (SAP). The general overview of the design is provided in section 3.1.
10.1
Sample Size and Accrual
The minimum clinically significant difference was defined as 0.4 points on the utility scale primary outcome, 
which corresponds to ~45% of the effect for IV rt-PA over placebo in the NINDS study (Table 4).59 With a 
maximum N=1200, this design provides at least 80% power to detect a treatment effect when the overall true 
utility benefit is 0.4 for one active arm in non-ET subjects (Table 7). If both treatment arms are equally effective 
at 0.4 utility above the control arm, power is 89%. The properties of the study design have been investigated 
through a series of simulations that assumed 30% of patients receive ET, and the treatment effect for ET 
patients is 50% of the effect in non-ET patients, corresponding to 25% of the treatment effect of rt-PA over
placebo. The impact of ET on treatment effect is unknown but we assumed the worst scenario, i.e., marked 
attenuation of effect. Table 7 shows power when only one treatment arm is effective. Power increases if <30% 
of patients receive ET.
Table 7 
Power for Varying Treatment Effects if only One Arm is Truly Effective
Utility Values Above rt-PA Alone
Scenario 1
Scenario 2
Scenario 3
Assumed True Effect Overall
(70% non-ET and 30% ET subjects)
0.26
0.34
0.425
Assumed True Effect for non-ET subjects
0.30
0.40
0.50
Assumed True Effect for ET subjects
(50% of non-ET effect)
0.15
0.20
0.25
Pr{Effective arm wins}
0.52
0.80
0.95
Pr{Other arm wins}
0.011
0.008
0.014
Numbers in gray are the utilities (difference in the expected treatment minus control).
Numbers in white are the power under 3 different scenarios (determined by simulation).
Given the non-inferiority of TNK and similarity in efficacy and safety between TNK and rt-PA,41 we do not 
anticipate treatment effect to be different between subjects treated with rt-PA versus TNK as standard of care 
thrombolysis. Further, our simulations included treatment effect as low as 0.255 utility points as detailed in our 
SAP. Thus, we have reasonable power even if there is some attenuation of treatment effect by thrombolysis 
approach. 
10.2
Data Analysis
10.2.1 Primary Efficacy Analysis
The primary analysis will be conducted on the intent-to-treat (ITT) analysis population, defined as all subjects 
randomized regardless of the treatment actually received. The primary analysis will be a two-sample 
comparison of each active arm compared to placebo mRS utility scores adjusting for severity (baseline 
NIHSS). If both active arms reach the end of the trial, they will each be compared to control independently.
The final analysis is Bayesian and includes a flexible normal dynamic linear model (NDLM) to account for 
different expected outcomes as a function of initial NIHSS. This is a flexible spline-like model that will capture 
that the average weighted mRS score in the control group as a (possibly non-linear) function of initial NIHSS. 
Meanwhile for a given treatment , 
, is the difference in the expected utility for the active treatment minus 
control. For each active arm, the hypothesis test is


MOST Stroke Trial Protocol
18
v6.3 2023-03-06
The treatment effect
2). Particularly, the prior probability that a drugis
beneficial is the same as the prior probability that it is harmful. If there is a high posterior probability that the 
treatment effect 
is positive, the treatment is declared efficacious. The posterior probability is conditional on 
the final results for all enrolled subjects. If two active arms remained in the trial all the way to the end, this 
posterior probability is computed for each, and potentially both arms can be declared to be successful.
The primary output of the final analysis is the posterior probability that 
, for any 
trial. If this probability is at least 0.985, the trial is considered a success. The threshold for defining significance 
is chosen so that the Type I error is no larger than 0.025. Criteria for success (critical value for posterior 
probability of a positive benefit) was inflated from 0.975 to 0.985 to account for the two study drugs and the 
repeated interim looks (e.g. the trial can be stopped when data look favorable enough that success is likely).
10.2.2 Interim Analyses
The interim evaluations of the primary efficacy outcome data are described in the Statistical Analysis Plan. A 
brief description is provided under section 3.1.
The primary safety outcome (sICH) proportion for each treatment group (overall and by ET/non-ET subgroups
and thrombolysis approach, i.e., TNK versus rt-PA) will be compared to the expected rate of 3%. The 
probability that the safety outcomes in an intervention arm exceeds the expected rate will be provided in each 
DSMB report. Stopping rules are non-binding and are to be used as a guideline by the DSMB and safety 
monitor in conjunction with other relevant data and careful judgement.
10.2.3 Secondary and Exploratory Analyses
The primary outcome of mRS utility values will be reanalyzed in a multiple linear regression adjusting for 
baseline NIHSS, age, time to IV thrombolysis, thrombolytic agent (rt-PA or TNK), location of LVO and time 
from onset to groin puncture in subjects undergoing ET. All secondary analyses will be tested at a significance 
level of two-
-
dinal outcomes each active treatment arm will be compared to control 
in a Wilcoxon Rank-Sum test and ordinal logistic regression. For continuous outcomes, each active treatment 
arm will be compared to control in a two-sample t-test. Kaplan Meier curves and log rank tests will be used to 
compare time to 90-day mortality by treatment group.
Exploratory analyses of the secondary outcomes will use either logistic regression (for binary outcomes), 
ordinal logistic regression (for categorical outcomes) or multiple linear regression (for continuous 
outcomes) to compare treatment groups after adjusting for age, baseline NIHSS, time to IV thrombolysis, 
thrombolytic agent, location of LVO and time to groin puncture in ET subjects.
10.2.4 Subgroup Analysis: Gender, Race, Ethnicity
Although we do not anticipate differential treatment effects based on gender, race, or ethnicity, our analyses 
will explore clinically important differences due to race/ethnicity. The mRS utility values will be reanalyzed in a 
multiple linear regression adjusting for baseline NIHSS including indicator variables of sex, racial group, and 
ethnic group and interaction terms with treatment group.
11
STUDY MONITORING
11.1
Data Monitoring
Monitoring for this study will be performed by the NDMC centrally for the US and Canada. The NDMC will 
perform on site and remote monitoring for US sites. The University of Calgary in partnership with NDMC will
perform on site and remote monitoring for Canadian sites.
include a combination of on-
monitoring (source document verification, including verification of written consent, may be performed remotely 


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medical records), and central monitoring (using web-based data validation rules, data manager review of 
entered data, statistical analysis, and on-going review of site metrics). 
 
In an effort to review informed consent forms in a timely manner, enrolling sites that are permitted to do so, will 
upload a PDF of the signed informed consent form, into the password protected clinical trial management 
system, WebDCUTM. The PDF file will be linked to the subject ID but will be stored on a secure server separate 
 is not backed up to prevent copies 
of files containing Individually identifiable health information from being copied and stored on non-NDMC back 
up servers. The files on these servers can only be accessed by designated study personnel upon entry of a 
second password. NDMC staff will remotely monitor the informed consent forms and issues identified will be 
relayed to the clinical site for corrective and preventative action. After remote monitoring is complete, the PDF 
file containing the informed consent form will be permanently deleted from the secure server. If a subject must 
be re-consented, the process will repeat itself. 
 
For the Canadian sites, the University of Calgary will manage informed consent verification according to 
Canadian regulations. 
 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at what level of 
detail monitoring will be performed, and the distribution of monitoring reports. 
 
11.2 
Data Management 
Data management will be handled by the StrokeNet NDMC which is housed in the Data Coordination Unit 
(DCU) in the Department of Public Health Sciences at the Medical University of South Carolina (MUSC) which 
is described below. All activities will be conducted in coordination with the study PIs, the StrokeNet National 
Coordinating Center, and the clinical sites (StrokeNet and non-StrokeNet). In addition to the study database, 
the NDMC will provide the clinical site staff access (via password) to a standard set of web-enabled tools, 
including subject visit calendar, subject accrual status, case report form completion status, and outstanding 
data queries pertaining to their respective clinical sites. 
 
11.3 
Quality Assurance and Quality Control 
Data quality assurance processes at the NDMC include: 
 
Logic and rule checks built into the study database; 
 
Real-time, central monitoring by the data managers and statistical programmers at the NDMC; and 
 
Remote and on-site risk-based source verification monitoring by site monitors and data managers at 
the NDMC. 
Quality control (QC) procedures will be implemented beginning with the data entry system, and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written procedures as detailed in the monitoring plan, the monitors will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the protocol, 
GCP, and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP). 
The investigational site will provide direct access to all trial-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
 


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12
HUMAN SUBJECTS
 
12.1 
Institutional Review Board (IRB)/Research Ethics Board (REB) and Informed 
Consent 
United States 
The University of Cincinnati Institutional Review Board will serve as the National Central Institutional Review 
Board for participating sites in the United States. The Central Institutional Review Board (CIRB) for 
multicenter protocols is the single IRB of record for those sites. It has regulatory responsibility for assuring 
the protection of the rights and welfare of research participants in accordance with Standard Operating 
Procedure ADM 12; Central Institutional Review Board Reporting. The National Institute of Neurological 
Disorders and Stroke (NINDS) selected the University of Cincinnati Institutional Review Board (IRB) to serve 
as the CIRB for the NIH StrokeNet (StrokeNet) for sites in the United States. 
Canada 
Each site in Canada will utilize a REB to review research involving humans to ensure the protocol is 
conducted according to the Canada Tri-Council Policy Statement: Ethical Conduct for Research Involving 
Humans (2018) and international standards for Good Clinical Practice. Applicable government regulations 
and site institution research policies and procedures will also be followed. The REB will be responsible for 
reviewing the protocol and the informed consent documentation. 
Article 3.8 in the TCPS-2 outlines when REBs may grant deferral of consent/waiver of consent.60 Canadian 
sites may seek deferral of consent where possible.   
 
12.2 
Recruitment of Minorities and Women 
The individual age, race, and gender of each participant will be transferred to the NINDS at fixed intervals per 
place in communities where there are diverse populations. 
Inclusion of Women 
All eligible patients of both genders will be approached to participate in the MOST trial. Only pregnant females 
are systematically excluded by this protocol because of potential risks to the unborn fetus. While there have 
been historical disparities in the proportion of women enrolled in stroke trials, our Phase 2 trials suggest we 
should adequately enroll equal numbers of both genders into MOST: 
 
Table 8 - Inclusion of Women in the Phase 2 Trials
Trial
Women, N (%)
Men, N (%)
ARTTS
36 (55)
29 (45)
ARTSS-2
40 (44)
50 (56)
CLEAR
39 (42)
55 (58)
CLEAR-ER
60 (48)
66 (52)
CLEAR-FDR
14 (52)
13 (48)
 
Further, upper age limits in other stroke clinical trials may contribute to a bias towards enrolling more men than 
women since women tend to be older than men at the time of a first stroke. Thus, the absence of an upper age 
limit in MOST will allow us to avoid this bias by enrolling all eligible patients aged 18 or older. Overall, we 
expect to enroll approximately equal proportions of men and women. Further, while we do not anticipate 
differential treatment effects based on gender, our analyses will explore clinically important differences due to 
gender. 
Inclusion of Minorities 
All eligible patients of all races and ethnic groups will be approached to participate in MOST. In our analysis of 
discharged ischemic stroke patients in the Medicare Provider and Analysis Review (MEDPAR) administrative 
dataset, StrokeNet hospitals tended to have a lower proportion of white patients compared with non-StrokeNet 
hospitals (76.5% versus 82.8%) (Adeoye International Stroke Conference 2015). Thus, the stroke patients that 
will be available within StrokeNet for MOST are up to 23.5% non-white/minority. Particularly, StrokeNet 
centers such as University of Texas, Houston (city population is 24% Black or African American and 44%  


MOST Stroke Trial Protocol
 
 
 
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Hispanic or Latino), Emory University (city population is 54% Black or African American), University of Miami 
(city population is 66% Hispanic or Latino), among others should facilitate adequate representation of 
minorities enrolled. In addition, we have solicited participation from non-StrokeNet sites with diverse patient 
populations.  
 
