Immunosuppression in Amyotrophic Lateral Sclerosis (ALS)

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).

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.

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.