Conditions: Stroke
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 313
Healthy volunteers: no

Brief summary:
PRISMS is a double-blind, multicenter, randomized, Phase IIIb study to evaluate the efficacy and safety of intravenous (IV) alteplase in participants with mild acute ischemic strokes that do not appear to be clearly disabling. Participants will be randomized in a 1:1 ratio to receive within 3 hours of last known well time either 1) one dose of IV alteplase and one dose of oral aspirin placebo or 2) one dose of IV alteplase placebo and one dose of oral aspirin 325 milligrams (mg).

Detailed description:

Arms:
arm 1: Participants will receive single dose of IV alteplase placebo and aspirin orally. arm 2: Participants will receive single dose of IV alteplase and aspirin placebo orally.

Interventions: intervention 1: Alteplase intervention 2: Alteplase Placebo intervention 3: Aspirin intervention 4: Aspirin Placebo
Intervention descriptions: intervention 1: Single dose of alteplase will be administered at 0.9 milligrams per kilogram (mg/kg) IV (maximal dose of 90 mg). intervention 2: Single dose of alteplase placebo will be administered as IV injection. intervention 3: Single dose of aspirin will be administered at 325 mg orally. intervention 4: Single dose of aspirin placebo will be administered orally.

Protocol document:
Prot_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Type: 
Protocol 
Official Title: 
A Phase IIIB, Double-Blind, Multicenter Study to Evaluate the Efficacy 
and Safety of Alteplase in Patients With Mild Stroke: Rapidly 
Improving Symptoms and Minor Neurologic Deficits (PRISMS) 
NCT Number: 
NCT02072226 
Document Date(s): 
Protocol version 1: 27 November 2013 
Protocol version 2: 22 August 2014 
Protocol version 3: 8 January 2015 




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PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE IIIb, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ALTEPLASE IN PATIENTS WITH MILD 
STROKE: RAPIDLY IMPROVING SYMPTOMS AND 
MINOR NEUROLOGIC DEFICITS (PRISMS) 
PROTOCOL NUMBER: ML29093 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
3811 
TEST PRODUCT: 
Alteplase (RO5532960) 
LEAD PRINCIPAL 
INVESTIGATOR: 
MEDICAL MONITOR: 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080-4990 U.S.A 
I agree to conduct the study in accordance with the current protocol. 
, M.D. 
, M.D. 
Principal Investigator’s Name (print) 
Principal Investigator’s Signature 
Date 
Please return a copy of this form as instructed by your local study monitor and retain a 
copy for your study files. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
344/aCSR ML29093
7 


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post-randomization. The difference in the proportion of mRS 0−1 responders (favorable 
outcome) at 90 days post-randomization between the IV alteplase arm and the standard 
medical care arm will be compared via a Cochran-Mantel-Haenszel test, stratified by pre­
treatment NIHSS score (0 − 2 vs. 3 − 5), age (< 65 vs. ≥ 65), and last known well time to treatment 
(0 − 2 hours vs. 2 − 3 hours). The primary efficacy analysis will include all randomized patients, 
with patients grouped according to the treatment assigned at randomization adhering to the 
intent-to-treat (ITT) principle. As a sensitivity analysis, results from the univariate Pearson’s chi-
square test will also be presented. 
Determination of Sample Size 
A sample size of 856 is required in order to achieve 80% power in the primary analysis to detect 
effect size of 9% absolute difference in the proportion of patients with favorable outcomes 
between alteplase and control arms. The above power consideration assumes a control 
proportion of 65% and Type I error probabilities of 0.025 (one-sided), and uses a group 
sequential design with one interim analysis for futility (non-binding), based on O’Brien and 
Fleming boundary, after 50% of the anticipated sample size have completed the 90-day 
follow-up assessments. 
was used in sample size calculation. 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard against 
dilution of the treatment effect associated with an approximate 5% non-adherence rate (due to 
lost to follow-up, consent withdrawal, and treatment crossovers), the above sample needs to be 
inflated by a factor of 1/0.952 or 1.108 (Friedman et al. 1998). Therefore, a total sample size of 
948 is required for this study. 
Interim Analysis 
One interim analysis of the primary efficacy outcome is planned for clear futility, conducted 
according to the beta-spending approach with O’Brien and Fleming-type boundaries. This 
futility analysis will occur after approximately 50% of patients (or 474) have completed the 
90-day assessment. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
349/aCSR ML29093
12 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
AESI 
AIS 
aPTT 
BI 
CES-D 
CRO 
CT 
DW 
EC 
eCRF 
EDC 
EQ-5D 
FDA 
FLAIR 
GOS 
GRE 
HIPAA 
ICH 
ID 
iDCC 
iDMC 
IMP 
IND 
INR 
IRB 
IST-3 
ITT 
IU 
IV 
IxRS 
LHH 
LPLV 
MCA 
MedDRA 
adverse event 
adverse event of special interest 
acute ischemic stroke 
activated partial thromboplastin time 
Barthel Index 
Center for Epidemiologic Studies, Depression 
contract research organization 
computed tomography 
diffusion-weighted 
Ethics Committee 
electronic Case Report Form 
electronic data capture 
European Quality of Life questionnaire 
U.S. Food and Drug Administration 
fluid attenuated inversion recovery 
Glasgow Outcome Scale 
gradient echo 
Health Insurance Portability and Accountability Act 
intracranial hemorrhage 
identification 
independent Data Coordinating Center 
independent Data Monitoring Committee 
investigational medicinal product 
Investigational New Drug (application) 
international normalized ratio 
Institutional Review Board 
third International Stroke Trial 
intent-to-treat 
international units 
intravenous 
Interactive Voice/Web Response System 
likelihood of being helped vs. harmed 
last patient’s last visit 
middle cerebral artery 
Medical Dictionary for Regulatory Activities 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
350/aCSR ML29093
13 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation 
Definition 
MRI 
mRS 
NIHSS 
NINDS 
NNH 
NNT 
PRO 
RISS 
rPH 
SAE 
SAP 
sICH 
SIS-16 
STIAMP 
SWFI 
SW 
t-PA 
U.S. 
USPI 
WHO 
magnetic resonance imaging 
modified Rankin Scale 
National Institutes of Health Stroke Scale 
National Institute of Neurological Disorders and Stroke 
number needed to harm 
number needed to treat 
patient-reported outcome 
rapidly improving stroke symptoms 
remote parenchymal hematoma 
serious adverse event 
Statistical Analysis Plan 
symptomatic intracranial hemorrhage 
Stroke Impact Scale-16 
Suspected Transmission of an Infectious Agent via a 
Medicinal Product 
sterile water for injection 
susceptibility-weighted 
tissue plasminogen activator 
United States 
U.S. Package Insert 
World Health Organization 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
351/aCSR ML29093
14 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
BACKGROUND 
1.1 
BACKGROUND ON ACUTE ISCHEMIC STROKE 
Stroke is the fourth leading cause of death and a leading cause of disability in the   
United States (U.S.). Nearly 800,000 strokes occur in the U.S. annually; of these, 
approximately 85% are ischemic in nature (Rosamond et al. 2007).  Treatment options 
are limited, as the only approved therapy for acute ischemic stroke (AIS) is alteplase, 
which is to be used in eligible patients and started within 3 hours from the onset of stroke 
symptoms.  Stroke with “only minor or rapidly improving stroke symptoms” is considered 
a relative exclusion by national clinical guidelines, as these patients were largely 
excluded from definitive trials to date (Jauch et al. 2013).  Consistent with this 
recommendation, only 15% of alteplase recipients have mild strokes (Smith et al. 2011). 
More than half of all ischemic stroke patients have mild strokes at initial presentation in 
population-based studies (Dhamoon et al. 2009; Reeves et al. 2013).  Yet, a substantial 
proportion (31% − 52%) of ischemic stroke patients who arrive within 2−3 hours of 
symptom onset are not treated with intravenous (IV) alteplase primarily due to mild 
symptoms at the time of the treatment decision (Smith et al. 2011; De Los Rios la Rosa 
et al. 2012).  In a national registry, among 93,517 cases arriving to Emergency 
Departments within 2 hours, 29,200 (31%) were not treated solely due to mild or 
improving symptoms, and 80.1% of untreated cases had a National Institutes of Health 
Stroke Scale (NIHSS) score ≤ 5 (Smith et al. 2011). 
While treatment of mild stroke is generally uncommon, leading stroke centers vary 
widely in their approach. For example, the proportion of mild stroke patients (NIHSS < 4) 
treated with reperfusion therapies at National Institutes of Health/National Institute of 
Neurological Disorders and Stroke (NINDS) Specialized Programs of Translational 
Research in Acute Stroke (SPOTRIAS) centers ranged from 2% − 16% in 2008 − 2009 
(Wiley et al. 2012).  This variability in approach is also evident upon discussion with 
former leaders of the pivotal NINDS trials; some physicians treat all eligible stroke 
patients regardless of severity, and others treat only a minority of patients 
( 
, personal communication).  There is unquestionable community 
equipoise regarding the acute treatment of the mild stroke population. 
1.2 
BACKGROUND ON ALTEPLASE 
1.2.1 
Fibrinolysis and Tissue Plasminogen Activator 
Physiologic dissolution of a thrombus depends primarily on the proteolytic action of 
plasmin formed from plasminogen at the site of a clot.  The mechanism for this activation 
in vivo has not been definitively established. Plasminogen, the zymogen precursor of 
plasmin, may be activated by substances found in the plasma milieu, in tissue (tissue 
plasminogen activator [t-PA]), in urine (urokinase), and in bacteria (streptokinase).  The 
generated plasmin may be inhibited by plasma proteins such as α2-antiplasmin and 
α2-macroglobulin (Robbins 1982). 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
352/aCSR ML29093
15 


 
 
 
 
 
Kinetic analyses suggest that plasminogen activation in the presence of fibrin 
occurs after the binding of plasminogen and t-PA at the clot site.  t-PA has a high affinity 
for fibrin, thereby efficiently activating the fibrin-bound plasminogen and converting it to 
plasmin. Plasmin, which when bound to fibrin is protected from rapid inactivation by 
α2-antiplasmin, then proceeds to digest the fibrin clot. 
See the alteplase Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Alteplase is the only approved therapeutic agent for the treatment of AIS and is widely 
accepted as the standard of care for eligible patients (Edlow et al. 2013; Jauch et al. 
2013). The currently approved Activase® (alteplase) U.S. Package Insert (USPI) 
contains wording that recommends against use of alteplase in patients with “minor 
neurological deficit or with rapidly improving stroke symptoms” due to the fact this patient 
population has not been evaluated.  Furthermore, the current American Heart 
Association/American Stroke Association Council Guidelines include “minor and rapidly 
improving stroke symptoms (clearing spontaneously)” as a relative exclusion criterion for 
alteplase (Jauch, et al. 2013).  This is largely due to the aforementioned label wording 
not recommending treatment of patients with minor neurological deficit or with rapidly 
improving stroke symptoms (RISS), the lack of a consistent and consensus definition on 
who constitutes this patient population, and the absence of definitive evidence of 
alteplase efficacy in this setting (TREAT Task Force 2013).  Therefore, this trial is 
designed to evaluate the efficacy and safety of alteplase in confirmed AIS patients with 
minor neurological deficit or with RISS, which will be referred to collectively as “mild 
stroke” throughout the protocol. 
To date, all completed major randomized acute stroke trials have excluded patients with 
mild strokes to varying degrees.  In the two NINDS trials, such patients were excluded 
according to the protocol (largely to prevent patients with transient ischemic attacks from 
being enrolled if they were having rapidly improving symptoms), but did not include an 
explicit definition of mild stroke except for pure sensory stroke, isolated ataxia, isolated 
dysarthria, and isolated facial weakness (NINDS rt-PA Study Group 1995).  The 
operational definition for stroke symptoms too mild to treat was left to the judgment of 
the randomizing physician (TREAT Task Force 2013).  Interestingly, a post hoc analysis 
of the 624 patients in the NINDS trial revealed that there were 58 patients (9%) enrolled 
with an NIHSS score ≤ 5, none of whom had isolated motor symptoms, isolated facial 
droop, isolated ataxia, dysarthria, isolated sensory, and three or fewer of each of 
additional isolated deficits (Khatri et al. 2010).  Perhaps more significantly, 2971 patients 
were excluded primarily due to “rapidly improving” or “minor symptoms.” However, a 
significant unmet medical need exists for patients with mild stroke.  Available outcome 
data for patients with mild stroke who do not receive alteplase consistently demonstrate 
a high rate of suboptimal outcomes.  Specifically, in two different prospective databases 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
353/aCSR ML29093
16 


 
 
 
 
 
 
 
 
 
 
 
of patients with mild deficits (NIHSS score ≤ 5) and no baseline disability, approximately 
one-third (29%−32%) were significantly disabled (as measured by modified Rankin 
Scale [mRS] score 2 − 6) at 90 days (Fischer et al. 2010; Khatri et al. 2012; 
, personal communication). 
Existing, albeit limited, data suggest that the potential benefit-risk ratio for alteplase in 
mild stroke should be favorable.  Gonzales et al. demonstrated better functional 
outcomes among mild strokes treated with IV alteplase compared to those not treated in 
a large, single-center, retrospective cohort; this was shown with two different thresholds 
of stroke severity (NIHSS ≤ 7 and NIHSS ≤ 3) (Gonzales et al. 2006).  Additionally, a 
recent post hoc analysis of the subset of the third International Stroke Trial (IST-3) 
patients with mild strokes (pre-treatment NIHSS ≤ 5 who met all other NINDS rt-PA 
study eligibility criteria) showed a trend toward benefit for alteplase ( 
, 
personal communication).  For PRISMS, the primary efficacy outcome assumption  
(mRS 0 − 1) is a 9% absolute treatment effect of alteplase relative to placebo.  This 
assumption is based on several retrospective analyses of a similar patient populations 
(Köhrmann et al. 2009; Fischer el al. 2010; Hassan et al. 2010b; Khatri et al. 2012) as 
well as the aforementioned IST-3 trial subgroup analysis ( 
, personal 
communication). 
The most prevalently reported and life-threatening adverse event (AE) associated with 
alteplase treatment for acute ischemic stroke is symptomatic intracranial hemorrhage 
(sICH). Post hoc analyses, case series, and retrospective studies in patients with mild 
stroke suggest an absolute sICH rate of 0 − 2% with alteplase treatment (NINDS rt-PA 
Study Group 2005; Baumann 2006; Gonzales et al. 2006; Köhrmann et al. 2009; 
Steffenhagen et al. 2009; Hassan et al. 2010a; Hassan et al. 2010b; Huisa et al. 2012).  
These data are consistent with analyses of IV alteplase trials of more severe patients 
suggesting that stroke severity, as measured by the NIHSS score, is a strong predictor 
of sICH risk (Khatri et al. 2007).  No data exist to estimate the sICH rate for patients with 
mild stroke who did not receive t-PA; therefore, for this study, we are using a 0% sICH 
rate for the placebo arm, which is likely a conservative estimate.  An absolute sICH 
difference of 2% at 36 hours (primary safety endpoint) has been assumed for the 
alteplase arm vs. the placebo control arm in the proposed study.  For this study, sICH 
has been defined as any neurologic decline attributed to intracranial hemorrhage (ICH) 
seen on imaging by the local investigator within 36 hours of study drug administration, 
consistent with the NINDS trial definition for sICH (NINDS rt-PA Study Group 1995). 
Assuming the proposed study demonstrates both a 9% absolute treatment effect rate, 
the number of patients needed to treat (NNT) to show benefit (i.e., mRS score of 0 − 1) 
for one patient is 11.  Assuming a 2% absolute difference in sICH rate in patients treated 
with alteplase, the corresponding value for the number needed to harm (NNH), 
specifically for sICH, is conservatively estimated to be 50.  The actual number NNH, or 
the number of patients who would have worse outcomes at 90 days with alteplase 
compared to placebo treatment, is likely to be much higher than is reflected by the sICH 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
354/aCSR ML29093
17 


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A full schedule of assessments is provided in Appendix 1. 
Figure 1 Abbreviated Study Schema 
ASA = aspirin; CT= computed tomography; IV = intravenous; MRI = magnetic resonance imaging; 
mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale. 
Due to the emergency nature of randomization in acute stroke clinical trials, treatment 
assignments must be made in an expeditious manner that also ensures even distribution 
in the treatment groups. A “step forward” randomization regimen stratified by site will be 
used to ensure that a randomized treatment assignment is available upon patients’ 
arrival at the hospital and treatment can initiate immediately upon signing informed 
consent and eligibility confirmation.  Further details on step forward randomization can 
be found in Section 4.2, Method of Treatment Assignment and Blinding. 
An independent Data Monitoring Committee (iDMC) will provide ongoing review of 
potential safety concerns and review efficacy and safety outcomes to inform a futility 
interim analysis after 50% of patients have achieved the primary endpoint (following 
completion of the Day 90 visit).  The composition of the iDMC and analysis will be 
documented in detail in a separate iDMC charter. 
3.2 
LENGTH OF STUDY 
Based on study enrollment projections, this study is estimated to take approximately 
4 years to complete, from first patient in to last patient’s last visit (LPLV), when the final 
patient completes the 90-day follow-up. 
3.3 
END OF STUDY 
The end of the study is defined as the date when the LPLV occurs.  The LPLV is 
expected to occur approximately 90 days (± 14 days) after the last patient is enrolled into 
the study. 
3.3.1 
Number of Patients 
Approximately 948 patients with AIS and mild strokes will be enrolled in the study across 
75 sites in the U.S. and Canada. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
357/aCSR ML29093
20 


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It is notable that the alteplase USPI (Activase USPI 2011) distinguishes patients with 
minor neurological deficit from those with RISS.  However, PRISMS combines these two 
patient groups into one operationally defined patient population (mild stroke):  all eligible 
patients with an NIHSS score ≤ 5 at the time of randomization without clearly disabling 
symptoms, irrespective of previous NIHSS scores.  Data demonstrating low alteplase 
use in patients with NIHSS scores ≤ 5 do not distinguish between whether the patient’s 
deficit was persistently mild or improved to this status (Smith et al. 2011).  Furthermore, 
no data exist that suggest patients who improved to a mild status at the time of treatment 
with alteplase have different outcomes from patients whose neurologic deficit is 
persistently mild.  To date, available data suggest that alteplase therapy would 
potentially be beneficial in both patients with RISS who improve to an NIHSS score ≤ 5 
and patients with persistently mild symptoms with an NIHSS score ≤ 5. 
Conversely, patients who improve to an NIHSS score > 5 at the time of treatment 
decision will be excluded from PRISMS as they are not considered to have RISS.  
Current clinical practice suggests that these patients would still have a moderate or 
severe stroke at the time of treatment decision and should receive alteplase, if eligible, 
rather than be randomized to a study.  Such patients should not be defined as rapidly 
improving, given that they have not improved to an NIHSS score low enough to merit 
withholding therapy.  This definition of RISS is consistent with a recent consensus 
statement by leading stroke and emergency medicine experts (TREAT Task Force 
2013). 
PRISMS will also exclude patients who are assessed at the time of pre-treatment to 
likely be clearly disabled at 90 days, as defined by specific criteria described in the study 
protocol. These deficits at presentation include, but are not limited to, homonymous 
hemianopsia, severe limb weakness, severe aphasia, hemineglect, or cortical blindness.  
Patients with clearly disabling deficits will be excluded from this study irrespective of the 
NIHSS score at time of randomization, as current clinical practice and ethical 
responsibility suggest that these patients should be evaluated to receive alteplase rather 
than be enrolled in a randomized study where they may receive placebo. 
3.4.3 
Rationale for Control Group 
The overall rationale for this trial is to determine whether IV alteplase improves 
outcomes in patients with mild stroke.  The control group (i.e., mild stroke patients who 
receive standard of care) has been included so that outcomes in the active treatment 
group can be compared to those who receive standard of care.  The control group will 
receive IV alteplase placebo and 325 mg of oral aspirin.  The rationale for the control 
group receiving aspirin is that it would be unethical to withhold a dose of aspirin from 
patients who would not be receiving active study drug.  The standard of care for patients 
suffering from AIS who are ineligible for IV alteplase therapy is oral aspirin administered 
within the first 24 hours after the onset of their stroke symptoms.  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
360/aCSR ML29093
23 


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4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alteplase 
Alteplase is a single polypeptide containing 527 amino acids; it has three carbohydrate 
side chains and is predominantly one-chain t-PA.  It is a recombinant protein produced in 
a continuous mammalian tissue culture system and is purified by a series of 
chromatographic steps.  The manufacturing process includes fermentation with use of 
the antibiotic gentamicin; however, the presence of the antibiotic is not detectable in the 
final product. 
Alteplase is a sterile, white to pale yellow, lyophilized powder for IV administration after 
reconstitution with sterile water for injection (SWFI), USP, without preservatives.  
Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for 
pH adjustment. Biologic potency is determined by an in vitro clot lysis assay 
and is expressed in international units (IU) as tested against the World Health 
Organization (WHO) standard.   
Each 50-mg vial of Activase contains 50 mg of alteplase, 1.7 g of L-arginine, 5 mg of 
polysorbate 80, and 0.5 g of phosphoric acid. 
Each kit will contain 2 vials of 50-mg of alteplase labeled for “clinical trial use only.” 
Vials of 50-mg alteplase must be stored at 2°C−30°C and protected from light. 
4.3.1.2 
Alteplase Placebo 
Alteplase placebo is the same formulation as the active without the alteplase protein. 
Each 50-cc vial contains 1.7 g of L-arginine, 5 mg of polysorbate 80, and 0.5 g of 
phosphoric acid. 
Each kit will contain 2 vials of 50 mg of alteplase placebo labeled for “clinical trial use 
only.” 
Alteplase placebo vials should be stored at 2°C−30°C and protected from light.  
4.3.1.3 
Aspirin 
Aspirin (325 mg) will be packaged for the study.  Each kit will contain one bottle, which 
has 100 tablets labeled for “clinical trial use only.”  Only one tablet will be administered 
to the patient, and the remainder of the bottle will be kept at the site for drug 
accountability.    
Aspirin tablets should be stored at 25°C with excursions permitted between 15°C−30°C. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
366/aCSR ML29093
29 


 
 
 
 
 
 
 
 
4.3.1.4 
Aspirin Placebo 
Aspirin placebo will be identical to active aspirin in appearance to maintain treatment 
blinding. Each bottle of aspirin placebo contains 100 tablets labeled for “clinical trial use 
only.” Only one tablet will be administered to the patient, and the remainder of the bottle 
will be kept at the site for drug accountability. 
Placebo tablets should be stored in the same manner as aspirin tablets:  25°C with 
excursions permitted between 15°C−30°C. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alteplase 
For AIS, the recommended dose is 0.9 mg/kg infused over 60 minutes with 10% of the 
total dose administered as an initial IV bolus over 1 minute.  The total dose should not 
exceed 90 mg. 
Because alteplase and alteplase placebo contain no antibacterial preservatives, 50-mg 
vials should be reconstituted immediately before use by adding 50 mL of SWFI, USP, to 
the vial; this yields a concentration of 1 mg/mL.  Using aseptic technique, direct the flow 
of SWFI directly into the lyophilized cake of study drug.  It is recommended that an 
18-gauge needle be used for the reconstitution of the 50-mg vial.  Once reconstituted, 
gently swirl the vial. Do not shake. Slight foaming upon reconstitution is not unusual; 
allowing the vial to stand undisturbed for several minutes is usually sufficient to allow 
dissipation of any large bubbles.  Before further dilution or administration, the product 
should be visually inspected for particulate matter and discoloration.  If a precipitate is 
seen, the product should not be used. 
After reconstitution, alteplase may be administered at 1 mg/mL.  Do not further dilute 
(e.g., < 1 mg/mL) the solution. The osmolality of this solution is approximately 
215 mOsm/kg.  Polyvinyl chloride bags, glass bottles, or polypropylene syringes are 
acceptable.  Do not use filter needles for infusion.  Alteplase is stable for up to 8 hours in 
these solutions at room temperature.  Exposure to light has no effect on the stability of 
these solutions.  Excessive agitation during dilution should be avoided; mixing should be 
accomplished with gentle swirling and/or slow inversion.   
No other medication should be added to infusion solutions containing alteplase.  Any 
unused infusion solution should be discarded. 
Each 50-mg vial of Activase contains 50 mg of alteplase, 1.7 g of L-arginine, 5 mg of 
polysorbate 80, and 0.5 g of phosphoric acid. 
See Appendix 2  (Alteplase Administration) and Appendix 3 (Reconstitution of 
50-mg Vials) for further details. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
367/aCSR ML29093
30 


 
 
 
 
 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
alteplase) will be provided by the Sponsor where required by local health authority 
regulations.  The investigational site will acknowledge receipt of IMPs using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received, dispensed, returned, and disposed of by the study 
site should be recorded on the Drug Inventory Log. 
4.3.4 
Investigational Medicinal Product 
4.3.4.1 
Alteplase and Placebo 
Test Product 
Patients randomized to the active arm will receive treatment with 0.9 mg/kg of 
IV alteplase (maximum 90 mg) per standard stroke dosing. 
Comparator 
Patients randomized to the placebo arm will receive IV alteplase placebo consisting of 
1.7 g of L-arginine, 5 mg of polysorbate 80, and 0.5 g of phosphoric acid. 
4.3.4.2 
Non-investigational Medicinal Products 
To maintain standard medical care, patients randomized to the IV alteplase placebo arm 
will receive 325 mg of oral aspirin at the same time that they receive IV alteplase 
placebo. 
Comparator 
Patients in the IV alteplase active arm will receive an oral aspirin placebo tablet at the 
same time they receive IV alteplase.  The placebo will be identical to active aspirin in 
appearance to maintain treatment blinding. 
4.3.5 
Post-Trial Access to Alteplase 
The Sponsor does not intend to provide alteplase, any investigational or non­
investigational products (specified in this protocol), or any other study interventions to 
patients after the conclusion of the study or who are withdrawn earlier.   
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
368/aCSR ML29093
31 


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4.5.1.6 
Other Disease-Specific Assessments 
Neuroimaging may consist of a non-contrast CT or MRI of the brain.  If an MRI is used in 
the acute setting (to determine study eligibility), it must include the following at a 
minimum:  (1) DW MRI, (2) either susceptibility-weighted [SW] imaging or gradient echo 
[GRE] sequences, and (3) FLAIR sequences. 
Non-contrast CT or MRI will be performed at baseline to ensure that the patient does not 
have evidence of acute ICH prior to study drug administration. 
An additional non-contrast CT or MRI will be performed at 22 to 36 hours from the 
initiation of study drug infusion.  The purpose of this is to evaluate for ICH in the patient.  
An NIHSS should be performed at the time this CT scan or MRI is performed, but prior to 
reviewing imaging results to avoid biasing the assessment.  If an MRI is performed, in 
addition to the above requirements for the baseline visit MRI, it must also include T1 and 
T2 sequences. 
Additional CT scans or MRIs should be performed based on the investigator’s discretion, 
or if any clinical findings suggest ICH (such as new headache, nausea, vomiting, 
significant deterioration of neurological status, or rapid increase of blood pressure).  If an 
ICH is identified, the NIHSS score should be reassessed at the time and recorded on the 
Adverse Event eCRF. 
CT scans or MRIs performed between 22 to 36 hours, and additional imaging performed 
due to clinical suspicion of deterioration up until 36 hours after study drug administration, 
will be evaluated by a central team of radiologists blinded to the clinical attributes of the 
case. 
4.5.2 
Patient-Reported Outcomes 
Patient-reported outcomes (PRO) data will be elicited from the patients in this study to 
more fully characterize the clinical profile of alteplase in this patient population.  The 
PRO questionnaires will be distributed by the investigator staff and completed in their 
entirety by the patient or their surrogate.    
This study will assess the impact of alteplase treatment on health-related quality of life, 
physical function, daily functioning, and symptoms of depression.  
Health-related quality of life will be assessed using the EQ-5D (Appendix 4).  The EQ-5D 
is a generic, preference-based health utility measure with questions about mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression that are used to build 
a composite of the patient’s health status.   
Physical functioning will be evaluated using the SIS-16 (Appendix 5), which is a 
validated, stroke-specific, quality of life measure to assess the impact of stroke on a 
patient’s health and life. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
371/aCSR ML29093
34 


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4.6.2 
Visit 2 (22 to 36 Hours after Treatment Initiation) 
A non-contrast cranial CT or MRI (including DW MRI, either SW or GRE, FLAIR, and T1 
and T2 sequences) will be performed at 22 to 36 hours after treatment with study drug is 
initiated. Either a CT scan or MRI may be performed, as consistent with the institutional 
standard of care; the main criterion is to perform radiographic imaging of the brain by a 
modality sensitive to the presence of blood.  An NIHSS will also be performed during this 
visit, but prior to review of the imaging results (or by an investigator blinded to the 
results). AEs and concomitant medications will also be assessed at this visit. 
4.6.3 
Visit 3 (Day 5 or Discharge from Hospital, if Sooner than Day 5) 
An NIHSS score will be performed at Day 5 or on the day of discharge from the hospital, 
if sooner than Day 5.  Furthermore, the discharge location of the patient will be recorded 
if available at this time.  If discharged after Day 5, the discharge location will be 
subsequently recorded.  Concomitant medications will also be assessed at this visit. 
4.6.4 
Visit 4 (Day 30 [30± 7 Days]) 
A phone call to the patient or caregiver will be made at Day 30 and an mRS will be 
assessed (see Appendix 8).  AEs, concomitant medications, and patient survival will be 
assessed at this visit.  Pregnancy will also be assessed for female patients of 
childbearing potential. 
4.6.5 
Visit 5 (Day 90 [± 14 Days]/Study Completion) 
Primary and secondary efficacy endpoints, as well as all exploratory endpoints, will be 
assessed at Day 90 during an in-person visit by the patient.  The following assessments 
will be performed: 
• 
NIHSS score (Appendix 7) 
• 
Patient survival 
• 
mRS (Appendix 8) 
• 
GOS (Appendix 9 
• 
BI (Appendix 10) 
• 
EQ-5D (Appendix 4) 
• 
SIS-16 (Appendix 5) 
• 
CES-D (Appendix 6) 
• 
Cognitive assessments (Appendix 11) 
– 
Animal Naming test 
– 
Controlled Oral Word Association test  
– 
Digit symbol coding from the Wechsler Adult Intelligence Scale 
– 
Hopkins Verbal Learning test  
– 
15-item Boston Naming test 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
373/aCSR ML29093
36 


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Management of Bleeding 
Patients will be excluded for the presence of conditions related to risks of bleeding  
(as outlined in Section 4.1.2, Exclusion Criteria).  A non-contrast cranial CT or MRI 
(including either SW or GRE to detect ICH) should be performed at baseline to ensure 
that the patient does not have evidence of ICH prior to study drug administration. 
Fibrin, which is part of the hemostatic plug formed at needle puncture sites, may be 
lysed during alteplase therapy.  Therefore, alteplase therapy requires careful attention to 
potential bleeding sites, e.g., catheter-insertion sites and arterial-puncture sites.  Arterial 
and venous punctures should be minimized. Non-compressible arterial, as well as 
internal jugular and subclavian venous punctures, should be avoided to minimize 
bleeding from non-compressible sites.  In the event of serious bleeding (not controllable 
by local pressure) or occurring in a critical location (intracranial, gastrointestinal, 
retroperitoneal, or pericardial), study drug should be discontinued immediately.  
Supportive care and medical management of AEs are at the discretion of the investigator. 
5.1.2 
Risk of Allergic Reactions 
Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual 
angioedema, rash, and urticaria, have been reported.  When such reactions occur, they 
usually respond to conventional therapy.  
There have been postmarketing reports of orolingual angioedema associated with the 
use of alteplase. Most were patients treated for AIS.  Many of these patients received 
concomitant angiotensin-converting enzyme inhibitors, and most cases resolved with 
prompt treatment. 
Management of Allergic Reaction 
If an anaphylactic reaction occurs, the infusion of study drug should be discontinued 
immediately and appropriate therapy should be promptly instituted. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious adverse events of special interest (AESI), measurement of protocol-
specified vital signs, and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.2.2. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
376/aCSR ML29093
39 


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events). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better and is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent. Every effort should be made to follow all SAEs considered to 
be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For SAEs, AESI, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures. 
The investigator is not required to actively monitor patients for AEs after the end of the 
AE reporting period (defined as 90 days after administration of study drug).  However, 
the Sponsor should be notified if the investigator becomes aware of any death, other 
SAE, or non-serious AESI occurring after the end of the AE reporting period, regardless 
of causality. The Sponsor should also be notified if the investigator becomes aware of 
the development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a female patient exposed to study drug. 
The investigator should report these events directly to Safety Risk Management via 
telephone at 1-888-835-2555. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
386/aCSR ML29093
49 


 
 
 
 
 
 
 
 
  
 
 
 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-serious AESI against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference document: 
• 
Alteplase Investigator's Brochure 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL METHODS 
This study will test whether treatment of patients with mild stroke with IV alteplase will 
lead to a higher proportion (9% absolute difference) of patients with a favorable outcome 
(mRS of 0 or 1) at 90 days. 
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of 856 is required in order to achieve 80% power in the primary analysis 
to detect effect size of 9% absolute difference in the proportion of patients with favorable 
outcomes between the alteplase and control arms.  The above power consideration 
assumes a control proportion of 65% and Type I error of 0.025 (one-sided), and uses a 
group sequential design with one interim analysis for futility (non-binding), based on 
O’Brien and Fleming boundary, after 50% of the anticipated sample size have completed 
90-day follow-up assessments. 
was used in sample size calculation. 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard 
against dilution of the treatment effect associated with an approximate 5% 
non-adherence rate (due to lost to follow-up, consent withdrawal, and treatment 
crossovers), the above sample size needs to be inflated by a factor of 1/0.952 or 1.108 
(Friedman et al. 1998). Therefore, a total sample size of 948 is required for this study.  
PRIMARY ANALYSIS 
The primary efficacy analysis will test the hypothesis of superiority of IV alteplase 
therapy over standard medical care in AIS patients with mild symptoms.  The primary 
efficacy outcome is the proportion of patients with a favorable outcome, defined by 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
387/aCSR ML29093
50 
6.2 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mRS score of 0 or 1 at 90 days post-randomization.  The difference in the proportion of 
mRS 0−1 responders (favorable outcome) at 90 days post-randomization between the 
IV alteplase arm and the standard medical care arm will be compared via a 
Cochran-Mantel-Haenszel test, stratified by pre-treatment NIHSS score (0 − 2 vs. 3 − 5), 
age (< 65 vs. ≥ 65), and last known well time to treatment (0 − 2 hours vs. 2 − 3 hours). 
The primary efficacy analysis will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization adhering to the ITT principle. 
A patient is considered enrolled and randomized in the trial, and included in the ITT 
population, as soon as study drug begins.  As a sensitivity analysis, results from the 
univariate Pearson’s chi-square test will also be presented. 
As a supportive, secondary analysis, an ordinal (or “shift”) analysis of the distribution of the 
mRS will be analyzed via proportional odds model if the proportionality assumption holds, 
and by the Mann-Whitney superiority measure if the proportionality assumption does not 
hold. The proportionality assumption will be assessed using the score test as well as 
clinical judgment on the similarities of the different odds ratios.  Other secondary efficacy 
outcomes of interest include NIHSS score, BI, GOS, and global outcome scale at 90 days.  
These results will be treated as supportive evidence (or lack thereof) of the treatment 
effect rather than conclusive evidence, the significance of each test is determined at the 
two-sided alpha level of 0.05. The specific statistical model for analyzing each of these 
outcome measures will be detailed in the Statistical Analysis Plan (SAP). 
6.3 
SAFETY ANALYSIS 
Incidence and severity of AEs will be described for all treated patients by treatment 
group as received and by the Medical Dictionary for Regulatory Activities (MedDRA) 
classification. 
Primary safety outcomes include incidence of sICH within 36 hours, any ICH within 
36 hours, overall mortality, and stroke-related and neurological deaths within 90 days of 
study drug initiation. The cumulative incidences of each outcome will be compared via 
Fisher’s exact test.  Mortality will be analyzed by Log-Rank test and the Kaplan-Meier 
estimates will be plotted over the observation period of 90 days.  No alpha adjustment 
for multiple testing on the safety endpoints is foreseen because those analyses will be 
exploratory. 
6.4 
EXPLORATORY ANALYSES 
As exploratory analyses, heterogeneity of treatment effect of alteplase will be evaluated 
by various pre-specified baseline covariates.  The primary pre-specified variables and 
their analytic thresholds are defined by: 
• 
Age (< 65 vs. ≥ 65) 
• 
Pre-treatment NIHSS score (0 − 2 vs. 3 − 5) 
• 
Last known well time to treatment (0 − 2 vs. 2 − 3 hours) 
• 
Stroke subgroup (RISS vs. non-RISS) 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
388/aCSR ML29093
51 


 
 
 
 
 
 
 
 
 
 
 
 
 
Additional heterogeneity analyses will be considered and detailed in the SAP.  Forest 
plots will be constructed to illustrate subgroup analyses.  In addition, the two-way 
interactions of IV alteplase treatment effect with age, NIHSS score, and stroke 
subgroups (RISS vs. non-RISS) on the primary outcome will be explored through 
multivariable logistic regression.  Additional exploratory analyses will be conducted to 
explore treatment effects on quality of life endpoints and other exploratory endpoints. 
6.5 
INTERIM ANALYSIS 
One interim analysis of the primary efficacy outcome is planned for clear futility, 
conducted according to the beta-spending approach (Pampallona et al. 2001) with 
O’Brien and Fleming-type boundaries.  This futility analysis will occur after approximately 
50% of patients (or 474) have completed the 90-day assessment. 
An independent Data Coordinating Center (iDCC) will be responsible for the preparation 
and review of unmasked data. Further details will be provided in the interim SAP and 
the iDMC charter. 
An iDMC will be organized for review of the interim analysis results.  The composition of 
the iDMC and analysis in detail will be documented in a separate iDMC charter. 
6.6 
MISSING DATA HANDLING 
Under the ITT principle, all patients who are randomized will be included in the analysis.  
The multiple-imputation method will be used for handling missing data, including the last 
observation among the variables employed in imputation. As supportive analyses, 
missing primary outcome data will be imputed by 1) using last observation carried 
forward and 2) assuming missing outcomes to be unfavorable. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC using 
eCRFs. Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data with the input from the Sponsor.  For this study, local laboratories 
will be used and data will be captured in the EDC system and will then be transferred to 
the Sponsor. This will include the eCRF data using the Sponsor’s standard procedures 
and processes to transfer data. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
389/aCSR ML29093
52 


 
 
 
 
 
 
 
 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
The EDC vendor has back-ups for data stored, and records retention for the study data 
will be consistent with the CRO’s standard procedures.  
Data from paper PRO questionnaires will be entered into the EDC system by site staff.   
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have eCRF completion guidelines for the eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (e.g., source data) entered into the eCRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents.  Source documents 
(paper or electronic) are those in which patient data are recorded and documented for 
the first time.  They include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Study Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
390/aCSR ML29093
53 


 
 
 
 
 
  
 
 
 
 
 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the International Conference on 
Harmonisation E6 guideline for Good Clinical Practice and the principles of the 
Declaration of Helsinki, or the laws and regulations of the country in which the research 
is conducted, whichever affords the greater protection to the individual.  The study will 
comply with the requirements of the International Conference on Harmonisation E2A 
guideline (Clinical Safety Data Management:  Definitions and Standards for Expedited 
Reporting). Studies conducted in the United States or under a U.S. Investigational New 
Drug (IND) application will comply with FDA regulations and applicable local, state, and 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
391/aCSR ML29093
54 


 
 
8.2 
federal laws. Studies conducted in the EU/EEA will comply with the EU Clinical Trial 
Directive (2001/20/EC). 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the U.S., each Consent Form may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
392/aCSR ML29093
8.3 
55 


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10. 
REFERENCES 
Activase® (alteplase) U.S. Package Insert, Genentech, Inc., 2011. 
Baumann CR, Baumgartner RW, Gandjour J, et al. Good outcomes in ischemic stroke 
patients treated with intravenous thrombolysis despite regressing neurological symptoms. 
Stroke 2006,37:1332−3. 
De Los Rios La Rosa F, Khoury J, Kissela BM, et al. Eligibility of intravenous 
recombinant tissue-type plasminogen activator within a population: the effect of the 
European cooperative acute stroke study (ECASS) III trial. Stroke 2012,43(6):1592−5. 
Demaerschalk BM. Thrombolytic therapy for acute ischemic stroke: the likelihood of 
being helped versus harmed. Stroke 2007;38:2215-16. 
Dhamoon MS, Moom YP, Boden-Albala B, et al. Long-term functional recovery after first 
ischemic stroke: the Northern Manhattan Study. Stroke 2009;40:2805−11. 
Edlow JS, Smith EE, Stead LG, et al. Clinical policy: Use of t-PA for the management of 
acute ischemic stroke in the Emergency Department. Ann Emerg Med 2013;61:225−43. 
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. Third ed. 1998, 
New York, NY:Springer:108. 
Fischer U, Baumgartner A, Arnold M, et al. What is minor stroke? Stroke 2010;41:661-6.  
Gonzales NR, Albright KC, Noser KC, et al. “Mild stroke” should not exclude patients 
from thrombolytic therapy. Stroke 2006;37:621. 
Hassan AE, Hassanzadeh B, Tohidi V, et al. Very mild stroke patients benefit from 
intravenous tissue plasminogen activator without increase of intracranial hemorrhage. 
South Med J 2010a;103(5):398 − 402. 
Hassan AE, Zacharoatos H, Hassanzadeh B, et al. Does Mild deficit for patients with 
stroke justify use of intravenous tissue plasminogen activator? J Stroke Cerebrovasc Dis 
2010b;19:116-20.  
Huisa BN, Raman R, Neil W, et al. Intravenous tissue plasminogen activator for patients 
with minor ischemic stroke. J Stroke Cerebrovasc Dis 2012;21:733-6. 
Jauch EC, Saver JL, Adams HP, 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 Council, Council on 
Cardiovascular Nursing, Council on Peripheral Vascular Disease and Council on Clinical 
Cardiology: the American Academy of Neurology affirms the value of this guideline as an 
educational tool for neurologists. Stroke 2013;44:1655-11. 
Khatri P, Conaway MR, Johnston KC; Acute Stroke Accurate Prediction Study (ASAP) 
Investigators. Ninety-day outcome rates of a prospective cohort of consecutive patients 
with mild stroke. Stroke 2012;43:560-62. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
396/aCSR ML29093
59 


 
 
 
 
 
Khatri P, Kleindorfer DO, Yeatts SD, et al. Strokes with minor symptoms: an exploratory 
analysis of the National Institute of Neurological disorders and stroke recombinant tissue 
plasminogen activator trials. Stroke 2010;41:2581-6. 
Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with 
revascularization therapies. Stroke 2007,38(2):431-40. 
Köhrmann M, Nowe T, Huttner HB, et al. Safety and outcome after thrombolysis in 
stroke patients with mild symptoms. Cerebrovasc Dis 2009;27(2):160-66. 
National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study Group. 
Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581−8. 
National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study Group. 
Recombinant tissue plasminogen activator for minor strokes: the National Institute of 
Neurological Disorders and Stroke rt-PA Stroke Study Experience. Ann Emerg Med. 
2005;46:243−52. 
Pampallona S, Tsiatis AA, Kim K. Interim monitoring of group sequential trials using 
spending functions for the type I and type II error probabilities. Drug Inf J 
2001;35:1113−21. 
Reeves M, Khoury J, Alwell K, et al. Distribution of NIHSS in the Cincinnati/Northern 
Kentucky Stroke Study. Stroke 2013; In press. 
Rosamond W, Flegal K, Friday G, et al; American Heart Association Statistics 
Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics— 
2007 update: a report from the American Heart Association Statistics Committee and 
Stroke Statistics Subcommittee. Circulation 2007;115:e69--171. 
Robbins KC. The plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, 
Marder VJ, et al., editors. Hemostasis and thrombosis: basic principles and clinical 
practice. Philadelphia: JP Lippincott. 1982:623−39. 
Saver J. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number 
needed to harm. Stroke 2007;38:2279-2283. 
Smith EE, Gonarow GC, Reeves MJ, et al. Outcomes in mild or rapidly improving stroke 
not treated with intravenous recombinant tissue-type plasminogen activator: findings 
from Get With The Guidelines-Stroke. Stroke 2011;42:3110-15.  
Steffenhagen N, Hill MD, Poppe AY, et al. Should you thrombolyze all or any stroke 
patients with baseline National Institutes of Health Stoke Scale scores ≤ 5? Cerebrovasc 
Dis 2009;28:201-02. 
The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force. Review, 
historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: 
part 1: rapidly improving stroke symptoms. Stroke 2013 Jul 11. Epub ahead of print. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
397/aCSR ML29093
60 


  
 
 
 
Wahlgren N, Ahmed N, Dávalos 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;369:275−82. 
Willey JZ, Stillman J, Rivolta JA, et al. Too good to treat? Outcomes in patients not 
receiving thrombolysis due to mild deficits or rapidly improving symptoms.  Int J Stroke 
2012;7(3):202-06. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
398/aCSR ML29093
61 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1  
Schedule of Assessments  
ASSESSMENTS 
Screening and 
Baseline 
(Visit 1) 
Study Drug 
Administration 
22−36 Hours 
from Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 (± 14) 
Days/ Study 
Completion 
In-Person 
Visit (Visit 5) 
Early Discontinuation 
(Phone call, if possible) 
Informed consent 
x 
Review of eligibility 
x 
Medical history and 
baseline conditions a 
x 
Demographics 
x 
Neurological examination b
 x 
Vital signs c 
x 
Complete blood count d
 x 
Coagulation status e
 x 
Pregnancy test f
 x 
Serum blood glucose g
 x 
Imaging modality sensitive 
to presence of intracranial 
hemorrhage (either CT or 
MRI with DW MRI, either 
SW or GRE, and FLAIR 
images). Visit 2 MRIs 
should also include T1 and 
T2 sequences h 
x 
x 
NIHSS score i 
x 
x 
x 
x 
Study drug administration 
x 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
399/aCSR ML29093
62 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1 (cont.)  
Schedule of Assessments  
ASSESSMENTS 
Screening and 
Baseline 
(Visit 1) 
Study Drug 
Administration 
22−36 Hours 
from Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 (± 14) 
Days/ Study 
Completion 
In-Person 
Visit (Visit 5) 
Early Discontinuation 
(Phone call, if possible) 
Discharge location 
x 
x 
Patient survival 
x 
x 
x 
mRS j 
x 
x 
GOS
 
x 
BI k 
x 
EQ-5D k 
x 
CES-D k 
x 
SIS-16 k 
x 
Cognitive assessments 
x 
Walking speed l 
x 
Concomitant medications m
 x 
x 
x 
x 
x 
x 
Assessment of pregnancy 
x 
Adverse event n 
x 
x 
x 
x 
x 
x 
CES-D = Centers for Epidemiologic Studies, Depression; CT = computed tomography; DW MRI = diffusion-weighted MRI; European Quality of 
Life = EQ-5D; FLAIR = fluid attenuated inversion recovery; GOS = Glasgow Outcome Scale; ICH = intracranial hemorrhage; MRI = magnetic resonance 
imaging; mRS modified Rankin Scale; NIHSS = NIH Stroke Scale; Stroke Impact Scale-16 = SIS-16; SW MRI= susceptibility-weighted MRI. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
400/aCSR ML29093
63 


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Appendix 3  
Reconstitution of 50-mg Vials  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
403/aCSR ML29093
66 


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Appendix 4 (cont.)  
European Quality of Life-5D (EQ-5D) Questionnaire  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
405/aCSR ML29093
68 


 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 5  
Stroke Index Scale (SIS-16)  
In the past 2 weeks, how 
difficult was it to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Could not 
do at all 
a. Dress the top part of your 
body? 
5 
4 
3 
2 
1 
b. Bathe yourself? 
5 
4 
3 
2 
1 
c. Get to the toilet on time? 
5 
4 
3 
2 
1 
d. Control your bladder (not 
have an accident)? 
5 
4 
3 
2 
1 
e. Control your bowels (not 
have an accident)? 
5 
4 
3 
2 
1 
f. Stand without losing 
balance? 
5 
4 
3 
2 
1 
g. Go shopping? 
5 
4 
3 
2 
1 
h. Do heavy household chores 
(e.g., vacuum, laundry or yard 
work)? 
5 
4 
3 
2 
1 
i. Stay sitting without losing 
your balance? 
5 
4 
3 
2 
1 
j. Walk without losing your 
balance? 
5 
4 
3 
2 
1 
k. Move from a bed to a chair? 
5 
4 
3 
2 
1 
l. Walk fast? 
5 
4 
3 
2 
1 
m. Climb one flight of stairs? 
5 
4 
3 
2 
1 
n. Walk one block? 
5 
4 
3 
2 
1 
o. Get in and out of a car? 
5 
4 
3 
2 
1 
p. Carry heavy objects (e.g. 
bag of groceries) with your 
affected hand? 
5 
4 
3 
2 
1 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
406/aCSR ML29093
69 


 
 
 
 
Appendix 6 
Center for Epidemiologic Studies, Depression (CES-D) Scale,
NIMH 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
407/aCSR ML29093
70 


 
 
 
 
 
 
Appendix 7  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
408/aCSR ML29093
71 


 
 
 
 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
409/aCSR ML29093
72 


 
 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
410/aCSR ML29093
73 


 
 
 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
411/aCSR ML29093
74 


 
 
 
 
 
 
Appendix 8  
Modified Rankin Scale (mRS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
412/aCSR ML29093
75 


 
 
 
 
 
 
 
Appendix 9  
Glasgow Outcome Scale (GOS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
413/aCSR ML29093
76 


 
 
 
 
 
 
Appendix 10  
Barthel Index (BI)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
414/aCSR ML29093
77 


 
 
 
Appendix 10 (cont.)  
Barthel Index (BI)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
415/aCSR ML29093
78 






 
 
 
 
Appendix 11 (cont.)  
Cognitive Assessments  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
418/aCSR ML29093
81 












 
 
 
 
 
Appendix 11 (cont.)  
Cognitive Assessments  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
424/aCSR ML29093
87 


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Appendix 13  
Preferred Terms for Intracranial Hemorrhage  
An Intracranial Hemorrhage (ICH) is considered symptomatic if it is not seen on 
computed tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and 
any neurologic decline is attributed to it by the local investigator. Below is the list of 
preferred terms (PT’s) using the MedDRA term to describe the ICH event: 
• 
Basal ganglia hemorrhage 
• 
Brain stem hematoma 
• 
Brain stem hemorrhage 
• 
Brain stem microhemorrhage 
• 
Central nervous system hemorrhage 
• 
Cerebellar hematoma 
• 
Cerebellar hemorrhage 
• 
Cerebellar microhemorrhage 
• 
Cerebral arteriovenous malformation hemorrhagic 
• 
Cerebral hematoma 
• 
Cerebral hemorrhage 
• 
Cerebral microhemorrhage 
• 
Extradural hematoma 
• 
Hemorrhage intracranial 
• 
Hemorrhagic cerebral infarction 
• 
Hemorrhagic stroke 
• 
Hemorrhagic transformation stroke 
• 
Intracranial hematoma 
• 
Intraventricular hemorrhage 
• 
Meningorrhagia 
• 
Pituitary hemorrhage 
• 
Purpura cerebri 
• 
Putamen hemorrhage 
• 
Subarachnoid hemorrhage 
• 
Subdural hematoma 
• 
Subdural hemorrhage 
• 
Thalamus hemorrhage 
• 
Traumatic intracranial hemorrhage 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
428/aCSR ML29093
91 


 
 
 
 
 
 
 
 
 
 
Appendix 14  
WHO Toxicity Grading Scale for Determining the Severity of  
Adverse Events  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
429/aCSR ML29093
92 


 
 
 
 
 
Appendix 14 (cont.) 
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
430/aCSR ML29093
93 


 
 
 
 
 
Appendix 14 (cont.) 
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
94 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
431/aCSR ML29093


 
 
 
 
 
 
Appendix 14 (cont.) 
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 1 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
432/aCSR ML29093
95 


 
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If a clinical situation arises in which the investigator thinks it is necessary to unblind 
in the interest of patient safety, the Medical Monitor must be notified immediately to 
discuss the intended unblinding. Unblinding should occur only in settings where 
identification of the study treatment is critical for treatment decisions.  IWRS will be 
used for the unblinding process. All unblinded patients will remain in the study and 
require all follow-up visits. 
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CT scans or MRIs performed at baseline, between 22 to 36 hours, and additional 
imaging performed due to clinical suspicion of deterioration up until 36 hours after study 
drug administration, will be evaluated by a central team of radiologists blinded to the 
clinical attributes of the case.  These images will need to be sent to the central 
radiologists by the local site. 
SECTION 4.5.2: Patient-Reported Outcomes 
The EQ-5D, SIS-16, and CES-D will be provided in Spanish for those patients 
requiring translations. 
SECTION 4.6.1: Screening/Baseline (Visit 1) 
• 
Complete blood count without differential 
• 
AEs 
All screening evaluations with the exception of certain laboratory results 
(e.g., coagulation and plateletcomplete blood count) must be completed and reviewed to 
confirm that patients have met all eligibility criteria prior to treatment.   
SECTION 4.6.2: Visit 2 (22 to 36 Hours after Treatment Initiation) 
A non-contrast cranial CT or MRI (including DW MRI, either SW or GRE, FLAIR, and T1 
and T2 sequences) will be performed at 22 to 36 hours after treatment with study drug 
has been initiated. (bolus). 
AEs1 and concomitant medications will also be assessed at this visit. 
1AE/SAE collection should be started as soon as study drug administration (bolus) is initiated. 
SECTION 4.6.3: Visit 3 (Day 5 or Discharge from Hospital, if Sooner than 
Day 5) 
An NIHSS score will be performed at On Day 5 (or on the day of discharge from the 
hospital, if sooner than Day 5. Furthermore, the), NIHSS score, stroke etiology, AEs, 
and concomitant medications will be collected. Discharge location of the patient will be 
recorded if availablecollected at thisthe time. If discharged after Day 5, the discharge 
location will be subsequently recorded.  Concomitant medications will also be assessed 
at this visit of hospital discharge. 
SECTION 4.6.4: Visit 4 (Day 30 [30 ± 7 Days]) 
AEs, concomitant medications, and patient survival will be assessed atduring this phone 
visit. 
SECTION 4.6.5: Visit 5 (Day 90 [± 14 Days]/Study Completion) 
Primary and secondary efficacy endpoints, as well as all exploratory endpoints, will be 
assessed at Day 90 during an in person visit bywith the patient.   
• 
Cognitive assessments (Appendix 11) 
Animal Naming test 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
443/aCSR ML29093
11 


– 
HVLT-R trials 1, 2, and 3 
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– 
Benton Judgment of Line Orientation test, form V 
– 
HVLT-R trial 4 and recognition 
– 
Animal Naming test 
– 
BNT 15-item short form 
The above cognitive assessments will be provided in Spanish for those 
patients requiring translations with the exception of the BNT 15-item 
short form. 
x 
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x 
SAEs and certain AEs (See Section 5.3.1) 
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VKRXOGmay EHXQEOLQGHG if blood products (to reverse the biological activity of IV 
alteplase) are indicated. ,I,&+LVQRWVHHQVWXG\GUXJLQIXVLRQVKRXOGLPPHGLDWHO\EH
UHVWDUWHG up to 5.5 hours after the last known well time at the same rate as the previous 
infusion until the remainder of study drug is infused
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Stroke recurrence:  report if the AE resulted in a substantial disruption of a 
person’s ability to conduct normal life functions (i.e., the AE resulted in a 
significant, persistent, or permanent change; impairment; or damage or disruption 
in the patient’s body function/structure, physical activities, and/or quality of life. 
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SECTION 5.3.1: Adverse Event Reporting Period 
After informed consent has been obtained, but prior to initiation of study drug, only SAEs 
caused by a protocol mandated intervention should be reported. 
After initiation of study drug, all AEs, (including serious and non-serious AEs), 
regardless of relationship to study drug, will be reported until 30 days after 
administration of study drug. 
After 30 days until 90 days after administration of study drug. , the following AEs 
should be record on the AE CRF: 
• 
All SAEs 
• 
Non-serious ICHs 
• 
Non-serious AESIs 
• 
All AEs that resulted in withdrawal from the study 
All SAEs and non-serious AESIs require immediate reporting to the Sponsor (see 
Section 5.4). 
After this period90 days, the investigator is not required to actively monitor patients for 
adverse eventsAEs; however, the Sponsor should be notified if the investigator becomes 
aware of any post study serious adverse events or non serious adverse events of 
special interest-study SAEs (see Section 5.6). 
SECTION 5.3.3.8: Lack of Efficacy or Worsening of Acute Ischemic Stroke 
Medical occurrences or symptoms of deterioration that are considered part of the disease 
course or disease process should be recorded as an AE if judged by the investigator to 
have unexpectedly worsened in severity or frequency or unexpectedly changed in nature 
at any time during the study.  If there is uncertainty, it should be reported as an 
AE.  When recording unexpected worsening of AIS on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
descriptors of the event.Medical occurrences or symptoms of deterioration that are 
anticipated as part of AIS should be recorded as an AE if judged by the investigator to 
have unexpectedly worsened in severity or frequency or changed in nature at any time 
during the study.  When recording such an AE on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
descriptors (e.g., "accelerated acute ischemic stroke"). 
SECTION 5.4.1: Emergency Medical Contacts 
PPD Medical Monitor contact information: 
Medical Monitor: 
Areen SaidAndy Graber, M.D. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
445/aCSR ML29093
13 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION 5.6: POST-STUDY ADVERSE EVENTS 
However, the Sponsor should be notified if the investigator becomes aware of any death, 
or other SAE occurring after the end of the AE reporting period.  The Sponsor should 
also be notified if the investigator becomes aware of the development of cancer, or a 
congenital anomaly/birth defect in a subsequently conceived offspring of a female 
patient exposed to study drug. 
SECTION 6.1: DETERMINATION OF SAMPLE SIZE 
The above power considerationsample size calculation assumes a control proportion of 
65% and Type I error probability of 0.025 (one-sided)… 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard 
against dilution of the treatment effect associated with an approximate 5% 
non-adherence rate (due to lost to follow-up, consent withdrawal, and treatment 
crossovers, and stroke mimics), the above sample size needs to be inflated by a factor 
of 1/0.952 or 1.108 (Friedman et al. 1998).   
SECTION 6.2: PRIMARY ANALYSIS 
The primary efficacy analysis will test the hypothesis of superiority of IV alteplase 
therapy over standard medical care in AIS patients with mild symptomsdeficits. … The 
difference in the proportion of mRS 0−1 responders (favorable outcome) at 90 days 
post-randomization between the IV alteplase arm and the standard medical care arm will 
be compared via a Cochran-Mantel-Haenszel test, stratified by pre-treatment NIHSS 
score (0 − 2 vs. 3 − 5), age (< 65 vs. ≥ 65), and last known well time to treatment (0 − 2 
hours vs. > 2 − 3 hours). … A patient is considered enrolled and randomized in the trial, 
and included in the ITT population, as soon as study drug begins. 
OtherAs a secondary efficacy outcomes of interest include NIHSS score, BI, GOS, 
andoutcome, the global outcome scalescore at 90 days will be analyzed using the global 
odds ratio test based on the generalized estimating equations analysis (Wald-type χ2 
test) with unstructured covariance-correlation matrix. 
SECTION 6.3: SAFETY ANALYSIS 
Primary Safety outcomes include incidence of sICH within 36 hours, (primary safety 
assessment),… 
SECTION 6.4: EXPLORATORY ANALYSES 
The primary pre-specified variables and their analytic thresholds are defined by: 
• 
Last known well time to treatment (0 − 2 vs. > 2 − 3 hours) 
SECTION 6.5: INTERIM ANALYSIS 
Further details will be provided in the interim SAP and the iDMC charter. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
446/aCSR ML29093
14 


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Levine SR, Khatri P, Broderick JP, et al. Review, historical context, and clarifications 
of the NINDA rt-PA stroke trials exclusion criteria part 1: rapidly improving stroke 
symptoms. Stroke 2013;44(9):250005. 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIIb, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ALTEPLASE IN PATIENTS WITH MILD 
STROKE: RAPIDLY IMPROVING SYMPTOMS AND 
MINOR NEUROLOGIC DEFICITS (PRISMS) 
PROTOCOL NUMBER: ML29093 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
3811 
TEST PRODUCT: 
Alteplase (RO5532960) 
LEAD PRINCIPAL 
INVESTIGATOR: 
MEDICAL MONITOR: 
SPONSOR: 
Genentech, Inc. 
I agree to conduct the study in accordance with the current protocol. 
, M.D. 
, M.D. 
Principal Investigator’s Name (print) 
Principal Investigator’s Signature 
Date 
Please return a copy of this form as instructed by your local study monitor and retain a 
copy for your study files. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
453/aCSR ML29093
21 


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Determination of Sample Size 
A sample size of 856 is required in order to achieve 80% power for the primary analysis to 
detect an effect size of 9% absolute difference in the proportion of patients with favorable 
outcomes between the alteplase and control arms. The above sample size calculation 
assumes a control proportion of 65% and Type I error probability of 0.025 (one-sided), and uses 
a group sequential design with one interim analysis for futility (non-binding), based on an 
O’Brien-Fleming boundary, after 50% of the anticipated sample size have completed the 90-day 
follow-up assessments. 
was used in sample size calculation. 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard against 
dilution of the treatment effect associated with an approximate 5% non-adherence rate (due to 
lost to follow-up, consent withdrawal, treatment crossovers, and stroke mimics), the above 
sample needs to be inflated by a factor of 1/0.952 or 1.108 (Friedman et al. 1998). Therefore, a 
total sample size of 948 is required for this study. 
Interim Analysis 
One interim analysis of the primary efficacy outcome is planned for clear futility, conducted 
according to the beta-spending approach (Pampallona et al. 2001) with an 
O’Brien-Fleming-type boundary. This futility analysis will occur after approximately 50% of 
patients (or 474) have completed the 90-day assessment. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
458/aCSR ML29093
26 


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Abbreviation 
Definition 
LHH 
LPLV 
MCA 
MedDRA 
MRI 
mRS 
NIHSS 
NINDS 
NNH 
NNT 
PRO 
RISS 
rPH 
SAE 
SAP 
sICH 
SIS-16 
STIAMP 
SWFI 
SW 
t-PA 
U.S. 
USPI 
WAIS III 
WHO 
likelihood of being helped vs. harmed 
last patient’s last visit 
middle cerebral artery 
Medical Dictionary for Regulatory Activities 
magnetic resonance imaging 
modified Rankin Scale 
National Institutes of Health Stroke Scale 
National Institute of Neurological Disorders and Stroke 
number needed to harm 
number needed to treat 
patient-reported outcome 
rapidly improving stroke symptoms 
remote parenchymal hematoma 
serious adverse event 
Statistical Analysis Plan 
symptomatic intracranial hemorrhage 
Stroke Impact Scale-16 
Suspected Transmission of an Infectious Agent via a 
Medicinal Product 
sterile water for injection 
susceptibility-weighted 
tissue plasminogen activator 
United States 
U.S. Package Insert 
Wechsler Adult Intelligence Scale III 
World Health Organization 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
460/aCSR ML29093
28 


 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
BACKGROUND 
1.1 
BACKGROUND ON ACUTE ISCHEMIC STROKE 
Stroke is the fourth leading cause of death and a leading cause of disability in the United 
States (U.S.). Nearly 800,000 strokes occur in the U.S. annually; of these, 
approximately 85% are ischemic in nature (Rosamond et al. 2007).  Treatment options 
are limited, as the only approved therapy for acute ischemic stroke (AIS) is alteplase, 
which is to be used in eligible patients and started within 3 hours from the onset of stroke 
symptoms.  Stroke with “only minor or rapidly improving stroke symptoms” is considered 
a relative exclusion by national clinical guidelines, as these patients were largely 
excluded from definitive trials to date (Jauch et al. 2013).  Consistent with this 
recommendation, only 15% of alteplase recipients have mild strokes (Smith et al. 2011). 
More than half of all ischemic stroke patients have mild strokes at initial presentation in 
population-based studies (Dhamoon et al. 2009; Reeves et al. 2013).  Yet, a substantial 
proportion (31% − 52%) of ischemic stroke patients who arrive within 2− 3 hours of 
symptom onset are not treated with intravenous (IV) alteplase primarily due to mild 
symptoms at the time of the treatment decision (Smith et al. 2011; De Los Rios la Rosa 
et al. 2012).  In a national registry, among 93,517 cases arriving to Emergency 
Departments within 2 hours, 29,200 (31%) were not treated solely due to mild or 
improving symptoms, and 80.1% of untreated cases had a National Institutes of Health 
Stroke Scale (NIHSS) score ≤ 5 (Smith et al. 2011). 
While treatment of mild stroke is generally uncommon, leading stroke centers vary 
widely in their approach. For example, the proportion of mild stroke patients (NIHSS ≤ 3) 
treated with reperfusion therapies at National Institutes of Health/National Institute of 
Neurological Disorders and Stroke (NINDS) Specialized Programs of Translational 
Research in Acute Stroke (SPOTRIAS) centers ranged from 2% − 16% in 2008 − 2009 
(Wiley et al. 2012).  This variability in approach is also evident upon discussion with 
former leaders of the pivotal NINDS trials; some physicians treat all eligible stroke 
patients regardless of severity, and others treat only a minority of patients 
( 
, personal communication).  There is unquestionable community  
equipoise regarding the acute treatment of the mild stroke population. 
1.2 
BACKGROUND ON ALTEPLASE 
1.2.1 
Fibrinolysis and Tissue Plasminogen Activator 
Physiologic dissolution of a thrombus depends primarily on the proteolytic action of 
plasmin formed from plasminogen at the site of a clot.  The mechanism for this activation 
in vivo has not been definitively established. Plasminogen, the zymogen precursor of 
plasmin, may be activated by substances found in the plasma milieu, in tissue (tissue 
plasminogen activator [t-PA]), in urine (urokinase), and in bacteria (streptokinase).  The 
generated plasmin may be inhibited by plasma proteins such as α2-antiplasmin and 
α2-macroglobulin (Robbins 1982). 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
461/aCSR ML29093
29 


 
 
 
 
 
 
 
 
 
 
Kinetic analyses suggest that plasminogen activation in the presence of fibrin 
occurs after the binding of plasminogen and t-PA at the clot site.  t-PA has a high affinity 
for fibrin, thereby efficiently activating the fibrin-bound plasminogen and converting it to 
plasmin. Plasmin, which when bound to fibrin is protected from rapid inactivation by 
α2-antiplasmin, then proceeds to digest the fibrin clot. 
See the Activase® (alteplase) U.S. Package Insert (USPI) for additional details on 
nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Alteplase is the only approved therapeutic agent for the treatment of AIS and is widely 
accepted as the standard of care for eligible patients (Edlow et al. 2013; Jauch et al. 
2013). The currently approved alteplase USPI contains wording that recommends 
against use of alteplase in patients with “minor neurological deficit or with rapidly 
improving stroke symptoms” due to the fact this patient population has not been 
evaluated. Furthermore, the current American Heart Association/American Stroke 
Association Council Guidelines include “minor and rapidly improving stroke symptoms 
(clearing spontaneously)” as a relative exclusion criterion for alteplase (Jauch, et al. 
2013). This is largely due to the aforementioned label wording not recommending 
treatment of patients with minor neurological deficit or with rapidly improving stroke 
symptoms (RISS), the lack of a consistent and consensus definition on who constitutes 
this patient population, and the absence of definitive evidence of alteplase efficacy in this 
setting (Levine et al. 2013).  Therefore, this trial is designed to evaluate the efficacy and 
safety of alteplase in confirmed AIS patients with minor neurological deficit or with RISS, 
which will be referred to collectively as “mild stroke” throughout the protocol. 
To date, all completed major randomized acute stroke trials have excluded patients with 
mild strokes to varying degrees.  In the two NINDS trials, such patients were excluded 
according to the protocol (largely to prevent patients with transient ischemic attacks from 
being enrolled if they were having rapidly improving symptoms), but did not include an 
explicit definition of mild stroke except for pure sensory stroke, isolated ataxia, isolated 
dysarthria, and isolated facial weakness (NINDS rt-PA Study Group 1995).  The 
operational definition for stroke symptoms too mild to treat was left to the judgment of 
the randomizing physician (Levine et al. 2013). Interestingly, a post hoc analysis of the 
624 patients in the NINDS trial revealed that there were 58 patients (9%) enrolled with 
an NIHSS score ≤ 5, none of whom had isolated motor symptoms, isolated facial droop, 
isolated ataxia, dysarthria, isolated sensory, and three or fewer of each of additional 
isolated deficits (Khatri et al. 2010).  Perhaps more significantly, 2971 patients were 
excluded primarily due to “rapidly improving” or “minor symptoms.”  However, a 
significant unmet medical need exists for patients with mild stroke.  Available outcome 
data for patients with mild stroke who do not receive alteplase consistently demonstrate 
a high rate of suboptimal outcomes.  Specifically, in two different prospective databases 
of patients with mild deficits (NIHSS score ≤ 5) and no baseline disability, approximately 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
462/aCSR ML29093
30 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
one-third (29%− 32%) were significantly disabled (as measured by modified Rankin 
Scale [mRS] score 2 − 6) at 90 days (Fischer et al. 2010; Khatri et al. 2012; 
, personal communication).  
Existing, albeit limited, data suggest that the potential benefit-risk ratio for alteplase in 
mild stroke should be favorable.  Gonzales et al. demonstrated better functional 
outcomes among mild strokes treated with IV alteplase compared to those not treated in 
a large, single-center, retrospective cohort; this was shown with two different thresholds 
of stroke severity (NIHSS ≤ 7 and NIHSS ≤ 3) (Gonzales et al. 2006).  Additionally, a 
recent post hoc analysis of the subset of the third International Stroke Trial (IST-3) 
patients with mild strokes (pre-treatment NIHSS ≤ 5 who met all other NINDS rt-PA study 
eligibility criteria) showed a trend toward benefit for alteplase ( 
, personal  
communication). For PRISMS, the primary efficacy outcome assumption (mRS 0 − 1) is 
a 9% absolute treatment effect of alteplase relative to placebo.  This assumption is 
based on several retrospective analyses of similar patient populations (Köhrmann et al. 
2009; Fischer el al. 2010; Hassan et al. 2010b; Khatri et al. 2012) as well as the 
aforementioned IST-3 trial subgroup analysis ( 
, personal communication).  
The most prevalently reported and life-threatening adverse event (AE) associated with 
alteplase treatment for acute ischemic stroke is symptomatic intracranial hemorrhage 
(sICH). Post hoc analyses, case series, and retrospective studies in patients with mild 
stroke suggest an absolute sICH rate of 0−2% with alteplase treatment (NINDS rt-PA 
Study Group 2005; Baumann 2006; Gonzales et al. 2006; Köhrmann et al. 2009; 
Steffenhagen et al. 2009; Hassan et al. 2010a; Hassan et al. 2010b; Huisa et al. 2012).  
These data are consistent with analyses of IV alteplase trials of more severe patients 
suggesting that stroke severity, as measured by the NIHSS score, is a strong predictor 
of sICH risk (Khatri et al. 2007).  No data exist to estimate the sICH rate for patients with 
mild stroke who did not receive t-PA; therefore, for this study, we are using a 0% sICH 
rate for the placebo arm, which is likely a conservative estimate.  An absolute sICH 
difference of 2% at 36 hours (primary safety endpoint) has been assumed for the 
alteplase arm vs. the placebo control arm in the proposed study.  For this study, sICH 
has been defined as any neurologic decline attributed to intracranial hemorrhage (ICH) 
seen on imaging by the local investigator within 36 hours of study drug administration, 
consistent with the NINDS trial definition for sICH (NINDS rt-PA Study Group 1995). 
Assuming the proposed study demonstrates both a 9% absolute treatment effect rate, 
the number of patients needed to treat (NNT) to show benefit (i.e., mRS score of 0 − 1) 
for one patient is 11.  Assuming a 2% absolute difference in sICH rate in patients treated 
with alteplase, the corresponding value for the number needed to harm (NNH), 
specifically for sICH, is conservatively estimated to be 50.  The actual number NNH, or 
the number of patients who would have worse outcomes at 90 days with alteplase 
compared to placebo treatment, is likely to be much higher than is reflected by the sICH 
rate alone, as many patients who experience sICH have severe baseline infarcts and are 
destined for poor outcomes (Saver 2007).   
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
463/aCSR ML29093
31 


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1. 
One dose of alteplase 0.9 mg/kg IV (not to exceed 90 mg) and one dose of oral 
aspirin placebo, OR 
2. 
One dose of IV alteplase placebo and one dose of oral aspirin 325 mg (Figure 1). 
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Every effort should be made to ensure both study drugs are initiated within 3 hours of 
last known well time.  If institutional policies on oral medications make it challenging 
to administer the oral aspirin/aspirin placebo within 3 hours of last known well time, 
the oral study drug may be given up to 24 hours after the last known well time.  IV 
alteplase/IV alteplase placebo MAY NOT be initiated beyond 3 hours of last known well 
time under any circumstances. 
A full schedule of assessments is provided in Appendix 1 . 
Figure 1 Abbreviated Study Schema 
ASA = aspirin; CT= computed tomography; IV = intravenous; MRI = magnetic resonance imaging; 
mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale. 
Due to the emergency nature of randomization in acute stroke clinical trials, treatment 
assignments must be made in an expeditious manner that also ensures even distribution 
in the treatment groups. A “step forward” randomization regimen stratified by site will be 
used to ensure that a randomized treatment assignment is available upon patients’ 
arrival at the hospital and treatment can initiate immediately upon signing informed 
consent and eligibility confirmation.  Further details on step forward randomization can 
be found in Section 4.2, Method of Treatment Assignment and Blinding. 
An independent Data Monitoring Committee (iDMC) will provide ongoing review of 
potential safety concerns and review efficacy and safety outcomes to inform a futility 
interim analysis after 50% of patients have achieved the primary endpoint (following 
completion of the Day 90 visit).  The composition of the iDMC and analysis will be 
documented in detail in a separate iDMC charter. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
466/aCSR ML29093
34 


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Table 2 
NIHSS Exclusion Criteria of Recently Completed and Ongoing 
Acute Ischemic Stroke Trials 
Recently Completed AIS Trials 
Exclusion 
Ongoing AIS Trials 
Exclusion 
Combined Approach to Lysis 
Utilizing Eptifibatide and rt-PA in 
Acute Ischemic Stroke (CLEAR 
Stroke) Trial 
NIHSS ≤ 5 
ARTSS 
NIHSS ≤ 9 
Intravenous Thrombolysis Plus 
Hypothermia for Acute Treatment 
of Ischemic Stroke 
NIHSS ≤ 6 
SHINE 
NIHSS < 3 
Albumin in Acute Ischemic Stroke 
Trial (ALIAS) Part One 
NIHSS ≤ 5 
The Intravascular Cooling in the 
Treatment of Stroke 2/3 (ICTuS 
2/3) Trial (ICTuS2/3) 
NIHSS ≤ 6 
Study of the Combination 
Therapy of rt-PA and 
Eptifibati5.3.3.8de to Treat Acute 
Ischemic Stroke (CLEAR-ER) 
NIHSS ≤ 5 
Safety/Feasibility of Autologous 
Mononuclear Bone Marrow 
Cells in Stroke Patients 
NIHSS ≤ 5 
Albumin in Acute Ischemic Stroke 
Trial (ALIAS) Part Two 
NIHSS ≤ 5 
SWIFT PRIME 
NIHSS ≤ 7 
Mechanical Retrieval and 
Recanalization of Stroke Clots 
Using Embolectomy (MR 
RESCUE) 
NIHSS ≤ 5 
PENUMBRA THERAPY 
NIHSS ≤ 7 
NeuroThera Efficacy and Safety 
Trial-3 (NEST3) 
NIHSS ≤ 6 
PENUMBRA 3D 
NIHSS ≤ 7 
CLOTBUST-ER 
NIHSS ≤ 9 
AIS = acute ischemic stroke; NIHSS = National Institutes of Health Stroke Scale. 
Source: www.clinicaltrials.gov. Accessed August 2013. Note that the NIHSS criteria for the 
trials listed are mentioned in the inclusion criteria, whereas the entries in the above table were 
adapted to list the corresponding exclusion criteria. 
It is notable that the alteplase USPI (2011) distinguishes patients with minor neurological 
deficit from those with RISS.  However, PRISMS combines these two patient groups into 
one operationally defined patient population (mild stroke):  all eligible patients with an 
NIHSS score ≤ 5 at the time of randomization without clearly disabling symptoms, 
irrespective of previous NIHSS scores.  Data demonstrating low alteplase use in patients 
with NIHSS scores ≤ 5 do not distinguish between whether the patient’s deficit was 
persistently mild or improved to this status (Smith et al. 2011).  Furthermore, no data 
exist that suggest patients who improved to a mild status at the time of treatment with 
alteplase have different outcomes from patients whose neurologic deficit is persistently 
mild. To date, available data suggest that alteplase therapy would potentially be 
beneficial in both patients with RISS who improve to an NIHSS score ≤ 5 and patients 
with persistently mild deficits with an NIHSS score ≤ 5. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
469/aCSR ML29093
37 


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3.5.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence of sICH within 36 hours (primary safety assessment) 
sICH is defined as any neurological decline attributed to new ICH seen on 
imaging by the investigator. New ICH seen on imaging will be later confirmed 
on independent reading by blinded central study radiologists. 
• 
Any ICH within 36 hours 
• 
Overall mortality within 90 days 
• 
Stroke-related and neurological deaths within 90 days 
• 
Incidence, severity, and spectrum of all AEs and SAEs 
Symptomatic Intracranial Hemorrhage 
In this study, an ICH is considered symptomatic if it is not seen on computed 
tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and any 
neurologic decline is attributed to it by the local investigator.  To detect intracranial 
hemorrhage, neuroimaging (CT or MRI) scan is required at 22 to 36 hours.  Additional 
neuroimaging should be performed at any time based on the investigator’s discretion 
that clinical findings suggested hemorrhage. Details on MRI types are described in 
Section 4.5.1.6. 
Intracranial hemorrhage events will include classifications of intracerebral hemorrhage 
(hemorrhagic infarct type 1 or type 2, parenchymal hematoma type 1 or type 2, or 
remote intraparenchymal hemorrhage type 1 or type 2).  Descriptions of each type of 
intracerebral hemorrhage are shown in the table below.  Additionally, subarachnoid 
hemorrhage, subdural hemorrhage, or epidural hemorrhage should be noted. 
Table 3 
Intracerebral Hemorrhage Definitions 
Type 
Description 
HI type 1 
HI type 2 
PH type 1 
PH type 2 
rPH type 1 
rPH type 2 
Small petechiae along margin of infarct 
More confluent petechiae within the infarcted area but without space-
occupying effect 
Hematoma in ≤ 30% of the infarcted area with some slight space-occupying 
effect 
Dense hematoma > 30% total of the infarcted area with substantial space-
occupying effect or any hemorrhagic area outside the infarcted area 
Small or medium sized blood clots located remote from the actual infarct; a 
mild space-occupying effect could be present. Remote primary 
intracerebral hemorrhage 
Large confluent dense blood clots in an area remote from the actual infarct; 
substantial space-occupying effect might be present. 
HI = hemorrhagic infarct; PH = parenchymal hematoma; rPH = remote parenchymal hematoma. 
Source: Wahlgren et al. 2007. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
471/aCSR ML29093
39 


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enter drug kit IDs into IWRS and indicate that the kits were not used.  IWRS will then 
assign a new set of drug kit IDs for the pharmacist to label with “Use Next” labels.  The 
pharmacist will properly dispose of the pre-mixed IV drug and the matching 
aspirin/aspirin-placebo kit in accordance with institutional guidelines. 
Prior to the first patient enrolled at a site, a site will register with IWRS as part of site 
activation, which will assign drug kit IDs ahead of time for the first potential patient.  
Once the first patient is enrolled at a site, the procedure described above will commence. 
Study Unblinding 
If a clinical situation arises in which the investigator thinks it is necessary to unblind 
in the interest of patient safety, the Medical Monitor must be notified immediately to 
discuss the intended unblinding. Unblinding should occur only in settings where 
identification of the study treatment is critical for treatment decisions.  IWRS will be 
used for the unblinding process. All unblinded patients will remain in the study and 
require all follow-up visits. 
If the investigator wishes to know the identity of the study drug for any other reason, he 
or she must contact the Medical Monitor.  Treatment codes should not be broken except 
under circumstances deemed necessary by the site investigator.  The investigator 
should document and provide an explanation for any premature unblinding (e.g., 
unblinding due to sICH or severe systemic bleeding that requires blood products if IV 
alteplase was administered, or unblinding due to clinical worsening during the IV 
alteplase time window that would lead to IV alteplase administration if not already 
given). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alteplase 
Alteplase is a single polypeptide containing 527 amino acids; it has three carbohydrate 
side chains and is predominantly one-chain t-PA.  It is a recombinant protein produced in 
a continuous mammalian tissue culture system and is purified by a series of 
chromatographic steps.  The manufacturing process includes fermentation with use of 
the antibiotic gentamicin; however, the presence of the antibiotic is not detectable in the 
final product. 
Alteplase is a sterile, white to pale yellow, lyophilized powder for IV administration after 
reconstitution with sterile water for injection (SWFI), USP, without preservatives.  
Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
475/aCSR ML29093
43 


 
 
 
 
 
 
 
pH adjustment. Biologic potency is determined by an in vitro clot lysis assay 
and is expressed in international units (IU) as tested against the World Health 
Organization (WHO) standard.   
Each 50-mg vial of Activase contains 50 mg of alteplase, 1.7 g of L-arginine, 5 mg of 
polysorbate 80, and 0.5 g of phosphoric acid. 
Each kit will contain 2 vials of 50-mg of alteplase labeled for “clinical trial use only.” 
Vials of 50-mg alteplase must be stored at 2°C−30°C and protected from light. 
4.3.1.2 
Alteplase Placebo 
Alteplase placebo is the same formulation as the active without the alteplase protein. 
Each 50-cc vial contains 1.7 g of L-arginine, 5 mg of polysorbate 80, and 0.5 g of 
phosphoric acid. 
Each kit will contain 2 vials of 50 mg of alteplase placebo labeled for “clinical trial use 
only.” 
Alteplase placebo vials should be stored at 2°C−30°C and protected from light. 
4.3.1.3 
Aspirin 
Aspirin (325 mg) will be packaged for the study.  Each kit will contain one bottle, which 
has 100 tablets labeled for “clinical trial use only.”  Only one tablet will be administered 
to the patient, and the remainder of the bottle will be kept at the site for drug 
accountability.    
Aspirin tablets should be stored at 25°C with excursions permitted between 15°C−30°C. 
4.3.1.4 
Aspirin Placebo 
Aspirin placebo will be identical in appearance to active aspirin to maintain treatment 
blinding. Each bottle of aspirin placebo contains 100 tablets labeled for “clinical trial use 
only.” Only one tablet will be administered to the patient, and the remainder of the bottle 
will be kept at the site for drug accountability. 
Placebo tablets should be stored in the same manner as aspirin tablets:  25°C with 
excursions permitted between 15°C−30°C. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alteplase 
For AIS, the recommended dose is 0.9 mg/kg infused over 60 minutes with 10% of the 
total dose administered as an initial IV bolus over 1 minute.  The total dose should not 
exceed 90 mg. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
476/aCSR ML29093
44 


 
 
 
 
 
 
Because alteplase and alteplase placebo contain no antibacterial preservatives, 50-mg 
vials should be reconstituted immediately before use by adding 50 mL of SWFI, USP, to 
the vial; this yields a concentration of 1 mg/mL.  Using aseptic technique, direct the flow 
of SWFI directly into the lyophilized cake of study drug.  It is recommended that an 
18-gauge needle be used for the reconstitution of the 50-mg vial.  Once reconstituted, 
gently swirl the vial. Do not shake. Slight foaming upon reconstitution is not unusual; 
allowing the vial to stand undisturbed for several minutes is usually sufficient to allow 
dissipation of any large bubbles.  Before further dilution or administration, the product 
should be visually inspected for particulate matter and discoloration.  If a precipitate is 
seen, the product should not be used. 
After reconstitution, alteplase should be administered at 1 mg/mL.  As an alternative, 
the reconstituted solution may be diluted further immediately before administration in 
an equal volume of 0.9% sodium chloride injection, USP, or 5% dextrose injection, 
USP, to yield a concentration of 0.5 mg/mL. The osmolality of this solution is 
approximately 215 mOsm/kg.  Polyvinyl chloride bags, glass bottles, or polypropylene 
syringes are acceptable.  Do not use filter needles for infusion.  Alteplase is stable for up 
to 8 hours in these solutions at room temperature.  Exposure to light has no effect on the 
stability of these solutions.  Excessive agitation during dilution should be avoided; mixing 
should be accomplished with gentle swirling and/or slow inversion.   
No other medication should be added to infusion solutions containing alteplase.  Any 
unused infusion solution should be discarded. 
See Appendix 2 (Alteplase Administration) and Appendix 3 (Reconstitution of 
50-mg Vials) for further details. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study will be 
provided by the Sponsor where required by local health authority regulations.  The 
investigational site will acknowledge receipt of IMPs using the IWRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received, dispensed, returned, and disposed of by the study 
site should be recorded on the Drug Inventory Log. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
477/aCSR ML29093
45 


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Additional CT scans or MRIs should be performed based on the investigator’s discretion, 
or if any clinical findings suggest ICH (such as new headache, nausea, vomiting, 
significant deterioration of neurological status, or rapid increase of blood pressure).  If an 
ICH is identified, the NIHSS score should be reassessed at the time and recorded on the 
Adverse Event eCRF. 
CT scans or MRIs performed at baseline, between 22 to 36 hours, and additional 
imaging performed due to clinical suspicion of deterioration up until 36 hours after study 
drug administration, will be evaluated by a central team of radiologists blinded to the 
clinical attributes of the case.  These images will need to be sent to the central 
radiologists by the local site. 
4.5.2 
Patient-Reported Outcomes 
Patient-reported outcomes (PRO) data will be elicited from the patients in this study to 
more fully characterize the clinical profile of alteplase in this patient population.  The 
PRO questionnaires will be distributed by the investigator staff and completed in their 
entirety by the patient or their surrogate.    
This study will assess the impact of alteplase treatment on health-related quality of life, 
physical function, daily functioning, and symptoms of depression.  
Health-related quality of life will be assessed using the EQ-5D (Appendix 4). The EQ-5D 
is a generic, preference-based health utility measure with questions about mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression that are used to build 
a composite of the patient’s health status.   
Physical functioning will be evaluated using the SIS-16 (Appendix 5), which is a 
validated, stroke-specific, quality of life measure to assess the impact of stroke on a 
patient’s health and life. 
The CES-D (Appendix 6) will be used to evaluate the proportion of patients with 
depressive symptoms (defined as a score of ≥ 16 at 90 days). 
The EQ-5D, SIS-16, and CES-D will be provided in Spanish for those patients 
requiring translations. 
AE reports will not be derived from PRO data by the Sponsor.  However, any PRO 
responses suggestive of a possible AE identified during site review of the PRO data 
should be reported as outlined in Section 5.3.3.11. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
481/aCSR ML29093
49 


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investigator blinded to the results).  AEs1 and concomitant medications will also be 
assessed at this visit. 
4.6.3 
Visit 3 (Day 5 or Discharge from Hospital, if Sooner than Day 5) 
On Day 5 (or discharge from hospital, if sooner than Day 5), NIHSS score, stroke 
etiology, AEs, and concomitant medications will be collected.  Discharge location will be 
collected at the time of hospital discharge. 
4.6.4 
Visit 4 (Day 30 [30± 7 Days]) 
A phone call to the patient or caregiver will be made at Day 30 and an mRS will be 
assessed (see Appendix 8). AEs, concomitant medications, and patient survival will be 
assessed during this phone visit. Pregnancy will also be assessed for female patients of 
childbearing potential. 
4.6.5 
Visit 5 (Day 90 [± 14 Days]/Study Completion) 
Primary and secondary efficacy endpoints, as well as all exploratory endpoints, will be 
assessed at Day 90 with the patient.  The following assessments will be performed: 
• 
NIHSS score (Appendix 7) 
• 
Patient survival 
• 
mRS (Appendix 8) 
• 
GOS (Appendix 9) 
• 
BI (Appendix 10) 
• 
EQ-5D (Appendix 4) 
• 
SIS-16 (Appendix 5) 
• 
CES-D (Appendix 6) 
• 
Cognitive assessments (Appendix 11) 
– 
Controlled Oral Word Association test  
– 
HVLT-R trials 1, 2, and 3 
– 
Digit symbol coding from the WAIS III 
– 
Forward and Backward Digit Span test 
– 
Benton Judgment of Line Orientation test, form V 
– 
HVLT-R trial 4 and recognition 
– 
Animal Naming test 
1 AE/SAE collection should be started as soon as study drug administration (bolus) is initiated. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
483/aCSR ML29093
51 


– 
BNT 15-item short form 
The above cognitive assessments will be provided in Spanish for those 
patients requiring translations with the exception of the BNT 15-item 
short form. 
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SAEs and certain AEs (See Section 5.3.1) 
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administration of study drug. 
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After 30 days until 90 days after administration of study drug, the following AEs should 
be record on the AE CRF: 
• 
All SAEs 
• 
Non-serious ICHs 
• 
Non-serious AESIs 
• 
All AEs that resulted in withdrawal from the study 
All SAEs and non-serious AESIs require immediate reporting to the Sponsor (see 
Section 5.4). 
After 90 days, the investigator is not required to actively monitor patients for AEs; 
however, the Sponsor should be notified if the investigator becomes aware of any 
post-study SAEs (see Section 5.6). 
5.3.2 
Assessment of Severity of Adverse Events 
The WHO toxicity grading scale (see Appendix 14) will be used for assessing adverse 
event severity. Table 4 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale. 
Table 4 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
2 
3 
4 
Mild; transient or mild discomfort (< 48 hours); no medical intervention or 
therapy required 
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required 
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible 
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable 
Notes: Developed by the Division of Microbiology and Infectious Diseases.  
Regardless of severity, some events may also meet seriousness criteria. Refer to definition of a  
serious adverse event (see Section 5.2.2).  
5.3.3 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration 
(see also Table 5): 
• 
Temporal relationship of event onset to the initiation of study drug 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
489/aCSR ML29093
57 


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5.3.3.6 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (Section 5.3.1) 
regardless of relationship to study drug, must be recorded on the Adverse Event eCRF 
and immediately reported to the Sponsor (see Section 5.2.2). This includes death 
attributed to progression of AIS. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. The term "sudden death" should only be used for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death. 
If the death is attributed to progression of AIS, "acute ischemic stroke progression" 
should be recorded on the Adverse Event eCRF. 
5.3.3.7 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., more 
frequent headaches"). 
5.3.3.8 
Lack of Efficacy or Worsening of Acute Ischemic Stroke 
Medical occurrences or symptoms of deterioration that are considered part of the disease 
course or disease process should be recorded as an AE if judged by the investigator to 
have unexpectedly worsened in severity or frequency or unexpectedly changed in nature 
at any time during the study.  If there is uncertainty, it should be reported as an 
AE.  When recording unexpected worsening of AIS on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
descriptors of the event. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
493/aCSR ML29093
61 


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5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant within 30 (± 7) days after the last dose of study drug.  
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and submitted via the EDC system.  
A pregnancy report will automatically be generated and sent to Safety Risk Management.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus. Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
SAEs associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF. 
In the event that the EDC system is unavailable, a Clinical Trial Pregnancy Reporting 
Form and fax cover sheet should be completed and faxed to Safety Risk Management or 
its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
using the fax numbers provided in Section 5.4.2. Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
5.4.3.2 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as an SAE, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). Any spontaneous abortion should be reported in the same 
fashion (as the Sponsor considers spontaneous abortions to be medically significant 
events). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better and is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent. Every effort should be made to follow all SAEs considered to 
be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
496/aCSR ML29093
64 


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6. 
STATISTICAL METHODS 
This study will test whether treatment of patients with mild stroke with IV alteplase will 
lead to a higher proportion (9% absolute difference) of patients with a favorable outcome 
(mRS of 0 or 1) at 90 days. 
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of 856 is required in order to achieve 80% power in the primary analysis 
to detect an effect size of 9% absolute difference in the proportion of patients with 
favorable outcomes between the alteplase and control arms.  The above sample size 
calculation assumes a control proportion of 65% and Type I error probability of 0.025 
(one-sided), and uses a group sequential design with one interim analysis for futility 
(non-binding), based on an O’Brien-Fleming boundary, after 50% of the anticipated 
was used for 
sample size have completed the 90-day follow-up assessments. 
this sample size calculation. 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard 
against dilution of the treatment effect associated with an approximate 5% 
non-adherence rate (due to lost to follow-up, consent withdrawal, treatment crossovers, 
and stroke mimics), the above sample size needs to be inflated by a factor of 1/0.952 or 
1.108 (Friedman et al. 1998).  Therefore, a total sample size of 948 is required for this 
study. 
6.2 
PRIMARY ANALYSIS 
The primary efficacy analysis will test the hypothesis of superiority of IV alteplase 
therapy over standard medical care in AIS patients with mild deficits. The primary 
efficacy outcome is the proportion of patients with a favorable outcome, defined by 
mRS score of 0 or 1 at 90 days post-randomization.  The difference in the proportion of 
mRS 0−1 responders (favorable outcome) at 90 days post-randomization between the 
IV alteplase arm and the standard medical care arm will be compared via a 
Cochran-Mantel-Haenszel test, stratified by pre-treatment NIHSS score (0 − 2 vs. 3 − 5), 
age (< 65 vs. ≥ 65), and last known well time to treatment (0 − 2 hours vs. > 2 − 3 hours). 
The primary efficacy analysis will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization adhering to the ITT principle. As a 
sensitivity analysis, results from the univariate Pearson’s chi-square test will also be 
presented. 
As a supportive, secondary analysis, an ordinal (or “shift”) analysis of the distribution of 
the mRS will be analyzed via proportional odds model if the proportionality assumption 
holds, and by the Mann-Whitney superiority measure if the proportionality assumption 
does not hold.  The proportionality assumption will be assessed using the score test as 
well as clinical judgment on the similarities of the different odds ratios.  As a secondary 
efficacy outcome, the global outcome score at 90 days will be analyzed using the global 
odds ratio test based on the generalized estimating equations analysis (Wald-type χ2 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
498/aCSR ML29093
66 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
test) with unstructured covariance-correlation matrix. These results will be treated as 
supportive evidence (or lack thereof) of the treatment effect rather than conclusive 
evidence. The significance of each test is determined at the two-sided alpha level of 
0.05. The specific statistical model for analyzing each of these outcome measures will 
be detailed in the Statistical Analysis Plan (SAP). 
6.3 
SAFETY ANALYSIS 
Incidence and severity of AEs will be described for all treated patients by treatment 
group as received and by the Medical Dictionary for Regulatory Activities (MedDRA) 
classification. 
Safety outcomes include incidence of sICH within 36 hours (primary safety assessment), 
any ICH within 36 hours, overall mortality, and stroke-related and neurological deaths 
within 90 days of study drug initiation.  The cumulative incidences of each outcome will 
be compared via Fisher’s exact test.  Mortality will be analyzed by Log-Rank test and the 
Kaplan-Meier estimates will be plotted over the observation period of 90 days.  No alpha 
adjustment for multiple testing on the safety endpoints is foreseen because those 
analyses will be exploratory. 
6.4 
EXPLORATORY ANALYSES 
As exploratory analyses, heterogeneity of treatment effect of alteplase will be evaluated 
by various pre-specified baseline covariates.  The primary pre-specified variables and 
their analytic thresholds are defined by: 
• 
Age (< 65 vs. ≥ 65) 
• 
Pre-treatment NIHSS score (0 − 2 vs. 3 − 5) 
• 
Last known well time to treatment (0 − 2 vs. > 2 − 3 hours) 
• 
Stroke subgroup (RISS vs. non-RISS) 
Additional heterogeneity analyses will be considered and detailed in the SAP.  Forest 
plots will be constructed to illustrate subgroup analyses.  In addition, the two-way 
interactions of IV alteplase treatment effect with age, NIHSS score, and stroke 
subgroups (RISS vs. non-RISS) on the primary outcome will be explored through 
multivariable logistic regression.  Additional exploratory analyses will be conducted to 
explore treatment effects on quality of life endpoints and other exploratory endpoints. 
6.5 
INTERIM ANALYSIS 
One interim analysis of the primary efficacy outcome is planned for clear futility, 
conducted according to the beta-spending approach (Pampallona et al. 2001) with an 
O’Brien-Fleming-type boundary.  This futility analysis will occur after approximately 50% 
of patients (or 474) have completed the 90-day assessment. 
An independent Data Coordinating Center (iDCC) will be responsible for the preparation 
and review of unmasked data. 
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An iDMC will be organized for review of the interim analysis results.  The composition of 
the iDMC and analysis in detail will be documented in a separate iDMC charter. 
6.6 
MISSING DATA HANDLING 
Under the ITT principle, all patients who are randomized will be included in the analysis.  
The multiple-imputation method will be used for handling missing data, including the last 
observation (e.g., the Day 30 mRS) among the variables used in imputation.  As 
supportive analyses, missing primary outcome data will be imputed by 1) using last 
observation carried forward and 2) assuming missing outcomes to be unfavorable. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC using 
eCRFs. Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data with the input from the Sponsor.  For this study, local laboratories 
will be used and data will be captured in the EDC system and will then be transferred to 
the Sponsor. This will include the eCRF data using the Sponsor’s standard procedures 
and processes to transfer data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
The EDC vendor has back-ups for data stored, and records retention for the study data 
will be consistent with the CRO’s standard procedures.  
Data from paper PRO questionnaires will be entered into the EDC system by site staff.   
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have eCRF completion guidelines for the eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
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All eCRFs should be completed by designated trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (e.g., source data) entered into the eCRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents.  Source documents 
(paper or electronic) are those in which patient data are recorded and documented for 
the first time.  They include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Study Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the International Conference on 
Harmonisation E6 guideline for Good Clinical Practice and the principles of the 
Declaration of Helsinki, or the laws and regulations of the country in which the research 
is conducted, whichever affords the greater protection to the individual.  The study will 
comply with the requirements of the International Conference on Harmonisation E2A 
guideline (Clinical Safety Data Management:  Definitions and Standards for Expedited 
Reporting). Studies conducted in the United States or under a U.S. Investigational New 
Drug (IND) application will comply with FDA regulations and applicable local, state, and 
federal laws. Studies conducted in the European Union (EU)/European Economic Area 
(EEA) will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
502/aCSR ML29093
70 


 
 
  
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the U.S., each Consent Form may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (Section 9.5). 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC. 
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient ID number. This means that patient 
names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
503/aCSR ML29093
71 


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9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
506/aCSR ML29093
74 


 
 
 
 
 
10. 
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receiving thrombolysis due to mild deficits or rapidly improving symptoms. Int J Stroke 
2012;7(3):202−06. 
Alteplase—Genentech, Inc. 
Protocol ML2 9093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
509/aCSR ML29093
77 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1  
Schedule of Assessments  
ASSESSMENTS 
Screening and 
Baseline 
(Visit 1) 
Study Drug 
Administration 
22−36 Hours 
from Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 (± 14) 
Days/Study 
Completion 
(Visit 5) 
Early Discontinuation 
(Phone call, if possible) 
Informed consent 
X 
Review of eligibility 
X 
Medical history and 
baseline conditions a 
X 
Demographics 
X 
Neurological examination b 
X 
Vital signs c 
X 
Complete blood count d 
X 
Coagulation status e 
X 
Pregnancy test f 
X 
Serum blood glucose g 
X 
Imaging modality sensitive 
to presence of intracranial 
hemorrhage (either CT or 
MRI with DW MRI, either 
SW or GRE, and FLAIR 
images). Visit 2 MRIs 
should also include T1 and 
T2 sequences h 
X 
X 
NIHSS score i 
X 
X 
X 
X 
Study drug administration 
X 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
510/aCSR ML29093
78 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1 (cont.)  
Schedule of Assessments  
ASSESSMENTS 
Screening and 
Baseline 
(Visit 1) 
Study Drug 
Administration 
22−36 Hours 
from Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 (± 14) 
Days/Study 
Completion 
(Visit 5) 
Early Discontinuation 
(Phone call, if possible) 
Discharge location 
X 
X 
Patient survival 
X 
X 
X 
mRS j 
X
 X
 
GOS
 
X
 
BI k 
X 
EQ-5D k 
X 
CES-D k 
X 
SIS-16 k 
X 
Cognitive assessments l 
X 
Walking speed m 
X 
Concomitant medications n 
X 
X 
X 
X 
X 
X 
Assessment of pregnancy 
X 
Adverse event o 
X 
X 
X 
X 
X 
X 
BI = Barthel Index; BNT = Boston Naming Test; CES-D = Centers for Epidemiologic Studies, Depression; CT = computed tomography; DW 
MRI = diffusion-weighted MRI; European Quality of Life = EQ-5D; FLAIR = fluid-attenuated inversion recovery; GOS = Glasgow Outcome Scale; 
GRE = gradient echo; HVLT-R = Hopkins Verbal Learning Test-Revised; ICH = intracranial hemorrhage; INR = international normalized ratio; 
MRI = magnetic resonance imaging; mRS modified Rankin Scale; NIHSS = NIH Stroke Scale; Stroke Impact Scale-16 = SIS-16; 
SW MRI= susceptibility-weighted MRI; WAIS III = Wechsler Adult Intelligence Scale III. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
511/aCSR ML29093
79 


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anticoagulant HJGDELJDWUDQULYDUR[DEDQDSL[DEDQHGR[DEDQ), or patient or family report of patient currently taking a low-molecular-
weight heparin (e.g., dalteparin, enoxaparin) within the last 48 hours. 
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J 6HUXPJOXFRVHYDOXHVRIPJG/DUHFRQWUDLQGLFDWHGIRUDOWHSODVH
K 05,RU&7VFDQVKRXOGEHSHUIRUPHGLIDQ\FOLQLFDOILQGLQJVVXJJHVW,&+
L 1,+66VFRUHVKRXOGEHDVVHVVHGDQGUHFRUGHGDWWKHWLPHRIDQ\FOLQLFDOILQGLQJVWKDWVXJJHVW,&+
M 7KHP56PD\EHSHUIRUPHGE\WHOHSKRQHLIQHFHVVDU\IRUYLVLWVRQ'D\VDQG
N 7KH%,&(6'(4'DQG6,6FDQEHDGPLQLVWHUHGE\SKRQHLQWHUYLHZLIDQLQSHUVRQSDWLHQWYLVLWFDQQRWEHVFKHGXOHGLQWKHDOORWWHGWLPH
O Assessments include: Controlled Oral Word Association test; HVLT-R trials 1, 2, and 3; digit symbol coding from the WAIS III; Forward and 
Backward Digit Span test; Benton Judgment of Line Orientation, form V; HVLT-R trial 4 and recognition; semantic fluency (Animal Naming 
test); and BNT (15-item short form). 
P $VVHVVPHQWRIZDONLQJVSHHGUHTXLUHVDQLQSHUVRQSDWLHQWYLVLWDQGLVEHVWFRPELQHGZLWKDGPLQLVWUDWLRQRIWKH%,&(6'(4'DQG6,6
Q &RQFRPLWDQWPHGLFDWLRQVLQFOXGHDQ\SUHVFULSWLRQPHGLFDWLRQVRURYHUWKHFRXQWHUSUHSDUDWLRQVXVHGE\WKHSDWLHQWZLWKLQGD\VSULRUWR
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DQG(PD\EHGRQHYLDWHOHSKRQHLQWHUYLHZLIQHFHVVDU\), DQGat HDUO\GLVFRQWLQXDWLRQ Refer to Section 5.3.1 (Adverse Event Reporting 
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Appendix 3  
Reconstitution of 50-mg Vials  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
514/aCSR ML29093
82 


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Appendix 4 (cont.)  
European Quality of Life-5D (EQ-5D) Questionnaire  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
516/aCSR ML29093
84 


 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 5  
Stroke Index Scale (SIS-16)  
In the past 2 weeks, how 
difficult was it to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Could not 
do at all 
a. Dress the top part of your 
body? 
5 
4 
3 
2 
1 
b. Bathe yourself? 
5 
4 
3 
2 
1 
c. Get to the toilet on time? 
5 
4 
3 
2 
1 
d. Control your bladder (not 
have an accident)? 
5 
4 
3 
2 
1 
e. Control your bowels (not 
have an accident)? 
5 
4 
3 
2 
1 
f. Stand without losing 
balance? 
5 
4 
3 
2 
1 
g. Go shopping? 
5 
4 
3 
2 
1 
h. Do heavy household chores 
(e.g., vacuum, laundry or yard 
work)? 
5 
4 
3 
2 
1 
i. Stay sitting without losing 
your balance? 
5 
4 
3 
2 
1 
j. Walk without losing your 
balance? 
5 
4 
3 
2 
1 
k. Move from a bed to a chair? 
5 
4 
3 
2 
1 
l. Walk fast? 
5 
4 
3 
2 
1 
m. Climb one flight of stairs? 
5 
4 
3 
2 
1 
n. Walk one block? 
5 
4 
3 
2 
1 
o. Get in and out of a car? 
5 
4 
3 
2 
1 
p. Carry heavy objects (e.g. 
bag of groceries) with your 
affected hand? 
5 
4 
3 
2 
1 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
517/aCSR ML29093
85 


 
 
 
 
Appendix 6 
Center for Epidemiologic Studies, Depression (CES-D) Scale,
NIMH 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
518/aCSR ML29093
86 


 
 
 
 
 
 
Appendix 7  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
519/aCSR ML29093
87 


 
 
 
 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
520/aCSR ML29093
88 


 
 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
521/aCSR ML29093
89 




 
 
 
 
 
 
Appendix 8  
Modified Rankin Scale (mRS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
523/aCSR ML29093
91 


 
 
 
 
 
 
 
Appendix 9  
Glasgow Outcome Scale (GOS)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
524/aCSR ML29093
92 


 
 
 
 
 
 
Appendix 10  
Barthel Index (BI)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
525/aCSR ML29093
93 


 
 
 
Appendix 10 (cont.)  
Barthel Index (BI)  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
526/aCSR ML29093
94 






 
 
 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
529/aCSR ML29093
97 










 
 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
534/aCSR ML29093
102 




 
 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
536/aCSR ML29093
104 


 
 
 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
537/aCSR ML29093
105 


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Appendix 13  
Preferred Terms for Intracranial Hemorrhage  
An intracranial hemorrhage (ICH) is considered symptomatic if it is not seen on 
computed tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and 
any neurologic decline is attributed to it by the local investigator.  Below is the list of 
preferred terms (PTs) using the MedDRA term to describe the ICH event: 
• 
Basal ganglia hemorrhage 
• 
Brain stem hematoma 
• 
Brain stem hemorrhage 
• 
Brain stem microhemorrhage 
• 
Cerebellar hematoma 
• 
Cerebellar hemorrhage 
• 
Cerebellar microhemorrhage 
• 
Cerebral arteriovenous malformation hemorrhagic 
• 
Cerebral hematoma 
• 
Cerebral hemorrhage 
• 
Cerebral microhemorrhage 
• 
Epidural hemorrhage 
• 
Extradural hematoma 
• 
Hemorrhage intracranial 
• 
Hemorrhagic cerebral infarction 
• 
Hemorrhagic stroke 
• 
Hemorrhagic transformation stroke 
• 
Intracranial hematoma 
• 
Intraventricular hemorrhage 
• 
Meningorrhagia 
• 
Pituitary hemorrhage 
• 
Putamen hemorrhage 
• 
Subarachnoid hemorrhage 
• 
Subdural hematoma 
• 
Subdural hemorrhage 
• 
Thalamus hemorrhage 
• 
Traumatic intracranial hemorrhage 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
541/aCSR ML29093
109 


 
 
 
 
 
 
 
 
 
 
Appendix 14  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
542/aCSR ML29093
110 


 
 
 
 
 
 
Appendix 14 (cont.)  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
111 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
543/aCSR ML29093


 
 
 
 
 
 
Appendix 14 (cont.)  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
112 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
544/aCSR ML29093


 
 
 
 
 
 
 
 
 
Appendix 14 (cont.)  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
113 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
545/aCSR ML29093


 
Title
08-Jan-2015 22:46:09
Date and Time (UTC)
Approver's Name
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, M.D. 
, M.D. 
PROTOCOL 
TITLE: 
A PHASE IIIb, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ALTEPLASE IN PATIENTS WITH 
MILD STROKE: RAPIDLY IMPROVING 
SYMPTOMS AND MINOR NEUROLOGIC 
DEFICITS (PRISMS) 
PROTOCOL NUMBER: 
ML29093 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
3811 
TEST PRODUCT: 
Alteplase (RO5532960) 
LEAD PRINCIPAL 
INVESTIGATOR: 
MEDICAL MONITOR: 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1: 27 November 2013 
DATE AMENDED: 
Version 2: 22 August 2014 
Version 3: See electronic date stamp below 
PROTOCOL APPROVAL 
CONFIDENTIAL STATEMENT 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board. It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
546/aCSR ML29093


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eCRF. The initial severity (intensity or grade) of the event should be recorded at the 
time the event is first reported.  If a persistent AE becomes more severe, and the most 
extreme severity should also be updated to reflect the most extreme severity any time 
the event worsens. If the event becomes serious,recorded on the Adverse Event eCRF 
should be updated to reflect this. If the event becomes serious, it should be reported to 
the Sponsor immediately (i.e., no more than 24 hours after learning that the event 
became serious; see Section 5.4.1 for reporting instructions).  The Adverse Event eCRF 
should be updated by changing the event from "non-serious" to "serious," providing 
the date that the event became serious, and completing all data fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs. Each recurrence of an AE should be recorded as a separately 
event on the Adverse Event eCRF. 
SECTION 5.3.3.4: Abnormal Laboratory Values 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not only be repeatedly recorded once on the Adverse Event eCRF unless the 
etiology changes. The initial severity of the event should be recorded, and the severity 
or seriousness should be updated any time the event worsens(see Section 5.3.3.3 for 
details on recording persistent AEs). 
SECTION 5.3.3.5: Abnormal Vital Sign Values 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not only be repeatedly recorded once on the Adverse Event eCRF unless the 
etiology changes.  The initial severity of the event should be recorded, and the severity 
or seriousness should be updated any time the event worsens(see Section 5.3.3.3 for 
details on recording persistent AEs). 
SECTION 5.3.3.10: Adverse Events Associated with an Overdose or Error 
in Drug Administration 
…If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.1). 
SECTION 5.4: IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
…The following is a list of events that the investigator must report to the Sponsor within 
24 hours after learning of the event, regardless of relationship to study drug: 
• 
SAEs (see Section 5.4.2 for further details) 
• 
Non-serious AESIs (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
Alteplase—Genentech, Inc. 
4/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
549/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION 5.4.2: Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
After initiation of study drug, SAEs and non-serious AESIs will be reported until 90 
days after the last dose of study drug.  For reports of SAEs and non serious AESIs, 
iInvestigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to the 
Sponsor’s Safety Risk Management department by the EDC system. 
In the event that the EDC system is unavailable, a paperthe Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form and fax cover sheet provided 
to investigators should be completed and faxed submitted to Safety Risk 
Managementthe Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax numbers or email address provided belowto investigators (and below). Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system. 
Sites: 
Fax No.:          (650) 225-4682 
Alternate Fax No.: (650) 225-5288 
Instructions for reporting post-study AEs are provided in Section 5.6. 
SECTION 5.4.3.1: Pregnancies in Female Patients 
In the event that the EDC system is unavailable, a the Clinical Trial Pregnancy Reporting 
Form and fax cover sheetprovided to investigators should be completed and 
submittedfaxed to Safety Risk Managementthe Sponsor or its designee immediately (i.e., 
no more than 24 hours after learning of the pregnancy), either by faxing or scanning 
and emailing the form using the fax number or email addresss provided in 
Section 5.4.1to investigators. Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
SECTION 5.5.1: Investigator Follow-Up 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
SECTION 5.6: POST-STUDY ADVERSE EVENTS 
The investigator is not required to actively monitor patients for AEs after the end of the 
AE reporting period (defined as 90 days after administration of study drug for SAEs and 
non-serious AESIs, and 30 days for non-serious AEs). However, the Sponsor should be 
notified if the investigator becomes aware of any SAE, death, development of cancer, or 
Alteplase—Genentech, Inc. 
5/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
550/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
a congenital anomaly/birth defect in a subsequently conceived offspring of a female 
patient exposed to study drug within 90 days after administration of study drug. 
The investigator should report these events directly to Safety Risk Managementthe 
Sponsor via telephone at 1-888-835-2555. 
SECTION 8.2: INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Caregiver's Home Nursing Informed 
Consent Form, if applicable) will be provided to each site. … 
SECTION 9.5: PUBLICATION OF DATA AND PRTOECTION OF TRADE 
SECRETS 
This section was added per protocol template standards. 
APPENDIX 1: Schedule of Assessments 
The Schedule of Assessments has been revised to reflect updates to protocol template 
language. 
Alteplase—Genentech, Inc. 
6/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
551/aCSR ML29093


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIIb, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ALTEPLASE IN PATIENTS WITH MILD 
STROKE: RAPIDLY IMPROVING SYMPTOMS AND 
MINOR NEUROLOGIC DEFICITS (PRISMS) 
PROTOCOL NUMBER: ML29093 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
3811 
TEST PRODUCT: 
Alteplase (RO5532960) 
LEAD PRINCIPAL 
INVESTIGATOR: 
MEDICAL MONITOR: 
SPONSOR: 
Genentech, Inc. 
I agree to conduct the study in accordance with the current protocol. 
, M.D. 
, M.D. 
Principal Investigator’s Name (print) 
Principal Investigator’s Signature 
Date 
Please return a copy of this form as instructed by your local study monitor and retain a 
copy for your study files. 
Alteplase—Genentech, Inc. 
13/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
558/aCSR ML29093


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randomization adhering to the intent-to-treat (ITT) principle. As a sensitivity analysis, results 
from the univariate Pearson’s chi-square test will also be presented. 
Determination of Sample Size 
A sample size of 856 is required in order to achieve 80% power for the primary analysis to 
detect an effect size of 9% absolute difference in the proportion of patients with favorable 
outcomes between the alteplase and control arms. The above sample size calculation assumes 
a control proportion of 65% and Type I error probability of 0.025 (one-sided), and uses a group 
sequential design with one interim analysis for futility (non-binding), based on an O’Brien-
Fleming boundary, after 50% of the anticipated sample size have completed the 90-day 
follow-up assessments. 
was used in sample size calculation. 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard against 
dilution of the treatment effect associated with an approximate 5% non-adherence rate (due to 
lost to follow-up, consent withdrawal, treatment crossovers, and stroke mimics), the above 
sample needs to be inflated by a factor of 1/0.952 or 1.108 (Friedman et al. 1998). Therefore, a 
total sample size of 948 is required for this study. 
Interim Analysis 
One interim analysis of the primary efficacy outcome is planned for clear futility, conducted 
according to the beta-spending approach (Pampallona et al. 2001) with an 
O’Brien-Fleming-type boundary. This futility analysis will occur after approximately 50% of 
patients (or 474) have completed the 90-day assessment. 
Alteplase—Genentech, Inc. 
18/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
563/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
AESI 
AIS 
aPTT 
BI 
BNT 
CES-D 
CRO 
CT 
DW 
EC 
eCRF 
EDC 
EEA 
EQ-5D 
EU 
FDA 
FLAIR 
GOS 
GRE 
HIPAA 
HVLT-R 
ICH 
ID 
iDCC 
iDMC 
IMP 
IND 
INR 
IRB 
IST-3 
ITT 
IU 
IV 
IWRS 
adverse event 
adverse event of special interest 
acute ischemic stroke 
activated partial thromboplastin time 
Barthel Index 
Boston Naming Test 
Center for Epidemiologic Studies, Depression 
contract research organization 
computed tomography 
diffusion-weighted 
Ethics Committee 
electronic Case Report Form 
electronic data capture 
European Economic Area 
European Quality of Life questionnaire 
European Union 
U.S. Food and Drug Administration 
fluid-attenuated inversion recovery 
Glasgow Outcome Scale 
gradient echo 
Health Insurance Portability and Accountability Act 
Hopkins Verbal Learning Test-Revised 
intracranial hemorrhage 
identification 
independent Data Coordinating Center 
independent Data Monitoring Committee 
investigational medicinal product 
Investigational New Drug (application) 
international normalized ratio 
Institutional Review Board 
third International Stroke Trial 
intent-to-treat 
international units 
intravenous 
Interactive Web Response System 
Alteplase—Genentech, Inc. 
19/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
564/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation 
Definition 
LHH 
LPLV 
MCA 
MedDRA 
MRI 
mRS 
NIHSS 
NINDS 
NNH 
NNT 
PRO 
RISS 
rPH 
SAE 
SAP 
sICH 
SIS-16 
STIAMP 
SWFI 
SW 
t-PA 
U.S. 
USPI 
WAIS III 
WHO 
likelihood of being helped vs. harmed 
last patient’s last visit 
middle cerebral artery 
Medical Dictionary for Regulatory Activities 
magnetic resonance imaging 
modified Rankin Scale 
National Institutes of Health Stroke Scale 
National Institute of Neurological Disorders and Stroke 
number needed to harm 
number needed to treat 
patient-reported outcome 
rapidly improving stroke symptoms 
remote parenchymal hematoma 
serious adverse event 
Statistical Analysis Plan 
symptomatic intracranial hemorrhage 
Stroke Impact Scale-16 
Suspected Transmission of an Infectious Agent via a 
Medicinal Product 
sterile water for injection 
susceptibility-weighted 
tissue plasminogen activator 
United States 
U.S. Package Insert 
Wechsler Adult Intelligence Scale III 
World Health Organization 
Alteplase—Genentech, Inc. 
20/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
565/aCSR ML29093


 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
BACKGROUND 
1.1 
BACKGROUND ON ACUTE ISCHEMIC STROKE 
Stroke is the fourth leading cause of death and a leading cause of disability in the United 
States (U.S.). Nearly 800,000 strokes occur in the U.S. annually; of these, 
approximately 85% are ischemic in nature (Rosamond et al. 2007). Treatment options 
are limited, as the only approved therapy for acute ischemic stroke (AIS) is alteplase, 
which is to be used in eligible patients and started within 3 hours from the onset of stroke 
symptoms.  Stroke with “only minor or rapidly improving stroke symptoms” is considered 
a relative exclusion by national clinical guidelines, as these patients were largely 
excluded from definitive trials to date (Jauch et al. 2013). Consistent with this 
recommendation, only 15% of alteplase recipients have mild strokes (Smith et al. 2011). 
More than half of all ischemic stroke patients have mild strokes at initial presentation in 
population-based studies (Dhamoon et al. 2009; Reeves et al. 2013). Yet, a substantial 
proportion (31% − 52%) of ischemic stroke patients who arrive within 2− 3 hours of 
symptom onset are not treated with intravenous (IV) alteplase primarily due to mild 
symptoms at the time of the treatment decision (Smith et al. 2011; De Los Rios la Rosa 
et al. 2012).  In a national registry, among 93,517 cases arriving to Emergency 
Departments within 2 hours, 29,200 (31%) were not treated solely due to mild or 
improving symptoms, and 80.1% of untreated cases had a National Institutes of Health 
Stroke Scale (NIHSS) score ≤ 5 (Smith et al. 2011). 
While treatment of mild stroke is generally uncommon, leading stroke centers vary 
widely in their approach. For example, the proportion of mild stroke patients (NIHSS ≤ 3) 
treated with reperfusion therapies at National Institutes of Health/National Institute of 
Neurological Disorders and Stroke (NINDS) Specialized Programs of Translational 
Research in Acute Stroke (SPOTRIAS) centers ranged from 2% − 16% in 2008 − 2009 
(Willey et al. 2012). This variability in approach is also evident upon discussion with 
former leaders of the pivotal NINDS trials; some physicians treat all eligible stroke 
patients regardless of severity, and others treat only a minority of patients 
(
 personal communication).  There is unquestionable community 
equipoise regarding the acute treatment of the mild stroke population. 
1.2 
BACKGROUND ON ALTEPLASE 
1.2.1 
Fibrinolysis and Tissue Plasminogen Activator 
Physiologic dissolution of a thrombus depends primarily on the proteolytic action of 
plasmin formed from plasminogen at the site of a clot.  The mechanism for this activation 
in vivo has not been definitively established. Plasminogen, the zymogen precursor of 
plasmin, may be activated by substances found in the plasma milieu, in tissue (tissue 
plasminogen activator [t-PA]), in urine (urokinase), and in bacteria (streptokinase).  The 
generated plasmin may be inhibited by plasma proteins such as α2-antiplasmin and 
α2-macroglobulin (Robbins 1982). 
Alteplase—Genentech, Inc. 
21/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
566/aCSR ML29093


 
 
 
 
 
 
 
  
Kinetic analyses suggest that plasminogen activation in the presence of fibrin 
occurs after the binding of plasminogen and t-PA at the clot site.  t-PA has a high affinity 
for fibrin, thereby efficiently activating the fibrin-bound plasminogen and converting it to 
plasmin. Plasmin, which when bound to fibrin is protected from rapid inactivation by 
α2-antiplasmin, then proceeds to digest the fibrin clot. 
See the Activase® (alteplase) U.S. Package Insert (USPI) for additional details on 
nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Alteplase is the only approved therapeutic agent for the treatment of AIS and is widely 
accepted as the standard of care for eligible patients (Edlow et al. 2013; 
Jauch et al. 2013). The currently approved alteplase USPI contains wording that 
recommends against use of alteplase in patients with “minor neurological deficit or with 
rapidly improving stroke symptoms” due to the fact this patient population has not been 
evaluated. Furthermore, the current American Heart Association/American Stroke 
Association Council Guidelines include “minor and rapidly improving stroke symptoms 
(clearing spontaneously)” as a relative exclusion criterion for alteplase 
(Jauch et al. 2013). This is largely due to the aforementioned label wording not 
recommending treatment of patients with minor neurological deficit or with rapidly 
improving stroke symptoms (RISS), the lack of a consistent and consensus definition on 
who constitutes this patient population, and the absence of definitive evidence of 
alteplase efficacy in this setting (Levine et al. 2013). Therefore, this trial is designed to 
evaluate the efficacy and safety of alteplase in confirmed AIS patients with minor 
neurological deficit or with RISS, which will be referred to collectively as “mild stroke” 
throughout the protocol. 
To date, all completed major randomized acute stroke trials have excluded patients with 
mild strokes to varying degrees.  In the two NINDS trials, such patients were excluded 
according to the protocol (largely to prevent patients with transient ischemic attacks from 
being enrolled if they were having rapidly improving symptoms), but did not include an 
explicit definition of mild stroke except for pure sensory stroke, isolated ataxia, isolated 
dysarthria, and isolated facial weakness (NINDS rt-PA Study Group 1995). The 
operational definition for stroke symptoms too mild to treat was left to the judgment of 
the randomizing physician (Levine et al. 2013). Interestingly, a post hoc analysis of the 
624 patients in the NINDS trial revealed that there were 58 patients (9%) enrolled with 
an NIHSS score ≤ 5, none of whom had isolated motor symptoms, isolated facial droop, 
isolated ataxia, dysarthria, isolated sensory, and three or fewer of each of additional 
isolated deficits (Khatri et al. 2010). Perhaps more significantly, 2971 patients were 
excluded primarily due to “rapidly improving” or “minor symptoms.”  However, a 
significant unmet medical need exists for patients with mild stroke.  Available outcome 
data for patients with mild stroke who do not receive alteplase consistently demonstrate 
a high rate of suboptimal outcomes.  Specifically, in two different prospective databases 
Alteplase—Genentech, Inc. 
22/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
567/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of patients with mild deficits (NIHSS score ≤ 5) and no baseline disability, approximately 
one-third (29%− 32%) were significantly disabled (as measured by modified Rankin 
Scale [mRS] score 2 − 6) at 90 days (Fischer et al. 2010; Khatri et al. 2012; 
, personal communication). 
Existing, albeit limited, data suggest that the potential benefit-risk ratio for alteplase in 
mild stroke should be favorable.  Gonzales et al. demonstrated better functional 
outcomes among mild strokes treated with IV alteplase compared to those not treated in 
a large, single-center, retrospective cohort; this was shown with two different thresholds 
of stroke severity (NIHSS ≤ 7 and NIHSS ≤ 3) (Gonzales et al. 2006). Additionally, a 
recent post hoc analysis of the subset of the third International Stroke Trial (IST-3) 
patients with mild strokes (pre-treatment NIHSS ≤ 5 who met all other NINDS rt-PA study 
eligibility criteria) showed a trend toward benefit for alteplase ( 
, personal 
communication). For PRISMS, the primary efficacy outcome assumption (mRS 0 − 1) is 
a 9% absolute treatment effect of alteplase relative to placebo.  This assumption is 
based on several retrospective analyses of similar patient populations (Köhrmann et al. 
2009; Fischer el al. 2010; Hassan et al. 2010b; Khatri et al. 2012) as well as the 
aforementioned IST-3 trial subgroup analysis ( 
, personal communication). 
The most prevalently reported and life-threatening adverse event (AE) associated with 
alteplase treatment for acute ischemic stroke is symptomatic intracranial hemorrhage 
(sICH). Post hoc analyses, case series, and retrospective studies in patients with mild 
stroke suggest an absolute sICH rate of 0−2% with alteplase treatment (NINDS rt-PA 
Study Group 2005; Baumann 2006; Gonzales et al. 2006; Köhrmann et al. 2009; 
Steffenhagen et al. 2009; Hassan et al. 2010a; Hassan et al. 2010b; Huisa et al. 2012). 
These data are consistent with analyses of IV alteplase trials of more severe patients 
suggesting that stroke severity, as measured by the NIHSS score, is a strong predictor 
of sICH risk (Khatri et al. 2007). No data exist to estimate the sICH rate for patients with 
mild stroke who did not receive t-PA; therefore, for this study, we are using a 0% sICH 
rate for the placebo arm, which is likely a conservative estimate.  An absolute sICH 
difference of 2% at 36 hours (primary safety endpoint) has been assumed for the 
alteplase arm vs. the placebo control arm in the proposed study.  For this study, sICH 
has been defined as any neurologic decline attributed to intracranial hemorrhage (ICH) 
seen on imaging by the local investigator within 36 hours of study drug administration, 
consistent with the NINDS trial definition for sICH (NINDS rt-PA Study Group 1995). 
Assuming the proposed study demonstrates both a 9% absolute treatment effect rate, 
the number of patients needed to treat (NNT) to show benefit (i.e., mRS score of 0 − 1) 
for one patient is 11.  Assuming a 2% absolute difference in sICH rate in patients treated 
with alteplase, the corresponding value for the number needed to harm (NNH), 
specifically for sICH, is conservatively estimated to be 50.  The actual number NNH, or 
the number of patients who would have worse outcomes at 90 days with alteplase 
compared to placebo treatment, is likely to be much higher than is reflected by the sICH 
Alteplase—Genentech, Inc. 
23/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
568/aCSR ML29093


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2. 
One dose of IV alteplase placebo and one dose of oral aspirin 325 mg (Figure 1). 
Every effort should be made to ensure both study drugs are initiated within 3 hours of 
last known well time.  If institutional policies on oral medications make it challenging to 
administer the oral aspirin/aspirin placebo within 3 hours of last known well time, the oral 
study drug may be given up to 24 hours after the last known well time.  IV alteplase/IV 
alteplase placebo MAY NOT be initiated beyond 3 hours of last known well time under 
any circumstances. 
A full schedule of assessments is provided in Appendix 1 . 
Figure 1 Abbreviated Study Schema 
ASA = aspirin; CT= computed tomography; IV = intravenous; MRI = magnetic resonance imaging; 
mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale. 
Due to the emergency nature of randomization in acute stroke clinical trials, treatment 
assignments must be made in an expeditious manner that also ensures even distribution 
in the treatment groups. A “step forward” randomization regimen stratified by site will be 
used to ensure that a randomized treatment assignment is available upon patients’ 
arrival at the hospital and treatment can initiate immediately upon signing informed 
consent and eligibility confirmation.  Further details on step forward randomization can 
be found in Section 4.2, Method of Treatment Assignment and Blinding. 
An independent Data Monitoring Committee (iDMC) will provide ongoing review of 
potential safety concerns and review efficacy and safety outcomes to inform a futility 
interim analysis after 50% of patients have achieved the primary endpoint (following 
completion of the Day 90 visit).  The composition of the iDMC and analysis will be 
documented in detail in a separate iDMC charter. 
Alteplase—Genentech, Inc. 
26/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
571/aCSR ML29093


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Table 2 
NIHSS Exclusion Criteria of Recently Completed and Ongoing 
Acute Ischemic Stroke Trials 
Recently Completed AIS Trials 
Exclusion 
Ongoing AIS Trials 
Exclusion 
Combined Approach to Lysis 
Utilizing Eptifibatide and rt-PA in 
Acute Ischemic Stroke (CLEAR 
Stroke) Trial 
NIHSS ≤ 5 
ARTSS 
NIHSS ≤ 9 
Intravenous Thrombolysis Plus 
Hypothermia for Acute Treatment 
of Ischemic Stroke 
NIHSS ≤ 6 
SHINE 
NIHSS < 3 
Albumin in Acute Ischemic Stroke 
Trial (ALIAS) Part One 
NIHSS ≤ 5 
The Intravascular Cooling in the 
Treatment of Stroke 2/3 (ICTuS 
2/3) Trial (ICTuS2/3) 
NIHSS ≤ 6 
Study of the Combination 
Therapy of rt-PA and 
Eptifibati5.3.3.8de to Treat Acute 
Ischemic Stroke (CLEAR-ER) 
NIHSS ≤ 5 
Safety/Feasibility of Autologous 
Mononuclear Bone Marrow 
Cells in Stroke Patients 
NIHSS ≤ 5 
Albumin in Acute Ischemic Stroke 
Trial (ALIAS) Part Two 
NIHSS ≤ 5 
SWIFT PRIME 
NIHSS ≤ 7 
Mechanical Retrieval and 
Recanalization of Stroke Clots 
Using Embolectomy (MR 
RESCUE) 
NIHSS ≤ 5 
PENUMBRA THERAPY 
NIHSS ≤ 7 
NeuroThera Efficacy and Safety 
Trial-3 (NEST3) 
NIHSS ≤ 6 
PENUMBRA 3D 
NIHSS ≤ 7 
CLOTBUST-ER 
NIHSS ≤ 9 
AIS = acute ischemic stroke; NIHSS = National Institutes of Health Stroke Scale. 
Source: www.clinicaltrials.gov. Accessed August 2013. Note that the NIHSS criteria for the 
trials listed are mentioned in the inclusion criteria, whereas the entries in the above table were 
adapted to list the corresponding exclusion criteria. 
It is notable that the alteplase USPI (2011) distinguishes patients with minor neurological 
deficit from those with RISS.  However, PRISMS combines these two patient groups into 
one operationally defined patient population (mild stroke):  all eligible patients with an 
NIHSS score ≤ 5 at the time of randomization without clearly disabling symptoms, 
irrespective of previous NIHSS scores.  Data demonstrating low alteplase use in patients 
with NIHSS scores ≤ 5 do not distinguish between whether the patient’s deficit was 
persistently mild or improved to this status (Smith et al. 2011). Furthermore, no data 
exist that suggest patients who improved to a mild status at the time of treatment with 
alteplase have different outcomes from patients whose neurologic deficit is persistently 
mild. To date, available data suggest that alteplase therapy would potentially be 
beneficial in both patients with RISS who improve to an NIHSS score ≤ 5 and patients 
with persistently mild deficits with an NIHSS score ≤ 5. 
Alteplase—Genentech, Inc. 
29/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
574/aCSR ML29093


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3.5.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence of sICH within 36 hours (primary safety assessment) 
sICH is defined as any neurological decline attributed to new ICH seen on 
imaging by the investigator.  New ICH seen on imaging will be later confirmed on 
independent reading by blinded central study radiologists. 
• 
Any ICH within 36 hours 
• 
Overall mortality within 90 days 
• 
Stroke-related and neurological deaths within 90 days 
• 
Incidence, severity, and spectrum of all AEs and SAEs 
Symptomatic Intracranial Hemorrhage 
In this study, an ICH is considered symptomatic if it is not seen on computed 
tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and any 
neurologic decline is attributed to it by the local investigator.  To detect intracranial 
hemorrhage, neuroimaging (CT or MRI) scan is required at 22 to 36 hours.  Additional 
neuroimaging should be performed at any time based on the investigator’s discretion 
that clinical findings suggested hemorrhage. Details on MRI types are described in 
Section 4.5.1.6. 
Intracranial hemorrhage events will include classifications of intracerebral hemorrhage 
(hemorrhagic infarct type 1 or type 2, parenchymal hematoma type 1 or type 2, or 
remote intraparenchymal hemorrhage type 1 or type 2).  Descriptions of each type of 
intracerebral hemorrhage are shown in the table below.  Additionally, subarachnoid 
hemorrhage, subdural hemorrhage, or epidural hemorrhage should be noted.   
Table 3 
Intracerebral Hemorrhage Definitions 
Type 
Description 
HI type 1 
HI type 2 
PH type 1 
PH type 2 
rPH type 1 
rPH type 2 
Small petechiae along margin of infarct 
More confluent petechiae within the infarcted area but without space-
occupying effect 
Hematoma in ≤ 30% of the infarcted area with some slight space-occupying 
effect 
Dense hematoma > 30% total of the infarcted area with substantial space-
occupying effect or any hemorrhagic area outside the infarcted area 
Small or medium sized blood clots located remote from the actual infarct; a 
mild space-occupying effect could be present. Remote primary 
intracerebral hemorrhage 
Large confluent dense blood clots in an area remote from the actual infarct; 
substantial space-occupying effect might be present. 
HI = hemorrhagic infarct; PH = parenchymal hematoma; rPH = remote parenchymal hematoma. 
Source: Wahlgren et al. 2007. 
Alteplase—Genentech, Inc. 
31/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
576/aCSR ML29093


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D&650/


 
 
 
 
 
 
 
In the case when pre-mixed IV drug is not used (e.g., patient is determined to be 
ineligible for study or declines informed consent prior to drug administration), sites will 
enter drug kit IDs into IWRS and indicate that the kits were not used.  IWRS will then 
assign a new set of drug kit IDs for the pharmacist to label with “Use Next” labels.  The 
pharmacist will properly dispose of the pre-mixed IV drug and the matching 
aspirin/aspirin-placebo kit in accordance with institutional guidelines. 
Prior to the first patient enrolled at a site, a site will register with IWRS as part of site 
activation, which will assign drug kit IDs ahead of time for the first potential patient.  
Once the first patient is enrolled at a site, the procedure described above will commence. 
Study Unblinding 
If a clinical situation arises in which the investigator thinks it is necessary to unblind in 
the interest of patient safety, the Medical Monitor must be notified immediately to discuss 
the intended unblinding.  Unblinding should occur only in settings where identification of 
the study treatment is critical for treatment decisions.  IWRS will be used for the 
unblinding process.  All unblinded patients will remain in the study and require all 
follow-up visits. 
Treatment codes should not be broken except under circumstances deemed necessary 
by the site investigator. The investigator should document and provide an explanation 
for any premature unblinding (e.g., unblinding due to sICH or severe systemic bleeding 
that requires blood products if IV alteplase was administered, or unblinding due to 
clinical worsening during the IV alteplase time window that would lead to IV alteplase 
administration if not already given).  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alteplase 
Alteplase is a single polypeptide containing 527 amino acids; it has three carbohydrate 
side chains and is predominantly one-chain t-PA.  It is a recombinant protein produced in 
a continuous mammalian tissue culture system and is purified by a series of 
chromatographic steps.  The manufacturing process includes fermentation with use of 
the antibiotic gentamicin; however, the presence of the antibiotic is not detectable in the 
final product. 
Alteplase is a sterile, white to pale yellow, lyophilized powder for IV administration after 
reconstitution with sterile water for injection (SWFI), USP, without preservatives.  
Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for 
Alteplase—Genentech, Inc. 
35/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
580/aCSR ML29093


 
 
 
 
 
 
 
pH adjustment. Biologic potency is determined by an in vitro clot lysis assay 
and is expressed in international units (IU) as tested against the World Health 
Organization (WHO) standard.   
Each 50-mg vial of Activase contains 50 mg of alteplase, 1.7 g of L-arginine, 5 mg of 
polysorbate 80, and 0.5 g of phosphoric acid. 
Each kit will contain 2 vials of 50-mg of alteplase labeled for “clinical trial use only.” 
Vials of 50-mg alteplase must be stored at 2°C−30°C and protected from light. 
4.3.1.2 
Alteplase Placebo 
Alteplase placebo is the same formulation as the active without the alteplase protein. 
Each 50-cc vial contains 1.7 g of L-arginine, 5 mg of polysorbate 80, and 0.5 g of 
phosphoric acid. 
Each kit will contain 2 vials of 50 mg of alteplase placebo labeled for “clinical trial use 
only.” 
Alteplase placebo vials should be stored at 2°C−30°C and protected from light. 
4.3.1.3 
Aspirin 
Aspirin (325 mg) will be packaged for the study.  Each kit will contain one bottle, which 
has 100 tablets labeled for “clinical trial use only.”  Only one tablet will be administered 
to the patient, and the remainder of the bottle will be kept at the site for drug 
accountability.    
Aspirin tablets should be stored at 25°C with excursions permitted between 15°C−30°C. 
4.3.1.4 
Aspirin Placebo 
Aspirin placebo will be identical in appearance to active aspirin to maintain treatment 
blinding. Each bottle of aspirin placebo contains 100 tablets labeled for “clinical trial use 
only.” Only one tablet will be administered to the patient, and the remainder of the bottle 
will be kept at the site for drug accountability. 
Placebo tablets should be stored in the same manner as aspirin tablets:  25°C with 
excursions permitted between 15°C−30°C. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alteplase 
For AIS, the recommended dose is 0.9 mg/kg infused over 60 minutes with 10% of the 
total dose administered as an initial IV bolus over 1 minute.  The total dose should not 
exceed 90 mg. 
Alteplase—Genentech, Inc. 
36/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
581/aCSR ML29093


 
 
 
Because alteplase and alteplase placebo contain no antibacterial preservatives, 50-mg 
vials should be reconstituted immediately before use by adding 50 mL of SWFI, USP, to 
the vial; this yields a concentration of 1 mg/mL.  Using aseptic technique, direct the flow 
of SWFI directly into the lyophilized cake of study drug.  It is recommended that an 
18-gauge needle be used for the reconstitution of the 50-mg vial.  Once reconstituted, 
gently swirl the vial. Do not shake. Slight foaming upon reconstitution is not unusual; 
allowing the vial to stand undisturbed for several minutes is usually sufficient to allow 
dissipation of any large bubbles.  Before further dilution or administration, the product 
should be visually inspected for particulate matter and discoloration.  If a precipitate is 
seen, the product should not be used. 
After reconstitution, alteplase should be administered at 1 mg/mL.  As an alternative, the 
reconstituted solution may be diluted further immediately before administration in an 
equal volume of 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP, to 
yield a concentration of 0.5 mg/mL.  The osmolality of this solution is approximately 
215 mOsm/kg.  Polyvinyl chloride bags, glass bottles, or polypropylene syringes are 
acceptable.  Do not use filter needles for infusion.  Alteplase is stable for up to 8 hours in 
these solutions at room temperature.  Exposure to light has no effect on the stability of 
these solutions.  Excessive agitation during dilution should be avoided; mixing should be 
accomplished with gentle swirling and/or slow inversion.   
No other medication should be added to infusion solutions containing alteplase.  Any 
unused infusion solution should be discarded. 
See Appendix 2 (Alteplase Administration) and Appendix 3 (Reconstitution of 
50-mg Vials) for further details. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study will be 
provided by the Sponsor where required by local health authority regulations.  The 
investigational site will acknowledge receipt of IMPs using the IWRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received, dispensed, returned, and disposed of by the study 
site should be recorded on the Drug Inventory Log. 
Alteplase—Genentech, Inc. 
37/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
582/aCSR ML29093


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Additional CT scans or MRIs should be performed based on the investigator’s discretion, 
or if any clinical findings suggest ICH (such as new headache, nausea, vomiting, 
significant deterioration of neurological status, or rapid increase of blood pressure).  If an 
ICH is identified, the NIHSS score should be reassessed at the time and recorded on the 
Adverse Event eCRF. 
CT scans or MRIs performed at baseline, between 22 to 36 hours, and additional 
imaging performed due to clinical suspicion of deterioration up until 36 hours after study 
drug administration, will be evaluated by a central team of radiologists blinded to the 
clinical attributes of the case.  These images will need to be sent to the central 
radiologists by the local site. 
4.5.2 
Patient-Reported Outcomes 
Patient-reported outcomes (PRO) data will be elicited from the patients in this study to 
more fully characterize the clinical profile of alteplase in this patient population.  The 
PRO questionnaires will be distributed by the investigator staff and completed in their 
entirety by the patient or their surrogate.    
This study will assess the impact of alteplase treatment on health-related quality of life, 
physical function, daily functioning, and symptoms of depression.  
Health-related quality of life will be assessed using the EQ-5D (Appendix 4). The EQ-5D 
is a generic, preference-based health utility measure with questions about mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression that are used to build 
a composite of the patient’s health status.   
Physical functioning will be evaluated using the SIS-16 (Appendix 5), which is a 
validated, stroke-specific, quality of life measure to assess the impact of stroke on a 
patient’s health and life. 
The CES-D (Appendix 6) will be used to evaluate the proportion of patients with 
depressive symptoms (defined as a score of ≥ 16 at 90 days). 
The EQ-5D, SIS-16, and CES-D will be provided in Spanish for those patients requiring 
translations. 
AE reports will not be derived from PRO data by the Sponsor.  However, any PRO 
responses suggestive of a possible AE identified during site review of the PRO data 
should be reported as outlined in Section 5.3.3.11. 
Alteplase—Genentech, Inc. 
41/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
586/aCSR ML29093


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investigator blinded to the results).  AEs1 and concomitant medications will also be 
assessed at this visit. 
4.6.3 
Visit 3 (Day 5 or Discharge from Hospital, if Sooner than Day 5) 
On Day 5 (or discharge from hospital, if sooner than Day 5), NIHSS score, stroke 
etiology, AEs, and concomitant medications will be collected.  Discharge location will be 
collected at the time of hospital discharge. 
4.6.4 
Visit 4 (Day 30 [30 ± 7 Days]) 
A phone call to the patient or caregiver will be made at Day 30 and an mRS will be 
assessed (see Appendix 8). AEs, concomitant medications, and patient survival will be 
assessed during this phone visit.  Pregnancy will also be assessed for female patients of 
childbearing potential. 
4.6.5 
Visit 5 (Day 90 [± 14 Days]/Study Completion) 
Primary and secondary efficacy endpoints, as well as all exploratory endpoints, will be 
assessed at Day 90 with the patient.  The following assessments will be performed: 
• 
NIHSS score (Appendix 7) 
• 
Patient survival 
• 
mRS (Appendix 8) 
• 
GOS (Appendix 9) 
• 
BI (Appendix 10) 
• 
EQ-5D (Appendix 4) 
• 
SIS-16 (Appendix 5) 
• 
CES-D (Appendix 6) 
• 
Cognitive assessments (Appendix 11) 
– 
Controlled Oral Word Association test  
– 
HVLT-R trials 1, 2, and 3 
– 
Digit symbol coding from the WAIS III 
– 
Forward and Backward Digit Span test 
– 
Benton Judgment of Line Orientation test, form V 
– 
HVLT-R trial 4 and recognition  
– 
Animal Naming test 
1 AE/SAE collection should be started as soon as study drug administration (bolus) is initiated. 
Alteplase—Genentech, Inc. 
43/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
588/aCSR ML29093


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D&650/


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
After initiation of study drug, all AEs (including serious and non-serious AEs), 
regardless of relationship to study drug, will be reported until 30 days after administration 
of study drug. 
After 30 days until 90 days after administration of study drug, the following AEs should 
be recorded on the AE CRF: 
• 
All SAEs 
• 
Non-serious ICHs 
• 
Non-serious AESIs 
• 
All AEs that resulted in withdrawal from the study 
All SAEs and non-serious AESIs require immediate reporting to the Sponsor (see 
Section 5.4). 
After 90 days, the investigator is not required to actively monitor patients for AEs; 
however, the Sponsor should be notified if the investigator becomes aware of any 
post-study SAEs (see Section 5.6). 
5.3.2 
Assessment of Severity of Adverse Events 
The WHO toxicity grading scale (see Appendix 14) will be used for assessing adverse 
event severity. Table 4 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale. 
Table 4 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
2 
3 
4 
Mild; transient or mild discomfort (< 48 hours); no medical intervention or 
therapy required 
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required 
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible 
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable 
Notes: Developed by the Division of Microbiology and Infectious Diseases.  
Regardless of severity, some events may also meet seriousness criteria. Refer to definition of a  
serious adverse event (see Section 5.2.2).  
Alteplase—Genentech, Inc. 
49/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
594/aCSR ML29093


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.3.3 for 
details on recording persistent AEs). 
5.3.3.6 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (Section 5.3.1) 
regardless of relationship to study drug, must be recorded on the Adverse Event eCRF 
and immediately reported to the Sponsor (see Section 5.2.2). This includes death 
attributed to progression of AIS. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. The term "sudden death" should only be used for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death. 
If the death is attributed to progression of AIS, "acute ischemic stroke progression" 
should be recorded on the Adverse Event eCRF. 
5.3.3.7 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., more 
frequent headaches"). 
5.3.3.8 
Lack of Efficacy or Worsening of Acute Ischemic Stroke 
Medical occurrences or symptoms of deterioration that are considered part of the 
disease course or disease process should be recorded as an AE if judged by the 
investigator to have unexpectedly worsened in severity or frequency or unexpectedly 
changed in nature at any time during the study.  If there is uncertainty, it should be 
reported as an AE.  When recording unexpected worsening of AIS on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors of the event.  
Alteplase—Genentech, Inc. 
53/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
598/aCSR ML29093


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Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant within 30 (± 7) days after the last dose of study drug.  
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and submitted via the EDC system.  
A pregnancy report will automatically be generated and sent to Safety Risk Management.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus. Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
SAEs associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or scanning and emailing the form using the fax number or email 
address provided to investigators. Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as an SAE, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.1). Any spontaneous abortion should be reported in the same 
fashion (as the Sponsor considers spontaneous abortions to be medically significant 
events). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better and is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent. Every effort should be made to follow all SAEs considered to 
be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
Alteplase—Genentech, Inc. 
56/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
601/aCSR ML29093


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6. 
STATISTICAL METHODS 
This study will test whether treatment of patients with mild stroke with IV alteplase will 
lead to a higher proportion (9% absolute difference) of patients with a favorable outcome 
(mRS of 0 or 1) at 90 days. 
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of 856 is required in order to achieve 80% power in the primary analysis 
to detect an effect size of 9% absolute difference in the proportion of patients with 
favorable outcomes between the alteplase and control arms.  The above sample size 
calculation assumes a control proportion of 65% and Type I error probability of 0.025 
(one-sided), and uses a group sequential design with one interim analysis for futility 
(non-binding), based on an O’Brien-Fleming boundary, after 50% of the anticipated 
sample size have completed the 90-day follow-up assessments. 
 was used for 
this sample size calculation. 
The ITT principle will be applied to the primary analysis and, therefore, to safeguard 
against dilution of the treatment effect associated with an approximate 5% 
non-adherence rate (due to lost to follow-up, consent withdrawal, treatment crossovers, 
and stroke mimics), the above sample size needs to be inflated by a factor of 1/0.952 or 
1.108 (Friedman et al. 1998). Therefore, a total sample size of 948 is required for this 
study. 
6.2 
PRIMARY ANALYSIS 
The primary efficacy analysis will test the hypothesis of superiority of IV alteplase 
therapy over standard medical care in AIS patients with mild deficits.  The primary 
efficacy outcome is the proportion of patients with a favorable outcome, defined by 
mRS score of 0 or 1 at 90 days post-randomization.  The difference in the proportion of 
mRS 0−1 responders (favorable outcome) at 90 days post-randomization between the 
IV alteplase arm and the standard medical care arm will be compared via a 
Cochran-Mantel-Haenszel test, stratified by pre-treatment NIHSS score (0 − 2 vs. 3 − 5), 
age (< 65 vs. ≥ 65), and last known well time to treatment (0 − 2 hours vs. > 2 − 3 hours). 
The primary efficacy analysis will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization adhering to the ITT principle. As a 
sensitivity analysis, results from the univariate Pearson’s chi-square test will also be 
presented. 
As a supportive, secondary analysis, an ordinal (or “shift”) analysis of the distribution of 
the mRS will be analyzed via proportional odds model if the proportionality assumption 
holds, and by the Mann-Whitney superiority measure if the proportionality assumption 
does not hold.  The proportionality assumption will be assessed using the score test as 
well as clinical judgment on the similarities of the different odds ratios.  As a secondary 
efficacy outcome, the global outcome score at 90 days will be analyzed using the global 
odds ratio test based on the generalized estimating equations analysis (Wald-type χ2 
Alteplase—Genentech, Inc. 
58/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
603/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
test) with unstructured covariance-correlation matrix.  These results will be treated as 
supportive evidence (or lack thereof) of the treatment effect rather than conclusive 
evidence. The significance of each test is determined at the two-sided alpha level of 
0.05. The specific statistical model for analyzing each of these outcome measures will 
be detailed in the Statistical Analysis Plan (SAP). 
6.3 
SAFETY ANALYSIS 
Incidence and severity of AEs will be described for all treated patients by treatment 
group as received and by the Medical Dictionary for Regulatory Activities (MedDRA) 
classification. 
Safety outcomes include incidence of sICH within 36 hours (primary safety assessment), 
any ICH within 36 hours, overall mortality, and stroke-related and neurological deaths 
within 90 days of study drug initiation.  The cumulative incidences of each outcome will 
be compared via Fisher’s exact test.  Mortality will be analyzed by Log-Rank test and the 
Kaplan-Meier estimates will be plotted over the observation period of 90 days.  No alpha 
adjustment for multiple testing on the safety endpoints is foreseen because those 
analyses will be exploratory. 
6.4 
EXPLORATORY ANALYSES 
As exploratory analyses, heterogeneity of treatment effect of alteplase will be evaluated 
by various pre-specified baseline covariates.  The primary pre-specified variables and 
their analytic thresholds are defined by: 
• 
Age (< 65 vs. ≥ 65) 
• 
Pre-treatment NIHSS score (0 − 2 vs. 3 − 5) 
• 
Last known well time to treatment (0 − 2 vs. > 2 − 3 hours) 
• 
Stroke subgroup (RISS vs. non-RISS) 
Additional heterogeneity analyses will be considered and detailed in the SAP.  Forest 
plots will be constructed to illustrate subgroup analyses.  In addition, the two-way 
interactions of IV alteplase treatment effect with age, NIHSS score, and stroke 
subgroups (RISS vs. non-RISS) on the primary outcome will be explored through 
multivariable logistic regression.  Additional exploratory analyses will be conducted to 
explore treatment effects on quality of life endpoints and other exploratory endpoints. 
6.5 
INTERIM ANALYSIS 
One interim analysis of the primary efficacy outcome is planned for clear futility, 
conducted according to the beta-spending approach (Pampallona et al. 2001) with an 
O’Brien-Fleming-type boundary.  This futility analysis will occur after approximately 50% 
of patients (or 474) have completed the 90-day assessment. 
An independent Data Coordinating Center (iDCC) will be responsible for the preparation 
and review of unmasked data. 
Alteplase—Genentech, Inc. 
59/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
604/aCSR ML29093


 
 
 
 
 
An iDMC will be organized for review of the interim analysis results.  The composition of 
the iDMC and analysis in detail will be documented in a separate iDMC charter. 
6.6 
MISSING DATA HANDLING 
Under the ITT principle, all patients who are randomized will be included in the analysis.  
The multiple-imputation method will be used for handling missing data, including the last 
observation (e.g., the Day 30 mRS) among the variables used in imputation.  As 
supportive analyses, missing primary outcome data will be imputed by 1) using last 
observation carried forward and 2) assuming missing outcomes to be unfavorable. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC using 
eCRFs. Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data with the input from the Sponsor.  For this study, local laboratories 
will be used and data will be captured in the EDC system and will then be transferred to 
the Sponsor. This will include the eCRF data using the Sponsor’s standard procedures 
and processes to transfer data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
The EDC vendor has back-ups for data stored, and records retention for the study data 
will be consistent with the CRO’s standard procedures.  
Data from paper PRO questionnaires will be entered into the EDC system by site staff.   
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have eCRF completion guidelines for the eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
Alteplase—Genentech, Inc. 
60/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
605/aCSR ML29093


 
 
 
 
 
 
 
 
 
All eCRFs should be completed by designated trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (e.g., source data) entered into the eCRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents.  Source documents 
(paper or electronic) are those in which patient data are recorded and documented for 
the first time.  They include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Study Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
Alteplase—Genentech, Inc. 
61/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
606/aCSR ML29093


 
 
  
 
 
 
 
 
 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the International Conference on 
Harmonisation E6 guideline for Good Clinical Practice and the principles of the 
Declaration of Helsinki, or the laws and regulations of the country in which the research 
is conducted, whichever affords the greater protection to the individual.  The study will 
comply with the requirements of the International Conference on Harmonisation E2A 
guideline (Clinical Safety Data Management:  Definitions and Standards for Expedited 
Reporting). Studies conducted in the United States or under a U.S. Investigational New 
Drug (IND) application will comply with FDA regulations and applicable local, state, and 
federal laws. Studies conducted in the European Union (EU)/European Economic Area 
(EEA) will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission. The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Alteplase—Genentech, Inc. 
62/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
607/aCSR ML29093


 
 
  
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the U.S., each Consent Form may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (Section 9.6). 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC. 
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient ID number.  This means that patient 
names are not included in data sets that are transmitted to any Sponsor location. 
Alteplase—Genentech, Inc. 
63/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
608/aCSR ML29093


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9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
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requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal 
publication of the study in which contribution of Sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator 
and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating 
from the use of data from this study will become and remain the exclusive and 
unburdened property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
Alteplase—Genentech, Inc. 
66/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
611/aCSR ML29093


 
 
 
 
 
10. 
REFERENCES 
Activase® (alteplase) U.S. Package Insert, Genentech, Inc., 2011. 
Baumann CR, Baumgartner RW, Gandjour J, et al. Good outcomes in ischemic stroke 
patients treated with intravenous thrombolysis despite regressing neurological symptoms. 
Stroke 2006,37:1332−3. 
De Los Rios La Rosa F, Khoury J, Kissela BM, et al. Eligibility of intravenous 
recombinant tissue-type plasminogen activator within a population: the effect of the 
European cooperative acute stroke study (ECASS) III trial. Stroke 2012,43(6):1592−5. 
Demaerschalk BM. Thrombolytic therapy for acute ischemic stroke: the likelihood of 
being helped versus harmed. Stroke 2007;38:2215−16. 
Dhamoon MS, Moom YP, Boden-Albala B, et al. Long-term functional recovery after first 
ischemic stroke: the Northern Manhattan Study. Stroke 2009;40:2805−11. 
Edlow JS, Smith EE, Stead LG, et al. Clinical policy: Use of t-PA for the management of 
acute ischemic stroke in the Emergency Department. Ann Emerg Med 2013;61:225−43. 
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. Third ed. 1998, 
New York, NY:Springer:108. 
Fischer U, Baumgartner A, Arnold M, et al. What is minor stroke? Stroke 2010;41:661−6. 
Gonzales NR, Albright KC, Noser KC, et al. “Mild stroke” should not exclude patients 
from thrombolytic therapy. Stroke 2006;37:621. 
Hassan AE, Hassanzadeh B, Tohidi V, et al. Very mild stroke patients benefit from 
intravenous tissue plasminogen activator without increase of intracranial hemorrhage. 
South Med J 2010a;103(5):398−402. 
Hassan AE, Zacharoatos H, Hassanzadeh B, et al. Does Mild deficit for patients with 
stroke justify use of intravenous tissue plasminogen activator? J Stroke Cerebrovasc Dis 
2010b;19:116−20. 
Huisa BN, Raman R, Neil W, et al. Intravenous tissue plasminogen activator for patients 
with minor ischemic stroke. J Stroke Cerebrovasc Dis 2012;21:733−6. 
Jauch EC, Saver JL, Adams HP, 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 Council, Council on 
Cardiovascular Nursing, Council on Peripheral Vascular Disease and Council on Clinical 
Cardiology: the American Academy of Neurology affirms the value of this guideline as an 
educational tool for neurologists. Stroke 2013;44:870−947. 
Khatri P, Conaway MR, Johnston KC; Acute Stroke Accurate Prediction Study (ASAP) 
Investigators. Ninety-day outcome rates of a prospective cohort of consecutive patients 
with mild stroke. Stroke 2012;43:560−2. 
Alteplase—Genentech, Inc. 
67/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
612/aCSR ML29093


 
 
 
 
 
Khatri P, Kleindorfer DO, Yeatts SD, et al. Strokes with minor symptoms: an exploratory 
analysis of the National Institute of Neurological disorders and stroke recombinant tissue 
plasminogen activator trials. Stroke 2010;41:2581−6. 
Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with 
revascularization therapies. Stroke 2007,38(2):431−40. 
Köhrmann M, Nowe T, Huttner HB, et al. Safety and outcome after thrombolysis in 
stroke patients with mild symptoms. Cerebrovasc Dis 2009;27(2):160−6. 
Levine SR, Khatri P, Broderick JP, et al. Review, historical context, and clarifications of 
the NINDA rt-PA stroke trials exclusion criteria part 1: rapidly improving stroke symptoms. 
Stroke 2013;44(9):2500−5. 
National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study Group. 
Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581−8. 
National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study Group. 
Recombinant tissue plasminogen activator for minor strokes: the National Institute of 
Neurological Disorders and Stroke rt-PA Stroke Study Experience. Ann Emerg Med. 
2005;46:243−52. 
Pampallona S, Tsiatis AA, Kim K. Interim monitoring of group sequential trials using 
spending functions for the type I and type II error probabilities. Drug Inf J 
2001;35:1113−21. 
Reeves M, Khoury J, Alwell K, et al. Distribution of NIHSS in the Cincinnati/Northern 
Kentucky Stroke Study. Stroke 2013;In press. 
Rosamond W, Flegal K, Friday G, et al; American Heart Association Statistics 
Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics— 
2007 update: a report from the American Heart Association Statistics Committee and 
Stroke Statistics Subcommittee. Circulation 2007;115:e69−171. 
Robbins KC. The plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, 
Marder VJ, et al., editors. Hemostasis and thrombosis: basic principles and clinical 
practice. Philadelphia: JP Lippincott. 1982:623−39. 
Saver J. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number 
needed to harm. Stroke 2007;38:2279−83. 
Smith EE, Gonarow GC, Reeves MJ, et al. Outcomes in mild or rapidly improving stroke 
not treated with intravenous recombinant tissue-type plasminogen activator: findings 
from Get With The Guidelines-Stroke. Stroke 2011;42:3110−15. 
Steffenhagen N, Hill MD, Poppe AY, et al. Should you thrombolyze all or any stroke 
patients with baseline National Institutes of Health Stoke Scale scores ≤ 5? Cerebrovasc 
Dis 2009;28:201−02. 
Alteplase—Genentech, Inc. 
68/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
613/aCSR ML29093


 
 
 
 
Wahlgren N, Ahmed N, Dávalos 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;369:275−82. 
Willey JZ, Stillman J, Rivolta JA, et al. Too good to treat? Outcomes in patients not 
receiving thrombolysis due to mild deficits or rapidly improving symptoms. Int J Stroke 
2012;7(3):202−06. 
Alteplase—Genentech, Inc. 
69/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
614/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1  
Schedule of Assessments  
ASSESSMENTS 
Screening and 
Baseline 
(Visit 1) 
Study Drug 
Administration 
22−36 Hours 
from Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 (± 14) 
Days/Study 
Completion 
(Visit 5) 
Early Discontinuation 
(Phone call, if possible) 
Informed consent 
X 
Review of eligibility 
X 
Medical history and 
baseline conditions a 
X 
Demographics 
X 
Neurological examination b 
X 
Vital signs c 
X 
Complete blood count d 
X 
Coagulation status e 
X 
Pregnancy test f 
X 
Serum blood glucose g 
X 
Imaging modality sensitive 
to presence of intracranial 
hemorrhage (either CT or 
MRI with DW MRI, either 
SW or GRE, and FLAIR 
images). Visit 2 MRIs 
should also include T1 and 
T2 sequences h 
X 
X 
NIHSS score i 
X 
X 
X 
X 
Study drug administration 
X 
Alteplase—Genentech, Inc. 
70/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
615/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1 (cont.)  
Schedule of Assessments  
ASSESSMENTS 
Screening and 
Baseline 
(Visit 1) 
Study Drug 
Administration 
22−36 Hours 
from Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 (± 14) 
Days/Study 
Completion 
(Visit 5) 
Early Discontinuation 
(Phone call, if possible) 
Discharge location 
X 
X 
Patient survival 
X 
X 
X 
mRS j 
X
 X
 
GOS
 
X
 
BI k 
X 
EQ-5D k 
X 
CES-D k 
X 
SIS-16 k 
X 
Cognitive assessments l 
X 
Walking speed m 
X 
Concomitant medications n 
X 
X 
X 
X 
X 
X 
Assessment of pregnancy 
X 
Adverse event o 
X 
X 
X 
X 
X 
X 
BI = Barthel Index; BNT = Boston Naming Test; CES-D = Centers for Epidemiologic Studies, Depression; CT = computed tomography; DW 
MRI = diffusion-weighted MRI; European Quality of Life = EQ-5D; FLAIR = fluid-attenuated inversion recovery; GOS = Glasgow Outcome Scale; 
GRE = gradient echo; HVLT-R = Hopkins Verbal Learning Test-Revised; ICH = intracranial hemorrhage; INR = international normalized ratio; 
MRI = magnetic resonance imaging; mRS modified Rankin Scale; NIHSS = NIH Stroke Scale; Stroke Impact Scale-16 = SIS-16; 
SW MRI= susceptibility-weighted MRI; WAIS III = Wechsler Adult Intelligence Scale III. 
Alteplase—Genentech, Inc. 
71/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
616/aCSR ML29093


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Appendix 3  
Reconstitution of 50-mg Vials  
Alteplase—Genentech, Inc. 
74/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
619/aCSR ML29093


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Appendix 4 (cont.)  
European Quality of Life-5D (EQ-5D) Questionnaire  
Alteplase—Genentech, Inc. 
76/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
621/aCSR ML29093


 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 5  
Stroke Index Scale (SIS-16)  
In the past 2 weeks, how 
difficult was it to... 
Not difficult 
at all 
A little 
difficult 
Somewhat 
difficult 
Very 
difficult 
Could not 
do at all 
a. Dress the top part of your 
body? 
5 
4 
3 
2 
1 
b. Bathe yourself? 
5 
4 
3 
2 
1 
c. Get to the toilet on time? 
5 
4 
3 
2 
1 
d. Control your bladder (not 
have an accident)? 
5 
4 
3 
2 
1 
e. Control your bowels (not 
have an accident)? 
5 
4 
3 
2 
1 
f. Stand without losing 
balance? 
5 
4 
3 
2 
1 
g. Go shopping? 
5 
4 
3 
2 
1 
h. Do heavy household chores 
(e.g., vacuum, laundry or yard 
work)? 
5 
4 
3 
2 
1 
i. Stay sitting without losing 
your balance? 
5 
4 
3 
2 
1 
j. Walk without losing your 
balance? 
5 
4 
3 
2 
1 
k. Move from a bed to a chair? 
5 
4 
3 
2 
1 
l. Walk fast? 
5 
4 
3 
2 
1 
m. Climb one flight of stairs? 
5 
4 
3 
2 
1 
n. Walk one block? 
5 
4 
3 
2 
1 
o. Get in and out of a car? 
5 
4 
3 
2 
1 
p. Carry heavy objects (e.g. 
bag of groceries) with your 
affected hand? 
5 
4 
3 
2 
1 
Alteplase—Genentech, Inc. 
77/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
622/aCSR ML29093


 
 
 
 
Appendix 6 
Center for Epidemiologic Studies, Depression (CES-D) Scale,
NIMH 
Alteplase—Genentech, Inc. 
78/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
623/aCSR ML29093


 
 
 
 
 
 
Appendix 7  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
79/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
624/aCSR ML29093


 
 
 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
80/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
625/aCSR ML29093


 
 
 
Appendix 7 (cont.)  
National Institutes of Health Stroke Scale (NIHSS)  
Alteplase—Genentech, Inc. 
81/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
626/aCSR ML29093




 
 
 
 
 
Appendix 8  
Modified Rankin Scale (mRS)  
Alteplase—Genentech, Inc. 
83/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
628/aCSR ML29093


 
 
 
 
 
 
Appendix 9  
Glasgow Outcome Scale (GOS)  
Alteplase—Genentech, Inc. 
84/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
629/aCSR ML29093


 
 
 
 
 
 
Appendix 10  
Barthel Index (BI)  
Alteplase—Genentech, Inc. 
85/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
630/aCSR ML29093


 
 
Appendix 10 (cont.)  
Barthel Index (BI)  
Alteplase—Genentech, Inc. 
86/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
631/aCSR ML29093






 
 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
89/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
634/aCSR ML29093










 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
94/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
639/aCSR ML29093


 
 
 
 
 
 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
G. Boston Naming Test (BNT) 15-Item Short Form 
Alteplase—Genentech, Inc. 
95/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
640/aCSR ML29093


 
 
 
 
Appendix 11 (cont.)  
Cognitive and Behavioral Assessments  
Alteplase—Genentech, Inc. 
96/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
641/aCSR ML29093




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Appendix 13  
Preferred Terms for Intracranial Hemorrhage  
An intracranial hemorrhage (ICH) is considered symptomatic if it is not seen on 
computed tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and 
any neurologic decline is attributed to it by the local investigator.  Below is the list of 
preferred terms (PTs) using the MedDRA term to describe the ICH event: 
• 
Basal ganglia hemorrhage 
• 
Brain stem hematoma 
• 
Brain stem hemorrhage 
• 
Brain stem microhemorrhage 
• 
Cerebellar hematoma 
• 
Cerebellar hemorrhage 
• 
Cerebellar microhemorrhage 
• 
Cerebral arteriovenous malformation hemorrhagic 
• 
Cerebral hematoma 
• 
Cerebral hemorrhage 
• 
Cerebral microhemorrhage 
• 
Epidural hemorrhage 
• 
Extradural hematoma 
• 
Hemorrhage intracranial 
• 
Hemorrhagic cerebral infarction 
• 
Hemorrhagic stroke 
• 
Hemorrhagic transformation stroke 
• 
Intracranial hematoma 
• 
Intraventricular hemorrhage 
• 
Meningorrhagia 
• 
Pituitary hemorrhage 
• 
Putamen hemorrhage 
• 
Subarachnoid hemorrhage 
• 
Subdural hematoma 
• 
Subdural hemorrhage 
• 
Thalamus hemorrhage 
• 
Traumatic intracranial hemorrhage 
Alteplase—Genentech, Inc. 
101/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
646/aCSR ML29093


 
 
 
 
 
 
 
 
 
 
Appendix 14  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
102/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
647/aCSR ML29093


 
 
 
 
 
Appendix 14 (cont.)  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
103/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
648/aCSR ML29093


 
 
 
 
 
Appendix 14 (cont.)  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
104/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
649/aCSR ML29093


 
 
 
 
 
 
Appendix 14 (cont.)  
World Health Organization (WHO) Toxicity Grading Scale for  
Determining the Severity of Adverse Events  
Alteplase—Genentech, Inc. 
105/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
650/aCSR ML29093

SAP_000.pdf: 
 
Document Type: 
SAP 
Official Title: 
A Phase IIIB, Double-Blind, Multicenter Study to Evaluate the Efficacy 
and Safety of Alteplase in Patients With Mild Stroke: Rapidly 
Improving Symptoms and Minor Neurologic Deficits (PRISMS) 
NCT Number: 
NCT02072226 
Document Date(s): 
SAP: 17 May 2017 
 
 


Confidential 
Page 1 
This is a Genentech, Inc. document that contains confidential information. Nothing herein is to be 
disclosed without written consent from Genentech, Inc. 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
1/ML29093   
5/17/2017 
STATISTICAL ANALYSIS PLAN 
DATE DRAFT: 
IND NUMBER: 
PLAN PREPARED BY: 
PROTOCOL NUMBER: 
SPONSOR: 
STUDY DRUG: 
TITLE: 
VERSION: 
16 May 2017 
3811 
 
 
ML29093 / NCT02072226
Genentech, Inc. 
Alteplase (RO5532960) 
A PHASE IIIB, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ALTEPLASE IN PATIENTS WITH 
MILD STROKE (RAPIDLY IMPROVING 
SYMPTOMS AND MINOR NEUROLOGIC 
DEFICITS (PRISMS) 
1.0 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
762/aCSR ML29093


TABLE OF CONTENTS 
 
 
Page 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
2/ML29093   
5/17/2017 
1. 
BACKGROUND ................................................................................................. 5 
2. 
STUDY DESIGN ............................................................................................... 6 
2.1 
Synopsis ................................................................................................. 6 
2.2 
Outcome Measures ................................................................................ 6 
2.2.1 
Primary Efficacy Outcome Measures ........................................ 6 
2.2.2 
Secondary Efficacy Outcome Measures ................................... 6 
2.2.3 
Exploratory Efficacy Outcome Measures .................................. 7 
2.2.4 
Safety Outcome Measures ........................................................ 7 
2.3 
Determination of Sample Size ................................................................ 8 
2.4 
Analysis Timing....................................................................................... 9 
3. 
STUDY CONDUCT ........................................................................................... 9 
3.1 
Randomization Issues ............................................................................ 9 
3.2 
Data Monitoring .................................................................................... 10 
3.2.1 
Safety Review Timing ............................................................. 10 
4. 
STATISTICAL METHODS ............................................................................... 11 
4.1 
Analysis Populations ............................................................................. 11 
4.1.1 
Intent-to-Treat Population........................................................ 11 
4.1.2 
Per-Protocol Population .......................................................... 11 
4.1.3 
Safety Population .................................................................... 12 
4.2 
Analysis of Study Conduct .................................................................... 12 
4.3 
Analysis of Treatment Group Comparability ......................................... 12 
4.4 
Efficacy Analyses.................................................................................. 13 
4.4.1 
Primary Efficacy Endpoint ....................................................... 14 
4.4.2 
Secondary Efficacy Endpoints ................................................. 15 
4.4.3 
Exploratory Efficacy Endpoints ................................................ 17 
4.4.4 
Subgroup Analyses ................................................................. 19 
4.5 
Cognitive, Behavioral and Patient Reported Outcome 
Analyses ............................................................................................... 22 
4.5.1 
Cognitive Assessments ........................................................... 22 
4.5.2 
Ambulatory Performance......................................................... 23 
4.5.3 
Patient Reported Outcomes .................................................... 23 
4.6 
Safety Analyses .................................................................................... 25 
4.6.1 
Exposure to Study Medication ................................................. 25 
4.6.2 
Adverse Events ....................................................................... 26 
4.6.3 
Neuroimaging .......................................................................... 27 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
763/aCSR ML29093


TABLE OF CONTENTS (cont’d) 
 
 
Page 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
3/ML29093   
5/17/2017 
4.6.4 
Laboratory Data ...................................................................... 29 
4.6.5 
Vital Signs ............................................................................... 30 
4.6.6 
Mortality................................................................................... 30 
4.6.7 
Previous and Concomitant Medications .................................. 30 
4.7 
Handling of Dropouts, Missing/Incomplete Data, or 
Outliers ................................................................................................. 30 
4.8 
Interim Analyses and/or Safety Reviews .............................................. 31 
5. 
REFERENCES ................................................................................................ 31 
 
TABLES AND FIGURES 
Table 1 Estimated Power for the Final Sample Size (N=313) ................................... 9 
Table 2 Summary of Efficacy Analyses .................................................................. 21 
Table 3 Cognitive Assessments ............................................................................. 22 
Table 4 Intermediate Variables for the Next Allocation Probability ......................... 44 
Table 5 Decisions Based on Site and Overall Imbalance ....................................... 44 
Table 6 Baseline Characteristics to be Evaluated for Imbalance ............................ 50 
 
Figure 1 Study Flowchart ....................................................................................... 42 
Figure 2 Study Randomization Schema ................................................................. 45 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
764/aCSR ML29093


TABLE OF CONTENTS (cont’d) 
 
 
Page 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
4/ML29093   
5/17/2017 
APPENDICES 
Appendix A Protocol Synopsis 
Appendix B Schedule of Assessment and Study Flow Chart 
Appendix C Randomization Scheme 
Appendix D Statistical Methods Requiring Input 
Appendix E Documentation of Additional Analyses Performed after 
Database Lock 
Appendix F Data Handling Rules 
Appendix G Programming Codes for Statistical Analysis 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
765/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
5/ML29093   
5/17/2017 
 
1. 
BACKGROUND 
Stroke is the fourth leading cause of death and a leading cause of disability in the 
United States (U.S.). More than half of all ischemic stroke patients have mild strokes 
at initial presentation in population-based studies (3; 10). Alteplase is the only 
approved therapeutic agent for the treatment of AIS (acute ischemic stroke) and is 
widely accepted as the standard of care for eligible patients (4; 6). The currently 
approved Activase® (alteplase) U.S. Package Insert (USPI) contains wording that 
recommends against use of alteplase in patients with “minor neurological deficit or 
with rapidly improving stroke symptoms” due to the fact this patient population has 
not been evaluated. Furthermore, the current American Heart Association/American 
Stroke Association Council Guidelines include “minor and rapidly improving stroke 
symptoms (clearing spontaneously)” as a relative exclusion criterion for alteplase 
(6). This is largely due to the aforementioned label wording not recommending 
treatment of patients with minor neurological deficit or with rapidly improving stroke 
symptoms (RISS), the lack of a consistent and consensus definition of who 
constitutes this patient population, and the absence of definitive evidence of 
alteplase efficacy in this setting (TREAT Task Force 2013). Therefore, this trial is 
designed to evaluate the efficacy and safety of alteplase in confirmed AIS patients 
with minor neurological deficit or with RISS, which will be referred to collectively as 
“mild stroke”. 
For further background information see Section 1 of the protocol. 
The original plan was for approximately 948 patients with mild stroke to be enrolled 
and randomized in a 1:1 ratio to two treatment groups. However the study 
enrollment was prematurely terminated due to recruitment below target in December 
2016 (at approximately 1/3 of original planned enrollment of 948) and the analysis 
will be performed using available data from patients randomized prior to study 
termination. 
This Statistical Analysis Plan (SAP) describes the statistical methods to be used for 
the clinical study report of study ML29093. This version of the SAP has been 
developed using version 3 of the study protocol dated 08 Jan 2015. The SAP will be 
finalized by 
 and approved by Genentech, Inc. before 
database lock and unblinding. 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
766/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
6/ML29093   
5/17/2017 
 
 
2. 
STUDY DESIGN 
This is a double-blind, multicenter, randomized, Phase IIIb study to evaluate the 
efficacy and safety of IV alteplase in AIS patients with mild strokes that do not 
appear to be clearly disabling. The trial will consist of a screening assessment and 
randomization, treatment followed by a 30-day phone call and a 90-day follow-up 
visit. Treatment with the IV study drug should start within 3 hours from last known 
well time (stroke symptom onset). 
All subjects randomized before the study was terminated will be followed to 
complete all assessments as originally planned. 
 
2.1 
SYNOPSIS 
The protocol synopsis is provided in Appendix A and the schedule of assessments is 
provided in Appendix B. The study flow chart is provided in Figure 1 in Appendix B. 
 
2.2 
OUTCOME MEASURES 
 
2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is: 
• A favorable functional outcome, defined by a modified Rankin Scale (mRS) of 0 
or 1 at Day 90 post randomization 
All mRS assessments will be performed by investigators blinded to treatment 
assignment that are trained and certified in mRS administration. 
 
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcomes are measured at Day 90 and include: 
• Ordinal mRS 
• Global favorable recovery (Global Outcome Measure derived from mRS 0-1, 
National Institutes of Health Stroke Scale [NIHSS] 0-1, Barthel Index [BI] ≥ 95, 
and Glasgow Outcome Scale [GOS] 1) 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
767/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
7/ML29093   
5/17/2017 
 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
The following exploratory outcome measures for this study are measured at day 90 
and included in the analyses described in this SAP: 
• Total score of NIHSS at day 90 
• Instrumental activities of daily living, as measured by the Total score of the BI at 
day 90 
• Raw score of the GOS at day 90 
• Cognition and behavior (modified 30-minute battery):  
– 
Controlled Oral Word Association test;  
– 
Hopkins Verbal Learning Test-Revised [HVLT-R] trials 1, 2, and 3;  
– 
digit symbol coding from the Wechsler Adult Intelligence Scale III [WAIS III]; 
Forward and Backward Digit Span test;  
– 
Benton Judgment of Line Orientation test, form V;  
– 
HVLT-R trial 4 and recognition;  
– 
semantic fluency [Animal Naming test];  
– 
Boston Naming Test [BNT; 15-item short form] 
• Ambulatory performance (as measured by walking speed) 
• Depression (CES-D [Center for Epidemiologic Studies, Depression]) score  
• Quality of Life (EQ-5D [European Quality of Life] questionnaire) 
• Stroke Impact Scale-16 (SIS-16) 
 
2.2.4 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• Symptomatic Intracranial Hemorrhage (sICH) within 36 hours of receiving IV 
study drug (primary safety assessment)  
 
sICH is defined as any neurological decline attributed to new ICH seen on 
imaging by the investigator (based on AE reporting). New ICH seen on imaging 
will be later confirmed on independent reading by blinded central study 
radiologists 
• Any ICH (based on central neuroimaging reading) within 36 hours of receiving IV 
study drug 
• Mortality within 90 days 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
768/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
8/ML29093   
5/17/2017 
 
• Stroke-related and neurological deaths within 90 days 
• Incidence, severity, and spectrum of all adverse events (AEs) and serious AEs 
(SAEs). 
The exploratory safety measure for this study is: 
• Stroke recurrence (based on AE monitoring) within 90 days 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
The sample size was originally determined as follows.  
A sample size of 856 is required in order to achieve 80% power in the primary 
analysis to detect effect size of 9% absolute difference in the proportion of patients 
with favorable outcomes [mRS of 0 or 1 at Day 90] between the alteplase and 
control arms. The above power consideration assumes a control proportion of 65% 
and Type I error of 0.025 (one-sided), and uses a group sequential design with one 
interim analysis for futility (non-binding), based on O’Brien and Fleming boundary, 
conducted after 50% of the anticipated sample size have completed 90-day follow-
up assessments. 
 was used in sample size calculation. 
The intention-to-treat principle will be applied to the primary analysis and, therefore, 
to safeguard against dilution of the treatment effect associated with an approximate 
5% non adherence rate (due to loss to follow-up, consent withdrawal, treatment 
crossovers and stroke mimics), the above sample size was inflated by a factor of 
1.108 (5). Therefore, a total sample size of 948 was planned for this study.  
The study enrollment was terminated early in December 2016, after 313 patients 
were randomized. The analysis will be carried out based on all available data from 
patients randomized prior to termination. With this sample size, power calculations 
show that the study will be substantially underpowered to conduct superiority tests 
(Table 1). Therefore, all efficacy analyses will include estimation of treatment effects 
with the associated two-sided 95% confidence intervals. 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
769/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
9/ML29093   
5/17/2017 
 
Table 1 
Estimated Power for the Final Sample Size (N=313) 
Assumed Effect Size 
7% 
8% 
9% 
Statistical Power a 
25% 
31% 
38% 
a Based on he t-test for the observed proportions of mRS 0-1 at Day 90, using type I error of 0.025, one-sided. 
Assumptions are based on a blinded evaluation of non-adherences in the Jan 2017 Development Safety Update Report 
(DSUR) datacut: 
- Control response rate among confirmed strokes is 74%.  
- 10% of randomized subjects are stroke mimics and 80% of those stroke mimics will have favorable outcome. 
- 1% of subjects received concomitant tPA 
- 7.4% subjects without Day 90 outcome (290 effective sample size) 
 
 
2.4 
ANALYSIS TIMING 
One interim analysis of the primary efficacy outcome was planned for clear futility 
once 50% of the subjects were enrolled.  The interim analysis was to be conducted 
according to the beta-spending approach (9) with an O’Brien - Fleming-type 
boundary. Because of the early termination of the study, the interim analysis will not 
be performed. 
 
3. 
STUDY CONDUCT 
 
3.1 
RANDOMIZATION ISSUES 
Due to the emergency nature of randomization in acute stroke clinical trials, 
treatment assignments must be made in an expeditious manner that also ensures 
even distribution in the treatment groups. A “step forward” randomization regimen 
will be used to ensure that a randomized treatment assignment is available upon 
patients’ arrival at the hospital and treatment can initiate immediately upon signing 
the informed consent and eligibility confirmation (16).  
This procedure will be implemented using an Interactive Web Response System 
(IWRS). Before the first patient is enrolled at a site, the site will register with IWRS 
as part of site activation and "Use Next" drug kit IDs will be allocated for the first 
potential patient. This assigned kit will be used to treat the first patient enrolled at the 
site. Next, the study site enters identification information of the patient AFTER 
he/she is treated (within 8 hours of initiation of the patient’s study treatment). IWRS 
will then assign "Use Next" drug kit IDs for the next patient that becomes eligible at 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
770/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
10/ML29093   
5/17/2017 
 
that site.  Randomization is triggered as soon as the “Use Next” drug kits are used to 
treat an eligible patient. 
Allocation of the “Use Next” kits will be determined by a dynamic randomization 
algorithm. Particularly, allocation will be balanced within the site using the urn 
method (17). In case of perfect balance within site, the overall allocation will be 
balanced using the biased coin method (14, 15). More details are available in 
Appendix C. 
 
3.2 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will provide ongoing review of 
safety outcomes and review efficacy and safety outcomes to inform a futility interim 
analysis after 50% of patients have completed or withdrawn from the study.  
The iDMC will be composed of external advisors. The iDMC will perform functions 
such as: 
• Review all accumulated safety data at periodic safety reviews 
• Make recommendation to the Sponsor as to whether it is appropriate to 
discontinue the study after assessing the interim efficacy and safety data in 
aggregate  
An independent Data Coordinating Center (iDCC) will be responsible for the 
preparation and review of unmasked data.  
Details on iDMC membership, activities and timing are available in the Charter for 
the iDMC. Elaboration of the analyses that were to be conducted by the iDCC at the 
Interim Analysis is contained in the Interim SAP that was developed and signed-off 
for this study. 
 
3.2.1 
Safety Review Timing 
Scheduled iDMC meetings to review safety data were planned to occur after 5% 
(50), 25% (237), 50% (474), and 75% (711) of patients had been enrolled or 
approximately annually. The last iDMC meeting prior to study termination was held 
on 03 May 2016, and included 225 enrolled subjects. Safety monitoring reviews 
included an unblinded evaluation of all adverse events (AEs), serious adverse 
events (SAEs), adverse events of special interest (AESI) including sICH, and any 
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other protocol-specified tests deemed critical to the safety evaluation of the study.  
However, the sponsor, investigators and other responsible for study conduct 
remained blinded. 
 
4. 
STATISTICAL METHODS 
Descriptive statistics will be produced for all endpoints.  Data listings will be 
generated for specific endpoints as appropriate. 
Categorical variables will be summarized as the number and percentage of patients 
or occurrences in each response category. Continuous variables will be summarized 
using descriptive statistics (number of observations, mean, standard deviation, 
median, minimum, maximum). Any required confidence intervals (CIs) will be 
constructed as two-sided 95% CIs. 
 
4.1 
ANALYSIS POPULATIONS 
 
4.1.1 
Intent-to-Treat Population 
All randomized patients are included in the intent-to-treat (ITT) population to adhere 
to the ITT principle. For efficacy analyses, treatment groups will be assigned as 
randomized (IV Alteplase 0.9 mg/kg + Aspirin Placebo, IV Alteplase Placebo + 
Aspirin 325 mg). 
 
4.1.2 
Per-Protocol Population 
The per-protocol (PP) population is defined as the subset of the ITT population 
excluding major protocol violators deemed to have the potential to affect patient 
outcome in terms of efficacy. No analyses will be performed for the PP population 
given the early enrollment termination. However, major protocol deviations will be 
identified in a blinded fashion prior to database lock and will be summarized. These 
deviations will be determined based on the medical monitors’ records, as well as 
programmatically, using the following criteria at a minimum: 
• Did not receive alteplase treatment as randomized 
• Received any additional reperfusion therapy (e.g. IV or IA alteplase and/or 
endovascular therapy)  
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4.1.3 
Safety Population 
The Safety population is defined as all patients who received any amount of study 
drug. For safety analyses, treatment groups will be assigned according to the IV 
alteplase/alteplase placebo actually received. Thus, patients who receive active IV 
alteplase will be assigned to IV Alteplase 0.9 mg/kg + Aspirin Placebo group, and 
patients who receive IV alteplase placebo or did not receive the IV study drug (very 
rare) will be assigned to IV Alteplase Placebo + Aspirin 325 mg group. Group 
assignment will not take into account the actual dose of aspirin; however, it is 
expected that the majority of cases will follow the randomized treatment. Cases who 
did not receive treatment as randomized will be listed as described in Section 4.6.1. 
 