Despite the availability of representative populations, available literature suggests barriers persist in the 
participation of minorities in clinical trials. Thus, we will take the following additional steps to ensure 
representative enrollment of minorities: 
 
1.
Emphasize the goal of recruiting a diverse population of stroke patients to participating sites. 
 
2.
Make clear to potential participants that patients of all races and ethnicities are being recruited. 
 
3.
Make consent form documents available in Spanish. 
 
4.
Review blinded aggregate information on demographic characteristics of enrolled patients after each 
100 enrollments, and consider refocusing recruitment efforts towards sites with larger proportions of 
minorities as warranted. 
 
Finally, while we do not anticipate differential treatment effects based on race or ethnicity, our analyses will 
explore clinically important differences due to race/ethnicity. 
 
12.3 
Subject Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsor(s) 
and their agents. Therefore, the study protocol, documentation, data, and other information generated will be 
held in strict confidence. No information about the study or data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
The study monitor, other authorized representatives of the sponsor, Food and Drug Administration (FDA), 
Health Canada, and representatives of the NCC, NDMC and CIRB/REBs may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records and 
pharmacy records for the participants in this study. The clinical study site will permit access to such records. 
 
use during 
the study. At the end of the study, all records will continue to be kept in a secure location for the duration 
specified by the StrokeNet Standard Operating Procedure (SOP) or longer as dictated by the CIRB/REBs 
and local country regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored for the duration of the study and analysis at the NDMC. The study data entry and  
study management systems used by clinical sites and by the NDMC research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and a Public Use Dataset 
(PUDS) will be archived with NINDS. 
 
12.4 
Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the DSMB, CIRB/REBs, the NINDS, the 
sponsor, the OHRP, the FDA, Health Canada, or other government agencies as part of their duties to 
ensure that research subjects are protected. 


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13
TRIAL ADMINISTRATIVE STRUCTURE 
 
13.1 
 
 
 
 
13.2 
StrokeNet National Coordinating Center and National Data Management Center 
The clinical coordination of the MOST Trial operations will be centralized through the following: 
 
NIH StrokeNet National Coordinating Center (NCC) 
University of Cincinnati 
260 Stetson Street, Suite 2300 
Cincinnati, Ohio 45267-0525 
 
A Project Manager at the NCC will be assigned to coordinate the following study oversight: trial 
communication, required training activities, site assessment and or initiation visits, collection of trial related 
regulatory documents, recruitment performance tracking and performance analysis. 
 
The data coordination and analysis of the MOST Trial will be centralized through the following: 
NIH StrokeNet National Data Management Center (NDMC)  
Medical University of South Carolina 
135 Cannon Street 
Charleston, SC 29425-8350 
 
user-friendly web-based database system, developed and validated by the NDMC, will be used for 
regulatory document management, subject randomization, data entry, data validation, project progress 
monitoring, subject tracking, user customizable report generation and secure data transfer. 
 
13.3 
Data Safety and Monitoring Board (DSMB) 
MOST will have an independent Data Safety Monitoring Board (DSMB) appointed by the NIH to oversee study 
safety. We do not expect safety concerns in non-ET patients based on our Phase 2 trials. Given the ARTSS-IA 
data, we do not expect combination therapy in the setting of ET will prove to be unsafe early in the conduct of 
the trial. The DSMB may stop an arm at any point for safety concerns. The DSMB will specify the content and 
frequency of data reports to be generated by the NDMC. 
 
 
Figure 9  MOST Organizational Chart  
NCC  
StrokeNet 
National 
Coordinating 
Center 


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13.4
Independent Medical Safety Monitor
An Independent Medical Safety Monitor will review all SAE reports submitted by the clinical sites throughout 
the trial and will determine if reported intracranial hemorrhages are symptomatic. He/she also will be 
responsible for ensuring good clinical practice and to identify safety concerns quickly. The IMSM may suggest 
protocol modifications to prevent the occurrence of particular AEs, e.g., modifying the protocol to require 
frequent measurement of laboratory values predictive of the event or to improve expeditious identification of 
SAEs. To minimize bias, he/she will evaluate SAEs blinded to treatment assignment, unless the DSMB 
approves partial or complete unblinding. In the event of unexpected SAEs or an unduly high rate of SAEs, the 
IMSM will promptly contact the Lead PI and the NINDS Program Official who will notify the DSMB Chair. 
 
13.5 
Endovascular Safety Monitor 
The endovascular safety monitor will review all SAE reports submitted by clinical sites that involve ET cases to 
assess safety particular to ET. He/she will ensure there are no safety issues particular to ET, including as 
performed by individual interventionists or sites. The endovascular safety monitor may suggest protocol 
modifications to prevent the occurrence of particular AEs, e.g., modifying the protocol to require frequent 
measurement of laboratory values predictive of the event or to improve expeditious identification of SAEs. To 
minimize bias, he/she will evaluate SAEs blinded to treatment assignment, unless the DSMB approves partial 
or complete unblinding. In the event of unexpected SAEs or an unduly high rate of SAEs particular to ET 
subjects, the endovascular safety monitor will promptly contact the Lead PI and the NINDS Program Official 
who will notify the DSMB Chair. 
 
13.6 
Executive Committee 
The Executive Committee will provide overall clinical guidance and leadership for the execution of the MOST 
Trial. This committee will provide a means of partnership between the investigators, the NINDS, and the 
sponsors. The Executive committee, composed of experts in emergency medicine, vascular neurology, 
endovascular therapy and neuroimaging, and biostatistics will provide the overall scientific guidance for the 
study. The committee will meet at least quarterly by phone (1 hour) for the full duration of the study. 
Responsibilities include oversight of the overall conduct of the study with regard to protocol compliance and 
modifications/amendments, study progress, and problem-solving. The Lead PI will chair the executive 
committee. 
 
13.7 
National Institute of Neurological Disorders and Stroke (NINDS) 
The NINDS will provide funding for all aspects of this trial via the NIH StrokeNet. An identified Program Official 
will be responsible for oversight of this trial. 
 
14 
 PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures developed by the 
Executive Committee. Any presentation, abstract, or manuscript will be made available for review by the 
sponsor and the NINDS prior to submission.


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Menon BK, Buck BH, Singh N, Deschaintre Y, Almekhlafi M, Coutts SB, et al. Intravenous tenecteplase 
compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-
label, registry-linked, randomised, controlled, non-inferiority trial. The Lancet. 2022 Jul;400(10347):161-
169. 
45.
Rivero-Arias O, Ouellet M, Gray A, Wolstenholme J, Rothwell PM, Luengo-Fernandez R. Mapping the 
modified Rankin scale (mRS) measurement into the generic EuroQol (EQ-5D) health outcome. Med 
Decis Making. 2010;30(3):341-354. 
46.
Hong KS, Saver JL. Quantifying the value of stroke disability outcomes: WHO global burden of disease 
project disability weights for each level of the modified Rankin Scale. Stroke; a journal of cerebral 
circulation. 2009;40(12):3828-3833. 
47.
Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the 
Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational 
study. Lancet. 2007;369(9558):275-282. 
48.
Berger C, Fiorelli M, Steiner T, et al. Hemorrhagic transformation of ischemic brain tissue: 
asymptomatic or symptomatic? Stroke; a journal of cerebral circulation. 2001;32(6):1330-1335. 
49.
Broderick JP, Lu M, Kothari R, et al. Finding the most powerful measures of the effectiveness of tissue 
plasminogen activator in the NINDS tPA stroke trial. Stroke; a journal of cerebral circulation. 
2000;31(10):2335-2341. 
50.
Saver JL, Gornbein J. Treatment effects for which shift or binary analyses are advantageous in acute 
stroke trials. Neurology. 2009;72(15):1310-1315. 
51.
EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 
1990;16(3):199-208. 
52.
Savio K, Pietra GL, Oddone E, Reggiani M, Leone MA. Reliability of the modified Rankin Scale 
applied by telephone. Neurol Int. 2013;5(1):e2. 
53.
Janssen PM, Visser NA, Dorhout Mees SM, Klijn CJ, Algra A, Rinkel GJ. Comparison of telephone and 
face-to-face assessment of the modified Rankin Scale. Cerebrovasc Dis. 2010;29(2):137-139. 
54.
Wintermark M, Albers GW, Alexandrov AV, et al. Acute stroke imaging research roadmap. Stroke; a 
journal of cerebral circulation. 2008;39(5):1621-1628. 
55.
Jauch EC, Saver JL, Adams HP, Jr., et al. Guidelines for the early management of patients with acute 
ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American 
Stroke Association. Stroke; a journal of cerebral circulation. 2013;44(3):870- 947. 
56. 
Canadian Stroke Best Practices. Acute Stroke Management. 
Strokebestpractices.ca/recommendations/acute-stroke-management. Accessed on 12Oct2022. 
57.
Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, Johnston KC, Johnston SC, Khalessi 
AA, Kidwell CS, Meschia JF, Ovbiagele B, Yavagal DR. 2015 AHA/ASA Focused Update of the 2013 
Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular 


MOST Stroke Trial Protocol
 
 
 
                                    27 
 v6.3 2023-03-06 
Treatment. A Guideline for Healthcare Professionals From the American Heart Association/American 
Stroke Association. Stroke; a journal of cerebral circulation. 2015;46. 
58.
Adams HP, Jr., del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with 
ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke 
Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the 
Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary 
Working Groups: The American Academy of Neurology affirms the value of this guideline as an 
educational tool for neurologists. Circulation. 2007;115(20):e478-534. 
59.
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders 
and Stroke rt-PA Stroke Study Group. The New England journal of medicine. 1995;333(24):1581-1587. 
60.
Canada Panel on Research Ethics. TCPS 2 (2018)  Chapter 3: The Consent Process. 
https://ethics.gc.ca/eng/tcps2-eptc2_2018_chapter3-chapitre3.html. Accessed on 12Oct2022. 

