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)
Phase: PHASE3
Conditions: Stroke
Sponsor: Genentech, Inc.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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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. 
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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RIORFRPRWRUUHFRYHU\DIWHUVWURNH,Q&UDLN5$2DWLV&HGV*DLW$QDO\VLV7KHRU\DQG
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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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7UHDWPHQWZLWKZDUIDULQDQG,15! (Note:  INR does not need to be verified prior 
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tubal ligation 
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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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SULQFLSOH
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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. 
$OWHSODVH²*HQHQWHFK,QF
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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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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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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. 
Alteplase—Genentech, Inc. 
Protocol ML29093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
499/aCSR ML29093
67 

 
 
 
 
 
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 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
500/aCSR ML29093
68 

 
 
 
 
 
 
 
 
 
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.
501/aCSR ML29093
69 

 
 
  
 
 
 
 
 
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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Gonzales NR, Albright KC, Noser KC, et al. “Mild stroke” should not exclude patients 
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Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
507/aCSR ML29093
75 

 
 
 
 
 
Khatri P, Kleindorfer DO, Yeatts SD, et al. Strokes with minor symptoms: an exploratory 
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Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with 
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Köhrmann M, Nowe T, Huttner HB, et al. Safety and outcome after thrombolysis in 
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National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study Group. 
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Neurological Disorders and Stroke rt-PA Stroke Study Experience. Ann Emerg Med. 
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Reeves M, Khoury J, Alwell K, et al. Distribution of NIHSS in the Cincinnati/Northern 
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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 
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Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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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 ML2 9093, Version 2 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
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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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J 6HUXPJOXFRVHYDOXHVRIPJG/DUHFRQWUDLQGLFDWHGIRUDOWHSODVH
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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). 
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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 
Period) for further details. 
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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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RIORFRPRWRUUHFRYHU\DIWHUVWURNH,Q&UDLN5$2DWLV&HGV*DLW$QDO\VLV7KHRU\DQG
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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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D&650/

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

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
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Baumann CR, Baumgartner RW, Gandjour J, et al. Good outcomes in ischemic stroke 
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Demaerschalk BM. Thrombolytic therapy for acute ischemic stroke: the likelihood of 
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Edlow JS, Smith EE, Stead LG, et al. Clinical policy: Use of t-PA for the management of 
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Gonzales NR, Albright KC, Noser KC, et al. “Mild stroke” should not exclude patients 
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Hassan AE, Hassanzadeh B, Tohidi V, et al. Very mild stroke patients benefit from 
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67/Protocol ML29093, Version 3 
Abbreviated Clinical Study Report:  Alteplase—Genentech, Inc.
612/aCSR ML29093

 
 
 
 
 
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Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with 
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Köhrmann M, Nowe T, Huttner HB, et al. Safety and outcome after thrombolysis in 
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Pampallona S, Tsiatis AA, Kim K. Interim monitoring of group sequential trials using 
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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