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Study of Safety, Tolerability, and Biological Activity of LAM-002A in C9ORF72-Associated Amyotrophic Lateral Sclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05163886
Recruitment Status : Recruiting
First Posted : December 20, 2021
Last Update Posted : April 5, 2022
Sponsor:
Information provided by (Responsible Party):
AI Therapeutics, Inc.

Brief Summary:
This is a clinical trial to evaluate the safety, tolerability, and biological effect of LAM-002A in adults with C9ORF72-associated ALS (C9ALS).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis ALS Drug: LAM-002A Other: Placebo Phase 2

Detailed Description:

This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, biomarker- driven clinical trial to evaluate the safety, tolerability, and biological effect of LAM-002A in adults diagnosed with ALS who are confirmed to carry the Chromosome 9 Open Reading Frame 72 (C9ORF72) gene mutation (C9ALS).

Informed consent will be obtained prior to the conduct of any study-related procedures. Study eligibility will be assessed at the screening visit and during the screening period. Participants must satisfy the inclusion and exclusion criteria for the study.

Participants will receive either standard of care plus LAM-002A or standard of care and placebo (randomized 2:1) for the first 12 weeks of the study (Core Study). LAM-002A will be administered as oral capsules 125 mg BID (250 mg total daily dose). The LAM-002A dose may be reduced to 100 mg BID (200 mg total daily dose) if adverse effects develop.

Participants who complete the first 12 weeks on treatment will be eligible to receive active drug (LAM-002A capsules at maximum tolerated dose of 125 or 100 mg BID) for the remainder of the study [Open Label Extension (OLE)] up to Week 24, with a Week 28 telephone phone call planned 28 days after the last dose of study drug. After the start of treatment on Week 1, participants will be followed at Weeks 2, 4, 8, 12, 16, 20, 24, and 28. Participants can withdraw from the study at any time.

The study will employ an interim analysis by an independent Data Safety Monitoring Board (DSMB) for safety and clinical efficacy. The DSMB will be responsible for reviewing the interim safety and futility analyses and recommending study continuation, termination, or study design adaptation.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, placebo-controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blinded
Primary Purpose: Treatment
Official Title: A Phase IIa Trial to Evaluate the Safety, Tolerability, and Biological Activity of LAM-002A (Apilimod Dimesylate Capsules) in C9ORF72-Associated Amyotrophic Lateral Sclerosis
Actual Study Start Date : December 23, 2021
Estimated Primary Completion Date : November 10, 2022
Estimated Study Completion Date : November 10, 2022


Arm Intervention/treatment
Experimental: LAM-002A
LAM-002A will be administered orally in five 25 mg capsules twice a day (250 mg total daily dose).
Drug: LAM-002A
LAM-002A (apilimod dimesylate) is formulated in capsules containing 25 mg of apilimod dimesylate. The capsule is Swedish orange, size 0.

Placebo Comparator: Placebo
Placebo matching LAM-002A will be administered orally in 5 capsules twice a day.
Other: Placebo
Microcrystalline cellulose in Swedish orange, size 0 capsules.




Primary Outcome Measures :
  1. Safety of LAM-002A: occurrence of TEAEs [ Time Frame: 28 Weeks ]
    The occurrence of serious and non-serious treatment-emergent adverse events (TEAEs) and clinically significant treatment-emergent abnormalities in clinical and laboratory values.

  2. Tolerability of LAM-002A: completion of core study treatment [ Time Frame: 12 Weeks ]
    The percentage of participants who complete 12 weeks on study treatment during the Core Study.

  3. Plasma Pharmacokinetics of LAM-002A [ Time Frame: 24 Weeks ]
    The levels of LAM-002 and metabolites in plasma levels.

  4. CSF Pharmacokinetics of LAM-002A [ Time Frame: 24 Weeks ]
    The levels of LAM-002 and metabolites in cerebral spinal fluid (CSF) levels.


Secondary Outcome Measures :
  1. Changes in biomarkers [ Time Frame: 24 Weeks ]
    Changes in plasma and CSF levels of a LAM-002A-induced biomarker.

  2. Tolerability of LAM-002A: completion of open-label study treatment [ Time Frame: 12 Weeks ]
    Secondary measures of tolerability will consider completion of 12 weeks on open-label study treatment during the OLE.


Other Outcome Measures:
  1. Changes in ALSFRS-R [ Time Frame: 28 Weeks ]
    Change in Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) total and domain scores. Score ranges from 0-48 with the higher the score indicating better function.

  2. Changes in Vital Capacity [ Time Frame: 24 Weeks ]
    Change in vital capacity (VC).

  3. Permanent assisted ventilation-free survival [ Time Frame: 24 Weeks ]
    Change in percent of ventilation-free survival summaries.

  4. Changes in ALS-CBS [ Time Frame: 24 Weeks ]
    Change in Amyotrophic Lateral Sclerosis Cognitive Behavioral Scale (ALS-CBS). Comprised of two sub-scores. The cognitive sub-score is rated 0-20 with the higher the score the better patient cognitive function. The caregiver sub-score is rated 0-45 with the higher the score the better patient cognitive function as assessed by their caregiver.

  5. Exploratory biomarkers [ Time Frame: 24 Weeks ]
    Analysis of exploratory disease related biomarkers.



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
Criteria

Inclusion Criteria:

  1. Diagnosis of C9ORF72-associated ALS with BOTH of the following:

    1. Documentation of a clinical genetic test demonstrating the presence of a pathogenic repeat expansion in C9ORF72. If there is a strong clinical suspicion for C9ALS based on C9-positive family history and El Escorial Criteria consistent with a diagnosis of ALS, clinical testing for the C9ORF72 repeat expansion may be performed with study screening labs at the discretion of the Site Investigator (SI), medical monitor, and study sponsor.

      AND

    2. Must meet possible, laboratory-supported probable, probable, or definite criteria for diagnosing ALS by revised El Escorial criteria (Brooks 2000).
  2. Age 18 or older
  3. Capable of providing informed consent at the Screening Visit and complying with study procedures throughout the study, in the SI's opinion, and at the discretion of the medical monitor and study sponsor.
  4. In the case that a participant lacks the ability to provide informed consent. Informed consent will be sought from the participant's surrogate representative.
  5. Able to safely swallow study drug capsule at screening and throughout study. May use thickened substances to assist in swallowing drug.
  6. Vital Capacity greater than and equal to 50% of predicted at the time of the Screening Visit measured by Slow Vital Capacity (SVC), or, if required due to COVID-19 pandemic-related restrictions and with Sponsor approval, Forced Vital Capacity (FVC) measured in-person or via telemedicine.
  7. Participants must either not take or be on a stable dose of riluzole (as either a tablet or oral suspension) for greater than 30 days prior to the Screening Visit. Riluzole-naïve participants are permitted in the study.
  8. Participants must either not take edaravone or have completed at least one 14-day cycle with plan for continuation of edaravone prior to the Screening Visit. Participants must be off cycle and at least 2 days after the last dose administration of edaravone at the time of study visit. Edaravone-naïve participants are permitted in the study.
  9. Participants must be able to complete all study procedures, including the lumbar punctures (LP) at the time of the Screening Visit, in the SI's opinion.
  10. Geographically accessible to the site.

Exclusion Criteria:

  1. Clinically significant unstable medical condition (other than ALS) that would pose a risk to the participant, according to the SI's judgment [e.g., cardiovascular instability, systemic infection, or clinically significant laboratory abnormality or electrocardiogram (ECG) changes].

    1. Gastrointestinal disease (e.g., gastric, or intestinal bypass surgery, jejunostomy tube, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) that might interfere with drug absorption or with interpretation of gastrointestinal AEs. Gastrostomy tube placement is allowed prophylactically or to supplement nutrition/hydration but may not be used for study drug administration.
    2. Hepatic profile showing any of the following:

    i. Serum alanine aminotransferase (ALT) greater than 5 × upper limit of normal (ULN).

    ii. Serum aspartate aminotransferase (AST) greater than 5 × ULN.

    iii. Serum bilirubin greater than 1.5 × ULN.

    c. Renal profile showing an estimated creatinine clearance (eClCR) less than 30 mL/minute (with eClCR to be calculated by the method at the laboratory performing the serum creatinine test).

  2. Presence of a neurodegenerative cognitive or motor syndrome (e.g., Alzheimer's disease, Parkinson's disease) not related to the C9ORF72 repeat expansion.
  3. Presence of unstable psychiatric disease or substance abuse that would impair ability of the participant to provide informed consent, in the SI's opinion.
  4. Active cancer or history of cancer, except for the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin, cervical carcinoma in situ, prostatic carcinoma in situ, or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years. Active cancer includes cancers with current disease manifestations or therapy that could adversely affect subject safety and longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results.
  5. Prior solid organ transplantation.
  6. Ongoing immunosuppressive therapy including systemic or enteric corticosteroids at screening or for the duration of the trial, at the discretion of the site investigator and medical monitor.
  7. Use within 5 days prior to randomization or for the duration of the trial of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 or expected requirement for chronic use of a strong inhibitor or inducer of CYP3A4 during study therapy.
  8. Use within 5 days prior to randomization or for the duration of the trial of drug that is a moderate-to-strong substrate of CYP2C9 (including warfarin, tolbutamide, phenytoin, glimepiride) or expected requirement for chronic use of such drugs during study therapy, at the discretion of the site investigator and medical monitor.
  9. Use of investigational treatments for ALS (off-label use or active participation in a clinical trial) within 5 half-lives (if known) or 30 days (whichever is longer) prior to the Screening Visit.
  10. Exposure at any time to any gene therapies under investigation for the treatment of ALS (off-label use or investigational).
  11. If female, breastfeeding, known to be pregnant, planning to become pregnant during the study, or of child-bearing potential and unwilling to use effective contraception for the duration of the trial and for 3 months after discontinuing treatment.
  12. If male of reproductive capacity, unwilling to use effective contraception for the duration of the trial and for 3 months after discontinuing study treatment.
  13. Anything that would place the participant at increased risk or preclude the participant's full compliance with or completion of the study, in the SI's opinion.
  14. If a participant is being re-screened, the disqualifying condition has not been resolved, or the mandatory wash-out duration has not occurred.
  15. Contraindication to undergoing a lumbar puncture (LP) in the SI's opinion. Participants undergoing the LP must not be currently taking anticoagulation and antiplatelet medications such as warfarin and clopidogrel bisulfate (Plavix™), that would be a contraindication to LP; aspirin and non-steroidal anti-inflammatories are allowed.

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): NCT05163886


Contacts
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Contact: Kyle West 919-373-5390 kyle.west@iqvia.com

Locations
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United States, Iowa
University of Iowa Hospitals and Clinics Recruiting
Iowa City, Iowa, United States, 52242
United States, Maryland
Johns Hopkins University School of Medicine Recruiting
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
AI Therapeutics, Inc.
Investigators
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Principal Investigator: Suma Babu, M.D. Massachusetts General Hospital
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Responsible Party: AI Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05163886    
Other Study ID Numbers: LAM-002A-ALS-CLN01
First Posted: December 20, 2021    Key Record Dates
Last Update Posted: April 5, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AI Therapeutics, Inc.:
C9ORF72
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases