Phase IIa Randomized Placebo Controlled Trial: Mesenchymal Stem Cells as a Disease-modifying Therapy for iPD

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to select the safest and most effective number of repeat doses of allogeneic bone marrow-derived mesenchymal stem cell (MSC) infusions to slow the progression of Parkinson's disease (PD).

Detailed Description
-----------------
Single site phase IIa study of allogeneic MSC in a double blind randomized control trial as disease modifying therapy for PD. The design includes three treatment arms with 45 patients.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled Trial of Allogeneic Bone Marrow-derived Mesenchymal Stem Cells as a Disease-modifying Therapy for Idiopathic Parkinson's Disease

Conditions
-----------------
Parkinson's Disease

Intervention / Treatment
-----------------
* Drug: MSC+placebo
* Drug: MSC
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of Parkinson's disease by the UK brain bank criteria including the presence of 2 cardinal signs of PD plus bradykinesia. Mild microsomia to anosmia. A modified Hoehn and Yahr stage of 3 or less. Date of diagnosis of PD between 3 to 10 years Robust response to dopaminergic therapy. Exclusion Criteria: Atypical, vascular, or drug-induced Parkinsonism. An atypical DAT scan or MRI supporting an alternative explanation for PD symptoms. Patient not on levodopa containing medications. Clinical features of psychosis or refractory hallucinations. A Montreal Cognitive Assessment (MoCA) score of less than 25. Uncontrolled seizure disorder. Abnormal Kidney and liver function. Presence of clinically refractory orthostatic hypotension at the screening or baseline visit. Body mass index of greater than or equal to 35. Cardiac disease: History of congestive heart failure, clinically significant bradycardia, presence of 2nd, or 3rd-degree atrioventricular block. Pulmonary disease: COPD with oxygen-requirement at rest or with ambulation; or moderate to severe asthma. Active malignancy or diagnosis of malignancy within 5 years prior to the start of screening Any current suicidal ideation or behaviors. Any diagnosis of autoimmune disease or immunocompromised state History of medium or large size vessel cerebrovascular accidents. History of traumatic brain injury with loss of consciousness and residual neurologic symptoms. Major surgery within the previous 3 months or planned in the ensuing 6 months. History of use of an investigational drug within 90 days prior to the screening visit. History of brain surgery for PD. Substance abuse disorder. Active anticoagulation treatment and/or abnormal INR.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC+placebo<br>2 treatment doses + 1 placebo 3 months apart | Drug: MSC+placebo<br>* 2 infusions of 10 X 10^6 MSC/kg and 1 placebo every 3 months.<br>* Other names: allogeneic mesenchymal stem cell or similar placebo;|
| Experimental: MSC<br>3 treatment doses 3 months apart | Drug: MSC<br>* 3 infusions of 10 X 10^6 MSC/kg every 3 months.<br>* Other names: allogeneic mesenchymal stem cell;|
| Placebo Comparator: Placebo<br>3 placebo doses 3 months apart | Drug: Placebo<br>* 3 infusions of placebo every 3 months. Placebo will be identical to the investigational product but will not contain MSCs.<br>* Other names: Similar placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Screening | 
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Week 7, post infusion #1 | 
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Week 20, post infusion #2 | 
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Week 29, post-infusion #3 | 
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Week 39 follow-up | 
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Week 52 follow-up | 
| Safest number of effective doses of MSC as measured by the Part III of the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) scale |  | Week 78 follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as measured by serious adverse reactions. |  | Baseline,week 7,week 20,week 29,week 39,week 78 | 
| Safety and tolerability as measured by immunologic responses. | Donor specific antibodies (DSA) in serum of patients will be measured and compared to baseline to determine if there is a development of antibody response to donor HLA (human leukocyte antigen). This will determine if there is a possibility of anti-donor alloimmune response after the first or second infusion of MSC, which might lead to a subsequent antibody-mediated rejection (AMR) with the following infusion. Testing will be done at the these time points to determine if 2nd or 3rd infusions will continue. | Baseline,week 7,week 20,week 29,week 39,week 78 | 
