Randomized Double-Blind Placebo-Controlled Adaptive Design Trial Of Intrathecally Administered Autologous Mesenchymal Stem Cells In Multiple System Atrophy

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. There is no available treatment to slow or halt disease progression. The purpose of this study is to assess optimal dosing frequency, effectiveness and safety of adipose-derived autologous mesenchymal stem cells delivered into the spinal fluid of patients with MSA.

Funding source: FDA Office of Orphan Product Development (OOPD), Mayo Clinic Executive Dean for Research Transformational Award, Mayo Clinic Regenerative Medicine, and Mayo Clinic Department of Neurology.

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurodegenerative disease for which there is no disease-modifying treatment. Recent insights into pathophysiologic mechanisms suggest a crucial role of deprivation of neurotrophic factors which have been shown to be secreted by mesenchymal stem cells (MSCs). In a recent phase I/II study adipose-derived autologous MSCs were delivered intrathecally to patients with early MSA utilizing a dose-escalation design. At a dose of 50 million MSCs, injections were generally well tolerated, but thickening of cauda equina nerve roots was observed which was either asymptomatic or associated with low back pain. The rate of disease progression assessed using the Unified MSA Rating Scale (UMSARS) was markedly slower compared to a matched control group. An even more favorable side effect profile and virtually lack of disease progression was seen in an add-on cohort receiving 25 million MSCs per injection. Neurofilament light chain, an index of central axonal degeneration, decreased in all patients receiving that dose. MSC administrations resulted in a marked, dose-dependent increase of neurotrophic factors in CSF. 2-year survival was significantly higher than observed in natural history cohorts.

Based on these findings we are now conducting a double-blind, placebo-controlled, adaptive design phase II trial of adipose-derived intrathecal autologous MSCs in MSA with the goal to establish optimal treatment frequency and simultaneously derive placebo-controlled efficacy and safety data in preparation for a multicenter phase III trial. Up to 76 adult subjects with MSA will be enrolled. To ensure a homogenous patient population with comparable rates of disease progression, we will restrict the study to early cases but still fulfilling strictest diagnostic consensus criteria. Participants will undergo a subcutaneous fat biopsy to derive autologous MSCs, which are cultured, expanded, and prepared for delivery in Mayo's Cell Therapeutics Lab. In a first phase, subjects will be randomized 1:1:1 to receive 25 million MSCs at two different injection intervals (every 6 months or every 3 months) as the two active arms or lactated Ringer's solution as the placebo arm. A recruitment hold after half the subjects have been enrolled will allow for an interim futility and efficacy analysis to select the "winner" active treatment assuming futility criteria are not met. The study will then restart recruiting the second half of subjects utilizing 2:1 randomization ("winner" active: placebo). Patients undergo clinical assessments at baseline, 3, 6, 9, and 12 months to derive the primary endpoint, the rate of disease progression assessed using UMSARS total and a mixed effects regression model. MRI of the head and lumbar spine will be completed at baseline and 12 months to expand safety data and to assess the rate of atrophy of selected brain regions using morphometric measures as surrogate markers of disease progression. Spinal fluid before and after administrations, as well as stem cell product media will be collected to further explore biological properties and effects of MSCs and to explore selected spinal fluid markers as biomarkers of disease progression.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females aged 30-70 years, who are willing and able to give informed consent.
2. Clinical diagnosis of MSA, fulfilling consensus criteria for probable MSA.
3. UMSARS I (omitting question 11) between 5 and 17, and able to walk unaided (i.e. able to walk at least 50 yards without the use of a cane or walker, and without other support such as holding on to an arm or touching walls).
4. Anticipated survival of at least 3 years in the opinion of the investigator.
5. Normal cognition as assessed by the Montreal Cognitive Assessment (MOCA). We will require a value ≥26.

Exclusion Criteria:

1. Pregnant or breastfeeding women, and women of childbearing potential who do not agree to practice an acceptable method of birth control. Acceptable methods of birth control in this study are: surgical sterilization, intrauterine devices, partner's vasectomy, a double-protection method (condom or diaphragm with spermicide), hormonal contraceptive drug (i.e., oral contraceptive, contraceptive patch, long-acting injectable contraceptive) with a required second mode of contraception.
2. Participants with a clinically significant or unstable medical or surgical condition that, in the opinion of the investigator, might preclude safe completion of the study or might affect study results. These include conditions causing significant CNS or autonomic dysfunction, clinically significant peripheral neuropathy, active malignant neoplasm, amyloidosis, active autoimmune disease, immunocompromised state, active infection, congestive heart failure (NYHA III or IV), recent (\<6 months) myocardial infarction, history of stoke with residual deficits, uncontrolled diabetes mellitus, alcoholism, orthopedic problems that compromise mobility and activity of daily living, significant liver or kidney disease, thrombocytopenia (\<50 x 109/L), disorders affecting coagulation, and patients on active anticoagulation.
3. Participants who have taken any investigational products within 90 days prior to baseline, or with expected effects lasting beyond 60 days prior to baseline.
4. Medications that could affect clinical evaluations are permitted but need to be withdrawn at least four half-lives prior to study visits. Those include medications used to treat motor symptoms, such as levodopa and other anti-Parkinsonian medications.
5. Patients with contraindication to any of the study procedures, in particular MRI scanning.