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

Multiple Sclerosis Clinical Trial

— MIST  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03133403
• Other study ID #: DIMS 07/08/2011
• Secondary ID: 2012-004165-41
• Status: Recruiting
• Phase: Phase 2/Phase 3
• First received: April 21, 2016
• Last updated: March 27, 2018
• Start date: November 2013
• Est. completion date: December 31, 2021

Study information

• Verified date: March 2018
• Source: Sheffield Teaching Hospitals NHS Foundation Trust
• Contact: Jodie Keyworth
• Phone: 0114 2713431
• Email: jodie.keyworth[@]sth.nhs.uk
• Is FDA regulated: No
• Study type: Interventional

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Age between 18-55, inclusive.

• Diagnosis of MS using McDonald criteria of clinically definite MS

• An EDSS of 2.0 to 6.0

• Inflammatory disease despite treatment with standard disease modifying therapy including at least 6 months of interferon or glateramer acetate. Inflammatory disease is defined based on both MRI (gadolinium enhancing lesions) and clinical activity (acute relapses treated with IV or oral high dose corticosteroids and prescribed by a neurologist).

Minimum disease activity required for failure is defined as: a) two or more clinical relapses with documented neurologic changes and treated with steroids within the year prior to the study, or b) one steroid treated clinical relapse within the year prior to study and evidence on MRI of active inflammation (i.e., gadolinium enhancement) within the last 12 months on an occasion separate from the clinical relapse.

Exclusion Criteria:

• 1. Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy

• 2. Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix. Other malignancies for which the patient is judged to be cured, such as head and neck cancer, or breast cancer will be considered on an individual basis.

• 3. Positive pregnancy test

• 4. Inability or unwillingness to pursue effective means of birth control from the time of evaluation for eligibility until 6 months posttransplant (if on transplant) or until appropriate for non-transplant treatment (if on control arm). Effective birth control is defined as 1) abstinence defined as refraining from all acts of vaginal intercourse; 2) consistent use of birth control pills; 3) injectable birth control methods (Depo-provera, Norplant); 4) tubal sterilization or male partner who has undergone vasectomy; 5) placement of an intrauterine device (IUD); or 6) use, with every act of intercourse, of diaphragm with contraceptive jelly and/or condoms with contraceptive foam.

• 5. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy

• 6. FEV1/FVC < 60% of predicted after bronchodilator therapy (if necessary)

• 7. DLCO < 50% of predicted (for the transplant arm)

• 8. Resting LVEF < 50 %

• 9. Bilirubin > 2.0 mg/dl

• 10. Serum creatinine > 2.0 mg/dl

• 11. Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins, or to iron compounds/medications

• 12. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams

• 13. Diagnosis of primary progressive MS 14. Diagnosis of secondary progressive MS 15. Platelet count < 100,000/ul, WBC < 1,500 cells/mm3 16. Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible 17. Active infection except asymptomatic bacteriuria 18. Use of natalizumab (Tysabri) within the previous 6 months 19. Use of fingolimod (Gilenya) within the previous 3 months 20. Use of Teriflunomide (Aubagio) within the previous 2 years unless cleared from the body (plasma concentration < 0.02mcg/ml) following elimination from the body with cholestyramine 8g three times a day for 11 days 21. Prior treatment with CAMPATH (alemtuzumab) 22. Prior treatment with mitoxantrone 23. Any hereditary neurological disease such as Charcot-Marie-Tooth disease (CMT) or Spinocerebellar ataxia (SCA) are contraindications 24. Use of tecfidera within the previous 3 months

Related Conditions & MeSH terms

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

Intervention

Drug:
• Tecfidera (BG12)
Tecfidera (dimethyl fumarate) is the methyl ester of fumaric acid. It is an oral compound which has potent anti-inflammatory properties thought to be related to the induction of stress protein HO-1. There is also some evidence to suggest that Tecfidera include direct cytoprotective effects through upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and subsequent induction of an antioxidant response
• Gilenya
Gilenya is an oral sphingosine 1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction
• Tysabri®
Tysabri® is a recombinant humanized IgG4K monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementary -determining regions of a murine antibody that binds to a4-integrin. The molecular weight of natalizumab is 149 kilodaltons
• Avonex/Betaseron/Copaxone/Rebif
Avonex®, Betaseron®, Copaxone®, Rebif® is standard of care for RRMS. Except for flu-like symptoms from interferons, these drugs are generally well tolerated. The usual doses are: Copaxone: 20 mg subcutaneous once daily Avonex: 30ucg (6 million units) intramuscularly (IM) once a week Betaseron: 250 ucg subcutaneous every other day. To decrease flu-like side effects may gradually escalate from 62.5 ucg for 2 weeks then increased 62.5 ucg every two weeks until reaching 250 ucg every other day. Rebif®: 44ucg subcutaneous three times a week. To decrease flu-like side effects may gradually escalate from 8.8 ucg for 2 weeks then increased 22 ucg every for week 3 and 4 then 44 ucg starting week five

Procedure:
• Hematopoietic stem cell transplantation (HSCT)
Selection of the Conditioning Immunosuppressive Therapy, Harvesting Stem Cells , Rabbit-Derived Anti-Thymocyte Globulin

Locations

Country	Name	City	State
United Kingdom	Royal Hallamshire Hospital	Sheffield	South Yorkshire

Sponsors (1)

Lead Sponsor	Collaborator
Sheffield Teaching Hospitals NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the number of participants with no disease progression following the use of autologous PBSCT versus standard of care in treating RRMS		5 years