Protocol synopsis



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PROTOCOL SYNOPSIS



TITLE: A PHASE IIA, MULTI-CENTER, RANDOMIZED, SINGLE-BLIND, PLACEBO-CONTROLLED, CROSSOVER STUDY TO ASSESS THE SAFETY,

TOLERABILITY, AND PRELIMINARY EFFICACY OF A SINGLE INTRAVENOUS DOSE OF ALLOGENEIC HUMAN MESENCHYMAL STEM CELLS TO SUBJECTS WITH MILD TO MODERATE DEMENTIA DUE TO ALZHEIMER’S DISEASE

PROTOCOL NUMBER: STEM105-M-AD

INVESTIGATIONAL


PRODUCTS: Human Mesenchymal Stem Cells (hMSCs)
PHASE: IIa

INDICATION: Dementia due to Alzheimer’s disease

IND NUMBER: 16476

SPONSOR: Stemedica Cell Technologies, Inc.

5375 Mira Sorrento Place, Suite 100



San Diego, CA 92121

COLLABORATOR: Stemedica International SA

Route de la Corniche 9A 1066 Epalinges Switzerland


DATE OF DOCUMENT: May 22, 2015


STUDY OBJECTIVES


Primary:
To assess the safety and tolerability of ischemia-tolerant allogeneic human mesenchymal stem cells (hMSCs) manufactured by Stemedica versus placebo administered intravenously to subjects with mild to moderate dementia due to Alzheimer’s disease.

Secondary:


To assess the preliminary efficacy of hMSCs versus placebo in subjects with Alzheimer’s-related dementia, as evidenced by neurologic, functional, and psychiatric endpoints.

STUDY RATIONALE


Stemedica International has conducted extensive preclinical experiments using Stemedica- manufactured hMSCs in a mouse model of Alzheimer’s disease (APPPS1) that develops early and robust cerebral amyloid pathology. The APPPS1 transgenic model develops initial Abeta amyloid plaques in the cortex by 6 weeks of age. Preclinical experiments conducted by Stemedica International using intravenous (IV) delivery of hMSCs demonstrated efficient Abeta amyloid plaque removal in the brain parenchyma of the APPPS1 mouse model. The beneficial effect on Abeta plaques was accompanied by an overall decrease in neuroinflammation markers (e.g., reduction of microglia activation) without the appearance of amyloid clearance side effects such as cerebral amyloid angiopathy of microhemorrhages.

The positive impact of IV treatment with hMSCS on Alzheimer pathology achieved in transgenic mice constitute the preclinical basis for the translation of this stem cell therapy concept towards clinical application in Alzheimer patients.




EXPERIENCE IN HUMANS


Seventeen (17) subjects with ischemic stroke have been treated in a Phase I/IIa study with hMSCs manufactured by Stemedica. The objectives of this study were to assess the safety and tolerability of Stemedica-manufactured hMSCs administered intravenously, and to assess the study treatment’s effects on neurologic, functional and motor deficits. Demographic information is available for 15 subjects. Thirteen (13) males and 2 females, ranging from 38 to 84 years of age, were treated in this study. The Phase 1 dose-escalation portion of this trial has been completed. Three cohorts of patients, 5 patients in each cohort, were treated at doses of 0.5, 1.0, and 1.5 million cells per kg of patient’s body weight. A Data and Safety Monitoring Board was employed in this study and voted unanimously to proceed to the Phase 2 portion of the study at the dose of 1.5 million cells per kg of patient’s body weight. Two subjects have been treated in the Phase 2 portion of this trial. Safety assessments were performed on days 1, 2, 3, 4, 10 and on months 1, 3, 6, 9 and 12.

No patients discontinued the study due to an adverse event (AE). There were 33 AEs reported in 17 subjects treated: 15 were classified as mild and 18 were classified as moderate by the investigator(s); none were severe. Of these 33 AEs, 24 were classified as unrelated to study drug and 8 were classified as unlikely to be related to study drug by the investigator(s). Only one AE was classified as possibly related to study drug: “foul smell urine”. This AE was rated “mild” by the investigator. It commenced soon after study drug treatment with 1 million cells/kg and resolved within one day.



Seven (7) serious adverse events were reported in this study and all were classified as unrelated to study drug by the investigator(s). CT scans with and without contrast of the chest, abdomen and pelvis were reviewed; there were no clinically significant abnormalities on post-treatment scans. Also, there were no significant abnormalities on post-treatment physical exams or vital signs. In summary, participants with ischemic stroke have been treated with hMSCs manufactured by Stemedica at doses up to 1.5 million cells / kg with excellent tolerability and no apparent safety concerns.


STUDY DESIGN


This is a Phase IIa multi-center, randomized, single-blind, placebo-controlled, crossover study in subjects with mild to moderate dementia due to Alzheimer’s disease. Only the subject and their caregiver will be blinded to the study treatment. The study will consist of two cohorts of subjects (20 subjects per cohort), randomized in a 1:1 allocation to receive active study drug or placebo. Cohort 1 will receive a single intravenous dose of hMSCs of 1.5 million cells per kilogram body weight on their Study Day 1, and Cohort 2 will receive equal volume of Lactated Ringer’s Solution on their Study Day 1. At the six-month time point for each subject after their first infusion, Cohort 1 will receive a single intravenous dose of Lactated Ringer’s Solution and Cohort 2 will receive a single intravenous dose of hMSCs at 1.5 million cells per kilogram of the subject’s body weight. No subject will receive more than the maximum dosage of 150 million cells in this study. Approximately 40 subjects will be enrolled in this study. Subjects who discontinue the study before Month 6 will be replaced until at least 20 subjects in each cohort have been enrolled.

Subjects will be administered the intravenous dose of hMSCs or placebo with frequent monitoring until discharged from the clinic. Subjects will be evaluated per the following post- treatment schedule: Study Day 4, Day 10, Month 1, Month 3, Month 6, four (4) days after Month

6, ten (10) days after Month 6, Month 7, Month 9, Month 12, Month 15, and Month 18. If the subject terminates the study before Month 18, they will be fully evaluated at an Early Termination visit. During infusion and follow-up of subjects, the safety profile of hMSCs will be determined as well as efficacy assessments throughout the 18-month follow-up period. An independent Data and Safety Monitoring Board (DSMB) will conduct periodic safety reviews according to the following schedule: after 5 subjects in each treatment group have completed Day 10 study visit; after 10 subjects in each treatment group have completed Month 3 study visit; if a study drug-related serious adverse event occurs in a subject enrolled in this study; if a study drug-related unexpected adverse event occurs in a subject enrolled in this study; and at the end of



the study. An interim analysis of safety and efficacy data will be performed after at least 10 subjects in each treatment group have completed Month 6 visit assessments.
Figure 1 Clinical Trial Flowchart





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