Hematopoietic Stem Cell Therapy for Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy — MIST  

Multiple Sclerosis Clinical Trial

Official title: Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study

Status Recruiting

Clinical Trial Summary

The purpose of this study is to assess the efficacy of autologous PBSCT versus FDA approved standard of care (i.e. interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) for inflammatory MS failing alternate approved therapy.

Disease progression, defined as a 1-point increase in the Expanded Disability Status scale (EDSS) on consecutive evaluations at least 6 months apart and not due to a non-MS disease process. Patients will be followed for 5 years after randomization.

Clinical Trial Description

Hematopoietic stem cell transplantation (HSCT) was proposed as a treatment for multiple sclerosis (MS) in 1995 based on results of HSCT for experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Since that time, more than two hundred patients with MS have undergone HSCT worldwide. The usual clinical course of MS is initially relapsing and subsequently progressive, although a combination of the two or progression from onset occurs in a minority of patients. Relapsing remitting MS (RRMS) is punctuated by acute neural dysfunction that resolves completely or partially without baseline deterioration between acute attacks. Secondary progressive MS (SPMS) manifests as steadily worsening neurologic baseline in patients with prior RRMS. Neural function in primary progressive MS (PPMS) deteriorates progressively from onset without identifiable acute relapses, whereas relapsing progressive MS (RPMS) has intermittent acute attacks in addition to slow progressive deterioration.

The current therapies for MS consist of immune modulating agents such as interferons and glatiramer acetate, and anti-inflammatory and immune suppressive drugs such as glucocorticoids, methotrexate, mitoxantrone, cladribine, and cyclophosphamide. Autologous HSCT maximizes immune suppression to the point of transient immune ablation. In theory, the transplant conditioning regimen ablates the aberrant disease causing immune cells while hematopoietic stem cells (HSC) regenerate a new and antigen naive immune system.

Study Design:

All subjects will be examined at baseline and at 6 months and yearly thereafter with neuropsychological exams which shall include the Paced Auditory Serial Addition Test (PASAT) and where facilities exist a standardized, repeatable battery of tests consisting of the Selective Reminding Test (verbal learning), 7/24 Spatial Recall Test I (visuospatial learning), and Controlled Oral Word Association (verbal fluency and semantic retrieval). These cognitive functions, in addition to the PASAT, are most often disrupted in patients with MS. Administration of these tests and MS Functional Composite (which includes timed 25-foot walk, and 9-hole peg test in addition to the PASAT) will be performed by a trained professional and should take 40 - 50 minutes. Self-administered quality of life exams (MSQOL and SF-36) will also be obtained pre-transplant, 6 and 12 months post-transplant, and then yearly until 5 years post-transplant.

Patients may receive most FDA approved standard therapy (interferons, glatiramer acetate (Copaxone) mitoxantrone, natalizumab (Tysabri), fingolimod (Gilenya), Tecfidera ( BG-12) in the control arm, we recommend change from the therapy (s) which they failed to qualify for entry into the study. Patients in control arm may not receive teriflunomide (Aubagio). The decision of specific control arm therapy will be made by attending physicians based on clinical circumstances and discussion with the patient. If required for patient care, the dose of MS disease modifying therapies in the control arm may be adjusted by the treating physician.

The major hazard of this protocol is transplant-related morbidity and mortality. The marrow ablative regimen of cyclophosphamide will destroy the patient's immune/hematopoietic system and leave the patient susceptible to a wide variety of infections and bleeding complications until the reinfused stem cells engraft. Aggressive supportive care as described above will be used to prevent all avoidable risk. However, a small percentage of patients may die as a direct result of transplant related complications. Transplant related mortality is directly related to a patient's age, general medical condition, and prior exposure to prolonged or aggressive chemotherapy regimens. Transplant related complications include infections, bleeding, veno-occlusive disease of the liver, and failure to en-graft. This protocol is designed to minimize these complications.

Currently there exists insufficient data to determine progression rate on the HSCT arm. This is a randomized phase II study designed to determine progression rate post HSCT compared to an accepted intervention (mitoxantrone) to determine the feasibility and numbers of patients that would be required for a phase III study. A mitoxantrone study has shown a two year progression rate of 8% for the mitoxantrone arm and 25% for the control arm. Therefore, we expect the 5 year progression rate in the mitoxantrone arm to be between 20% (no change in progression rate) and 45% (progression rate similar to placebo immediately after mitoxantrone is stopped).

If the investigators assume an approximate estimate of the 5-year progression rate for mitoxantrone is 45%, a sample size of 110 with 55 in each arm will provide at least 90% power to detect a difference when the 5-year progression rate in the mitoxantrone arm is 45%, and the corresponding rate in the transplant arm is 15% or less. The same numbers provide at least 80% power to detect a difference exists when the 5-year progression rate in the mitoxantrone arm is 45%, and the corresponding rate in the transplant arm is 20% or less. The investigators will therefore recruit 55 patients to each treatment arm. ;

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

• NCT number: NCT03133403
• Study type: Interventional
• Source: Sheffield Teaching Hospitals NHS Foundation Trust
• Contact: Jodie Keyworth
• Phone: 0114 2713431
• Email: jodie.keyworth@sth.nhs.uk
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 2013
• Completion date: December 31, 2021