SAP_001.pdf: 
MOST SAP
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January 24, 2018
Page | 0
Jordan Elm, Renee H. Martin
Scott Berry, Todd Graves
Data Coordination Unit
Department of Public Health Sciences
Medical University of South Carolina
Charleston, SC 29425
Berry Consultants
STATISTICAL ANALYSIS PLAN
Multi-arm Optimization of Stroke
Thrombolysis Stroke Trial (MOST)
VERSION 2.0 | OCTOBER 20, 2020


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October 20, 2020
Table of Contents
1
Synopsis of the Study.....................................................................................................................2
2
Acronyms........................................................................................................................................ 2
3
Study Design................................................................................................................................... 3
3.1
Treatment Arms.....................................................................................................................3
4
Definition of the Target Population and Study Samples.............................................................. 3
4.1
Target Population ..................................................................................................................3
4.2
Enrollment Target .................................................................................................................. 4
4.3
Intent to Treat Sample (ITT) ..................................................................................................4
4.4
Per Protocol Sample .............................................................................................................. 4
4.5
Safety Sample ......................................................................................................................... 4
5
General Statistical Considerations ................................................................................................ 5
5.1
Subject Accountability........................................................................................................... 5
5.2
Randomization ....................................................................................................................... 5
5.3
Blinding ................................................................................................................................... 5
5.4
Missing Data ........................................................................................................................... 6
5.5
Treatment Group Comparability........................................................................................... 6
5.6
Multiplicity ............................................................................................................................. 7
6
Primary Efficacy Analysis ............................................................................................................... 8
6.1
Overview ................................................................................................................................ 8
6.2
Schematic of Trial Design ...................................................................................................... 9
6.2.1
Primary Efficacy Outcome ........................................................................................... 11
6.3
Final Analysis of the Primary Efficacy Outcome.................................................................11
6.3.1
Threshold for a Successful Trial................................................................................... 11
6.4
Predictive Probabilities........................................................................................................ 12
6.5
Interim Analyses................................................................................................................... 12
6.6
Stopping for Futility ............................................................................................................. 12
6.7
Stopping for Expected Success ........................................................................................... 13
6.8
If both treatments are better than control ........................................................................ 13


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7
Secondary and Tertiary Analyses................................................................................................13
7.1
Secondary Analysis of the Primary Outcome adjusting for baseline covariates .............. 13
7.2
Tertiary Analysis of the Primary Outcome: Adjusting for Subgroups ...............................14
7.3
Secondary Clinical Efficacy Outcomes ................................................................................ 16
7.4
Secondary Radiological Reperfusion Outcomes ................................................................16
Secondary Clinical Efficacy Outcomes—no. (%) ............................................................................ 16
7.5
Tertiary Efficacy Outcomes .................................................................................................17
7.6
Analysis of Secondary/Tertiary Outcomes .........................................................................17
7.7
Imaging Data ........................................................................................................................ 17
7.8
Subgroup Analysis: Gender, Race, Ethnicity.......................................................................17
7.9
Endovascular Therapy (Concomitant Therapy) .................................................................. 18
8
Safety Analyses ............................................................................................................................ 18
8.1
Primary Safety Outcome ..................................................................................................... 18
8.2
Secondary Safety Outcomes ............................................................................................... 19
8.3
Analysis of Safety Outcomes............................................................................................... 19
9
Sample Size Determination ......................................................................................................... 19
10
Appendix A: MOST Design and Analysis Plan......................................................................... 21
 


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October 20, 2020
1 Synopsis of the Study
This statistical analysis plan (SAP) is for the MOST trial. The SAP will define all “pre-specified, planned 
analyses.” If there are minor differences between the MOST protocol and the SAP, the SAP will 
take precedence.  
The MOST trial is a three-arm, adaptive, Phase-3, single blinded, randomized controlled clinical 
trial. The primary efficacy objective of the MOST trial is to determine if argatroban or eptifibatide 
improves 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic 
stroke (AIS) patients treated with IV thrombolysis within three hours of symptom onset.
2 Acronyms
Abbreviation
Description
AIS
Acute Ischemic Stroke
aPTT
activated Partial Thromboplastin Time
DSMB 
Data and Safety Monitoring Board
ET
Endovascular thrombectomy 
ICA 
Internal carotid artery
ITT
Intent to Treat 
IV  
Intravenous 
IQR 
Interquartile Range
LVO
Large Vessel Occlusion
MCA 
Middle Cerebral Artery 
MCMC 
Markov Chain Monte Carlo
mRS
modified Rankin Scale 
NDMC
National Data Management Center 
NIHSS 
NIH Stroke Scale 
NINDS
National Institute of Neurological Disorders and Stroke 
RAR
Response Adaptive Randomization
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
SD 
Standard Deviation
sICH
symptomatic Intracranial Hemorrhage
UW-mRS
Utility-Weighted modified Rankin Scale 


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October 20, 2020
3 Study Design
This trial is designed as a multicenter, prospective, randomized, adaptive phase III clinical trial.  
3.1 Treatment Arms
There are three treatment arms defined in the trial.
Study Arms
Subjects will receive the following for a total of 12 hours of
infusion
1
Argatroban 
Argatroban (1mg/ml) bolus +
Argatroban (1 mg/ml) 2-hour infusion + 
Argatroban (1mg/ml) 10-hour infusion 
2
Eptifibatide
Eptifibatide (1.35 mg/ml) bolus + 
Eptifibatide (0.25 mg/ml) 2-hour infusion + 
placebo 10-hour infusion 
3
Placebo
Placebo bolus + 
Placebo 2-hour infusion + 
placebo 10-hour infusion 
NOTE: Commercially available product is assembled into study drug kits. Investigators are unblinded to 
treatment arms, but subjects and LARs are blinded throughout the duration of the trial. 
4 Definition of the Target Population and Study Samples
4.1 Target Population
Acute ischemic stroke (AIS) patients treated with IV thrombolysis within three hours of symptom 
onset. The specific inclusion/exclusion criteria are listed in the protocol.


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October 20, 2020
4.2 Enrollment Target 
We will use 110 recruiting sites. Allowing for study startup and close down activities, we estimate 
an average of 0.3 patients/site/month or 396 patients/year during the peak enrollment period, 
consistent with StrokeNet estimates.
Enrollment Milestones and Timelines from MOST Grant Proposal
Task
Year 1
Year 2
Year 3
Year 4
Year 5
Q1Q2Q3Q4Q1Q2Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2Q3
Q4
Enrollment 
(goals by quarter)
10 40 65 85100100100100100100100100100100
4.3 Intent to Treat Sample (ITT) 
The primary analysis will use the ITT sample. The ITT sample will include all subjects randomized. 
For each interim analysis (e.g. RAR, interim assessment for efficacy and futility) the analysis 
population will include subjects who have been randomized  30 days from the time of the data 
freeze; the final analysis will occur once all subjects have the opportunity to complete the final 
90 days previously).   
 
4.4 Per Protocol Sample 
The Per Protocol sample will include all subjects randomized, who received at least the bolus of 
the study drug (within 75 minutes of thrombolysis administration) and who had no major 
eligibility violations (defined as either not having an acute ischemic stroke or not treated with IV 
thrombolysis within 3hrs and 15min from stroke onset). In case of administration errors, subjects 
will be classified by the treatment which they received. 
The primary and secondary efficacy analyses will be performed with both the ITT and Per 
Protocol samples, with the Per Protocol analyses being secondary and supportive of the primary 
ITT analyses. 
4.5 Safety Sample 
The Safety sample will include all subjects randomized, who received at least the bolus of study 
drug. In case of administration errors, subjects will be classified by the treatment which they 
received.
The safety analyses will be performed with the Safety sample. 


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October 20, 2020
5 General Statistical Considerations
5.1 Subject Accountability
A flowchart will be created to present a summary of participant status. This flowchart will list the 
number of subjects screened and randomized to each treatment group. Then, within each group, 
the  number of subjects who received at least some treatment, the number of subjects who did 
not receive any treatment, and the number of missing 90 day visits. 
5.2 Randomization  
The first 150 subjects will be randomized in a 1:1:1 ratio to either argatroban, eptifibatide, or 
placebo. From the 150th to the 500th subject enrollment, RAR) will favor the active arm showing 
the greatest benefit based on accrued data. After 500 subjects, one or both intervention arms 
may be carried forward for fixed randomization versus placebo.
A web-based central randomization system will be developed by the NDMC and installed on the 
WebDCU™ MOST study website. Age and NIHSS score will be included in the randomization 
algorithm to prevent imbalances, thereby enhancing the comparability of treatment groups. 
The detailed randomization scheme and source codes will be provided in the Randomization Plan 
document.
Response Adaptive Randomization  
RAR begins at 150 subjects and ends at 500 subjects. Allocation probabilities for the two active 
arms will be updated approximately every month, based on Bayesian predictive probabilities. 
After RAR updates, the allocation probabilities for the two active arms are proportional to their 
1:1 predictive probabilities, and the control arm receives randomization probability proportional 
to the maximum active arm.  
5.3 Blinding 
The NIH StrokeNet Central Pharmacy will assemble the commercially available study drug 
products into kits and ship to Clinical Performing Sites for study use. Investigators are unblinded 
to treatment arms, but subjects and LARs are blinded throughout the duration of the trial.
 
Argatroban and placebo subjects will initially receive a bolus followed by a 12-hour infusion. 
Eptifibatide arm subjects will receive a bolus followed by a 2-hour infusion. A 10-hour saline 
infusion will be administered after the 2-hour eptifibatide infusion to maintain the single blind. 
 
The two primary concerns of lack of blinding are: 1) knowledge of the treatment arm could bias 
endpoint assessments of efficacy (mRS at 90 days) or safety (sICH); and, 2) possibility that 


MOST SAP 
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October 20, 2020
knowledge of an active treatment could influence the decision to proceed with ET in some 
patients. Centralized blinded 90-day mRS assessments and centralized blinded adjudication of 
sICH will mitigate #1, and requiring a clinical decision regarding a plan to proceed to ET prior to 
randomization will mitigate #2. 
5.4 Missing Data
Under the ITT principle, all subjects who are randomized are included in the analysis.  Every 
attempt will be made to avoid missing outcome data, but missing data is anticipated with any 
longitudinal study. Reasons for missing data will be examined by comparing means and standard 
deviations for subjects with and without the relevant data. Missing data on the primary outcome 
(90-day mRS) will be imputed using a Bayesian multiple imputation method that accounts for 
baseline NIHSS and the 30-day mRS. If no 30 or 90 day mRS is available, the subject’s 30-day 
mRS is singley imputed using a hot-deck method which randomly selects the outcome from a 
pool of patients with observed mRS scores matched by treatment group, age and baseline 
NIHSS, time of symptom onset and EVT.
5.5 Treatment Group Comparability 
A description of the baseline characteristics of trial participants will be presented by treatment 
group. Dichotomous variables will be summarized as number (%). Percentages will be calculated 
based on the number of participants with available data for that variable. Continuous/ordinal 
variables will be summarized as either mean (SD) or median (IQR) depending on whether the 
distribution is skewed. In the case of variables with missing values, the denominator will be 
stated in the summary table or in a footnote to the summary table.
Baseline Characteristics
Control
(N= )
Argatroban   
(N= )
Eptifibatide 
(N= )
Age, median IQR
Female sex, count (%) 
Race, count (%)
White 
Black
Asian
Other 
Hispanic, count (%)
Type of IV thrombolysis  
rtPA 
TNK 
Stroke Onset to thrombolysis bolus (min) , mean 
(SD) 
Stroke Onset to randomization (min) , mean (SD) 
Baseline NIHSS, median (IQR) 


MOST SAP 
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October 20, 2020
Baseline aPTT, median (IQR) 
Prior use of , count (%)
Aspirin 
Clopidogrel 
Warfarin 
Other Antiplatelet 
Other Anticoagulant 
Statins  
Antihypertensives  
Diabetic medications 
Past medical history, number (%) 
Myocardial infarction 
Atrial fibrillation 
Hypertension 
Diabetes 
Prior Stroke (excluding the qualifying stroke) 
 Hypercholesterolemia
ASPECTS score on Baseline CT , median (IQR) 
Historical mRS, median IQR
Decision to go to ET at the time of randomization , 
count (%)
Presence of LVO at baseline** , count (%)
**Amongst those patients for whom the decision was made to go to ET at the time of randomization 
determined by central neuroimaging readers (unless CTA is not available because of the contrast in which case the LVO 
determination made at the time of ET initiation will be used.) 
 
