Immunosuppression in Amyotrophic Lateral Sclerosis (ALS)

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, 15-month study evaluating the effect of immunosuppression treatment on the rate of change on the ALS Functional Rating Scale (Revised) (ALSFRS-R) score in up to 33 subjects with Amyotrophic Lateral Sclerosis (ALS).

Detailed Description
-----------------
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.

Official Title
-----------------
A Novel Immunosuppression Intervention for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

Conditions
-----------------
Amyotrophic Lateral Sclerosis (ALS)

Intervention / Treatment
-----------------
* Drug: Basiliximab
* Drug: Methylprednisolone
* Drug: Prednisone
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for participants with symptom onset within the past 24 months: Male or female patients 18-65 years of age. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial Criteria. Symptom onset ≤ 24 months from screening visit. A score of ≥38 on the Revised ALS Functional Rating Scale. Slow vital capacity (SVC) measure >80% of predicted for gender, height and age at screening. Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days, prior to the screening visit (riluzole-naïve subjects are permitted in the study). Negative tuberculosis (TB) test within 3 months of Screening Visit. Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (i.e., no bleeding disorder, allergy to local anesthetics, or a skin infection at or near the LP site). Capable of providing informed consent and following study procedures. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study. Women of childbearing potential must have a negative pregnancy test at screening and be non-lactating. Geographic accessibility to the study site. Inclusion Criteria for participants with symptom onset greater than 24 months before screening: Male or female patients age 18 or older. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial Criteria. Symptom onset >24 months from screening visit. Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days, prior to the screening visit (riluzole-naïve subjects are permitted in the study). Negative tuberculosis (TB) test within 3 months of Screening Visit. Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (i.e., no bleeding disorder, allergy to local anesthetics, or a skin infection at or near the LP site). Capable of providing informed consent and following study procedures. Geographic accessibility to the study site. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study. Women of childbearing potential must have a negative pregnancy test at screening and be non-lactating. Exclusion Criteria Prior use of basiliximab, solumedrol, prednisone, tacrolimus or mycophenolate mofetil within 30 days of the Screening Visit. Known allergy or sensitivity to basiliximab, solumedrol, prednisone, tacrolimus or mycophenolate mofetil or a formulation of one of these drugs. Treatment with an immunosuppressant medication within 30 days of the Screening Visit. Active peptic ulcer disease. Any medical disorder that would make immunosuppression contraindicated including, but not limited to, human immunodeficiency virus (HIV), tuberculosis, or evidence of active cytomegalovirus (CMV) or infection. Subjects who have a diaphragm pacing system (DPS). Women who are pregnant, breastfeeding, or planning to become pregnant in the next 12 months. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Use of invasive or non-invasive mechanical ventilation (including Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP)) for any part of the day or night prior to the Screening Visit (participants with symptom onset within past 24 months only). Exposure to any other agent currently under investigation for the treatment of patients with ALS (off-label use or investigational) within 30 days of the Screening Visit. Inability to safely complete study activities based on the discretion of the site investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppression Regimen<br>Basiliximab Methylprednisolone Prednisone Tacrolimus Mycophenolate mofetil | Drug: Basiliximab<br>* 20 mg, IV (in the vein) on day 1 and 4.<br>* Other names: Simulect;Drug: Methylprednisolone<br>* 125 mg, IV (in the vein) on day 1.<br>* Other names: Solumedrol;Drug: Prednisone<br>* 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.<br>* Other names: Orasone;Drug: Tacrolimus<br>* 1-5 mg PO, twice a day (BID) days 2-180.<br>* Other names: Prograf;Drug: Mycophenolate mofetil<br>* 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.<br>* Other names: Cellcept;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Average Increase in ALSFRS-R Score of One Point Per Month | 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 is 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Rate of Change of ALSFRS-R Scores During Treatment Compared to Pre-Treatment | 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 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). Total scores range from 0 (most impaired) to 48 (normal ability). ALSFRS-R was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline in ability over time. | 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) | 
| Mean Rate of Change of Slow Vital Capacity (SVC) During Treatment Compared to Pre-Treatment | Vital capacity (VC), percent of predicted normal, was determined using the slow VC method. SVC measures the amount of air exhaled following a deep breath. For this test, participants hold a mouthpiece in their mouth, breathe in deeply, and breathe out as much air as they can. The test was done seated in a chair and then repeated while lying on an exam table at the Screening Visit. For all other visits, this test was done while seated in a chair. This test takes 15-20 minutes. SVC was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. SVC is a way to measure respiratory insufficiency in persons with ALS and SVC decreases as ALS progresses. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline over time. | 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) | 
| Mean Rate of Change of Hand-Held Dynamometry (HHD) During Treatment Compared to Pre-Treatment | Hand held dynamometry (HHD) is a measure of muscle strength and scores decrease as ALS progresses. Six proximal muscle groups were examined bilaterally in both upper and lower extremities. Mean and standard deviation for each muscle group are established from the initial values for each participant. Strength determinations were converted to Z scores and averaged to provide an HHD megascore. The Z-score indicates the number of standard deviations away from the mean of 0. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. HHD was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline in strength over time. | 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) | 
| Mean Rate of Change in Grip Strength Treatment Compared to Pre-Treatment | Hand grip was measured using a study approved dynamometer to test the maximum isometric strength of the hand and forearm muscles. The grip strength of the left and right hands were analyzed together. Grip strength was measured during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. Grip strength is a measurement of muscle strength and declines as ALS progresses. A positive value means that scores during treatment were higher than pre-treatment scores, indicating an increase in grip strength over time. | 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) | 
| Mean Rate of Change of T-cell Subsets in Blood Treatment Compared to Pre-Treatment | Blood was collected for ribonucleic acid (RNA) and the mean rate of decline of T-cells during the 6 month treatment period compared to the pre-treatment period was assessed (blood was collected twice during the 3-month long lead in period). The precise role that T-cells have in ALS is unknown and this study aims to further the understanding of how T-cells operate in persons with ALS. T-cell measurement is a ratio where the relative expression levels of FOXP3 messenger ribonucleic acid (mRNA) was calculated using the Comparative CT Method (ΔΔCT Method), normalizing to β-actin. Samples were obtained during the 3 month lead in period and the 6 month treatment period. A random slopes model was fit to the lead-in and treatment periods, with a change point when treatment started. The analysis was based on the difference in slope after the change point. A negative value means that scores during treatment were lower than pre-treatment scores, indicating a decline in T-cells over time. | Pre-Treatment Period (2 months prior to the start of treatment), Treatment Period (Day 1 and Months 1, 2, 4, 6) | 
| Collection of Cerebrospinal Fluid for Future Analysis of Cytokine Levels | Lumbar punctures (LPs) were performed to collect cerebrospinal fluid (CSF). CSF is banked for future use to characterize immune system markers and to further the understanding of the immune factors that contribute to disease progression in ALS. Cytokines are markers of neuroinflammation and can be categorized as neurotoxic or neuroprotective. The role that cytokines play in in ALS progression is still not yet fully understood. | Pre-Treatment Period (two months prior to the start of treatment), Treatment Period (Months 2 and 6), Post-Treatment Period (Month 12) | 
| Collection of Blood for Future Analysis of Peripheral Blood Mononuclear Cells (PBMCs) | Blood was drawn and banked for future use in order to characterize immune system markers and further the understanding of the immune factors that contribute to disease progression in ALS. | Pre-Treatment Period (2 months prior to the start of treatment), Treatment Period (Day 1 and Months 1, 2, 4, 6), Post-Treatment Period (Months 8 and 12) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALS, Immunosuppression, Neuromuscular Disorders