4.2 
ANALYSIS OF STUDY CONDUCT 
The number and percentage of patients who have signed informed consent, been 
randomized in IWRS, received treatment, and completed through Day 30 and Day 
90 (ie, completed the study) will be tabulated overall and for each treatment group. 
Reasons for not completing the study will also be tabulated overall and by treatment 
group using numbers and percentages. 
A summary of the duration of the patient participation in the study will be produced. 
Duration will be calculated as the later date of the last efficacy or last safety 
assessment minus the first study drug administration date + 1. 
The number and percentage of patients included and excluded from the analysis 
populations (ITT and safety) will be tabulated overall and for each treatment group. 
Reason(s) for exclusion from each population will be summarized. 
Major protocol deviations will be listed and summarized by treatment group. 
For those patients who are considered to have failed screening, the reason(s) for 
failure will be provided in a listing. 
 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Clinically important demographic and disease characteristics at screening will be 
summarized overall and for each treatment group. Summaries will be produced for 
the ITT population. 
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Continuous variables will be summarized among patients with non-missing values, 
by the mean, standard deviation, median, first and third quartiles, minimum and 
maximum values. The number of patients with non-missing values will be displayed 
as well. Categorical variables will be summarized using numbers and percentages of 
patients in each category; unknown or missing will be included as a separate 
category. 
The variables to be summarized include but are not restricted to the following: 
• Demographics: sex, ethnicity, race(s), age (continuous and categorized as < 65 
vs. ≥65) 
• Last known well time to treatment (continuous and categorized as 0-2 hours, > 2-
3 hours and >3 hours) 
• Stroke characteristics: previous stroke (Y/N), RISS or non-RISS, stroke etiology, 
location of stroke 
• NIHSS: total score (as continuous and categorical) 
• Baseline substance use status: smoking and drug/substance abuse 
• Medical History (MedDRA), in particular hypertension, diabetes mellitus, atrial 
fibrillation, and prior stroke 
• Baseline Vital Signs: systolic and diastolic blood pressure and pulse 
• Use of Aspirin / antiplatelet drugs within 7 days prior to screening/stroke onset 
• Use of Heparin / anticoagulant drugs within 7 days prior to screening/stroke 
onset 
• Prior medications 
• Baseline neuroimaging (central reading) 
• Baseline Lab Parameters: hematology (complete blood count without 
differential), chemistry (serum glucose), coagulation (international normalized 
ratio, partial thromboplastin time) 
Baseline for NIHSS, vital signs and lab parameters will be defined as the last 
available assessment prior to initiation of any study medication. 
 
4.4 
EFFICACY ANALYSES 
All efficacy analyses will be to estimate treatment effects and provide the associated 
two-sided 95% confidence intervals. 
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Endpoints based on mRS will generally use imputation to achieve the complete ITT 
set, with the exception of the repeated measures modeling. Other efficacy variables 
will use all available data in the ITT population. 
Assessment of efficacy will be conducted based on endpoints collected during the 
Day 90 visit. The protocol allows this visit to be scheduled within 14 days of the 
target 90 days post-treatment; however, a wider window of 30 days will be adopted 
for the purpose of efficacy analysis.  
More details of imputation approach for mRS are provided in Section 4.7 and 
Appendix D. 
 
4.4.1 
Primary Efficacy Endpoint 
The primary efficacy analysis will estimate the effect of treatment with IV alteplase 
therapy and with the standard medical care (aspirin) in AIS patients with mild 
symptoms. The primary efficacy outcome is derived from the mRS. 
The mRS is an assessment of disability with values from 0 (no symptoms at all) to 5 
(severe disability); death will be scored as a '6'. The mRS is collected at 30 and 90 
days after start of study drug administration. If death occurs prior to an assessment 
day (Day 30 or Day 90), the mRS will be considered available and will be set to 6.  
The proportion of patients within each treatment group with a favorable outcome, 
defined by mRS of 0 or 1 at 90 days post-randomization, will be estimated in the IV 
alteplase arm and in the standard medical care arm. Reasons for not performing the 
assessment of mRS at Day 90 will be summarized. 
The difference in proportions between the two groups will be estimated using the risk 
difference. The risk difference will be obtained from a linear model with the binary 
mRS 0-1 outcome as the response, treatment, and age, time from last known well to 
treatment, and baseline NIHSS as continuous covariates. Quadratic terms for the 
continuous covariates may be added to the model, if the Wald p-value for the 
quadratic term is <0.1. No interactions among the covariates will be included in this 
model. 
A common approach for implementation of this model is binary regression, a GLM 
with the Bernoulli distribution for the outcome and the identity link function. This 
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model has a possibility of non-convergence when the estimated response probability 
falls outside of the (0,1) interval. To circumvent the non-convergence problem, an 
approach of using the ordinary least squares with a robust standard error is used in 
this study. It was shown that if a robust standard error is used with the ordinary least 
squares estimation, the estimate of the risk difference is equal or similar to the 
estimate from the GLM with an identity link for Bernoulli outcome approach (22, 23). 
The primary efficacy analysis will include all ITT patients, with patients grouped 
according to the treatment assigned at randomization. Missing or out of window 
mRS at Day 90 will be imputed with LOCF or late Day 90 mRS, if available, or 
simulated with a hot deck method (see Section 4.7 for handling of missing mRS). 
As a supportive analysis of the primary efficacy endpoint, unadjusted or crude risk 
difference will be estimated along with the two-sided 95% CI using normal 
approximation. The standard error for the unadjusted risk difference will be derived 
from the group standard errors, assuming independence: 
 
where p and q are the observed group proportions and N1 and N2 are the group 
sample sizes. 
The treatment effect for the binary mRS outcome will also be evaluated using the 
odds ratio statistic, derived from either a logistic regression, or a repeated measures 
model. These are considered exploratory analyses and described in Section 4.4.3.1. 
 
4.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy outcomes include mRS (full scale) and global favorable recovery 
at Day 90. These results will further describe the treatment effect.  
4.4.2.1 Ordinal Modified Rankin Scale 
As a secondary endpoint, mRS at Day 90 will be further explored on the range of the 
values (0 to 6) where the values of 5 and 6 are grouped. The distribution of full range 
of mRS scores at Day 90 (imputed) will be summarized by treatment group. Both 
tabular displays and stacked bar charts will be prepared.  
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The comparison will be achieved by fitting a proportional odds model with mRS 
score at Day 90 as the dependent variable, and treatment group, pre-treatment 
NIHSS score, age, and last known well time to treatment as the continuous 
predictors (1, 8). Quadratic terms for the continuous covariates may be added to the 
model, if the Wald p-value for the quadratic term is <0.1. No interactions among the 
covariates will be included in this model. The adjusted odds ratio with its two-sided 
95% CI will be shown. Direction of the odds ratio will be chosen to reflect change in 
the odds of achieving a lower (better) mRS if treated with IV alteplase. 
The proportional odds assumption will be tested by the score test, and the p-value 
will be reported. If the proportional odds assumption does not hold, the resulting 
odds ratio will not be presented. The alternative analysis planned for this situation 
will provide the adjusted mean difference between mRS scores with two-sided 95% 
CI. Methodology for this estimation is similar to the primary outcome, but using the 
ordinal mRS as the dependent variable. 
4.4.2.2 Global Outcome Measure 
Global outcome measure is derived from mRS = 0 or 1, NIHSS = 0 or 1, BI ≥ 95, and 
GOS = 1 at Day 90, considered as a whole. If death occurs prior to Day 90, all four 
binary outcomes will be considered as not being achieved in the analysis. 
The NIHSS score is the total from scoring 11 items, assessed by a clinician. Items 
that are not applicable are not included in the total. It is not expected that any items 
will be applicable but missing; in such cases, the total score will be missing. The 
total score ranges from 0 to 42. NIHSS score will be collected pre-treatment, and 
then after 22-36 hours from start of study drug administration, after 5 days or at 
discharge from hospital, and at Day 90.  
The Barthel index (BI) measures activities of daily living by having an assessor rate 
10 items, with possible scores of 0, 5, 10 or 15. A total score, ranging from 0 to 100, 
is computed as the sum of the ratings from the 10 items. As this is a rater-completed 
assessment, no missing data are expected.  However, if any item is not scored, then 
a score of 0 will be given as it will be presumed the subject did not meet the defined 
criteria for the item (20). 
Glasgow Outcome Scale (GOS) is an evaluation of the outcome of stroke, assessed 
on a scale ranging from 1 to 5 by a clinician. The scale will be reversed from the 
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original published version (7) to assign lower scores to more favorable outcomes. 
The score is collected once in the study at Day 90.  
The observed proportion of patients with a favorable outcome within each treatment 
group will be provided for the NIHSS (=0 or 1), BI (≥95) and GOS (=1) components 
of the global outcome measure, in a similar fashion as described for the primary 
outcome. 
Treatment comparisons will be performed considering the four binary outcome 
measures as 4 dimensions of the outcome endpoint (12). These dimensions will be 
assumed to have a common odds ratio adjusted for pre-treatment NIHSS score, 
age, and last known well time to treatment. Quadratic terms for the continuous 
covariates may be added to the model, if the Wald p-value for the quadratic term is 
<0.1. No interactions among the covariates will be included in this model. Estimation 
will be performed using generalized estimating equations for a logistic model with 
correlation between the four outcomes of the same patient. Details of this model can 
be found in Appendix D. The estimated common odds ratio and its two-sided 95% CI 
will be reported.  
Each individual outcome measure will be evaluated separately: odds ratios with two-
sided 95% CIs will be derived from a logistic model with the same covariates as 
used for the global outcome measure to facilitate interpretation of the results.  
LOCF and hot deck imputation will be used for the missing mRS component, 
similarly to the primary analysis. No imputation is planned for the other missing 
components, other than the non-achievement imputation in the event of death. 
However, incomplete component sets can still contribute to the model and will be 
included. 
 
4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 Exploratory Analyses for the Primary Endpoint 
The primary analysis of the mRS 0-1 outcome will be complemented with 
exploratory supportive evaluations of treatment group differences. 
The following analyses will be conducted to construct risk differences for mRS 0-1. 
Missing values for day 90 mRS will be imputed in the same manner as for the 
primary efficacy analysis unless otherwise specified. 
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• Unadjusted risk difference. 
• Adjusted risk difference, from a linear regression with treatment, age, onset 
time to treatment, baseline NIHSS, and propensity score as covariates. The 
propensity score is derived from a logistic regression for treatment group with 
imbalanced covariates included in the model as covariates. This analysis will 
be triggered by presence of baseline imbalance. The criteria for baseline 
imbalance and details of this model are described in Appendix E. 
The following analyses will be conducted to construct the odds ratio for mRS 0-1 
such that the direction of the odds ratio reflects change in the likelihood of achieving 
a favorable outcome if treated with IV alteplase: 
• Logistic regression, adjusting for pre-treatment NIHSS score, age, and last 
known well time to treatment as continuous covariates. Quadratic terms for 
the continuous covariates may be added to the model, if the Wald p-value for 
the quadratic term is <0.1. No interactions will be included in this model.  
• Repeated measures model 
mRS outcomes at Day 30 and Day 90 will be modeled jointly by a logistic 
regression, using the GEE approach to account for the correlation between 
Day 30 and Day 90 outcomes of the same subject. Detailed description of this 
model is provided in Appendix D. No imputation will be performed for missing 
mRS for this particular analysis. 
4.4.3.2 Additional Exploratory Analyses 
To characterize treatment response among the subset of subjects with confirmed 
strokes, adjusted risk difference for the primary efficacy outcome will be repeated on 
the subset of patients with stroke mimics excluded. In addition, analyses as specified 
in section 4.4.2 for the secondary efficacy outcome measures will be produced for 
confirmed strokes. 
4.4.3.3 Modified Rankin Scale 
The mRS score will be used to evaluate the proportion of patients with a score = 0 
vs 1 or higher. Observed percentages and adjusted risk difference will be presented. 
The adjustment will be performed in the same way as for the primary endpoint. 
Adjusted odds ratio will be presented in a separate analysis for this outcome in the 
same fashion as for mRS 0-1. 
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4.4.3.4 National Institutes of Health Stroke Scale 
Descriptive statistics (n, mean, standard deviation, median, quartiles, minimum, and 
maximum) will be provided for NIHSS score by treatment group, both at Day 5 / 
Hospital discharge and at Day 90. Reasons for not performing the assessment of 
NIHSS at Day 90 will be summarized. 
The NIHSS score will be used to evaluate the proportion of patients with a score = 0 
vs 1 or higher, and separately, 0-1 vs. 2 or higher. Observed percentages and 
adjusted risk difference will be presented. The adjustment will be performed in the 
same way as for the primary endpoint. Adjusted odds ratio will be presented in a 
separate analysis for this outcome in the same fashion as for mRS 0-1. 
4.4.3.5 Barthel Index 
The BI total score will be used to evaluate the proportion of patients with complete 
independence (defined as a score = 100) and will be summarized by treatment 
group. Observed percentages and adjusted risk difference will be presented. The 
adjustment will be performed in the same way as for the primary endpoint.Reasons 
for not performing the assessment of BI will be summarized. 
4.4.3.6 Glasgow Outcome Scale 
Raw GOS score will be summarized by treatment group, and include the percentage 
of patients having each GOS score, and the proportion of patients with good 
recovery. Observed percentages and adjusted risk difference will be presented. The 
adjustment will be performed in the same way as for the primary endpoint. Reasons 
for not performing the assessment of GOS will be summarized. 
 
4.4.4 
Subgroup Analyses 
For the primary endpoint, consistency of treatment effect of alteplase will be 
evaluated by various pre-specified baseline covariates. The primary pre-specified 
variables and their analytic thresholds are defined by: 
• Age group (< 65 vs. ≥ 65) 
• Pre-treatment NIHSS score group (0-2 vs. 3-5) 
• Last known well time to treatment group (0-2 hours vs. > 2 hours) 
• Stroke subgroup (RISS vs. non-RISS) 
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Adjusted odds ratios by subgroup will be obtained from multivariable logistic 
regressions with the main effects for treatment, age, last known well time to 
treatment, and NIHSS, and fit separately for each level of the subgroup. 
Interactions of IV alteplase treatment effect with each of the subgroup variables will 
be explored by adding interactions of the subgroup variables with treatment to the 
logistic regression. The interactions will be included one at a time; thus, there will be 
4 separate models to test each interaction. Results from these models will not be 
reported, except when the interaction p-values is smaller than 0.1, in which case the 
p-values will be footnoted in the forest plot. 
A forest plot will be constructed to visually illustrate the subgroup analyses. The plot 
will show the odds ratios described above with two-sided 95% CIs, corresponding to 
each level of these subgroups. The plot will also show the common odds ratio 
estimate in different color or line pattern, as a reference. A subgroup analysis will be 
conducted only if there is at least 10 subjects per outcome (mRS 0-1, mRS >1), and 
the standard error of the odds ratio estimate is stable with the addition of the 
covariates. 
Analysis of the efficacy endpoints is summarized in Table 2. 
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Table 2 
Summary of Efficacy Analyses 
Analysis 
Statistical Method 
Missing Data Method 
Analysis Set(s) 
Primary 
 
 
 
 mRS 0-1 Day 90 
Risk difference via linear 
regression, CI 
LOCF + hot deck 
ITT 
 
 
 
 
Secondary 
 
 
 
 mRS ordinal Day 90 
Proportional odds model 
Descriptive, frequencies 
LOCF + hot deck 
ITT 
 
 
 
 
 
 
 
 
 
 
 
 
 Global outcome 
measure (Global test) 
Logistic regression with a 
4-dimensional outcome 
using GEE 
LOCF + hot deck for 
mRS, non-response for 
death * 
ITT 
 
 
 
 
Exploratory 
 
 
 
 mRS 0-1 Day 90 
Logistic regression 
LOCF + hot deck 
ITT 
 
Logistic regression with 
Day 30 and Day 90 
outcome using GEE 
Repeated Measures 
Model (No imputation) 
ITT  
 
 
 
 
 mRS 0 Day 90 
Descriptive, the risk 
difference via linear 
regression OR via logistic 
regression 
LOCF + hot deck 
ITT 
 
 
 
 
 NIHSS 0, Day 90 
Descriptive, the risk 
difference via linear 
regression OR via logistic 
regression 
No imputation 
ITT 
 
 
 
 
 NIHSS 0-1, Day 90 
Descriptive, the risk 
difference via linear 
regression OR via logistic 
regression 
No imputation 
ITT 
 
 
 
 
 BI 100, Day 90 
Descriptive, the risk 
difference via linear 
regression OR via logistic 
regression 
No imputation 
ITT 
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 GOS 1, Day 90 
Descriptive, the risk 
difference via linear 
regression OR via logistic 
regression 
No imputation 
ITT 
CIs = confidence intervals. 
* A full analysis set approach will be used, so that patients with missingness of some but not all Day 
90 endpoint components will be included the model and contr bute to the estimation of the 
common OR despite missing values on some of the end point components. Death before day 90 
is considerd as having not achieved the four binary end point components. 
 
 
4.5 
COGNITIVE, BEHAVIORAL AND PATIENT REPORTED OUTCOME ANALYSES  
All the cognitive, behavioral and patient reported outcomes are considered 
exploratory. 
 
4.5.1 
Cognitive Assessments 
A series of tests will be conducted at Day 90 to evaluate cognitive abilities of the 
patients. The tests and their outcomes are presented in the following table: 
Table 3 
Cognitive Assessments 
Test 
Outcome 
Controlled Oral Word Association test 
Number of words listed 
Hopkins Verbal Learning test 
Number of words recalled in 3 trials, Retention, 
and Recognition Discrimination Index 
Digit symbol coding from the Wechsler Adult 
Intelligence Scale 
Number of correctly coded digits 
Forward and Backward Digit Span test 
Maximum number of digits repeated, forward and 
backward scores 
Benton Judgment of Line Orientation, form V 
Total score 
Animal Naming test 
Number of unique animals named 
15-item Boston Naming test 
Total number of items answered correctly either 
spontaneously or after a stimulus cue 
 
 
Outcomes from each test will be summarized by treatment group (mean, standard 
deviation, median, quartiles, minimum and maximum). Mean difference between 
treatment groups with 95% unadjusted normal CI will be presented. Reasons for the 
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assessment not being performed will be summarized by the number and percentage 
in each category.  
 
4.5.2 
Ambulatory Performance 
The 10 meter walk test will be conducted at Day 90 visit to measure patient’s 
walking speed. The speed will be measured at a comfortable pace and a fast pace, 
giving two attempts for each pace level. Average speed from the two attempts 
obtained at each pace will be summarized descriptively by treatment group. If speed 
can only be calculated in one of the attempts at a pace level, this result will be used. 
Average speeds will be summarized by treatment group (mean, standard deviation, 
median, quartiles, minimum and maximum). Mean difference between treatment 
groups with 95% unadjusted normal CI will be presented. Reasons for the 
assessment not being performed will be summarized by the number and percentage 
in each category.  
 
4.5.3 
Patient Reported Outcomes 
The patient reported outcomes (PROs) for this study include the EQ-5D, the 16 item 
Stroke Impact Scale (SIS-16), and the Center for Epidemiologic Studies Depression 
Scale (CES-D). 
4.5.3.1 EQ-5D 
Health-related quality of life will be assessed using the EQ-5D. The EQ-5D is a 
generic, preference-based health utility measure with questions about mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression that are used to 
build a composite of the patient’s health status. The second component of the EQ-
5D is a visual analogue scale (VAS), asking patients to rate their health from 0 to 
100 where 0 represents the worst imaginable health state and 100 represents the 
best imaginable health state. 
Each question is scored as 1 for no problem, 2 as some problem, and 3 indicating 
extreme problem. Ambiguous values (eg. 2 boxes are ticked for a single dimension) 
will be treated as missing (neither value used). 
The 5 scores will then be converted into a single summary index by applying the 
time trade-off valuation technique for the US, published by EuroQol group. SAS 
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code to perform the calculation is provided in Appendix G. The resulting summary 
index is a continuous variable ranging from -0.11 (i.e., 3 for all questions) to 1.0 (i.e., 
1 for all questions) on a scale where 0.0 = death and 1.0 = perfect health (18). If any 
of the 5 scores are missing, the summary index will not be calculated and set to 
missing. 
The VAS is scored by the crossing point of the VAS with the response line, or with a 
horizontal line extended from the end point of the response line. Ambiguous values 
(eg. the line crosses the VAS twice) will be treated as missing. 
Scores to each question, the summary index, and the VAS result, will be 
summarized descriptively, and the two-sided 95% CI of the mean difference will be 
presented for the index and VAS.  
4.5.3.2 Stroke Impact Scale-16 (SIS-16) 
Physical functioning will be evaluated using the SIS-16, which is a validated, stroke-
specific, quality of life measure to assess the impact of stroke on a patient’s health 
and life. Each of the 16 items is rated using the following scale: 1 = could not do at 
all; 2 = very difficult; 3 = somewhat difficult; 4 = a little difficult; 5 = not difficult at all. 
The physical domain score is obtained by averaging the non-missing responses, 
provided that 9 or more questions are answered. The score is calculated as:  
Score = 100 x [(Mean – 1) / (5 – 1)] 
which ranges from 0 to 100 (19). 
Responses to individual questions and the physical domain score will be listed. The 
domain score will be summarized by treatment group and the two-sided 95% CI of 
the mean difference will be presented.  
4.5.3.3 Center for Epidemiologic Studies Depression Scale (CES-D) 
The CES-D is a short, self-report scale designed to measure depressive 
symptomatology. Responses to the 20 individual items will be scored to obtain an 
overall depression assessment, as follows.  
1. Assign scores 0 = rarely or none of the time, 1 = some or little of the time, 
2 = occasionally or moderate amount of time, 3 = most or all of the time. 
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2. Reverse positive items by subtracting their score from 3. Positive items are 4, 8, 
12, and 16. 
3. If 4 or fewer items are missing, sum the available item scores to determine the 
total score.  If more than 4 items are missing, no score is calculated. 
The total score will be used to evaluate the proportion of patients with depressive 
symptoms (defined as a score of  ≥ 16 at 90 days) and will be summarized by 
treatment group. 
Observed percentages and adjusted odds ratio will be presented. The adjustment 
will be performed in the same way as for the exploratory analysis of mRS 0-1. 
 
4.6 
SAFETY ANALYSES 
MedDRA (using the latest version at the time of reporting) will be used as the 
thesaurus for AEs and diseases, and the World Health Organization (WHO) drug 
dictionary will be used for treatments and MedDRA for procedures. A glossary of 
these codes will be produced. 
AEs with onset prior to initiation of study treatment which do not worsen after study 
treatment or with onset after Day 90 assessment, will be listed as non-treatment 
emergent and will not be included in the safety summaries. 
 
4.6.1 
Exposure to Study Medication 
Exposure data will be listed for both study drugs. The listing will show the 
randomized treatment as well as the treatment actually received.  
A summary of exposure to alteplase/alteplase placebo will be produced for the 
safety population. The total dose administered and duration of infusion will be 
summarized by active or placebo Alteplase, as actually received. For Aspirin, dose 
received will always be “325 mg”, and therefore will not be summarized. 
Compliance with study medications will be summarized for the safety population. For 
Alteplase, counts of infusion altered or stopped prematurely will be tabulated along 
with the reason. For aspirin, the number of patients who did not take study aspirin 
and a summary of reasons will be presented. 
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4.6.2 
Adverse Events 
AE safety endpoints in this study are: 
• Number and percentage of patients experiencing serious and non-serious AEs 
after receiving study drug 
• Number and percentage of patients experiencing serious and non-serious AEs of 
special interest  
AEs will be coded (using the latest MedDRA version at the time of reporting) and 
tabulated by system organ class (SOC); individual events within each SOC coded as 
preferred terms will be presented in descending frequency using the safety 
population. Treatment groups will be summarized according to the actual treatment 
received. 
AEs will also be tabulated by intensity (severity) and relationship to study drug, as 
indicated by the investigator. Intensity of AEs will be graded according to the WHO 
Toxicity Grading Scale for Determining the Severity of Adverse Events (see 
Appendix 14 of the protocol). Incidence and severity of AEs will be described for all 
treated patients by treatment group and by the MedDRA classification. 
A summary of incidence rates of all deaths and stroke-related or neurological deaths 
will be presented. Cumulative incidence of all deaths and stroke-related or 
neurological deaths will be presented by means of Kaplan-Meier plots if there are 
sufficient events (at least 5 in each group). 
Timing of the AEs relative to Day 30 and Day 90 will be determined, using 
imputation for partial AE start and stop dates if necessary, as described in 
Appendix D. AEs occurring after receipt of any study medication and before Day 90 
will be summarized. AEs leading to IV study drug modification will be listed. SAEs, 
ICH, AEs of special interest and AEs leading to study treatment discontinuation will 
be summarized through Day 90. In addition, non-serious AEs within 30 days will be 
summarized. 
4.6.2.2 
Adverse Events of Special Interest 
Non-serious AESIs are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 
5.4.2 of protocol for reporting instructions). 
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AESIs for this study include the following: 
• sICH events, if not already reported as an SAE (for a list of preferred terms for 
ICH see Appendix 13 of protocol) 
• Stroke recurrence, if not already reported as an SAE. 
Stroke recurrence is defined as a new ischemic stroke based on the AE 
reporting. Stroke events will be identified through a medical review of the AE 
preferred terms. 
• Suspected Transmission of an Infectious Agent via a Medicinal Product 
(STIAMP) by the study drug, if not already reported as an SAE. 
AESIs will be tabulated by SOC and preferred term within SOC by treatment group 
using the safety population.   
 
4.6.3 
Neuroimaging 
Neuroimaging may consist of a non-contrast computed tomography (CT) or 
magnetic resonance imaging (MRI) of the brain. Non-contrast CT or MRI will be 
performed at baseline to ensure that the patient does not have evidence of acute 
intracranial hemorrhage (ICH) prior to study drug administration. 
An additional non-contrast CT or MRI will be performed at 22 to 36 hours from the 
initiation (bolus) of study drug infusion. The purpose of this is to evaluate for ICH in 
the patient. Additional CT scans or MRIs should be performed based on the 
investigator’s discretion, or if any clinical findings suggest ICH. 
All CT and MRI scans will be evaluated by a central team of radiologists blinded to 
the clinical attributes of the case. Results from the evaluation of the CT or MRI scans 
by both local and central readings will be listed, as available. 
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4.6.3.1 
Intracranial Hemorrhage 
Intracranial hemorrhage events (ICH) are identified by neuroimaging and are 
recorded as AEs using one of the terms specified in protocol Appendix 13. The 
images obtained within the first 36 hours after treatment are further evaluated by 
central reading, which may or may not confirm ICH.  
While ICH may be identified at any time during the study, the first 36 hours after 
treatment are the key time interval. If multiple scans indicate ICH within 36 hours, it 
is interpreted as a single ICH event. ICH events identified after the first 36 hours will 
contribute to the general AE summaries. Timing of ICH will be determined according 
to the rules specified in Appendix D. 
Incidence of ICH within 36 hours by AE reporting will be presented by treatment 
group. Determination of ICH within 36 hours from local and central readings of scans 
will also be presented, and agreement between the local and central readings will be 
tabulated.  
Difference in percentage of subjects with ICH within 36 hours based on central and 
local scan reading will be reported by treatment group. A two-sided 95% CI around 
this difference will be constructed using the Miettinen-Nurminen score method (20). 
Additionally, central reading classifications will be used to further describe subtypes 
of any ICH. 
The central reading will classify ICH according to the following intracerebreal 
subtypes: 
• Hemorrhagic infarct type 1 or type 2 
• Parenchymal hematoma type 1 or type 2 
• Remote intraparenchymal hemorrhage type 1 or type 2 
In addition, subarachnoid hemorrhage, subdural hemorrhage, or epidural 
hemorrhage will be noted. ICH subtypes will be tabulated by treatment group. 
4.6.3.2 
Symptomatic Intracranial Hemorrhage 
The protocol specifies that ICH is considered symptomatic (sICH) if it is not seen on 
CT or MRI scan at baseline, and any neurologic decline is attributed to it by the local 
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investigator. Both serious sICH and non-serious sICH events are required to be 
reported by the investigator to the Sponsor immediately.  
sICH within 36 hours is considered the primary safety outcome. sICH events are 
captured through AE reporting. 
In addition to the primary definition of sICH, the following two definitions of sICH will 
be explored and reported in this study. 
• sICH using Heidelberg classification: either (1) PH2 as reported by radiology 
core, or (2) an sICH as classified by PRISMS but also associated with 4-point 
total NIHSS score worsening or 2 point worsening on any single NIHSS item 
when comparing scores immediately pre and post scan. 
• sICH using SITS-MOST definition (25): PH2 as listed by radiology core on CT 
scan between 22-36 hours, which is associated with deterioration of ≥4 points on 
the NIHSS from the lowest NIHSS value between baseline and 36 hours, but 
prior to repeat CT, or leading to death. 
Percentage of subjects with sICH within 36 hours will be presented for each 
definition by treatment group. Difference between treatment group percentages will 
be reported along with a two-sided 95% CI constructed using the Miettinen-
Nurminen score method (20). 
ICH symptomatology will be tabulated for confirmed strokes and separately for 
stroke mimics. 
 
4.6.4 
Laboratory Data 
Specimens for the laboratory tests will be analyzed by the site's local laboratory. 
Tests will be done at screening only and will include hematology (complete blood 
count without differential), serum glucose, coagulation values (INR, partial 
thromboplastin time), and pregnancy test. 
Lab results will be converted to SI units and summarized as part of the baseline 
treatment group comparability described in Section 4.3; no further analysis is 
planned. 
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4.6.5 
Vital Signs 
Vital signs will be collected at screening, and will include measurements of pulse 
and systolic/diastolic blood pressure (while patient is in a supine position). 
Vital signs will be summarized as part of the baseline treatment group comparability 
described in Section 4.3. 
 
4.6.6 
Mortality 
Incidence of mortality will be calculated by treatment group and overall. Details of 
any deaths will be presented in the form of individual patient listings. 
 
4.6.7 
Previous and Concomitant Medications 
Previous medications refer to those stopped prior to study day 1. Previous 
medications will be summarized by medication class and preferred term. Usage of 
Aspirin / antiplatelet drugs and Heparin / anticoagulant drugs up to 7 days prior to 
screening/stroke onset will be summarized. 
Concomitant medications refer to those ongoing during the study. Concomitant 
medications will be summarized by medication class and preferred term. Usage of 
reperfusion therapy will be summarized. Reperfusion therapy includes IV or IA 
alteplase and/or endovascular therapy, and will be adjudicated in a medical review. 
 
4.7 
HANDLING OF DROPOUTS, MISSING/INCOMPLETE DATA, OR OUTLIERS 
For the analyses of the mRS based endpoints, last observation carried forward will 
be used to impute missing or out of window assessments of mRS at Day 90. The 
mRS result carried forward needs to be on or after Day 4 to qualify for this 
imputation. If there is no in-window or LOCF assessment of mRS, then a late Day 90 
mRS will be used if available. 
ITT patients without any observed mRS past day 4 will have their Day 90 mRS 
simulated by a hot deck method. This will be an adjustment cells imputation (24), 
with the cells defined by treatment group, age (< 65 vs. ≥ 65), pre-treatment NIHSS 
score (0 − 2 vs. 3 − 5), and last known well time to treatment (0 − 2 hours vs. > 2 
hours). For each patient with a missing mRS score, a “donor” patient will be drawn at 
random from the pool of patients with available mRS and who belong to the same 
cell as the recepient (i.e. randomized to the same treatment group and having the 
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same categories for age, last known well time to treatment and baseline NIHSS). 
The imputed mRS will then be the mRS value of the “donor”. 
It is expected that only a small number of patients will need the hot deck imputation; 
therefore, the techniques recommended in (24) for a variance estimate that 
incorporates the additional variance from the missing information will not be 
implemented. 
No imputation of missing patient reported outcomes, cognitive assessments, or the 
10-meter walk test will be performed except as specified in the scoring rules for the 
assessment. Reasons for the assessment not being performed will be summarized 
by the number and percentage in each category by treatment group. 
 
4.8 
INTERIM ANALYSES AND/OR SAFETY REVIEWS 
One interim analysis of the primary efficacy outcome was planned for clear futility 
after approximately 50% of patients have completed or discontinued from the study, 
but this analysis was not performed due to early termination of the study. In addition, 
there were 4 planned safety reviews, of which two have occured after 5% (50), and 
25% (237) of patients have been enrolled.  
Details on the procedures for the safety reviews and the interim analysis are in the 
Charter for the iDMC.  
 
5. 
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20. Mahoney FI, Barthel D. Functional evaluation: the Barthel Index. Maryland State Medical 
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24. Andridge RR, Little RJA. A Review of Hot Deck Imputation for Survey Non-response. Int 
Stat Rev. 2010 April; 78(1): 40–64. 
25. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste 
M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; SITS-
MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe 
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observational study. Lancet 2007 Jan 27; 369 (9558): 275-82. 
 
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Appendix A 
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IIIB, DOUBLE-BLIND, MULTICENTER 
STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF ALTEPLASE IN PATIENTS WITH MILD STROKE 
(RAPIDLY IMPROVING SYMPTOMS AND MINOR 
NEUROLOGIC DEFICITS [PRISMS]) 
PROTOCOL NUMBER: 
ML29093 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
3811 
TEST PRODUCT: 
Alteplase (RO5532960) 
PHASE: 
IIIb 
INDICATION: 
Acute ischemic stroke 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1: 27 November 2013 
DATE AMENDED: 
Version 2: 22 August 2014 
Version 3: 17 December 2014 
Objectives 
Primary Objectives 
The primary objective of this study is to determine the efficacy of intravenous (IV) alteplase for 
treatment of acute ischemic stroke (AIS) in patients with mild stroke (also known as “minor 
neurologic deficit” and “rapidly improving stroke symptoms”), defined as a National Institutes of 
Health Stroke Scale (NIHSS) score ≤ 5 and not clearly disabling, within 3 hours of last known well 
time as measured by the proportion of patients with a modified Rankin Scale (mRS) score of 0−1 at 
Day 90. 
Secondary Objectives 
The secondary objectives of this study are as follows: 
To further evaluate efficacy of IV alteplase to improve mild stroke outcomes at Day 90 via: 
Ordinal mRS 
Global favorable recovery (Global Outcome Measure derived from mRS 0-1, NIHSS 0-1, 
Barthel Index [BI] ≥95, and Glasgow Outcome Scale [GOS] = 1) 
 
To evaluate safety as measured by:  
Symptomatic intracranial hemorrhage (sICH) within 36 hours − primary safety assessment 
Any intracranial hemorrhage (ICH) within 36 hours 
Mortality within 90 days 
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Stroke-related and neurological deaths within 90 days 
Incidence, severity, and spectrum of all adverse events (AEs) and serious adverse events 
(SAEs) 
 
Exploratory Objectives 
The exploratory objectives for this study include subgroup analyses of the primary efficacy outcome 
variable in subgroups defined by age (< 65 vs. ≥ 65), pre-treatment NIHSS score (0 − 2 vs. 3 − 5), 
last known well time to treatment (0 − 2 hours vs. > 2− 3 hours), and stroke subgroups (rapidly 
improving stroke symptoms [RISS] vs. non-RISS), respectively. 
 
The following endpoints will also be explored: 
NIHSS 
BI 
GOS 
Stroke recurrence (based on AE monitoring) within 90 days 
Cognition and behavior (modified 30-minute battery: Controlled Oral Word Association test; Hopkins 
Verbal Learning Test-Revised [HVLT-R] trials 1, 2, and 3; digit symbol coding from the 
Wechsler Adult Intelligence Scale III [WAIS III]; Forward and Backward Digit Span test; Benton 
Judgment of Line Orientation, form V; HVLT-R trial 4 and recognition; semantic fluency [Animal 
Naming test]; and Boston Naming Test [BNT; 15-item short form]) at Day 90 
Ambulatory performance (as measured by walking speed) at Day 90  
Center for Epidemiologic Studies-Depression (CES-D)  
Quality of life (European Quality of Life [EQ-5D] questionnaire) at Day 90 
Stroke Impact Scale-16 (SIS-16) at Day 90 
 
Study Design 
Description of Study 
PRISMS is a double-blind, multicenter, randomized, Phase IIIb study to evaluate the efficacy and 
safety of IV alteplase in AIS patients with mild strokes that do not appear to be clearly disabling. The 
trial will consist of a screening assessment, randomization, and treatment followed by a Day 5 visit, 
30-day phone call, and a 90-day follow-up visit. Treatment should start within 3 hours from last 
known well time (stroke symptom onset).  
Screening assessments will be used to determine the eligibility of the patient. Patients meeting 
eligibility criteria will be randomized in a 1:1 ratio to receive either:  
1. One dose of alteplase 0.9 mg/kg IV (not to exceed 90 mg) and one dose of oral aspirin placebo, 
OR  
2. One dose of IV alteplase placebo and one dose of oral aspirin 325 mg. 
Number of Patients 
Approximately 948 patients with AIS and mild strokes will be enrolled in the study across 75 sites in 
North America. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Age ≥ 18 years (no upper age limit) 
Mild ischemic stroke defined as the most recent pre-treatment NIHSS score of ≤ 5 and determined 
as not clearly disabling by the investigator. This includes patients with persistently mild deficits 
as well as those who improve to a pre-treatment NIHSS score ≤ 5 (also known as RISS). 
Study treatment can be initiated within 3 hours of last known well time without stroke symptoms 
(i.e., last seen normal). 
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Signed informed consent prior to initiation of any study-specific procedure or treatment. The patient 
or the patient’s legally authorized representative must be able to provide written informed 
consent and understand the potential risks and benefits from study enrollment and treatment. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Computed tomography (CT) or magnetic resonance imaging (MRI) findings consisting of one of the 
following: 
CT with clear large hypodensity that is greater than one-third middle cerebral artery (MCA) 
territory (or greater than 100 cc if not in MCA territory), 
MRI with clear large hyperintensity on concurrent diffusion-weighted (DW) and fluid-
attenuated inversion recovery (FLAIR) that is greater than one-third MCA territory (or greater 
than 100 cc if not in MCA territory), 
Imaging lesion consistent with acute hemorrhage of any degree, OR 
Evidence of intraparenchymal tumor 
Disability prior to the presenting stroke (historical mRS score ≥ 2) 
Standard contraindications to IV alteplase for patients treated within 3 hours of symptom onset, 
including: 
Head trauma or previous stroke within the previous 3 months 
Myocardial infarction within the previous 3 months 
Gastrointestinal or urinary tract hemorrhage within the previous 21 days 
Major surgery within the previous 14 days 
Arterial puncture at a non-compress ble site within the previous 7 days 
Any history of ICH with the exception of < 5 chronic microbleeds on MRI 
Elevated blood pressure (systolic > 185 mm Hg or diastolic > 110 mm Hg), or the use of 
aggressive measures (use of more than two intravenous agents to lower blood pressure) to 
achieve blood pressure within acceptable parameters 
Treatment with unfractionated heparin within the last 48 hours and activated partial 
thromboplastin time outside of the normal range as specified by the center’s local laboratory 
Blood glucose < 50 mg/dL 
International normalized ratio > 1.7 (Note: This does not need to be verified prior to 
randomization if there is no clinical suspicion of abnormality.) 
Platelet count of < 100,000/mm3 (Note: This does not need to be verified prior to 
randomization if there is no clinical suspicion of abnormality.) 
Treatment with a direct thrombin inhibitor or factor Xa inh bitor (including novel oral 
anticoagulants [e.g., dabigatran, rivaroxaban, apixaban, edoxaban]) within the last 48 hours 
Treatment with a low-molecular-weight heparin (e.g., dalteparin, enoxaparin) within the last 
48 hours 
Allergic reactions to study drug or aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) 
Females of childbearing age who are known to be pregnant and/or lactating, or who have a positive 
pregnancy test on admission 
Inability to swallow, which would prevent oral intake of aspirin or aspirin placebo tablet 
Other serious, advanced, or terminal illness that would confound the clinical outcome at 90 days 
Current or recent (within 3 months) participation in another investigational drug treatment protocol 
Anticipated inability to obtain 3-month follow-up assessments 
Previous enrollment in PRISMS 
Any other condition that the investigator feels would pose a significant hazard to the patient if 
treatment with alteplase is initiated 
 
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Length of Study 
Based on study enrollment projections, this study is estimated to take approximately 4 years to 
complete, from first patient in to last patient’s last visit (LPLV), when the final patient completes the 
90-day follow-up. 
End of Study 
The end of the study is defined as the date when the LPLV occurs. The LPLV is expected to occur 
approximately 90 days (± 14 days) after the last patient is enrolled into the study. 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is: 
A favorable functional outcome, defined by an mRS score of 0 or 1 at Day 90 post-randomization 
All mRS assessments will be made by investigators blinded to treatment assignment who 
are trained and certified in mRS administration 
 
The secondary efficacy outcomes at Day 90 include: 
Ordinal mRS 
Global favorable recovery (Global Outcome Measure derived from mRS 0-1, NIHSS 0-1, BI ≥95, 
and GOS 1) 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
Incidence of sICH within 36 hours (primary safety assessment) 
sICH is defined as any neurological decline attr buted to new ICH seen on imaging by the 
investigator. New ICH seen on imaging will be later confirmed on independent reading by 
blinded central study radiologists.  
Any ICH within 36 hours 
Overall mortality within 90 days 
Stroke-related and neurological deaths within 90 days 
Incidence, severity, and spectrum of all AEs and SAEs 
 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Patients randomized to the active arm will receive treatment with 0.9 mg/kg of IV alteplase 
(maximum 90 mg) per standard stroke dosing. 
Comparator 
Patients randomized to the placebo arm will receive IV alteplase placebo consisting of 1.7 g of 
L-arginine, 5 mg of polysorbate 80, and 0.5 g of phosphoric acid. 
Non-Investigational Medicinal Products 
Comparator 
To maintain standard medical care, patients randomized to the IV alteplase placebo arm will receive 
325 mg of oral aspirin at the same time that they receive IV alteplase placebo. 
Comparator 
Patients in the IV alteplase active arm will receive an oral aspirin placebo tablet at the same time 
they receive IV alteplase. The placebo will be identical in appearance to active aspirin to maintain 
treatment blinding. 
Statistical Methods 
Primary Analysis 
The primary efficacy analysis will test the hypothesis of superiority of IV alteplase therapy over 
standard medical care in AIS patients with mild deficits. The primary efficacy outcome is the 
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proportion of patients with a favorable outcome, defined by mRS score of 0 or 1 at 90 days post-
randomization. The difference in the proportion of mRS 0−1 responders (favorable outcome) at 90 
days post-randomization between the IV alteplase arm and the standard medical care arm will be 
compared via a Cochran-Mantel-Haenszel test, stratified by pre-treatment NIHSS score (0 − 2 vs. 3 
− 5), age (< 65 vs. ≥ 65), and last known well time to treatment (0 − 2 hours vs. > 2− 3 hours). The 
primary efficacy analysis will include all randomized patients, with patients grouped according to the 
treatment assigned at randomization adhering to the intent-to-treat (ITT) principle. As a sensitivity 
analysis, results from the univariate Pearson’s chi-square test will also be presented.  
Determination of Sample Size 
A sample size of 856 is required in order to achieve 80% power for the primary analysis to detect an 
effect size of 9% absolute difference in the proportion of patients with favorable outcomes between 
the alteplase and control arms. The above sample size calculation assumes a control proportion of 
65% and Type I error probability of 0.025 (one-sided), and uses a group sequential design with one 
interim analysis for futility (non-binding), based on an O’Brien-Fleming boundary, after 50% of the 
anticipated sample size have completed the 90-day follow-up assessments.
 was used in 
sample size calculation.  
The ITT principle will be applied to the primary analysis and, therefore, to safeguard against dilution 
of the treatment effect associated with an approximate 5% non-adherence rate (due to lost to follow-
up, consent withdrawal, treatment crossovers, and stroke mimics), the above sample needs to be 
inflated by a factor of 1/0.952 or 1.108 (Friedman et al. 1998). Therefore, a total sample size of 948 
is required for this study.  
Interim Analysis 
One interim analysis of the primary efficacy outcome is planned for clear futility, conducted 
according to the beta-spending approach (Pampallona et al. 2001) with an O’Brien-Fleming-type 
boundary. This futility analysis will occur after approximately 50% of patients (or 474) have 
completed the 90-day assessment. 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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Appendix B 
Schedule of Assessment and Study Flow Chart 
ASSESSMENTS 
Screening and 
Baseline  
(Visit 1) 
Study Drug 
Administration 
22−36 
Hours from 
Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 Days 
(± 14 Days)/ 
Study 
Completion 
Visit 
(Visit 5) 
Early 
Discontinuation 
(Phone call if 
possible) 
Informed consent 
X 
 
 
 
 
 
 
Review of elig bility 
X 
 
 
 
 
 
 
Medical history and baseline 
conditions a 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical examination b 
X 
 
 
 
 
 
 
Vital signs c 
X 
 
 
 
 
 
 
Complete blood count d 
X 
 
 
 
 
 
 
Coagulation status e 
X 
 
 
 
 
 
 
Pregnancy test f 
X 
 
 
 
 
 
 
Serum blood glucose g 
X 
 
 
 
 
 
 
Imaging modality sensitive to 
presence of intracranial 
hemorrhage (either CT or MRI 
with DW MRI, either SW or 
GRE, and FLAIR images). Visit 
2 MRIs should also include T1 
and T2 sequences 
h
 
X 
 
X 
 
 
 
 
NIHSS score i 
X 
 
X 
X 
 
X 
 
Study drug administration 
 
X 
 
 
 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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ASSESSMENTS 
Screening and 
Baseline  
(Visit 1) 
Study Drug 
Administration 
22−36 
Hours from 
Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 Days 
(± 14 Days)/ 
Study 
Completion 
Visit 
(Visit 5) 
Early 
Discontinuation 
(Phone call if 
possible) 
Discharge location 
 
 
 
X 
 
 
 
Patient survival 
 
 
X 
X 
X 
X 
x 
mRS j 
 
 
 
 
X 
X 
 
GOS 
 
 
 
 
 
X 
 
BI k 
 
 
 
 
 
X 
 
EQ-5D k 
 
 
 
 
 
X 
 
CES-D k 
 
 
 
 
 
X 
 
SIS-16 k 
 
 
 
 
 
X 
 
Cognitive assessment l 
 
 
 
 
 
X 
 
Wa king speed m 
 
 
 
 
 
X 
 
Concomitant medications n 
X 
 
X 
X 
X 
X 
X 
Assessment of pregnancy  
 
 
 
 
X 
 
 
Adverse event o 
X 
 
X 
X 
X 
X 
X 
BI = Barthel Index; BNT =Boston Naming Test; CES-D = Centers for Epidemiologic Studies, Depression; CT =computed tomography; DW MRI= 
diffusion-weighted MRI; European Quality of Life = EQ-5D; FLAIR = fluid-attenuated inversion recovery; GOS = Glasgow Outcome Scale; GRE= 
gradient echo; HVLT-R=Hopkins Verbal Learning Test-Revised; ICH = intracranial hemorrhage; INR = international normalized ratio; 
MRI=magnetic resonance imaging; mRS modified Rankin Scale; NIHSS= NIH Stroke Scale; Stroke Impact Scale-16= SIS-16; SWMRI= 
suscept bility-weighted MRI; WAIS III =Wechsler Adult Intelligence Scale III. 
a Includes smoking history and stroke history. 
b A partial neurological examination is to be performed for each patient. The NIHSS will be a component of the neurological examination and will 
be performed only by practitioners who are certified to perform an NIHSS assessment. Additional, or supplemental, neurological exams will also 
be performed, including assessment of mental status, cranial nerves, motor function and coordination. 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
801/aCSR ML29093


 
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ASSESSMENTS 
Screening and 
Baseline  
(Visit 1) 
Study Drug 
Administration 
22−36 
Hours from 
Start of 
Study Drug 
Administration 
(Visit 2) 
Day 5 
(or Discharge 
if Sooner) 
(Visit 3) 
30 Days 
(± 7 Days) 
Phone Call 
(Visit 4) 
90 Days 
(± 14 Days)/ 
Study 
Completion 
Visit 
(Visit 5) 
Early 
Discontinuation 
(Phone call if 
possible) 
c Includes pulse and systolic/diastolic blood pressure (while patient is in a supine position). 
d Complete blood count includes hemoglobin, hematocrit, white blood cell count, and platelet count. 
e Coagulation status includes INR values of > 1.7, activated partial thromboplastin time, patient or family report of patient currently taking an oral 
anticoagulant (e.g., dabigatran, rivaroxaban, apixaban, edoxaban), or patient or family report of patient currently taking a low-molecular-weight 
heparin (e.g., dalteparin, enoxaparin) within the last 48 hours. 
f Pregnancy status will be determined in women of childbearing potential. Serum or urine pregnancy test can be collected. 
g Serum glucose (values of < 50 mg/dL are contraindicated for alteplase). 
h MRI or CT scan should be performed if any clinical findings suggest ICH. 
i NIHSS score should be assessed and recorded at the time of any clinical findings that suggest ICH. 
j The mRS may be performed by telephone, if necessary, for visits on Days 30 and 90. 
k The BI, CES-D, EQ-5D, and SIS-16 can be administered by phone interview if an in-person patient visit cannot be scheduled in the allotted time. 
l  Assessments include: Controlled Oral Word Association test; HVLT-R trials 1, 2, and 3; digit symbol coding from the WAIS III; Forward and 
Backward Digit Span test; Benton Judgment of Line Orientation, form V; HVLT-R trial 4 and recognition; semantic fluency (Animal Naming test); 
and BNT (15-item short form). 
m Assessment of wa king speed requires an in-person patient visit and is best combined with administration of the BI, CES-D, EQ-5D, and SIS-16.  
n Concomitant medications include any prescription medications or over-the-counter preparations used by the patient within 7 days prior to 
screening. 
o Adverse event assessments will be performed during study drug administration; at 22−36 hours after study drug administration; on Days 5, 30, 
and 90 (may be done via telephone interview if necessary), and at early discontinuation. Refer to Section 5.3.1 (Adverse Event Reporting 
Period) for further details. 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
802/aCSR ML29093


 
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Figure 1 Study Flowchart 
 
ASA = aspirin; CT= computed tomography; IV = intravenous; MRI = magnetic resonance imaging; 
mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale. 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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Statistical Analysis Plan:  Alteplase—Genentech USMA 
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Appendix C 
Randomization Scheme 
Initialization of the algorithm: 
• Generate a randomization list for all sites such that half the sites receive 
Treatment Arm A, half the sites receive Treatment Arm B as the first treatment 
assignment.  Need to ensure that as each SITE is activated there is balance 
between Treatment Arm A and Treatment Arm B after every x sites have been 
activated (ie., use permuted block randomization with block size of x) 
• At the time of drug supply receipt verification, obtain the first "USE NEXT" 
treatment assignment sequentially from the pre-generated randomization list. 
When the “USE NEXT” treatment assignment is used on a patient or wasted, 
then the next "USE NEXT" treatment assignment is according to the algorithm in 
Steps 1 and 2. 
Note: If this assignment has not been done in time for the next patient’s arrival to the 
site, then the new patient will be randomized by a fair coin flip. This will be achieved 
by calling IWRS technical support.  
1. Identify the site for which the “USE NEXT” kits are to be assigned (Let “j” be the 
site number). 
2. Calculate the intermediate variables needed (see Table 4) and update the 
appropriate data set. 
3. Compare the appropriate intermediate variables to the specified threshold 
values, site first then overall (see Table 5). 
4. IWRS Service Provider will update the appropriate dataset with (a) USE NEXT 
numbers, (b) random number used by algorithm, (c) study-specific algorithm 
step at which treatment was determined. 
5. When patients have been treated with study drug kits and registered in the 
system, IWRS updates the enrolled numbers and USE NEXT kit numbers. 
Figure 2 displays the randomization steps for the step-forward randomization. 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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Table 4 
Intermediate Variables for the Next Allocation Probability 
Variable 
Definition 
S_j_A 
Number of enrolled patients in Treatment Arm A at Site j 
S_j_B 
Number of enrolled patients in Treatment Arm B at Site j 
S_j_AB 
Imbalance between treatment arms in enrolled patients at Site j, S_1_A - S_1_B 
S_j_Min 
Minimum number of enrolled patients in the two treatment arms at Site j, 
S_j_Min = min(S_j_A, S_j_B) 
S_j_PA 
Probability for assigning the use next kits to treatment arm A in Site j, 
S_j_PA = (S_j_Min - S_j_A + MTI-C) / (2*S_j_Min - S_j_A - S_j_B + 2*MTI-S) 
O_A 
Number of enrolled (ie, treated) patients in Treatment arm A  
O_B 
Number of enrolled patients in Treatment arm B 
O_AB 
Overall imbalance between treatment arms in enrolled patients, 
O_A - O_B, directionality required 
 
 
Table 5 
Decisions Based on Site and Overall Imbalance 
Step 
Site Threshold Comparison 
Type of 
Assignment 
USE NEXT Kit Assignment 
1 
If S_j_AB <= –MTI-S 
Deterministic  
Treatment Arm A. 
 
If S_j_AB >= + MTI-S  
Deterministic  
Treatment Arm B. 
 
if –MTI-S < S_j_AB < + MTI-S 
Go to STEP 2 
 
 
 
 
2 
If S_j_PA = 0.5 
Check overall imbalance, O_AB 
 
 
If O_AB <=  –MTI-O 
Probabilistic 
Treatment Arm A with probability P_BC 
 
 
If O_AB >= + MTI-O 
Probabilistic 
Treatment Arm A with probability 1 P_BC 
 
If S_j_PA ne 0.5 
 
Treatment Arm A with probability S_j_PA 
Note:  MTI-S is the site threshold level (ie, x). MTI-O is the overall threshold level (ie, y). P_BC is the 
biased coin probability (ie, 0.75). 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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Appendix D 
Statistical Methods Requiring Input 
Handling of incomplete start and stop dates of adverse events 
A missing day in a start date will be imputed with the first day of the month, but not 
earlier than the randomization date. A missing day in a stop date will be imputed with 
the last day of the month. 
A missing month/year in a start date will be imputed by the month/year of 
randomization. A missing month in a stop date will be imputed by the month of the 
last contact. A completely missing stop date will be treated as an ongoing AE and 
will not be imputed. 
Determination of ICH and sICH events 
For ICH and sICH events, the following rules will be used to determine their timing 
relative to 36 hours: 
• For ICH determination by scan reading (local or central), take the earliest 
post-baseline scan with bleeding identified. Use the evaluation time of that 
scan to compare to 36 hours. 
• For ICH determination by AE reporting, take the start date of the 
corresponding AE. Then find all scans with the same date of local reading, 
where bleeding is identified. Take the earliest such scan and use the 
evaluation time of that scan to compare to 36 hours. If no scan is found, use 
12:00 am on the AE start date to compare to 36 hours. 
When there are multiple scans associated with a PH2 bleed in a subject, the first of 
these scans will be used to select pre- and post-scan NIHSS scores.   
 
Logistic regression with correlated measures 
This model will be used to estimate the odds ratio describing the global favorable 
outcome, and to estimate the odds ratio of achieving mRS 0-1 at Day 90 in the 
context of repeated measures.  
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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The model is specified as follows: 
• Let Yik, be the correlated binary outcomes (1 = favorable outcome, 
0 = unfavorable outcome) for patient i, and let E(Yik) = µik be the marginal means 
of the outcomes conditional on the patient-specific covariates, including 
treatment.  
For the analysis of the global favorable outcome, k=1,...,4 will index the 4 
dimensions (mRS, NIHSS, BI, and GOS). 
For the analysis of mRS 0-1 k=1,2 will index the repeated evaluations of mRS 
(Day 30 and Day 90). 
• The linear predictor will include an outcome-specific intercept αk, treatment Ti, 
and the explanatory variables Xi. The link function transforming the marginal 
mean outcome µik into the linear predictor will be the logit function: 
logit(µik) = αk + βTi + γkXi 
Importantly, it will be assumed that all outcomes share the same treatment effect 
β. 
• The variance function of Yik will be determined by the binary distribution variance: 
Var(Yik) = µik(1 - µik) 
• The working correlation matrix structure for the outcomes from the same patient 
will be assumed to be unstructured: 
Corr(Yik,Yim) = ρkm, k ≠ m 
For the repeated measures model of mRS 0-1, a temporal correlation structure 
may be chosen instead, which takes into account the distance in time between 
the repeated measures: 
Corr(Yi1,Yi2) = ρ|d1-d2|, 
where d1 and d2 are study days of Day 30 and Day 90 assessments. 
Estimation will be carried out by the generalized estimating equaltions (GEE). 
Adjusted Risk Difference with logistic regression 
The logistic regression model defined for the mRS 0-1 outcome provides estimates 
of the odds of a favorable outcome. These odds can then be converted to 
probabilities, and thus the risk difference can be obtained as a non-linear contrast 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
808/aCSR ML29093


 
Statistical Analysis Plan:  Alteplase—Genentech USMA 
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between the treatment groups. Linearization of this contrast provides an estimate of 
the standard error, the approximation known as the delta method.  
This approach can be implemented with SAS PROC NLMIXED. Here is a sample 
code: 
proc nlmixed data=MRS; 
   eta=b0+b1*(TRTPN=1)+b2*AGE+b3*OTT+b4*NIHSS;    
   p=1/(1+exp(-eta)); 
   model respn ~ binomial(1,p); 
   estimate "tPA vs. Aspirin"  
      1/(1+exp(-(b0+b1+b2*&m1+b3*&m2+b4*&m3)) -  
      1/(1+exp(-(b0+b2*&m1+b3*&m2+b4*&m3)); 
run; 
 
where TRTPN=1 selects tPA treatment, and macro variables m1, m2 and m3 
resolve to the mean values of AGE, OTT and NIHSS, respectively. 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
809/aCSR ML29093


 
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Appendix E 
Documentation of Additional Analyses Performed after Database Lock 
Additional analysis for the primary outcome mRS 0-1 
Baseline imbalance as measured by standardized difference in additional 
explanatory variables listed in Table 6 will be explored. The standardized difference 
can be used to compare the mean of continuous and binary variables between 
treatment groups. For a continuous covariate, the standardized difference is defined 
as the difference in the sample means of treatment groups divided by the pooled 
standard error; see Austin (1) for the mathematical formula. The standardized 
difference compares the difference in means in units of the pooled standard 
deviation. Furthermore, it is not influenced by sample size and allows for the 
comparison of the relative balance of variables measured in different units. Although 
there is no universally agreed upon criterion as to what threshold of the standardized 
difference can be used to indicate important imbalance, a standardized difference 
that is less than 0.1 has been taken to indicate a negligible difference in the mean or 
prevalence of a covariate between treatment groups (1). 
The impact of baseline imbalance if present in at least one candidate variable will be 
evaluated on the adjusted risk difference for the primary efficacy endpoint through a 
propensity score approach. Specifically, when there is at least one candidate 
variable that shows a standardized difference larger than 0.1, propensity scores will 
be generated using a logistic regression model with the treatment group as the 
response variable and all variables listed in Table 6 as independent variables. The 
estimated propensity scores will then be included as an additional covariate in the 
linear regression model performed for the primary outcome. The adjusted risk 
difference will be reported from this model. Note that age, baseline NIHSS and onset 
time to treatment will not be included in the propensity score model, but instead will 
be explicitly adjusted for in the analysis model. 
Missing covariates will be imputed so that all patients have the propensity score 
defined. Continuous covariates will be imputed with their mean values. Categorical 
covariates will be collapsed to avoid rare categories.The least frequent categories 
will be merged together until there are at least 10 subjects per category and the 
propensity score model has no estimation problems. If there is a substantial number 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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of missing values in a categorical variable, missing may be considered as a 
standalone category for the purpose of generating a propensity score. 
 
 
Table 6 
Baseline Characteristics to be Evaluated for Imbalance 
 
 
Sex 
Prior anti-platelet drug use 
Race 
Prior anti-coagulant drug use 
Ethnicity 
Baseline glucose 
Smoking 
Baseline systolic blood pressure 
Medical History 
Baseline coagulation test: INR 
 - Hypertension 
 
 - Diabetes Mellitus  
 
 - Atrial Fibrillation 
 
 - Stroke 
 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
811/aCSR ML29093


 
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Appendix F 
Data Handling Rules 
The data handling rules will be provided as a separate document to be developed in 
conjunction with any dry runs and finalized before database lock for the interim 
analysis and separately for the final analysis. 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
812/aCSR ML29093


 
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Appendix G 
Programming Codes for Statistical Analysis 
Calculation of the EQ-5D summary index 
data LIBNAME.NEWDATANAME ; set LIBNAME.DATANAME ; 
 
/* Generate Dummy Variables for Levels 2 and 3 of Five Dimensions */ 
m1 =0 ; m2 =0 ; 
s1 =0 ; s2 =0 ; 
u1 =0 ; u2 =0 ; 
p1 =0 ; p2 =0 ; 
a1 =0 ; a2 =0 ; 
 
if mobility = 2 then m1 = 1 ; 
if mobility = 3 then m2 = 1 ; 
if selfcare = 2 then s1 = 1 ; 
if selfcare = 3 then s2 = 1 ; 
if activity = 2 then u1 = 1 ; 
if activity = 3 then u2 = 1 ; 
if pain = 2 then p1 = 1 ; 
if pain = 3 then p2 = 1 ; 
if anxiety = 2 then a1 = 1 ; 
if anxiety = 3 then a2 = 1 ; 
 
/* Generate Interaction Terms (I2, I2-squared, I3, I3-squared) */ 
m0 = 0 ; 
s0 = 0 ; 
u0 = 0 ; 
p0 = 0 ; 
a0 = 0 ; 
 
if m1 = 0 and m2 = 0 then m0 = 1 ; 
if s1 = 0 and s2 = 0 then s0 = 1 ; 
if u1 = 0 and u2 = 0 then u0 = 1 ; 
if p1 = 0 and p2 = 0 then p0 = 1 ; 
if a1 = 0 and a2 = 0 then a0 = 1 ; 
 
i2 = m1 + s1 + u1 + p1 + a1 ; 
i2 = i2 - 1 ; 
if i2<0 then i2 = 0 ; 
i22 = i2*i2 ; 
i3 = m2 + s2 + u2 + p2 + a2 ; 
i3 = i3 - 1 ; 
if i3<0 then i3 = 0 ; 
i32 = i3*i3 ; 
 
/* Generate D1 Term */ 
i1 = m0 + s0 + u0 + p0 + a0 ; 
d1 = 4 - i1 ; 
if d1<0 then d1 = 0 ; 
 
 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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/* Generate Raw Index Score */ 
pred =  .146016*m1  +  .557685*m2  +  .1753425*s1 + .4711896*s2  + 
        .1397295*u1 +  .3742594*u2 +  .1728907*p1 + .5371011*p2  + 
        .156223*a1  +  .4501876*a2 + -.1395949*d1 + .0106868*i22 + 
       -.1215579*i3 + -.0147963*i32 ; 
 
EQ_index = 1 - pred ; 
if (mobility = .) or (selfcare = .) or (activity = .) or (pain = .) or  
   (anxiety = .) then EQ_index = . ; 
 
/* Drop Variables Generated by Program */ 
drop m1 m2 s1 s2 u1 u2 p1 p2 a1 a2 m0 s0 u0 p0 a0 i1 i2 i22 i3 i32 d1  
pred ; 
 
run ; 
Ordinary Least Squares with Robust Standard Error 
proc reg data=mrs; 
   model mrs = trt age ott nihss / hcc hccmethod=0; 
run; 
 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
814/aCSR ML29093