5.6 Multiplicity 
Inflation of the type I error rate due to the planned interim analysis of the primary outcome is 
controlled by using Pr(
> 0)
0.985 rather than 0.975 (details below). This threshold was 
chosen to control the experiment-wise type I error probability at 0.025.   
 
If both treatments are better than control, then we will compare the two active treatment arms 
by using 
1
2
Pr(|
| 0)
0.975 . All secondary/tertiary analyses will be tested at a significance 
level of two-
 
 
For secondary outcomes, we will not account for multiplicity. These analyses are merely
supportive and exploratory and will be interpreted as such. The overall trial hinges on the
primary analysis and interpretation of secondary results is already tempered by their placement.
Accounting for multiple testing would also increase the risk that an interesting finding is not
subsequently pursued.  
 
Safety analyses will be tested at a significance level of two-


MOST SAP 
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October 20, 2020
6 Primary Efficacy Analysis
6.1 Overview
The MOST trial will be a single blinded, multi-arm, adaptive, randomized controlled Phase 3 
clinical trial at 110 sites to establish whether argatroban and/or eptifibatide is superior to 
placebo in improving 90-day functional outcomes in AIS patients who are treated with IV 
thrombolysis within three hours of symptom onset. We will enroll a maximum of 1200 patients. 
The first 150 subjects will be randomized 1:1:1 to argatroban:eptifibatide:placebo. From 150-500 
patients, response adaptive randomization (RAR) will favor the treatment arm(s) showing the 
greatest benefit based on accrued data. After 500 patients, one or both intervention arms may 
be carried forward for fixed randomization versus IV thrombolysis. When N=500, the trial may be 
stopped for futility if there is <20% chance of demonstrating benefit of either intervention 
(argatroban or eptifibatide) if the trial were to continue. Next, pre-specified thresholds will be 
used to stop the trial for futility when N=700 or N=900, if there is <5% chance of demonstrating 
benefit of either intervention if the trial were to continue. After 700 and 900 subjects are 
enrolled, an arm (or both) may be stopped for expected success. If an arm has an expected 
success predictive probab
that arm will occur when all enrolled subjects have been followed up at 90 days. If it is the last 
remaining active arm, the trial will stop altogether, and all subjects will be followed up to 
determine the success of the trial. If another arm remains after one arm stops for expected 
success, the trial will continue with 1:1 randomization between control and the remaining arm. 
These additional data may demonstrate both regimens have efficacy. Of note, the predictive 
probability takes into account the patients currently enrolled, but without complete follow-up, 
and estimates the potential attenuation in any observed treatment effect depending on whether 
there are many more patients to be enrolled (potential high attenuation) or whether only few 
patients remain (low likelihood of attenuation). This is different from a posterior probability
which does not depend on the remaining number of patients to be enrolled.  


MOST SAP 
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October 20, 2020
6.2 Schematic of Trial Design


MOST SAP
CONFIDENTIAL
Green boxes in columns indicate 
   randomization probabilities
Blue arrows indicate interim
     analyses
Fixed 
Randomization
Adaptive Randomization
updated ~ monthly
argatroban 
eptifibatide
control
1/3
1/3
1/3
r1
r2
max(r1, r2)
…
Fixed Randomization
(either 1:1 or 1:1:1) 
Total No. of Subjects Enrolled
|
  |
            |
       |
|
0
150
      500
   700
900
|
  |
            |
       |
   |
1/3
1/3
1/3
1/2
0
1/2
or
or
Yes
Stop
one 
arm
If N=500
Stop
Both 
arms  
futile.
Is 1:1 
predictive prob 
< 0.20?
No
Is 1:1:1 
predictive 
prob  <0.20 
for one arm?
Yes
Sto
on
arm
futi
If N=700 or 900
Stop
Both 
arms  
futile.
Is 1:1 
predictive prob 
< 0.05?
No
Is 1:1
predict
prob  <0
for one 
r1
r2
max(r1, r2)


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October 26, 2018
11
6.2.1 Primary Efficacy Outcome
Centrally determined 90-day mRS scores re-scaled using the patient-centered utility weighted 
mRS (UW-mRS) listed in the table below. 
 
6.3 Final Analysis of the Primary Efficacy Outcome
The primary analysis will be conducted on the intent-to-treat (ITT) analysis population. The final 
analysis is performed with either one or two active arms. If both active arms reach the end of the 
trial, they will each be compared to control independently. 
The parameter of interest is for a given treatment , 
, the difference in the expected utility for 
the active treatment minus control. For each active arm, the hypothesis test is 
:
0 
:
> 0
Define the primary efficacy outcome 
j
Y as the 90-day UW-mRS.
Also assume that 
2
(
,
)
j
i
d
d
Y
N
where 
d  is the difference in the expected utility for the 
active treatment minus control (with 
= 0 by convention and 
{0,1,2}) and 
i for  6
42  is function of the initial NIHSS (i). We model the 
flexibly, and assume that they come from 
a second order normal dynamic linear model (NDLM).   
6.3.1
Threshold for a Successful Trial
The primary output of the final analysis is the posterior probability that 
> 0, for any ’s that 
remain in the trial.  The trial is successful if in the final analysis, the posterior probability of a 
positive benefit is at least 0.985.  That is, success is claimed if 
 
Pr (
> 0)
0.985 
Utility Scores for Each mRS Score
mRS Score
0
1
2 
3 
4 
5 
6
MOST Trial utility weighted mRS (UW-mRS) 
10
9.1
7.6 
6.5 
3.3 
0 
0


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October 26, 2018
12
6.4 Predictive Probabilities 
The predictive probability of a successful final analysis will be calculated based on different 
assumptions about the remaining subjects to be enrolled. 
1. First, for each active arm, we assume that the remainder of the trial is 1:1 randomization 
between that arm and the control arm. We then calculate the predictive probability that 
the remaining patients generate data that lead to a significant result (high posterior 
probability of a positive treatment effect). These predictive probabilities will be used in 
futility decisions and RAR probabilities. For convenience we will refer to these predictive 
probabilities as 1:1 predictive probabilities. 
 
2. Second, we will assume that the remaining subjects are allocated 1:1:1 to the two active 
arms and control. We will calculate the predictive probability that those subjects 
generate data resulting in a significant final analysis for each arm. We refer to these 
predictive probabilities as 1:1:1 predictive probabilities.  
 
3. Third, we calculate the predictive probability that an arm would have a successful final 
analysis if enrollment were stopped immediately, based on predictions of results for 
enrolled subjects without final data. These predictive probabilities are referred to as 
expected success predictive probabilities. 
 
Details are in Appendix A. 
6.5 Interim Analyses 
Interim analyses for safety and futility will take place after 500 subjects are enrolled. Subsequent 
interim analyses (if the trial is not stopped at 500 patients) take place after 700 and 900 subjects. 
All interim analysis results will be confidential and only presented to the DSMB in a formal report 
prepared by the unblinded statistical team at the NDMC. Following review of the interim analysis 
results and safety data, the DSMB will make recommendations regarding stopping for safety, 
futility or expected success. These formal interim analyses are distinct from the monthly reports 
generated for ongoing safety monitoring throughout the trial.
6.6 Stopping for Futility 
There are multiple ways in which the trial may be stopped early for futility. When N=500, the 
trial may be stopped for futility if there is <20% chance of demonstrating benefit of either 
intervention if the trial were to continue. Next, if the trial proceeds beyond 500 subjects, the trial 
can be stopped altogether when N=700 or N=900, if there is <5% chance of demonstrating 
benefit of either intervention if the trial were to continue. Thus, the no-go criterion is predictive 
probabilities <20% at 500 subjects, or a predictive probability <5% at 700 or 900 patients.  
 


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October 26, 2018
13
6.7 Stopping for Expected Success 
After 700 and 900 subjects are enrolled, an arm (or both) may be stopped for expected success. 
success. The final analysis for that arm will occur when all enrolled subjects have been followed 
up at 90 days. If it is the last remaining active arm, the trial will stop altogether, and all subjects 
will be followed up to determine the success of the trial. If another arm remains after one arm 
stops for expected success, the trial will continue with 1:1 randomization between control and 
the remaining arm. These additional data may demonstrate both regimens have efficacy, which 
may yield another treatment option in cases of allergies or contraindications to one of the 
interventions. Of note, the predictive probability takes into account the patients currently 
enrolled, but without complete follow-up, and estimates the potential attenuation in any 
observed treatment effect depending on whether there are many more patients to be enrolled 
(potential high attenuation) or whether only few patients remain (low likelihood of attenuation). 
This is different from a posterior probability which does not depend on the remaining number of 
patients to be enrolled. Indeed, the posterior probability that an intervention is better than 
control would have to substantially exceed 99% (e.g., a boundary of <0.0001 as used in group 
sequential designs) for the predictive probability to be 99%.  
6.8 If both treatments are better than control 
If both arms are effective when compared with control, we will compare both active arms with 
each other as a secondary analysis using the approach described above and the following criteria 
for success
1
2
Pr(|
| 0)
0.95 . 
 
7 Secondary and Tertiary Analyses 
7.1 Secondary Analysis of the Primary Outcome adjusting for 
baseline covariates 
The primary outcome of UW-mRS values will be reanalyzed in a linear regression adjusting for 
baseline covariates: enrolling site, NIHSS, age, time to IV thrombolysis, thrombolysis type 
(TNK/rtPA) location of LVO at the time of start of ET (defined as intracranial ICA, MCA-M1, M2, or 
basilar occlusion, in which small categories may be combined into a single group) and time from 
onset to groin puncture in subjects undergoing ET.   
Each covariate is evaluated individually first with a model that includes a main effect of the 
covariates, dummy variables for the treatment groups, and interaction effects between the 
covariates and the treatment groups.  Then a multivariable model that includes all covariates and 


MOST SAP
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October 26, 2018
14
interaction terms that contributed significantly (p<0.05) individually will be constructed. We will 
check for collinearity, and re-fit a final model, dropping collinear terms if any are identified.
7.2 Tertiary Analysis of the Primary Outcome: Adjusting for 
Subgroups
Each subgroup is evaluated individually in a linear model of UW-mRS values that includes a main 
effect of the subgroup, dummy variables for the treatment groups, and interaction effects
between the subgroup levels and treatment group.  The p-values for the interaction terms will 
be reported. The adjusted mean difference in UW-mRS (95% CI) for the treatment effect versus 
control will be reported for each subgroup (for both active treatment groups).
 
Age (< 80 years, >80 years) 
 
Sex (Male, Female) 
 
Race (Asian, Black, White, Other, etc. Small race categories, such as Asian, Native 
American, Pacific Islander, may be combined into a single group) 
 
Ethnicity (Hispanic, Not Hispanic) 
 
Type of IV thrombolysis (rtPA/TNK) 
 
Time to IV thrombolysis (<2 hr, >2hr) 
 
Time to study drug initiation (<2 hr, >2hr) 
 
ASPECT score (< 6, 6-10) 
 
Decision to go to ET prior to randomization (Yes/No) 
 
Presence of LVO (Yes/No) 
 
Location of LVO (intracranial ICA, MCA-M1, M2, or basilar occlusion. Small categories may 
be combined into a single other group)  
 
Received ET (Yes/No) 
 
Time to reperfusion for ET (cutpoint TBD) 
A table/forest plot will be created with shows the following by Subgroup level:
Subgroup/ Number of Patients/ Mean (SD) UW-mRS for all 3 treatment group/ Mean difference 
from control  (95% CI) for each active arm/ p-value for the interaction terms (subgroup x indictor 
for each active treatment arm). 
 
Argatroban 
N=400
Eptifibatide 
N=400
Subgroup 
No of 
patients 
Mean  (95% CI) 
UW-mRS 
difference from 
control 
p-value for 
interaction term 
Mean  (95% 
CI) UW-mRS 
difference 
from control 
p-value for 
interaction 
term 
Age 
1200
 
* 
*
<80 yr 
>80 yr 
800 
600 
 


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Sex 
 
 
* 
* 
Male
Female
 
 
Race
 
 
* 
* 
White
Black
 
 
Asian
 
 
Other
Ethnicity, Hispanic
 
 
*
*
Not Hispanic 
 
 
Stroke Onset to thrombolysis
bolus 
*
*
<2hr 
 
 
 >2hr 
Type of IV Thrombolysis 
 
 
rtPA  
 
 
TNK
 
 
Time to study drug initiation 
 
 
* 
* 
<2hr 
 
 
 >2hr 
 
 
ASPECT score on Baseline CT 
 
 
* 
*
< 6  
 
 
6-10 
 
 
Decision to go to ET at the time 
of randomization
 
 
* 
*
No 
 
 
Yes 
 
 
Received ET 
 
 
* 
*
No
 
 
Yes 
Presence of LVO (for ET 
subgroup)
 
 
* 
*
No 
 
 
Yes 
 
 
LVO location (for ET subgroup) 
 
 
* 
* 
intracranial ICA 
 
 
MCA-M1
 
 
M2 
 
 
basilar occlusion
 
 
Time to reperfusion (for ET 
subgroup)** 
 
 
* 
*


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< Cutpoint 
 
 
> Cutpoint
**A small number of patients may not be able to be reperfused at the end of ET, and so these patients will be excluded. 
Additionally, some patients will have no occlusion at the start of ET, and so they will be excluded.  
 
7.3 Secondary Clinical Efficacy Outcomes 
1. proportion with 90-day mRS 0-1 (or return to their historical mRS)
2. proportion with 90-day mRS 0-2 (or return to their historical mRS)
3. 90-day ordinal analysis of the mRS
7.4 Secondary Radiological Reperfusion Outcomes  
1. proportion of participants who are 2b or 3 on the (Baseline) Modified TICI score 
of 2b or 3 prior to thrombectomy amongst those for whom there was a decision 
to go to ET
2. proportion of participants who have thrombectomy (Final TICI score of 2b or 3)
amongst those for whom there was a decision to go to ET
Control 
(N= )
Argatroban  
(N= ) 
Eptifibatide 
(N= ) 
Secondary Clinical Efficacy 
Outcomes—no. (%) 
No (%) 
No (%) 
Odds 
Ratio 
(95% CI) 
P 
value 
No (%) 
Odds 
Ratio 
(95% CI)
P 
value
90-day mRS 0-1   
 Xx (%)
Xx (%)
a
Xx (%)
a 
90-day mRS 0-2   
  Xx (%) 
Xx (%) 
a
 Xx (%) 
a 
90-day ordinal analysis of the 
mRS
median 
(IQR)
media
n (IQR)
----
b 
median 
(IQR)
----
b
Secondary Radiological 
Reperfusion Outcomes (for 
whom there was a decision 
to go to ET) —no. (%)
 N=nn
N=nn 
Odds 
Ratio 
(95% CI) 
P 
value 
 N=nn 
Odds 
Ratio 
(95% CI) 
P 
value
Modified TICI score of 2b or 3 
prior to thrombectomy 
 Xx (%)  
Xx (%)
a
Xx (%) 
 
a 
Thrombectomy: Final 
Modified TICI score of 2b or 3
Xx (%) 
Xx (%)
a
Xx (%) 
 
a 
(or return to their historical mRS) 
a Odds ratio will be expressed as an unadjusted risk ratio with its 95% confidence interval and p-value will 
compare treatment to control. 
b P value will compare treatment to control via Wilcoxon Rank Sum test (WMW). 


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7.5 Tertiary Efficacy Outcomes 
1.
2. change from baseline to 24-hour NIHSS 
3. 90-day EQ-5D
7.6 Analysis of Secondary/Tertiary Outcomes 
The difference between each active treatment group and control will be reported as absolute 
unadjusted mean difference (95% CI) and adjusted difference (95% CI)  for continuous outcomes, 
and absolute difference in proportions (95% CI)  and Risk/Odds Ratio (95% CI) for binary 
outcomes.
For Binary outcomes each active treatment arm will be compared to control in a two-sample test 
of proportions (or Fisher’s exact test if events are rare).  
 
The ordinal analysis of the 90-day mRS will use a Wilcoxon rank sum test to compare each 
treatment groups to control. For continuous outcomes, each active treatment arm will be 
compared to control in a two-sample t-test if normality assumption holds; otherwise, the rank 
sum test. 
 
Missing secondary/tertiary outcomes will be imputed using the hot deck method matched by 
age and baseline NIHSS, time to symptom onset, treatment group, ET, and earlier collected time 
points of the missing outcome measure. Multiple imputation methods may be conducted if the 
total amount of missing data exceeds 5%. 
 
7.7 Imaging Data  
The baseline ASPECT score, presence and location of LVO at baseline for ET patients will be 
determined by the central imaging readers for all enrolled patients and reported in the Table of 
baseline characteristics (Table 1). The presence of ICH, PH-1, and PH-2 on the 24 hour CT will be 
determined by the central imaging reader for all enrolled patients and reported as Safety 
Outcomes (see below). 
Other imaging data (e.g., M2 occlusions or collateral scores will be noted and included in 
exploratory analyses to be determined).  
7.8 Subgroup Analysis: Gender, Race, Ethnicity 
Recruitment and retention of women and minorities will be monitored by the DSMB and will be 
provided to the NINDS at fixed intervals and in the Final Progress Report.  


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Although we do not anticipate differential treatment effects based on sex, race, or ethnicity, our 
analyses will explore clinically important differences due to sex/race/ethnicity (See Subgroup 
analysis section 7.2). A clinically important interaction of the treatment effect by sex, race, or 
ethnicity, regardless of the statistical significance, will be reported to the NINDS in the Final 
Progress Report and to the scientific community in the primary paper.
7.9 Endovascular Therapy (Concomitant Therapy)
We expect ~30% of subjects will undergo Endovascular Therapy (ET).  ET is a potentially 
confounding therapy (i.e., intervention arm patients may show improvement and be less likely to 
need ET).   
We will closely monitor for confounding due to treatment effect as a possible reason for any 
differences in rates of ET between groups. A comparison of the proportion of participants who 
have groin puncture may not detect differences in treatment groups since the thrombectomy 
rates may still differ (i.e., a more effective intervention may obviate need for thrombectomy). As 
such, we will monitor the proportion of participants who have thrombectomy as a secondary 
outcome. If there is a statistically significant difference in the proportion of patients who receive 
thrombectomy by treatment group (in particular, a higher proportion in the control arm receive 
ET), then the intervention(s) may be reducing the need for thrombectomy. In this scenario, 
inference about the causal relationship between intervention arms and outcome will be explored 
using path diagrams and structural equation modeling which takes into account confounding of 
treatment with ET. 
  
In the event that there is a difference in the thrombectomy rate, or difference in Modified TICI 
score, exploratory analyses in ET subjects will use either general linear regression with a logit link 
for binary outcomes or multiple linear regression for continuous outcomes to compare 
treatment groups after adjusting for age, baseline NIHSS, type of IV thrombolysis (rtPA/TNK), 
time to IV thrombolysis, presence of LVO  (Yes/No), location of LVO (defined above), and time to 
groin puncture.  
A subgroup analysis of the primary outcome will be conducted by ET versus non-ET groups as 
described above.
8 Safety Analyses 
8.1 Primary Safety Outcome 
 sICH within 36 hours from randomization (3% expected rate)   


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8.2 Secondary Safety Outcomes 
parenchymal hemorrhage types 1 (PH-1) and 2 (PH-2) (determined by the central 
imaging readers) within 36 hours from randomization
 
any ICH on brain imaging within 36 hours from randomization (determined by the 
central imaging readers)
Major hemorrhage (requiring >2 units of packed red cells) other than intracranial 
hemorrhage within seven days
 
All-cause mortality within 90 days of randomization  (20% expected rate)  
 
8.3 Analysis of Safety Outcomes
Please refer to the MOST Safety Monitoring Plan for details of DSMB reporting, medical safety 
monitor, and endovascular safety monitor.
For each safety outcome, the proportion of patients will be reported by treatment group. At the 
end of the trial, each active treatment arm will be compared to control using Fisher’s exact test.  
Kaplan Meier curves and log rank tests will be used to compare time to 90-day mortality. At the 
end of the trial, we will compare each safety outcome by treatment groups by ET subgroup 
(Yes/No) in order to assess the safety of the combination of Eptifibatide/Argatroban/ET using 
Fisher’s exact test for the 3 x 2 table of treatment group and ET status (and with the ET subgroup 
comparing active to control if significant). Similarly, a subgroup analysis of sICH will be conducted 
by baseline ASPECTS score (< 6 or 6-10).  
 
At the end of the trial, SAEs will be reported by MedDRA body system. The proportion of patients 
in each body system will be reported by treatment group. Fisher’s exact test will be used to test 
for differences versus control for each body system.
9 Sample Size Determination 
The minimum clinically significant difference was defined as 0.4 points on the utility scale 
primary outcome, which corresponds to ~45% of the effect for IV rt-PA over placebo in the 
NINDS study.43 With a maximum N=1200, this design provides at least 80% power to detect a 
treatment effect when the overall true utility benefit is 0.4 for one active arm in non-ET subjects 
(Table 8). If both treatment arms are equally effective at 0.4 utility above the control arm, power 
is 89%. The properties of the study design have been investigated through clinical trial 
simulations that assumed 30% of patients receive ET, and the treatment effect for ET patients is 
50% of the effect in non-ET patients, corresponding to 25% of the treatment effect of IV rt-PA 


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over placebo. The impact of ET on treatment effect is unknown but we assumed the worst 
scenario, i.e., marked attenuation of effect. Also, only 10-30% of IV rt-PA eligible patients are 
eligible for ET,10,12 and clinical practice data from Get With the Guideline hospitals and StrokeNet 
suggest ~11-24% of IV rt-PA eligible patients undergo ET. We have assumed the upper end of 
possible ET subjects. Thus, our estimated power represents a conservative scenario for ET 
proportions and impact of ET on treatment effect. Table 8 shows power when only one 
treatment arm is effective. Power increases if <30% of patients receive ET. Although the 
maximum sample size is N=1200, the simulations conducted indicate the average sample size 
under the complete null scenario is 756 (SD=322) and under the scenario with all active arms 
equal to 0.4 is 1048 (SD=188). The type I error probability (incorrectly identifying treatment(s) to 
“win” that are truly no better than control) for the complete null scenario is <0.025.
Power for Varying Treatment Effects if only One Arm is Truly Effective
Utility Values Above IV rt-PA Alone
 
Scenario 1
Scenario 2
Scenario 3
Assumed True Effect Overall
(70% non-ET and 30% ET subjects)
0.26
0.34
0.425 
Assumed True Effect for non-ET 
subjects 
0.30
0.40
0.50 
Assumed True Effect for ET subjects  
(50% of non-ET effect) 
0.15
0.20
0.25 
Pr{Effective arm wins} (Power) 
0.52
0.80
0.95 
Pr{Other arm wins} (Power) 
0.011
0.008
0.014 
Numbers in gray are the utilities (difference in the expected treatment minus control).  
Numbers in white are the power under 3 different scenarios (determined by simulation).


