Clinical Trials Register

Summary
EudraCT Number:	2012-005749-18
Sponsor's Protocol Code Number:	B01-02
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-01-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2012-005749-18

A.3

Full title of the trial

Double-Blind, Randomized, Placebo-Controlled, Phase 2 Safety and Efficacy Trial of MultiStem® in Adults With Ischemic Stroke

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Double-Blind, Randomized, Placebo-Controlled, Phase 2 Safety and Efficacy Trial of MultiStem in Adults With Ischemic Stroke

A.3.2

Name or abbreviated title of the trial where available

Phase II Trial of MultiStem in Adults with Ischemic Stroke, 16May2012

A.4.1

Sponsor's protocol code number

B01-02

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01436487

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Athersys, Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Athersys, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Athersys Inc.
B.5.2	Functional name of contact point	Deborah Ladenheim
B.5.3	Address:
B.5.3.1	Street Address	3201 Carnegie Ave
B.5.3.2	Town/ city	Cleveland, Ohio
B.5.3.3	Post code	44115
B.5.3.4	Country	United States
B.5.4	Telephone number	17343583325
B.5.6	E-mail	dladenheim@athersys.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	MultiStem
D.3.4	Pharmaceutical form	Suspension for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MultiStem
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1200 million
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

acute ischemic stroke

E.1.1.1

Medical condition in easily understood language

Blockage of blood vessels in the brain resulting in damage to brain.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10055221
E.1.2	Term	Ischemic stroke
E.1.2	System Organ Class	100000004852

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10027580
E.1.2	Term	Middle cerebral artery stroke
E.1.2	System Organ Class	100000004852

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10042244
E.1.2	Term	Stroke
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives of this study are to:

-determine the highest safe and effective single dose of MultiStem in subjects that have had an ischemic stroke in the past 24-36 hours.

-determine the efficacy of MultiStem on functional outcome in subjects with ischemic stroke.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to:

-determine the safety of MultiStem in subjects with acute stroke.

-determine changes in ability to perform daily activities and improvement in stroke symptoms in subjects treated with MultiStem.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Clinical diagnosis of cortical cerebral ischemic stroke.

Occurrence of a moderate to moderately severe stroke with clear motor or speech deficit documented by NIHSS score of 8 to 20 (inclusive) that did not change by more than or equal to 4 points from the screening to baseline assessment. The NIHSS score must be confirmed during the baseline visit 24 to 32 hours from the time of stroke onset. Note: The NIHSS screening score used for eligibility should be the last score collected prior to the baseline reconfirmation NIHSS score. There should be at least 6 hours between baseline and the last NIHSS assessment during screening.

Onset of stroke must have occurred 24 to 36 hours prior to administering the investigational product. Time of onset is defined as the time point when symptoms first began. For stroke that occurred during sleep, time of onset is defined as the time point when the subject was last observed to be normal or was self-reported to be normal.

Confirmation of hemispheric cortical infarct with MRI including diffusion-weighted imaging (DWI) demonstrating an acute lesion measuring greater than or equal to 5 mL and less than or equal to 100 mL.

A Rankin score of 0 or 1, by either self-report or family report, prior to the onset of the symptoms of the current stroke.

Subjects who received either tPA up to 4.5 hours post-stroke, or underwent mechanical reperfusion are eligible if they meet all eligibility criteria.

E.4

Principal exclusion criteria

Presence of a lacunar or a brainstem infarct on MRI as the etiology of current stroke symptoms.

Reduced level of consciousness (score of greater than 2 for item 1a of NIHSS).

Occurrence of a hemorrhagic transformation of ischemic stroke as evidenced by computerized tomography (CT) or brain MRI scan that is clinically significant in the opinion of the investigator.

Ipsilateral focal neurological deficits from prior lesions in the brain that would complicate evaluation.

History of arrhythmias or QTc prolongation that is clinically significant in the opinion of the investigator.

Experienced seizures since the onset of stroke.

Experienced a major neurological event such as stroke or clinically significant head trauma within 6 months of screening.

Uncontrolled hypertension, defined as persistent systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg, despite antihypertensive therapy.

Blood glucose level <50 mg/dL or >350 mg/dL at baseline.

Known history of severe congestive heart failure or history of ejection fraction >30%.

Active unstable angina requiring daily treatment with nitrates or other medications
Known human immunodeficiency virus, ongoing systemic infection, severe local infection or who are immunocompromised.

Have other neurological disorders such as Alzheimer’s disease, Parkinson’s disease, or other degenerative disease that would affect the subject’s ability to participate in the trial or complicate evaluation.

Have a history of malignancy of any type, with the exception of adequately treated basal or squamous cell carcinoma of the skin.

Have severe lung disease requiring home oxygen.

Have a contraindication for MRI such as implanted pacemakers or other metallic prosthesis incompatible with MRI, body weight, or claustrophobia.

Have thrombocytopenia (platelet count <75,000/mm3) or heparin induced thrombocytopenia.

Have a life expectancy less than 90 days.

Have a known allergy or religious objections to human tissue or bovine or porcine products.

Previous surgical removal of the spleen.

Plan to have a neurovascular procedure (eg, carotid endarterectomy, stent placement, etc.) within the first year following stroke.

Received both tPA and mechanical reperfusion for the current stroke.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy parameter is the proportion of subjects with a modified Rankin Scale disability score of less than or equal to 2 (favorable outcome) at Day 90 in the MultiStem treatment group compared to the placebo treatment group.

The primary safety variable is the Dose Limiting Toxicity (DLT) between MultiStem and placebo defined as any of the following:

•Grade 3 or 4 infusion-related allergic adverse events that are related to investigational product consisting of perturbation of cardiovascular, respiratory function or allergic reactions (eg, rash, erythema) occurring in the first 24 hours post-infusion of investigational product

•Grade 3 or 4 adverse events that are related to investigational product assessed through 7 days post-infusion of investigational product

•Neurologic worsening that is related to investigational product and defined as a greater than or equal to a 4 point increase in NIHSS compared to baseline NIHSS assessed through 7 days post-infusion of investigational product.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 90 for the primary efficacy endpoint of Modified Rankin Scale score.

Through 7 days post-infusion for the primary safety endpoints.

E.5.2

Secondary end point(s)

The secondary efficacy parameters include an examination of the difference between the MultiStem and placebo treatment groups for the following:

• Functional outcome throughout the range of modified Rankin Scale scores by shift analysis at Day 90 and
•The proportion of subjects with an excellent outcome at Day 90 defined by all of the following criteria:
o Modified Rankin Scale score 0 to 1 (scale, 0 to 6);
o NIHSS total score 0 to 1; and
o Barthel Index greater than or equal to 95 (scale, 0 to 100)

The secondary safety variables are the differences in safety assessments including adverse events, vital signs (blood pressure, heart rate, respiration rate, temperature, and oxygen saturation), laboratory parameters, and the incidence of secondary infections (local and systemic) through Day 365 between the MultiStem and placebo treatment groups.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 90 for the secondary efficacy endpoints.

Through Day 365 for the secondary safety endpoints.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1