| Motor function as measured by the Timed-Up-and-Go (TUG) scale | This test uses the time that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down. A longer duration of time indicates a worse outcome | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Global measurement of disability as measured by the change in the screening Off modified Hoehn and Yahr (H&Y) |  | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Quality of life as measured by the modified Schwab and England activities of daily living scale (ADL) |  | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Quality of life as measured by the Parkinson's Disease Questionnaire 39 (PDQ-39) |  | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Quality of life as measured by the EuroQol- 5 Dimension (EQ-5D) |  | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Non-motor symtoms as measured by the The University of Pennsylvania Smell Identification Test (UPSIT- 40 odor test booklet). |  | Baseline,week 29,week 78 | 
| Cognitive function as measured by the the change in Montreal Cognitive Assessment (MoCA) |  | Baseline,week 29,week 78 | 
| Behavioral changes as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) | The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal ideation and behavior. It rates an individual's degree of suicidal ideation on a scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Exclusionary criteria views 1 or more positive answers in the last month as not eligible for participation. In follow up, one positive response requires further investigation. | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Behavioral changes as measured by the Geriatric Depression Scale-Short Form (GDS-SF) | The Geriatric Depression Scale Short form (GDS-SF) is a 15-item screening tool that is used to identify depression in older adults. Answers indicating depression are in bold and italicized; score one point for each bold one selected. A score of 0 to 5 is normal. A score greater than 5 suggests depression and requires evaluation, whereas a score of 10 or greater would require evaluation for treatment . | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Behavioral changes as measured by the Parkinson Anxiety Scale (PAS) |  | Baseline,week 7,week 20,week 29,week 39,week 52,week 78 | 
| Measurement of putative paracrine mechanism of MSCs using neuroimaging |  | Baseline,week 29,week 78 | 
| Measurement of putative paracrine mechanism of MSCs as measured by concentration of cytokines in patient blood sample. | Examples of these are IL-1beta, IL-6, TNF-alpha, COX-2 and PGE-2. These are measured by Magnetic Bead Panel - Multiplex Assay or ELISA, allowing for specificity in the blood. | Baseline,week 7,week 20,week 29,week 39,week 78 | 
| Measurement of putative paracrine mechanism of MSCs as measured by concentration of chemokines in patient blood sample. | Examples of these are CCL2 (MCP-1), CCL7 (MCP-3), CCL11 (Eotaxin) CCL2 (MDC), CXCL10 (IP-10), CX3CL1 (Fractalkine). These will be measured by Magnetic Bead Panel - Multiplex Assay or ELISA, allowing for specificity in the blood. | Baseline,week 7,week 20,week 29,week 39,week 78 | 
| Measurement of putative paracrine mechanism of MSCs as measured by concentration of growth factors | Examples of these are Glial Derived Neurotrophic Factor, Brain Derived Neurotrophic Factor and Vascular Epidermal Growth Factor . These will be measured by ELISA specific to blood and CSF. | Baseline,week 7,week 20,week 29,week 39,week 78 | 
| Measurement of putative paracrine mechanism of MSCs as measured by concentration of neurotransmitters | Examples of these are homovanillic acid and 5-hydroxytryptamine. These will be measured in CSF and blood by ELISA. | Baseline,week 7,week 20,week 29,week 39,week 78 | 
| Measurement of putative paracrine mechanism of MSCs as measured by alpha-synuclein oligomers in the blood (serum or plasma) |  | Basleline,week 29,week 39,week 78 | 
| Measurement of putative paracrine mechanism of MSCs as measured by alpha-synuclein oligomers in the cerebral spinal fluid |  | Baseline,week 39 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stem Cells, Mesenchymal stem cells, Inflammatory markers