| Eligibility |
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.
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