A Phase IIb, Multi-Center, Multinational, Double-Blind, Placebo-Controlled Study, With an Open Label Extension, to Evaluate Safety, Tolerability and Efficacy of PrimeC in Subjects With ALS

Study Overview
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Brief Summary
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69 subjects with ALS will be enrolled in the study and randomized at a 2:1 ratio to receive the study drug or placebo tablets. Randomization sequences will be in random block sizes and stratified for ENCALS risk category [high risk ≥ -4.5 vs. low risk < -4.5], and for background ALS treatment (riluzole and/or edaravone and/or sodium phenylbutyrate and/or taurursodiol) vs. no background ALS treatment. All subjects will be administered the drug/placebo twice daily (BID), two tablets each time, for 6 months. Subjects will be allowed to receive standard of care (SOC) treatment of approved products (i.e., riluzole and edaravone). Additionally, subjects will be allowed to receive treatment with off-label sodium phenylbutyrate and taurursodiol, which are accepted for ALS treatment. Subjects will be evaluated every 2 months for safety, tolerability (adverse events, safety laboratory, vital signs, ECG, withdrawal rates and reasons) and efficacy (e.g. biomarkers, clinical outcomes (ALSFRS-R and SVC, quality of life and survival). All subjects who complete the 6 months dosing will be switched to the active arm for a 12-month open label extension (OLE).

Official Title
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A Phase IIb, Randomized, Multi-Center, Multinational, Prospective, Double-Blind, Placebo-Controlled Study, With an Open Label Extension, to Evaluate Safety, Tolerability and Efficacy of PrimeC in Subjects With ALS

Conditions
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ALS, Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: PrimeC
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to comprehend and willing to sign an informed consent form (ICF) Males or females between the ages of 18 and 75 years of age, inclusive Diagnosis of familial or sporadic ALS (defined as meeting the laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the Gold Coast criteria) Disease duration after first symptom (muscle weakness) less than 30 months prior to screening Pre-enrollment ALSFRS-R slope from disease onset ≥ 0.3 points per month ALSFRS-R at screening ≥ 25 Item 3 (swallowing) in ALSFRS-R ≥ 3 Subjects may be treated in parallel with riluzole and/or edaravone and/or sodium phenylbutyrate and/or taurursodiol; 60 days of stable use prior to enrollment is required Upright slow vital capacity (SVC) ≥ 60% of predicted for age, height, weight and sex at screening according to the GLI-2012 18 < BMI < 30 A caregiver (if one is needed) Female subjects must be post-menopausal (≥ 1 year) OR sterilized, OR if of childbearing potential (i.e., females who have had their first period unless they are anatomically or physiologically incapable to become pregnant), must have a negative pregnancy test, and agree to use contraceptive drugs or devices (e.g., diaphragm plus spermicide, or oral contraceptives) for the duration of the study and 10 weeks after the last treatment dose AND require male partners to use a condom during sexual intercourse Exclusion Criteria: A past history of adverse reaction/hypersensitivity to either NSAIDs, celecoxib or fluoroquinolones, ciprofloxacin Any known clinically significant abnormal gastric mucosal erosion, ulcer or tumor or/and GI disorder and/or bariatric surgery Known history of clinically significant impairment of renal function (creatinine ≥ 1.5) Known or suspected symptomatic congestive heart and/or coronary heart disease, previous history of myocardial infarction, uncontrolled arterial hypertension, or rhythm abnormalities requiring permanent treatment Known history of QT/QTc prolongation, Torsade de pointes (TdP) (e.g. heart failure, hypokalemia, family history of Long QT syndrome) and the use of concomitant medications that prolong the QT/QTc interval Known or suspected diagnosis or family history of epilepsy in first degree relatives Known predisposition to tendinitis Known or suspected to be a poor CYP2C9 metabolizers who also uses pharmacologic agents (prescription or over-the-counter) or herbal products known or suspected to induce or inhibit CYP2C9 within 30 days before enrollment Tracheostomy or percutaneous gastrostomy use Presence at screening of any medically significant cardiac, pulmonary, musculoskeletal, or psychiatric illness that might interfere with the subject's ability to comply with study procedures or that might confound the interpretation of clinical safety data, including, but not limited to: Mean systolic blood pressure >160 mm Hg and/or mean diastolic blood pressure >100 mm Hg (measurements taken after a few minutes rest) that persist on 3 successive measurements taken at least 2 minutes apart NYHA Class II or greater congestive heart failure Chronic obstructive pulmonary disease or asthma requiring daily use of bronchodilator medications Poorly controlled or brittle diabetes mellitus Cognitive impairment, related to ALS or otherwise, sufficient to impair subject's ability to understand and/or comply with study procedures and provide informed consent Subject who is treated with chronic aspirin or NSAIDs and is at risk if stopped. Clopidogrel is allowed and can replace Aspirin. Any contraindication for ciprofloxacin and celecoxib according to the current prescribing information. Female who is pregnant or breastfeeding or with intention of becoming pregnant during the course of the study. Any impairment or social circumstance that, in the opinion of the Investigator, would render the subject not suitable to participate in the study. Subject, or subject's legal guardian(s) is/are unable to understand the nature, scope, and possible consequences of the study. Subject is participating in (or plans to participate in) any other investigational drug trial, or plans to be exposed to any other investigational agent, device and/or procedure, from 30 days prior to Screening through study completion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Active Comparator: PrimeC<br>2 tablets of PrimeC administered twice daily (4 tablets a day), at a daily dose of 1496 mg | Drug: PrimeC<br>* Ciprofloxacin and celecoxib combination extended release formulation<br>|
| Placebo Comparator: Placebo<br>2 tablets of Placebo administered twice daily (4 tablets a day). Placebo tablets are matched in size, color and taste. | Drug: Placebo<br>* Placebo matches active drug in size, color and taste<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Treatment emergent adverse event is any medical event associated with the drug | 6 months | 
| Number of subjects who discontinued treatment prematurely | Number of subjects whose treatment is stopped prematurely for any reason | 6 months | 
| Number of patients who discontinued treatment prematurely due to adverse events | Number of patients whose treatment is stopped prematurely specifically due to adverse events | 6 months | 
| Number of patients with clinically significant abnormal laboratory values |  | 6 months | 
| The mean difference between PrimeC and Placebo in serum concentration of NDE TDP-43 at month 6 |  | 6 months | 
| The mean difference between PrimeC and placebo in serum concentration of NDE PgJ2 at month 6 |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to 6 months in ALS functional rating scale - revised (ALSFRS-R) |  | 6 months | 
| Change from baseline to 6 months in slow vital capacity (SVC) |  | 6 months | 
| Change from baseline to 6 months in quality of life ALSSQOL-SF |  | 6 months | 
| Change from baseline to 6 months in PROMIS-10 quality of life questionnaire |  | 6 months | 
| Survival at 6 months of treatment | Overall Survival defined as time to death from any cause at 6 months of treatment | 6 months | 
| Composite survival at 6 months of treatment | Composite of overall survival, defined as time to death from any cause, or respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days) at 6 months of treatment | 6 months | 
| Composite survival at 6 months of treatment | Composite of overall survival, defined as time to death from any cause, or respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days), or time to hospitalization due to ALS-related complications at 6 months of treatment | 6 months | 
| Joint Assessment of Function and Survival after 6 months of treatment |  | 6 months |