Immunosuppression in Amyotrophic Lateral Sclerosis (ALS) (NIPALS2013)
|Amyotrophic Lateral Sclerosis (ALS)||Drug: Basiliximab Drug: Methylprednisolone Drug: Prednisone Drug: Tacrolimus Drug: Mycophenolate mofetil||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Novel Immunosuppression Intervention for the Treatment of Amyotrophic Lateral Sclerosis (ALS)|
- Number of Participants With an Average Increase in ALSFRS-R Score of One Point Per Month [ Time Frame: Pre-Treatment Period (3 months prior to the start of treatment, 2 months prior to the start of treatment, and 1 month prior to the start of treatment), Treatment Period (Day 1 and then monthly until Month 6) ]The ALS Functional Rating Scale - Revised (ALSFRS-R) is an ordinal rating scale (0 through 4) used to determine the ALS patient's self assessment of their ability and need for assistance in 12 activities or functions. This is a validated scale, both in person and by phone, which provides a total score (best of 48) from four sub-scores which assess speech and swallowing, (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). A clinical response will be defined as a rate of change of ALSFRS-R of +6 points over 6 months (mean of +1 point per month), where typically patients with ALS have a decline in ALSFRS-R by an average of -1/month.
- Change in Slow Vital Capacity (SVC) [ Time Frame: Screening, Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]Vital capacity (VC), percent of predicted normal, will be determined using the slow VC method. SVC measures the amount of air exhaled following a deep breath. For this test, participants will hold a mouthpiece in their mouth, breathe in deeply, and breathe out as much air as they can. The test will be done seated in a chair and then repeated while e lying on an exam table at the Screening Visit. For all other visits, this test will be done with seated in a chair. This test will take 15-20 minutes. At the Screening visit, eligibility for Group A will be determined utilizing upright SVC.
- Change in Hand-Held Dynamometry (HHD) [ Time Frame: Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]Hand held dynamometry (HHD) will be used as a quantitative measure of muscle strength for this study. Six proximal muscle groups will be examined bilaterally in both upper and lower extremities (shoulder flexion, elbow flexion, elbow extension, hip flexion, knee flexion, and knee extension), all of which have been validated against maximum voluntary isometric contraction (MVIC) testing. In addition, wrist extension, first dorsal interosseous contraction and ankle dorsiflexion will be measured bilaterally; these muscles are often affected in Amyotrophic Lateral Sclerosis.
- Change in Cytokine Levels in Cerebrospinal Fluid (CSF) [ Time Frame: Baseline Visit 2 and Months 2, 6 and 12. ]Lumbar punctures (LPs) will be done to collect cerebrospinal fluid in order to characterize markers of the participants immune system and further the understanding of the immune factors that contribute to disease progression in ALS
- Collection of Peripheral Blood Mononuclear Cells (PBMCs) in Blood [ Time Frame: Baseline Visit 2, Day 1, Months 1, 2, 4, 6, 8 and 12, and at the Final Safety Visit if a subject discontinues study drug early. ]Blood will be drawn in order to characterize markers of the participants immune system and further the understanding of the immune factors that contribute to disease progression in ALS.
- Change in Left Grip Strength [ Time Frame: Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]Left hand grip will be measured using a study approved dynamometer to test the maximum isometric strength of the hand and forearm muscles.
- Change in Right Grip Strength [ Time Frame: Baseline Visits 1, 2, and 3, Day 1, Months 1, 2, 3, 4, 5, 6, 8 ,10 , and 12, and at the Final Safety Visit, if a subject discontinues study drug early. ]Right Hand grip will be measured using a study approved dynamometer to test the maximum isometric strength of the hand and forearm muscles.
- Collection of T-cell Subsets in Blood [ Time Frame: Baseline Visit 2, Day 1, and Months 1, 2, 4, 6, 8 and 12, and at the Final Safety Visit if a subject discontinues study drug early ]Blood will be collected for ribonucleic acid (RNA).
|Study Start Date:||October 2013|
|Study Completion Date:||January 2016|
|Primary Completion Date:||January 2016 (Final data collection date for primary outcome measure)|
Experimental: Immunosuppression Regimen
Basiliximab Methylprednisolone Prednisone Tacrolimus Mycophenolate mofetil
20 mg, IV (in the vein) on day 1 and 4.
Other Name: SimulectDrug: Methylprednisolone
125 mg, IV (in the vein) on day 1.
Other Name: SolumedrolDrug: Prednisone
60 mg PO (by mouth) on days 2-7, 40 mg PO days 8-14, 20 mg PO days 15-21, and 10mg PO days 22-28.
Other Names:Drug: Tacrolimus
1-5 mg PO, BID (twice a day) days 2-180.
Other Name: PrografDrug: Mycophenolate mofetil
500 mg PO, BID days 2-7, 500 mg PO each morning and 1000 mg each night, days 8-14, 1000 mg PO BID days 15-180.
Other Name: Cellcept
In an ongoing safety trial of neural stem cell injections into the spinal cord of patients with ALS at Emory University, Atlanta, Georgia, one patient has demonstrated clear improvement by objective clinical and electrophysiological measures, a finding that is unheard of in patients with ALS.
This patient had an improvement in ALSFRS-R by 1.4 points per month. In 826 historical controls from the Northeast ALS Consortium (NEALS) and the Western ALS Consortium (WALS) database where ALSFRS-R was documented at 2 or more visits, there have been no patients that have shown improvement in ALSFRS as seen in this case. Additionally, 5 patients in the stem cell trial who were not on mechanical ventilators at the time of surgery seem to have very slow disease progression as compared to the expectation from current understanding of typical disease course. This observation raises consideration for a disease-modifying effect of the novel immunosuppression regimen used in this trial. Also, given that ALS is clinically an extraordinarily heterogeneous disease, the diagnosis of ALS may represent a group of phenotypically similar but pathogenically variable disorders. It is possible that there exists a subset of patients with an immune-responsive ALS subtype that has not been previously recognized.
Recent studies have furthered the understanding of the immune mechanisms that contribute to ALS progression. Microglia and lymphocytes have both neurotoxic and neuroprotective functions depending on activation states and physiologic conditions within the nervous system. Therefore, targeted immunotherapies that proportionally suppress neurotoxic immune elements, while sparing or promoting protective elements, seemingly have more potential to modify disease course in ALS than previously tested regimens. It is postulated that the immunosuppression treatment given to the stem cell patients may have exhibited neuroprotective effects by favorably promoting the ratio of regulatory T cells and other protective immune mediators in relation to neurotoxic immune modulators. It is hoped that this trial will optimize the chance of replicating these findings and advance knowledge about the complex changes that occur within the immune system in patients with ALS before and after treatment with an immunosuppression regimen.
The primary outcome measure will be rate of change of ALSFRS-R. A clinical response will be defined as a rate of change of ALSFRS-R of +6 points over a 6 month period (mean of change of +1 point per month).
Secondary outcome measures will include slow vital capacity (SVC), grip strength, and hand held dynamometry (HHD). The change in rate of progression in clinical measures will be monitored to look for a potential disease-modifying effect of the immunosuppression regimen. Blood and cerebrospinal fluid immune system markers will be also be studied.
If a clinical response is seen among study participants following treatment, further analyses will be conducted to explore any differential effects of immunosuppression in participants with early-stage disease and later-stage disease. To ensure adequate numbers of participants for conditional analyses stratifying by symptom onset date, participants will be enrolled based on symptom onset within 24 months of the screening visit or more than 24 months before screening. All participants will have the same treatment and will be treated as a single group for the analyses of the main study outcomes.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01884571
|United States, Georgia|
|Atlanta, Georgia, United States, 30322|
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|University of Massachusetts Medical School|
|Worcester, Massachusetts, United States, 01655|
|Principal Investigator:||Jonathan D Glass, MD||Emory University|
|Principal Investigator:||Christina N Fournier, MD||Emory University|