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10 Appendix A: MOST Design and Analysis Plan


 
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Design and Analysis Plan for the MOST Trial
October 20, 2020
1.0 Background
This is a plan for a Phase III trial to explore the efficacy of Argatroban and Eptifibatide in 
combination with thrombolysis in treating stroke patients.  One dose of each study drug 
will be compared to a control arm with respect to their ability to improve subjects’ 90-day 
scores on the modified Rankin scale (mRS).   Improvement will be quantified using 
patient-centered utility scores for mRS values.  
The trial is a Bayesian adaptive design that includes multiple key features:
1. adaptive sample size ranging from 500 to 1200 patients;
2. initial consideration of two active arms, with the ability to stop an arm for futility or 
safety and continue as a 1:1 comparison between control and one of the active 
arms;
3. response-adaptive randomization is used to favor promising active arms;
4. frequent interim analyses can result in the trial stopping early for futility or for 
expected success;
5. a utility function on 90-day mRS scores to reflect patient and society valuation of 
outcome health states;
6. mRS scores are analyzed adjusting for baseline stroke severity as measured by
the NIH Stroke Scale.  The relationship between stroke severity and outcomes is 
modeled flexibly;
7. a longitudinal model relating 30-day mRS scores to 90-day mRS scores is 
utilized to bring more information from patients without 90-day data to stopping 
and adaptive allocation decisions.
The structure of this document is as follows: the next section describes the design in 
general terms, Section 3 elaborates on the subject population and the final analysis, and 
Section 4 fills in further details about decisions made during the trial. Section 5 presents 
operating characteristics for the design obtained using simulation and based on a variety 
of assumed truths about the effectiveness of the drugs.   Appendices elaborate on the 
statistical models used in the final analysis and in the interim analyses and on default 
assumptions about the subject population.  


 
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2.0 Design Overview
For the first 150 subjects, the randomization probabilities for the three arms remain fixed 
at 1:1:1 for the two active arms and the control/placebo arm.  An interim analysis occurs 
at the 150th enrolled subject, and randomization probabilities for the active arms are 
adjusted, with the arm having the higher predictive probability of a successful final 
analysis assigned higher allocation probabilities.  Interim analyses continue every 4 
weeks.  
Beginning with the first interim analysis after the 150th subject is enrolled, the design 
implements response adaptive randomization between two active arms (based on 
predictive probability) where control gets the same randomization probability as the 
maximum active arm.
After 500 subjects have been enrolled, the stopping rule for futility is based on 20% 
predictive probability and there is a shift to equal randomization between control and one 
or two active arms. From this point until the end of the trial, all arms remaining in the 
trial have equal allocation probabilities.  
Interim analyses occur after 700 and 900 patients have been enrolled to allow for
stopping one active arm for futility (based on 5% predictive probability based on 
three arms continuing)
stopping the trial altogether for futility (based on 5% predictive probability based 
on two arms continuing)
stopping the trial for expected success of one or both active arms.
The trial enrolls at most 1200 subjects. When final data for all enrolled subjects are 
available, the final analysis is conducted, and it may result in showing a significant 
benefit for one or two active arms.  
Stopping decisions are based on Bayesian predictive probabilities, and in particular the 
predictive probability of a successful final analysis.  Details about these predictive 
probabilities will be given in Section 4.  
3.0 Study Population, Primary Endpoint, and Statistical Test
3.1 Entry criteria
The trial enrolls subjects with initial NIHSS scores of 6 or larger.  
3.2 Treatment arms
Three treatment arms are under consideration:
1. Control arm with iv-thrombolysis only;
2. Argatroban in addition to iv-thrombolysis;
3. Eptifibatide in addition to iv-thrombolysis;
Of the first 150 enrolled subjects, one-third will be assigned to the control arm and to 
each of the active arms.  


 
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3.3 Primary Endpoint
The primary endpoint for this trial is the 90-day mRS score.  We choose to analyze this 
standard endpoint by converting the mRS scores into weights that directly reflect patient 
and society valuation of outcome health states.  We then model a subject’s weighted 
mRS score as normally distributed with expected value depending on initial NIHSS and 
treatment assigned.
The weights assigned to the possible mRS scores are shown in Table 1 below.  These 
weights were obtained through a synthesis of studies (O. Rivero-Arias, et al, “Mapping 
the Modified Rankin Scale (mRS) Measurement into the Generic EuroQol (EQ-5D) 
Health Outcome,” Medical Decision Making 2010 30:341, and K.-S. Hong and J.L. 
Saver, “Quantifying the Value of Stroke Disability Outcomes: WHO Global Burden of 
Disease Project Disability Weights for Each Level of the Modified Rankin Scale: 
Supplemental Mathematical Appendix,” Stroke 2009 40:3828-3833).  Both these studies 
assigned utility values and confidence intervals to mRS scores; these are also shown in 
Table 1.  We renormalized these utilities to a scale where an mRS of 6 implies a utility of 
0 and an mRS of 0 implies a utility of 10.  The two scales are quite similar, and we take 
the mean of the renormalized utilities to obtain our own weights.  The second study 
reported more precise estimates, so in some cases the consensus value is closer to its 
value.  
Table 1: weights used for 90-day mRS score
Relative to an approach that dichotomizes the 7 possible mRS scores into two 
possibilities, weighting the 7 Rankin levels by utilities improves the precision of the scale 
as a measure of disability.  The weighted approach should also not be confused with an
approach based on the raw mRS scores, which would erroneously treat each single-
point increase in mRS as equally valuable to the subject.  
Figure 1 below gives an example of what treatment effects look like for this endpoint.  
Each vertical bar depicts a probability distribution: the height of the darkest blue 
represents the probability of an mRS of 0, the darkest red shows the probability of an 
mRS of 6, etc.  The leftmost bar shows the results of the control arm for the NINDS tPA 
study (Tissue plasminogen activator for acute ischemic stroke. The National Institute of 
Neurological Disorders and Stroke rt-PA Stroke Study Group. The New England journal 
of medicine 1995;333:1581-7), which represents an expected utility of 5.01, and the 
second bar shows the tPA arm in the NINDS study, which represents an expected utility 
of 5.91.  The remaining bars show distributions that represent improvements of 0.1 to
0.9 as compared to the tPA arm.
mRS
0
1
2
3
4
5
6
Rivero-Arias 
et al
10
8.7
7.3
6.0
2.8
-0.1
0
Hong & Saver
10
9.5
7.9
6.7
3.5
0.1
0
MOST Trial
10
9.1
7.6
6.5
3.3
0
0


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Figure 1: graphical depiction of mRS distributions.  The first two bars depict the two arms in the NINDS 
study, and the remaining nine bars depict further improvements to expected utility.  Dark blue represents the 
probability of an mRS of zero, dark red represents the probability of an mRS of 6, and so on.  


 
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Expected
Utility
mRS=0
mRS=1
mRS=2
mRS=3
mRS=4
mRS=5
mRS=6
0-1
NINDS 
Control
5.01
0.11
0.16
0.12
0.14
0.20
0.07
0.21
0.27
NINDS 
tPA arm
5.91
0.18
0.24
0.08
0.13
0.13
0.06
0.17
0.42
tPA + 
0.1
6.01
0.19
0.25
0.08
0.13
0.13
0.06
0.17
0.44
tPA + 
0.2
6.11
0.20
0.25
0.08
0.13
0.13
0.06
0.16
0.45
tPA + 
0.3
6.21
0.21
0.25
0.08
0.13
0.13
0.06
0.15
0.46
tPA + 
0.4
6.31
0.22
0.25
0.08
0.12
0.13
0.05
0.14
0.47
tPA + 
0.5
6.41
0.22
0.26
0.08
0.12
0.12
0.05
0.14
0.48
tPA + 
0.6
6.51
0.23
0.26
0.08
0.12
0.12
0.05
0.13
0.49
tPA + 
0.7
6.61
0.24
0.27
0.08
0.12
0.12
0.05
0.13
0.51
tPA + 
0.8
6.71
0.25
0.27
0.08
0.12
0.12
0.05
0.12
0.52
tPA + 
0.9
6.81
0.26
0.27
0.08
0.12
0.11
0.05
0.11
0.53
Table 2: translating treatment effects on the utility scale into changes in probabilities of the mRS outcomes.  
The point estimate of the effect of tPA in the NINDS study is 0.9 units of utility.  The table shows what further 
improvements to expected utility above tPA might do.  
3.4 Primary Analysis
The final analysis is Bayesian and includes a flexible normal dynamic linear model 
(NDLM) to account for different expected outcomes as a function of initial NIHSS.  This 
is a flexible spline-like model that will capture that the average weighted mRS score in 
the control group is a (possibly non-linear) function of initial NIHSS.  Meanwhile the 
average effect of a given treatment ,
, is the difference in the expected utility for the 
active treatment minus control. This average treatment effect, 
, is assumed to be 
equal over all values of initial NIHSS. Details of the statistical model are given in 
Appendix C1. For each active arm, the hypothesis test is
:
0
:
> 0


 
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The treatment effect
 is given a vague prior,  ~ N(0,2.52): in particular, the prior 
probability that a drug is beneficial is the same as the prior probability that it is harmful.  
Note: The largest treatment effect we considered in the simulations (an average of 0.50
unit benefit) is relatively small in comparison to the prior standard deviation. If there is a 
high posterior probability that the treatment effect 
 is positive, the treatment is declared 
to be efficacious. The posterior probability is conditional on the final results for all 
subjects enrolled in the trial.  If two active arms remained in the trial all the way to the 
end, this posterior probability is computed for each, and potentially both arms can be 
declared to be successful.  
3.5 Thresholds for a Successful Trial
The trial is successful if in the final analysis, the posterior probability of a positive benefit 
is at least 0.985. That is, success is claimed if
Pr (
> 0)
0.985
This threshold is chosen to control the experiment-wise type I error probability at 0.025.
3.6 Longitudinal Modeling of 30-day mRS Scores
Subjects with 30-day data but no 90-day data are also included in the interim analyses, 
and their data contribute to the adaptive allocation probabilities and the stopping and 
arm selection decisions.  A subject with only 30-day data is less influential than a subject 
with complete data, because the statistical model in effect takes into account the fact 
that different 90-day outcomes are still possible.  The relationship between 30-day and 
90-day data is initially assumed to be unknown, and is updated as more data from the 
trial come in.  Consequently, the trial will not make irreversible decisions as a result of 
incorrect beliefs about the relationship.  


