Effects of ACTHAR on Advanced MRI Surrogate Markers of Disease Activity and on Comprehensive Immune Signature During MS Relapses

Study Overview
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Brief Summary
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ACTHAR is a FDA approved drug for MS relapses. The purpose of the study is to examine the efficacy of this agent in improving relapses as measured by advanced MRI and laboratory techniques: Advanced serial MRI studies on patients during and after an acute MS relapse. MRI will be performed at baseline, 1 month after the 1st dose of ACTHAR, and months 3, 6, and 12. ACTHAR will be administered for 10 days. Patients will start ACTHAR within 48 hours of relapse assessment. Serial immune assays on patients during and after an acute MS relapse. Serum and blood samples with be collected at baseline, last day of ACTHAR (day 10 of therapy), 1 month post 1st dose, and months 3 and 6.

Detailed Description
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Multiple sclerosis (MS) is a demyelinating disease of the CNS. In a vast majority of patients, its clinical course is characterized by transient attacks of acute neurological compromise, followed by variable degree of recovery. Each relapse leaves a patient with some degree of residual disability. Higher number and longer duration of relapses are associated with greater loss of function. Hence, it is imperative that these relapses are optimally treated and curtailed in duration to allow for maximal recovery and repair. ACTH (ACTHAR or IV formulation) has long been used for the treatment of MS relapses. ACTH has equivalent efficacy to high-dose IV methylprednisolone in curtailing the duration of MS relapses. ACTH has an advantage over steroids in that it has a short half-life and much less deleterious steroid effect on bone and fat metabolism. Importantly, ACTH has a unique mechanism of action on immune and brain cells through melanocortin receptors (MCRs), which promote production of regulatory and anti-inflammatory cytokines and support oligodendrocyte precursors and neuronal function, all of which could lead to better repair of MS lesions and favorable clinical outcome. The studies proposed herein will provide a better understanding of the effects of ACTHAR in improving MRI lesion characteristics over time. The complementary immune and genetic studies will further provide evidence for the mechanism of action (MOA) of ACTHAR in improving immune dysfunction related to MS relapse. This is a one of a kind study, involving both advanced/state-of-the art MRI techniques and immune studies to assess the beneficial effects of ACTHAR in MS relapses in the same patients over time. The primary outcome of all MRI techniques is to determine whether there is an improvement and subsequent stabilization/repair over time of tissue damage caused by inflammatory MS disease activity. Multiple conventional and nonconventional MR imaging modalities are examined here to determine which of these are the most sensitive and reliable in detecting microstructural damage and repair over time. The results of this study will also greatly impact the design of future MS trials by providing a guide for selecting the most appropriate MRI and immune methods to assess treatment efficacy in MS. In terms of laboratory analysis, the following will be examined: Determine immune subset expression in CD4+FOXP3 Tregs and CD8+CD28- T suppressor cells by flow cytometry at each visit. Global gene expression profiling in MNC with 913,000 probes at each visit. Bioinformatics will include pathway analysis and ACTHAR-induced RNA signature. Serum protein profiling for immune-regulated cytokines (Th1, Th2, Th17, monokines…) and neuroprotective proteins (NGF, BDNF, ACTH, HGF, CNTF, IL-10…) at each visit. All data from protein and gene expression, as well as immune subset expression will be compared to our database generated from therapy-naïve stable and exacerbating MS. ACTHAR signature will analyzed based on these comparisons.

Official Title
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Effects of ACTHAR on Advanced MRI Surrogate Markers of Disease Activity and on Comprehensive Immune Signature During MS Relapses

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: ACTHar


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age > 18 undergoing a clinical relapse and associated MRI active lesion Exclusion Criteria: Recent infection, any use of any glucocorticoid 30 days prior to enrollment unable to consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated Group<br>Open label, single arm treatment study using MRI and laboratory markers to assess efficacy of ACTHAR in MS patients who are undergoing relapses. | Drug: ACTHar<br>* The patients will be given 80 Units subcutaneously of ACTHAR at the time of MS relapse daily for 10 days.<br>* Other names: repository corticotropin injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in T1 lesion relaxation time | T1 relaxation time is a MRI marker of injury. The change in this metric will be followed over 12 months to see if lesions recover post ACTHAR intervention. | 12 month after the completion of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in immune subset expression in CD4+FOXP3 Tregs by flow cytometry post ACTHAR intervention | Treg cells are unregulated during the healing process in MS relapses. Changes in this population of immune cells will be measured over a course of 6 months post ACTHAR intervention. | 6 month after the completion of intervention |