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NF-κB Inhibition in Amyotrophic Lateral Sclerosis (NIALS)

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ClinicalTrials.gov Identifier: NCT05031351
Recruitment Status : Recruiting
First Posted : September 1, 2021
Last Update Posted : June 6, 2022
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
ALS Drug: Withania somnifera Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Nuclear Factor Kappa Beta Inhibition in Patients With Amyotrophic Lateral Sclerosis: A Phase II Randomized Placebo Controlled Trial
Actual Study Start Date : October 19, 2021
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : September 2022

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

Primary Outcome Measures :
  1. Incidence of adverse events (safety) [ Time Frame: From Baseline visit until end of study visit (Week 9) ]
    Incidence of adverse events

Secondary Outcome Measures :
  1. Change in SICI values [ Time Frame: Baseline to 8 weeks ]
    Short-interval intracortical inhibition (SICI) measured by transcranial magnetic stimulation (TMS).

  2. Change in RMT values [ Time Frame: Baseline to 8 weeks ]
    Resting motor threshold (RMT) measured by transcranial magnetic stimulation (TMS).

  3. Change in recovery cycle [ Time Frame: Baseline to 8 weeks ]
    This is a lower motor neuron excitability parameter measured by threshold tracking nerve excitability testing (NET).

  4. Change in strength duration time constant [ Time Frame: Baseline to 8 weeks ]
    This is a lower motor neuron excitability parameter measured by threshold tracking nerve excitability testing (NET).

Other Outcome Measures:
  1. Incident cases of ALSFRS-R score changes of 4 or more points [ Time Frame: Baseline to 9 weeks ]
    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.

  2. Change in serum IL-6 levels [ Time Frame: Baseline to 8 weeks ]
    Serum IL-6 levels will serve as an indirect marker of NF-kB inhibition and target engagement.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05031351

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Contact: Jake Wimmer 416-480-6100 ext 87561 jake.wimmer@sri.utoronto.ca
Contact: Shirley Pham +1 (416)480-6860 shirley.pham@sunnybrook.ca

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Canada, Ontario
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Contact: Lorne Zinman       Lorne.Zinman@sunnybrook.ca   
Contact: Agessandro Abrahao       agessandro.abrahao@sunnybrook.ca   
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
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Principal Investigator: Agessandro Abrahao, MD, MSc Sunnybrook Research Institute, University of Toronto
Study Director: Lorne Zinman, MD, MSc Sunnybrook Research Institute, University of Toronto
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Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT05031351    
Other Study ID Numbers: 032-2017
First Posted: September 1, 2021    Key Record Dates
Last Update Posted: June 6, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sunnybrook Health Sciences Centre:
Withania somnifera
Nuclear Factor Kappa Beta Inhibition
Amyotrophic Lateral Sclerosis
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases