NF-κB Inhibition in Amyotrophic Lateral Sclerosis (NIALS)

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

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).

Study Overview

• Status: Recruiting
• Conditions: ALS
• Intervention / Treatment: Drug: Placebo; Drug: Withania somnifera

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 75
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jake Wimmer; Phone Number: 87561 416-480-6100; Email: jake.wimmer@sri.utoronto.ca
• Study Contact Backup: Name: Shirley Pham; Phone Number: +1 (416)480-6860; Email: shirley.pham@sunnybrook.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Lorne Zinman; Email: Lorne.Zinman@sunnybrook.ca
      • Contact: Agessandro Abrahao; Email: agessandro.abrahao@sunnybrook.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Substance abuse within the past year
  2. Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active malignancy or infectious disease
  3. Acquired Immunodeficiency Syndrome (AIDS) or AIDS-related complex
  4. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incident cases of ALSFRS-R score changes of 4 or more points	Any incident case of ≥ 4-point increase in the ALS Functional Rating Scale-Revised (ALSFRS-R) scores or significant clinical improvement at week 8 will be reported. Changes in pro-inflammatory tests (CRP and IL-6) from baseline to Week 8 will be assessed.	Baseline to 9 weeks
Change in serum IL-6 levels	Serum IL-6 levels will serve as an indirect marker of NF-kB inhibition and target engagement.	Baseline to 8 weeks

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Investigators: Principal Investigator: Agessandro Abrahao, MD, MSc, Sunnybrook Research Institute, University of Toronto; Study Director: Lorne Zinman, MD, MSc, Sunnybrook Research Institute, University of Toronto

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2021
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: August 5, 2021
• First Submitted That Met QC Criteria: August 26, 2021
• First Posted (Actual): September 1, 2021

Study Record Updates

• Last Update Posted (Actual): June 6, 2022
• Last Update Submitted That Met QC Criteria: June 1, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; Ashwagandha; Withania somnifera; Nuclear Factor Kappa Beta Inhibition
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: 032-2017

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No