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

• ClinicalTrials.gov Identifier: NCT04506073
• Recruitment Status: Completed
• First Posted: August 10, 2020
• Last Update Posted: December 5, 2023
• Sponsor: The University of Texas Health Science Center, Houston
• Collaborator: Michael J. Fox Foundation for Parkinson's Research
• Information provided by (Responsible Party): Mya Schiess, The University of Texas Health Science Center, Houston

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Parkinson's Disease	Drug: MSC+placebo; Drug: MSC; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: November 9, 2020
• Actual Primary Completion Date: July 30, 2023
• Actual Study Completion Date: July 30, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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 [ Time Frame: Screening ]
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 [ Time Frame: Week 7, post infusion #1 ]
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 [ Time Frame: Week 20, post infusion #2 ]
4. 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 [ Time Frame: Week 29, post-infusion #3 ]
5. 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 [ Time Frame: Week 39 follow-up ]
6. 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 [ Time Frame: Week 52 follow-up ]
7. 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 [ Time Frame: Week 78 follow-up ]

Secondary Outcome Measures :

1. Safety and tolerability as measured by serious adverse reactions. [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 78 ]
2. Safety and tolerability as measured by immunologic responses. [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 78 ]
   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.
3. Motor function as measured by the Timed-Up-and-Go (TUG) scale [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
   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
4. Global measurement of disability as measured by the change in the screening "Off" modified Hoehn and Yahr (H&Y) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
5. Quality of life as measured by the modified Schwab and England activities of daily living scale (ADL) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
6. Quality of life as measured by the Parkinson's Disease Questionnaire 39 (PDQ-39) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
7. Quality of life as measured by the EuroQol- 5 Dimension (EQ-5D) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
8. Non-motor symtoms as measured by the The University of Pennsylvania Smell Identification Test (UPSIT- 40 odor test booklet). [ Time Frame: Baseline,week 29,week 78 ]
9. Cognitive function as measured by the the change in Montreal Cognitive Assessment (MoCA) [ Time Frame: Baseline,week 29,week 78 ]
10. Behavioral changes as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
    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.
11. Behavioral changes as measured by the Geriatric Depression Scale-Short Form (GDS-SF) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
    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 .
12. Behavioral changes as measured by the Parkinson Anxiety Scale (PAS) [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 52,week 78 ]
13. Measurement of putative paracrine mechanism of MSCs using neuroimaging [ Time Frame: Baseline,week 29,week 78 ]
14. Measurement of putative paracrine mechanism of MSCs as measured by concentration of cytokines in patient blood sample. [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 78 ]
    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.
15. Measurement of putative paracrine mechanism of MSCs as measured by concentration of chemokines in patient blood sample. [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 78 ]
    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.
16. Measurement of putative paracrine mechanism of MSCs as measured by concentration of growth factors [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 78 ]
    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.
17. Measurement of putative paracrine mechanism of MSCs as measured by concentration of neurotransmitters [ Time Frame: Baseline,week 7,week 20,week 29,week 39,week 78 ]
    Examples of these are homovanillic acid and 5-hydroxytryptamine. These will be measured in CSF and blood by ELISA.
18. Measurement of putative paracrine mechanism of MSCs as measured by alpha-synuclein oligomers in the blood (serum or plasma) [ Time Frame: Basleline,week 29,week 39,week 78 ]
19. Measurement of putative paracrine mechanism of MSCs as measured by alpha-synuclein oligomers in the cerebral spinal fluid [ Time Frame: Baseline,week 39 ]

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 79 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Texas

The University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

Sponsors and Collaborators

The University of Texas Health Science Center, Houston

Michael J. Fox Foundation for Parkinson's Research

Investigators

• Principal Investigator: Mya C Schiess, MD; The University of Texas Health Science Center, Houston

More Information

Publications:

Dorsey ER, Sherer T, Okun MS, Bloem BR. The Emerging Evidence of the Parkinson Pandemic. J Parkinsons Dis. 2018;8(s1):S3-S8. doi: 10.3233/JPD-181474.

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. doi: 10.1016/s0197-4580(02)00065-9.

Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014 Apr 23-30;311(16):1670-83. doi: 10.1001/jama.2014.3654.

Jellinger KA. Basic mechanisms of neurodegeneration: a critical update. J Cell Mol Med. 2010 Mar;14(3):457-87. doi: 10.1111/j.1582-4934.2010.01010.x. Epub 2010 Jan 11.

Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. 2005 Feb;57(2):176-9. doi: 10.1002/ana.20369.

Gray MT, Woulfe JM. Striatal blood-brain barrier permeability in Parkinson's disease. J Cereb Blood Flow Metab. 2015 May;35(5):747-50. doi: 10.1038/jcbfm.2015.32. Epub 2015 Mar 11.

Orr CF, Rowe DB, Halliday GM. An inflammatory review of Parkinson's disease. Prog Neurobiol. 2002 Dec;68(5):325-40. doi: 10.1016/s0301-0082(02)00127-2.

Nagatsu T, Mogi M, Ichinose H, Togari A. Cytokines in Parkinson's disease. J Neural Transm Suppl. 2000;(58):143-51.

Stypula G, Kunert-Radek J, Stepien H, Zylinska K, Pawlikowski M. Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson's disease. Neuroimmunomodulation. 1996 Mar-Jun;3(2-3):131-4. doi: 10.1159/000097237.

Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med. 2010 Nov;5(6):933-46. doi: 10.2217/rme.10.72.

• Responsible Party: Mya Schiess, Professor and Adriana Blood Chair in Neurology, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT04506073
• Other Study ID Numbers: HSC-MS-20-0150
• First Posted: August 10, 2020
• Last Update Posted: December 5, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mya Schiess, The University of Texas Health Science Center, Houston:

Stem Cells; Mesenchymal stem cells; Inflammatory markers

Additional relevant MeSH terms:

Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases