NF-κB Inhibition in Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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This is a Phase II, single centre, randomized, parallel, double blind, placebo-controlled clinical trial to determine the safety of Withania somnifera in participants with Amyotrophic Lateral Sclerosis (ALS).

Detailed Description
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There will be up to 75 participants randomized 1:1:1 to receive either high dosage Withania somnifera extract (1088 mg daily), medium dosage Withania somnifera extract (544 mg daily) or matching placebo. The study will consist of a Screening Period, Randomization visit, Baseline visit, and Follow-up visits. The treatment period will be 8 weeks and a final follow up call will occur at Week 9.

Official Title
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Nuclear Factor Kappa Beta Inhibition in Patients With Amyotrophic Lateral Sclerosis: A Phase II Randomized Placebo Controlled Trial

Conditions
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ALS

Intervention / Treatment
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* Drug: Withania somnifera
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with laboratory supported probable, clinically possible, probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria (83) (Appendix A) Disease duration from symptom onset no greater than 36 months at the Screening Visit Aged 18 years or older Capable of providing informed consent and complying with study procedures If taking riluzole, on a stable dose for at least 30 days prior to Screening Visit If taking edaravone, on a stable dose for at least one cycle prior to Screening Visit If on BiPAP, average usage of no more than 12 hours per day at time of Screening Visit Able to swallow a capsule at Baseline Visit Fluency in English or French Exclusion Criteria: Exposure to any investigational agent or Withania somnifera (Ashwagandha) within 30 days prior to the Screening Visit; simultaneous participation in other observational studies is allowed upon Site Investigator approval Presence of any of the following clinical conditions: Substance abuse within the past year Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active malignancy or infectious disease Acquired Immunodeficiency Syndrome (AIDS) or AIDS-related complex Unstable psychiatric illness defined as psychosis (hallucinations or delusions) or untreated major depression within 90 days prior to the Screening Visit Hypersensitivity or allergy to Withania somnifera Uncontrolled diabetes with severe associated complications (such as neuropathy) Untreated hypertension, active stomach ulcers, or untreated thyroid disorder Previously diagnosed auto-immune condition with or without neurological manifestations (e.g. multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis, etc.) Current or planned use of oral, intramuscular or intravenous steroid drugs (such as prednisone, prednisolone, dexamethasone, triamcinolone, methylprednisolone, oxandrolone, and others) or immunosuppressant drugs (azathioprine, mycophenolate, tacrolimus, sirolimus, cyclophosphamide, and others) for more than 7 days Planned consumption of alcohol, other drugs or natural health products with sedative and anxiolytics properties while taking study drugs (8 week duration) Current or planned use of continuous subcutaneous, intravenous or oral anticoagulant drugs Scheduled for surgery under general anesthetic within 14 days of Screening Visit Pregnancy or planned pregnancy. Women of childbearing potential must have a negative pregnancy test and be non-lactating at the Screening Visit Insertion of a diaphragm pacing system

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High dosage Withania somnifera<br>544mg oral twice a day | Drug: Withania somnifera<br>* Nuclear Factor Kappa Beta Inhibitor<br>|
| Experimental: Medium dosage Withania somnifera<br>272mg oral twice a day | Drug: Withania somnifera<br>* Nuclear Factor Kappa Beta Inhibitor<br>|
| Placebo Comparator: Placebo<br>Matched capsules twice a day | Drug: Placebo<br>* Placebo Comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (safety) | Incidence of adverse events | From Baseline visit until end of study visit (Week 9) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in SICI values | Short-interval intracortical inhibition (SICI) measured by transcranial magnetic stimulation (TMS). | Baseline to 8 weeks | 
| Change in RMT values | Resting motor threshold (RMT) measured by transcranial magnetic stimulation (TMS). | Baseline to 8 weeks | 
| Change in recovery cycle | This is a lower motor neuron excitability parameter measured by threshold tracking nerve excitability testing (NET). | Baseline to 8 weeks | 
| Change in strength duration time constant | This is a lower motor neuron excitability parameter measured by threshold tracking nerve excitability testing (NET). | Baseline to 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Withania somnifera, Ashwagandha, Nuclear Factor Kappa Beta Inhibition, Amyotrophic Lateral Sclerosis