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
STUDY ENDPOINTS
Primary
The primary endpoint will be the safety and tolerability of hMSCs administered to subjects with mild to moderate Alzheimer’s disease-related dementia during the eighteen-month study period, as determined by the incidence and severity of adverse events, clinically significant changes on clinical laboratory tests, electrocardiograms (ECGs), brain MRIs (without contrast), CT scans of the chest (without contrast), vital signs, physical examinations, serum IgA, IgE, IgG, IgM, and lymphocyte proliferation panel, and the Columbia Suicide Severity Rating Scale (C-SSRS).
Secondary
The secondary endpoint will be the preliminary efficacy of hMSC administration, as shown by a change from baseline in the following assessment tools:
· Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
· Mini-Mental State Examination (MMSE)
· Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
· Geriatric Depression Scale (GDS)
· Neuropsychiatric Inventory Questionnaire (NPI-Q)
· Clinical Global Impression of Change Rating (CGIC)
· Neurological examinations
SUBJECT SELECTION
Subjects will be selected using the following inclusion and exclusion criteria.
Inclusion Criteria:
1. Males or females between 55-80 years of age.
2. Diagnosed with mild to moderate dementia for at least 3 months prior to enrollment, based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINDS-ADRDA) Alzheimer’s criteria.
3. MMSE between 12-24 (inclusive) at time of enrollment.
4. Amyloid-positive florbetapir PET scan.
5. Reasonable expectation that subject will attend all scheduled safety follow-up visits.
6. Subject or legally authorized representative provides written informed consent in compliance with local regulations prior to enrollment into this study.
7. The subject and caregiver are willing to participate in this study for at least 18 months
after enrollment.
Exclusion Criteria:
1. Prior treatment with stem cells.
2. History of intracranial, subdural, or subarachnoid hemorrhage.
3. Subjects with baseline brain MRI showing more than four (4) cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as “possible” or “definite”), and/or one (1) or more areas of superficial siderosis, and/or evidence of a prior macrohemorrhage. MRI must include fluid-attenuation inversion recovery (FLAIR) and T2*-weighted gradient-recalled-echo (GRE) sequences.
4. History of cancer within the past 5 years, with the exception of localized basal or squamous cell carcinoma.
5. History of seizure disorder.
6. Diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
7. History of cerebral neoplasm.
8. Myocardial infarction within six months of enrollment.
9. Major surgery within 4 weeks of enrollment.
10. Positive for hepatitis B, C or HIV.
11. Diabetes.
12. Presence of any other clinically significant medical condition, or laboratory abnormality that in the judgment of the Investigator or Sponsor for which participation in the study would pose a safety risk to the subject.
13. Participation in another study with an investigational drug or device within 3 months prior to enrollment.
14. Participation in another study concurrent with the duration of the trial.
15. History within the past year of drug or alcohol abuse.
16. Any co-existing or terminal disease that may limit life expectancy during the course of the study.
17. Females known to be pregnant, lactating or having a positive pregnancy test (women of child-bearing potential will be tested during screening) or planning to become pregnant during the study.
18. Allergies to bovine and porcine products.
19. Administration of corticosteroid within one month prior to study entry.
20. If subject is receiving a marketed Alzheimer’s disease drug, they must have been on a stable dose for at least 3 months prior to their infusion of hMSCs.
STUDY TREATMENT
hMSCs manufactured by Stemedica are derived from adult, human bone marrow cells. This study will consist of two cohorts of subjects (20 subjects per cohort), randomized in a 1:1 allocation to receive active study drug (hMSCs) or placebo. Cohort 1 will receive a single intravenous dose of hMSCs at 1.5 million cells per kilogram body weight on their Study Day 1 and Cohort 2 will receive an 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. The randomized treatment (i.e., Cohort 1 or 2) for each subject will be communicated to the clinical research site by the sponsor or its designee on a per-patient basis, after the patient has met all eligibility criteria.
Each clinical research site’s pharmacy will perform the final formulation of study drug (hMSCs) for administration to an individual study subject following the process detailed in Stemedica’s Pharmacy Manual. The final formulation process consists of thawing frozen hMSCs in cryovials, washing the cells in Lactated Ringer’s Solution (LRS), centrifugation, and re- suspending them in LRS. The formulation must undergo multiple tests (e.g., endotoxin, appearance, and gram stain tests) before being released by the clinical research pharmacy for intravenous administration by the investigator. In addition, a sample of each subject’s final formulation must undergo sterility testing by a laboratory approved by Stemedica. Unless the clinical research site’s pharmacy has liquid nitrogen tanks for long-term storage of frozen cryovials, a limited number of cryovials sufficient for an individual subject’s dose, will be shipped to the site upon subject’s randomization to active study drug.
After release by the clinical research pharmacy, the final formulation of hMSCs must be stored at 2°C to 8°C, and administered to the subject within 8 hours of preparation. Final formulation hMSCs that are not used within this period of time must be discarded.
Administration of Study Treatments
On the days that the subject will receive study treatment (Study Day 1 and Month 6), if the subject was randomized to receive hMSCs at that visit, the appropriate number of cryovials of hMSCs will be thawed and re-suspended in Lactated Ringer’s Solution (LRS) at a concentration of 1.0 million cells/mL by the clinical site pharmacy. If the subject was randomized to receive placebo at that visit, the pharmacy will prepare an equal volume of LRS. The syringes will be
masked and appear to be identical. Prior to administering the study drug to the subject, a skin test will be administered using 0.1 mL aliquot of the Final Formulation (hMSCs or placebo).
An intravenous line will be placed into an appropriate vein on the subject’s upper extremity or hand with 0.9% sodium chloride solution running to keep the vein open. The suspension described above will be taken up in an 18 gauge needle using a 60 mL syringe with an eccentric (offset) tip. The needle will be removed and an infusion set will be attached to the syringe. The syringe with infusion set will be placed in a metered dose syringe pump, positioned horizontally, and with the syringe rotated such that the syringe tip is at the lowest position. The study drug will be intravenously infused into the subject’s arm at a constant rate of approximately two million cells per minute (which is approximately 2mL per minute); up to three syringe loads may be used. After the entire dose is delivered, 25mL of LRS (without cells) will be taken into the syringe and infused over 15 minutes through the syringe and wingset; this is done to flush cells from the dead-volume of the syringe tip and wingset into the subject for more accurate dosing.