 
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4.0 Prospectively Planned Interim Analyses
The first interim analysis takes place after 150 subjects have been enrolled.  Subsequent 
interim analyses take place every four weeks (28 days) until 500 patients are enrolled, 
and less frequently thereafter.
4.1 Predictive Probabilities
Decisions made as a result of interim analyses are based on Bayesian predictive 
probabilities using the statistical model defined in Appendix C2.  The predictive 
probability of a successful final analysis is calculated based on different assumptions 
about the remaining subjects to be enrolled.  
First, for each active arm, we assume that the remainder of the trial consists of 1:1
randomization between that arm and the control arm, and calculate the predictive 
probability that the remaining patients generate data that lead to a significant result (high 
posterior probability of a positive treatment effect).  These predictive probabilities are 
used in futility decisions and response adaptive randomization probabilities. For 
convenience we will refer to these predictive probabilities as 1:1 predictive probabilities.
Second, we assume that the remaining subjects to be accrued are allocated 1:1:1 to the 
two active arms and to the control arm, and calculate the predictive probability that those 
subjects generate data resulting in a significant final analysis for the Argatroban arm, 
and respectively for the Eptifibatide arm.  We will refer to these predictive probabilities as 
1:1:1 predictive probabilities.
Third, we also calculate the predictive probability that an arm would have a successful 
final analysis if enrollment were stopped immediately, based on predictions of results for 
subjects enrolled in the trial but without final data.  This predictive probability is used to 
determine whether enrollment should be stopped early for expected success.  We will 
refer to these predictive probabilities as expected success predictive probabilities.
4.2 Interim Monitoring for Early Futility and Expected Success.  
Although the design assumes the trial cannot stop for futility or drop an arm before 500 
subjects, recommendations by the DSMB (such as for safety concerns) supersede this 
assumption. Interim analyses before 500 subjects update response adaptive 
randomization probabilities.
After 500 subjects have been enrolled, one of the arms can be dropped if its 1:1:1 
predictive probability is less than 20% or the trial can be stopped altogether if both active 
arms have 1:1 predictive probability is less than 20%.  
After 700 and 900 subjects have been enrolled, one of the arms can be dropped if its 
1:1:1 predictive probability is less than 5% or the trial can be stopped altogether if the 
1:1 predictive probability is less than 5%.  


 
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When 700 patients and 900 patients have been enrolled the trial may stop for expected 
success.  Beginning with the first analysis after this time, the expected success 
predictive probabilities are calculated.  If an active arm has an expected success 
predictive probability of at least 99%, that arm stops for expected success, and its final 
analysis is conducted when all subjects enrolled  are followed up for 90-day data.  If it is 
the last remaining active arm, the trial stops altogether, and all enrolled subjects are 
followed up to determine the success of the trial.  
4.3 Response-Adaptive Randomization
During the response-adaptive randomization regime, which begins at 150 subjects and 
ends when the 500th subject has been enrolled, the control arm’s randomization 
probability is set to be equal to the higher of the randomization probabilities for the active
arms. The allocation probabilities for the two active arms are set to be proportional to 
their 1:1 predictive probabilities.  For example, suppose that the two active arms have 
1:1 predictive probabilities of 0.2 and 0.8 respectively.  Setting the control arm 
randomization probability equal to that of the arm with 0.8 predictive probability, the 
three arms have randomization probabilities of 0.8 / (0.8 + 0.2 + 0.8) = 0.444 for control 
and the better of the two active arms, and 0.2 / (0.8 + 0.2 + 0.8) = 0.111 for the other 
active arm.
5.0 Operating Characteristics
In this section we present operating characteristics. These results are obtained through 
simulation as illustrated in Section 5, and are based on 1000 simulated trials per 
scenario, except for the null scenario whose results are based on 10000 simulated trials.
In all simulations, we assumed that 30% of patients receive endovascular therapy (ET)
in addition to the study drug or standard thrombolysis. The treatment effect for ET 
patients is 50% of the effect in non-ET patients. The impact of ET on treatment effect is 
unknown but we assumed the worst scenario, i.e., attenuation of the treatment effect. 
Patients with ET are assumed to have the same initial NIHSS distribution as those 
without.  
5.1 Operating characteristics when both active arms are equivalent
First we present estimates of power and sample size characteristics in scenarios in 
which both active arms have the same effect: specifically, an increase of zero (a null 
scenario), 0.3, 0.4, and 0.5 units for the non-ET subjects and 50% of these same effects 
for the ET subjects. (The assumed overall treatment effects were 0.255, 0.34, and 0.425 
for non-ET and ET subjects combined.) These effects benefit all injury severities equally 
with respect to expected utility.  Examples of the scenarios are pictured in Figure 2
below, which shows the assumed distribution of mRS as a function of initial NIHSS 
(shown on the x-axis), for the control arm (left plot), for an arm with a 0.5 unit effect 
(center plot), and for an arm with a 1.0 unit (right plot; this effect is unrealistically large).  
For example, examining the heights of the dark blue bars on the far left of the plots show 
that the probability of an mRS of zero for subjects with an initial NIHSS of 6 treated with 


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the control arm is assumed to be almost 60%.  An expected utility effect of 0.5 points 
raises this to about 70%, while an effect of 1.0 points raises it to about 85%.  
Figure 2: example distributions of mRS as a function of initial NIHSS.  
Since the trial involves two different active drugs and potentially both of them can be
successful, power has multiple aspects:
the probability that at least one active arm is successful;
the probability that the Argatroban arm is successful;
the probability that the Eptifibatide arm is successful (this should be the same as 
the probability that an Argatroban arm is successful for the scenarios examined 
in this section);
the probability that both active arms win.
Results based on 1000 simulated trials for each scenario, except with 10000 simulated 
trials for the null scenario, are shown in Table 3. Simulations of null scenarios are
presented in Section 5.3. Here we note that the Type I error in this single null scenario is 
less than 0.025. If the overall true effect is 0.425 units for both active arms, the design 
has high power of 97% to be successful for some arm, and each drug has a 17% chance 
of being unsuccessful.
Assumed True Effect Overall
(30% ET and 70% non-ET patients)
Null
0.255
0.34
0.425
Assumed True Effect 
For non-ET patients
0
0.30
0.40
0.50
Assumed True Effect 
for ET patients  
(50% of effect w/o ET)
0
0.15
0.20
0.25
Pr{Some Arm Wins}
0.0190
0.695
0.890
0.974
Pr{ A Arm Wins}
0.0089
0.453
0.644
0.832
Pr{E Arm Wins}
0.0107
0.459
0.678
0.833
Pr{A Arm and E Arm both win}
0.0006
0.217
0.432
0.691


 
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Table 3: power-related operating characteristics for scenarios in which both active arms are equally 
effective.  ET=endovascular
Further operating characteristics are shown in Table 4 below. The table displays the 
probability of a futility stop at exactly 500 subjects, and the probability that the design 
reaches full enrollment of 1200. The average and standard deviation of total sample 
sizes are also shown, as well as the averages for trials that were ultimately 
unsuccessful.  
Assumed True Effect Overall
(ET and non-ET patients)
Null
0.255
0.34
0.425
Pr{Futility at 500}
0.56
0.086
0.045
0.013
Pr{N = 1200}
0.34
0.725
0.555
0.363
Mean N
756
1080
1048
1004
SD(N)
322
218
188
155
Mean N (failed trials)
748
974
900
831
Table 4: sample size-related operating characteristics.  
5.2 Operating characteristics when arms differ
In this section we present operating characteristics for scenarios in which the Argatroban 
arm has a benefit of up to 0.5 units, while the Eptifibatide arm has no benefit, to explore 
how successful the design is at identifying the most promising arm. We have simulated 
scenarios in which Eptifibatide is less effective than Argatroban and not the reverse, but 
the two drugs are treated exchangeably, so those simulation results also apply to the 
analogous cases where Eptifibatide is the superior drug. 
We see from Table 5 that if one of the active arms has an overall effect of 0.425 units of 
utility, the design has approximately 95% power. If one drug is ineffective, the probability 
that the more effective drug will be successful is increased relative to Table 3 because 
the ineffective drug will likely be dropped. The probability that the ineffective drug is 
successful is small.


 
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Table 5: power characteristics for scenarios where the active arms differ.  
ET=endovascular therapy
5.3 Type I Error
In this section we explore several null scenarios to demonstrate evidence of control of 
Type I error.  The design is too complex to allow analytical control of Type I error, and 
the number of null scenarios is too large for exhaustive simulation study.  Instead, we 
identify four characteristics that define null scenarios and vary those characteristics to 
create a population of scenarios.  The scenarios are described in Table 6.  Scenario #1 
is the same null scenario as discussed in Section 5.1. 
Scenario
NIHSS 
Distn 
f(mRs) 
Effect Size
Longitudinal 
Model 
Accrual 
rate 
1
Default 
Standard
0
Default 
Default 
2
Default 
Standard
0
Default 
Fast
3
Default 
Standard
0
Default 
Slow 
4
Default
Standard
0
Uniform
Slow
5
Default 
Standard
0
Perfect 
Slow 
6
Default 
Standard+ 
0
Default 
Slow 
7
Default 
Standard–
0
Default 
Slow 
8
Default 
Flat
0
Default 
Slow 
9
Default 
Jagged
0
Default 
Slow 
10
Uniform
Standard
0
Default 
Slow 
11
Lower
Standard
0
Default 
Slow 
Table 6: Definition of null scenarios in Type I error simulations.  
Assumed True Effect Overall
(ET and non-ET patients)  for   Arm A 
only
(Arm E assumed to be 0)
0.255
0.34
0.425
Assumed True Effect for Arm A For 
non-ET patients
0.30
0.40
0.50
Assumed True Effect 
for ET patients for Arm A
(75% of effect w/o ET)
0.15
0.20
0.25
Pr{Some Arm Wins}
0.523
0.796
0.951
Pr{Arm A wins}
0.521
0.796
0.950
Pr{Arm E wins}
0.011
0.008
0.014
Pr{ A Arm and E arm both win}
0.009
0.008
0.013


 
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The other null scenarios differ by the following characteristics.
Accrual rate.  In the standard scenarios, the accrual rate is 5 patients per week.  
In Scenario 2, we assume an accrual rate of 10 patients per week, and in 
Scenario 3, we assume an accrual rate of 2.5 patients per week.  In many 
designs that feature early stopping for expected success with endpoints only 
observed after a delay, slow accrual rates tend to inflate Type I error.  This is 
because relatively few patients have incomplete data at the time of the decision 
to stop for expected success, so that expected success stopping decisions are 
made with information relatively close to the data in the eventual primary 
analysis.  Since slow accrual rates are the most challenging for designs to control 
Type I error, we also use the 2.5 patients per week rate in scenarios 4 through 
11.  Note that 2.5 patients per week is an unrealistically slow accrual rate for the 
trial, which would under that assumption require more than nine years to enroll a 
full 1200 patients, so this represents a very conservative set of scenarios to 
evaluate Type I error.
Longitudinal model.   In most of our scenarios, 30-day mRS is a good but not 
perfect predictor of 90-day mRS; see Appendix C3.3.   We also simulate null 
scenarios with extreme versions of the longitudinal model assumption.  In 
Scenario 4, 30-day mRS is simulated so that all of its possible values (i.e. 0 
through 5 if 90-day mRS is not 6, or 0 through 6 if 90-day mRS is 6) are equally 
likely; in this scenario 30-day data are not useful for predicting 90-day data.  In 
Scenario 5, 30-day mRS is simulated to always be exactly equal to 90-day mRS; 
in this scenario the longitudinal model should learn that 30-day data are highly 
predictive of 90-day data and make predictions accordingly.  
Distribution of mRS given initial NIHSS (the column describing this variable is 
denoted “f(mRS)” in Table 6).  In most scenarios, the distribution of 90-day mRS 
given initial NIHSS is as shown in Figure C2 in the appendix.  We also consider 
four other sets of distributions.  In Scenarios 6 and 7, the relationship between 
initial NIHSS and 90-day mRS is similar to Figure C2, but in Scenario 6, patients 
are systematically healthier and in Scenario 7, patients are systematically less 
healthy; see Figure 3.   In Scenario 8, we consider a “flat” scenario, the case 
where all patients have the same distribution of 90-day mRS regardless of initial 
NIHSS.  In Scenario 9, we consider a more “jagged” scenario, where NIHSS 6 
through 11 have one distribution, NIHSS 12 through 26 have another less 
favorable distribution, and NIHSS 27 through 42 have another unfavorable 
distribution.  The distributional assumptions in Scenarios 8 and 9 are shown in 
Figure 4.  
Initial NIHSS Distribution.  In Scenario 1 and most of the other null scenarios, 
small initial NIHSS scores are assumed to be most common, see the distribution 
in Figure C1 in the appendix.  In Scenario 10, all initial NIHSS scores are equally 
likely.  In Scenario 11, the initial NIHSS distribution is tilted further toward small 
values; see Figure 5.  Instead of being based on the exponential distribution with 
mean 10, it is based on the exponential distribution with mean 7.5.  For example, 
under the standard NIHSS distribution, 20% of patients have an initial NIHSS of 
21 or greater, while only 13% of patients do under Scenario 11.  
We do not vary the fraction of patients who receive endovascular therapy in the 
Type I error simulations, because we assume that the only effect of endovascular 


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therapy is to reduce the treatment effect by a factor, so that all assumptions 
about endovascular fraction lead to identical null scenarios.  
Figure 3: Distributions of mRS as a function of NIHSS in scenarios 6 and 7.  In Scenario 6, patients are 
likelier to have good outcomes compared to scenario 1, and in Scenario 7, patients are likelier to have poor 
outcomes.
Figure 4: Distributions of mRS as a function of NIHSS in scenarios 8 and 9.  In Scenario 8, all patients have 
the same distribution of mRS regardless of their initial NIHSS score.  In Scenario 9, there are three different 
distributions of mRS depending on initial NIHSS, and there are abrupt changes in the distributions.    
The Type I error operating characteristics are given in Table 7.  For each scenario, the 
table shows the probability that at least one arm wins (i.e. reaches the threshold of 
98.5% posterior probability of a benefit), the probability that arm A wins, the probability 
that arm E wins, and the probability that both active arms win.  Scenario 1 results are 
reproduced from Table 3. For all 11 null scenarios, the probability of a Type I error is 
less than 0.025.  The probability that a particular active arm attains statistical 
significance is less than 0.014 for all these scenarios.  


 
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Scenario
Pr{Some 
Arm 
Wins} 
Pr{A Wins}
Pr{E Wins}
Pr{A and E 
Both Win}
1 
0.0190
0.0089
0.0107
0.0006
2
0.0229
0.0138
0.0102
0.0011
3 
0.0205
0.0105
0.0108
0.0008
4 
0.0213
0.0106
0.0115
0.0008
5 
0.0222
0.0104
0.0126
0.0008
6 
0.0211
0.0119
0.0108
0.0016
7 
0.0199
0.0116
0.0094
0.0011
8 
0.0208
0.0104
0.0114
0.0010
9 
0.0211
0.0126
0.0098
0.0013
10
0.0202
0.0091
0.0118
0.0202
11
0.0194
0.0104
0.0096
0.0006
Table 7: Type I error operating characteristics.   For all 11 null scenarios considered, the probability 
of some arm winning is less than 0.025.  


 
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Appendix C1: Statistical Model for Final Analyses
Denote the ’th subject’s 90-day mRS by , and her resulting weight score by ;
=
 
if 
=
.  Further denote the th subject’s initial NIHSS by 
and the treatment to 
which she was randomized by 
(
is either 0 for control or 1, 2 for the active arms).  
Define, for 6
42 and 
{0,1,2},
Pr
= W
= ,
=
} =
( , ).
For the purposes of the final analysis, the 
( , ) are used to define the expected values 
of the weight scores. The expected values of the weight scores, , are modeled as 
Gaussian, with expected values that depend on i, with a common treatment effect 
with 
= 0 by convention, and with variances 
that depend on the treatment:
= ,
=
= 
( , )
= 
+
,
for all initial NIHSS scores i.  We model the 
flexibly, and assume that they come from 
a second order normal dynamic linear model (NDLM).  Specifically, the prior distribution 
for the 
assumes that for 8
42, we have 
~
(2
,
).
This form of the normal dynamic linear model encourages the 
to be linear.
We use the following prior distributions:
 ~ 
(0, 2.5 ) (
= 1,2)
 ~ 
 
 (1, 10) (
= 0,1,2), and
~ 
 
(10, 0.005).
The final analysis is performed with either one or two active arms.  We evaluate the 
posterior distribution of the parameters of this model using the Gibbs sampler.  
Conditionally on the other parameters, ( , ) have a multivariate normal distribution, and 
the remaining parameters have inverse Gamma conditional distributions.  
The primary output of the final analysis is the posterior probability that 
> 0, for any ’s 
that remain in the trial. If this probability is at least 0.985, the trial is considered to be a
success.  The threshold for defining significance is chosen so that the design has Type I 
error no larger than 0.025. Criteria for success (critical value for posterior probability of a 
positive benefit) was inflated from 0.975 to 0.985 to account for the two study drugs and 
the repeated interim looks (e.g. the trial can be stopped when data look favorable 
enough that a success is likely).   


 
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Appendix C2: Statistical Model for Interim Analyses
The statistical model used during the trial to compute predictive probabilities to 
determine allocation probabilities and make the decision to stop for futility or expected 
success, is more detailed than the final analysis model. We use a longitudinal model to 
impute values of final endpoints for subjects for whom we have 30-day mRS scores but 
not 90-day scores; we estimate the probability distribution of final endpoint values given 
early endpoint values.  Another major change is that we also estimate the distribution of 
initial NIHSS scores for enrolled subjects; for predicting whether the trial will be 
successful it is critical to be able to forecast what kinds of subjects will appear in the 
future.  
Whereas in the final analysis we use a noninformative prior with no information about the 
overall level of the 
or the overall slopes of the 
as a function of i, we now use the 
following prior distributions:
~ (5, 2.5 ),
 
~ (
, 0.25 ).
Writing 
for the 30-day mRS value for the jth subject, we estimate the probabilities 
= Pr
=
 
=
} using a multinomial model with prior distributions 
(
,
,
,
,
,
,
)~ 
(1
3 , 1
3 , 1
3 , 1
3 , 1
3 , 1
3 , 1
3) 
for 
= 0,1,2,3,4,5. We have 
= 1 and 
= 0 for 
< 6. As mentioned earlier, the 
longitudinal model plays no role in the final analysis.  The parameters of the longitudinal 
model are updated at each interim analysis and are based on all subjects with complete 
30-day and 90-day data to that point.  We note that we are not using data from other 
studies to inform the parameters of the longitudinal model.  We use the same 
longitudinal model for all arms (i.e. we pool the data for all subjects to estimate the 
probability distribution of 90-day outcome given 30-day outcome).  The final piece of the 
statistical model for interim analyses is the model for the initial NIHSS distribution
Pr
=
=
, which is also a Dirichlet-multinomial model with prior distribution
( ,
, … ,
) ~ 
 (1
3 , 1
3 , … , 1
3).
The prior distributions for the 
are as specified in the description of the final analysis.  
During an interim analysis, we estimate the parameters ( , ,
,
, , ) of this model 
using Gibbs sampling.  We then use these samples to estimate several predictive 
quantities.  First, for each active arm in the trial, we calculate the probability that the trial 
would end with a significant result if we assigned all remaining subjects 1:1 to control 
and that active arm, and enrolled subjects up to the maximum sample size. This 
calculation consists of the following steps: for a given Markov chain Monte Carlo 
(MCMC) sample, 
1. Using the s, impute 90-day endpoint values for the subjects enrolled and with 
30-day data.


 
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2. Simulate random initial NIHSS scores and treatment assignments for the 
subjects yet to be enrolled, using the ’s and assuming that all remaining subjects
are enrolled 1:1 to control and that active arm.  Augment this list of subjects with 
the subjects included in the trial who have not yet provided 30 day data.  
3. Calculate the probability, given that list of subjects, that final 90 day data will 
result in a significant trial. 
Steps 1, 2, and 3 will be repeated for each of a large number of MCMC samples. Next, 
we compute the average of the resulting probabilities.  These probabilities will be used to 
decide whether to make arm selection decisions and futility stopping decisions.
Second, we calculate the probability of a successful final analysis if the trial assigned all 
future subjects to control and the two active arms equally 1:1:1. This probability is used 
to decide whether to drop one active arm.  
Finally, we calculate the probability of a successful final analysis if the trial were to stop 
enrollment at once and then wait for final data for all enrolled patients.  This probability is 
based on predicting the final data for enrolled patients with no data yet, as well as those 
with 30-day data only.  


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Appendix C3: Default Population Assumptions
In this appendix we present the assumptions about the population that were used in the 
simulations.  First we present the assumed distribution of NIHSS scores for enrolled 
subjects.  Next we present the assumed distribution of mRS as a function of NIHSS for
control subjects.  Finally we present the assumed distribution of 90-day mRS given 30-
day mRS scores.  
Appendix C3.1:  Initial NIHSS Distribution
In Figure C1 we display the assumed distribution of initial NIHSS scores.  The 
distribution is based on an exponential distribution with mean 10 but with values less 
than 6 or more than 42 omitted.  This assumption was chosen to be roughly consistent 
with Reeves et al (Distribution of National Institutes of Health Stroke Scale in the 
Cincinnati/Northern Kentucky Stroke Study; Mathew Reeves, et al; Stroke. 2013; 
44:3211-3213).
Figure C1: the assumed distribution of initial NIHSS scores for enrolled subjects.  Lower scores are 
considerably more likely.  
Appendix C3.2:  Distribution of 90-Day mRS Given Initial NIHSS
Figure C2 below displays the distributions of 90-day mRS given initial NIHSS assumed 
for the control arm.  Good outcomes are expected to be very likely for NIHSS of 6 and 
very infrequent for initial NIHSS larger than 26.  


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Figure C2: distributions of 90-day mRS values conditional on initial NIHSS.
Appendix C3.3:  Distribution of 90-Day mRS Given 30-Day mRS
Table C1 below displays the assumed conditional distributions of 90-day mRS scores 
given 30-day mRS scores.  These were taken from Ovbiagele, Lyden, and Saver (2010; 
Ovbiagele B, Lyden PD, Saver JL,  Disability status at 1 month is a reliable proxy for 
final ischemic stroke outcome. Neurology 2010;75:688-92).  
30 \ 90
0
1
2
3
4
5
6
0
0.78
0.18
0.02
0.003
0.003
0
0.009
1
0.24
0.65
0.075
0.02
0.01
0.001
0.01
2
0.06
0.38
0.45
0.09
0.02
0
0.009
3
0.02
0.12
0.34
0.44
0.06
0.01
0.01
4
0.003
0.02
0.06
0.29
0.53
0.05
0.04
5
0
0.001
0.001
0.007
0.06
0.87
0.06
6
0
0
0
0
0
0
1
Table C1: conditional distribution of 90-day mRS given 30-day mRS.