Evaluation of Dazucorilant (CORT113176) Efficacy and Safety in Amyotrophic Lateral Sclerosis: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-514082-19-00
- Protocol
- CORT113176-652
- Sponsor
- Corcept Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of dazucorilant in patients with **Amyotrophic Lateral Sclerosis (ALS)**. This is clinically relevant as ALS is a progressive neurodegenerative disease with limited treatment options, and assessing the efficacy and safety of new therapeutic agents is crucial for improving patient outcomes.
Secondary objectives include:
- Assessing the effect of dazucorilant on muscle strength.
- Evaluating the impact on scales assessing Quality of Life and function, including Slow Vital Capacity (SVC).
- Determining the effect on time to event for patients experiencing full-time or nearly full-time respiratory support, death, or a combination of these outcomes.
- Assessing the effect on the Combined Assessment of Function and Survival (CAFS).
- Evaluating the pharmacokinetics (PK) of dazucorilant in patients with ALS.
Participants
The clinical trial involves a total of **24 participants** diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. The study population includes both male and female subjects aged 18 years and older, as defined by the Gold Coast criteria. Participants were selected based on their risk of ALS progression, characterized by an ENCALS risk profile score between -6 and -3. The trial includes individuals with either sporadic or familial ALS. Participants are required to be on stable doses of any regulatory-authority-approved therapies for ALS, such as riluzole, edaravone, and sodium phenylbutyrate and taurursodiol, for a specified period prior to screening. The study population is medically able to undergo study procedures and adhere to the visit schedule. Both male and female participants of childbearing potential must agree to use a protocol-specified method of contraception during the study and for 28 days after the last dose of the study drug. The trial includes a vulnerable population, and all participants have provided written informed consent for participation.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the safety and efficacy of **dazucorilant** in patients with **Amyotrophic Lateral Sclerosis** (ALS). The trial is structured as a Phase 2, multicenter investigation, with an estimated duration from November 14, 2022, to March 31, 2027. Participants will be randomly assigned to receive either the active treatment, dazucorilant, in the form of soft or hard capsules, or a placebo. The primary objective is to assess changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to Week 24, alongside monitoring the incidence of adverse events (AEs) and serious adverse events (SAEs).
The study involves several key visits, beginning with a screening visit to confirm eligibility based on criteria such as age, ALS diagnosis according to Gold Coast criteria, and stability on any concurrent ALS therapies. Following successful screening, participants will undergo regular follow-up visits to monitor efficacy and safety endpoints, including assessments of muscle strength, vital capacity, and quality of life measures. A dedicated pharmacokinetic (PK) substudy will be conducted at the Week 3 visit for a subset of approximately 20% of participants to evaluate the pharmacokinetics of dazucorilant.
The expected length of participant involvement is up to 156 weeks, with conditions for early termination including the occurrence of severe adverse events or non-compliance with study protocols. The end-of-study visit will conclude the trial for each participant, ensuring comprehensive data collection and final assessments. Throughout the trial, participants are required to adhere to protocol-specified methods of contraception and maintain compliance with scheduled visits and study procedures.
Treatment
The clinical trial involves the administration of **dazucorilant**, an investigational medication, under the product name CORT113176. This compound is provided in two pharmaceutical forms: **softgel capsules** and **hard shell capsules**. Both forms contain the active substance dazucorilant, a chemical compound developed by Corcept Therapeutics Inc. The maximum daily dose of dazucorilant is 300 mg, with a total maximum dose of 46,800 mg over a treatment period of 156 days. The medication is administered orally, and the trial aims to evaluate its safety and efficacy in patients with Amyotrophic Lateral Sclerosis (ALS). Participant compliance with the dosing schedule is monitored throughout the study.
In addition to the experimental medication, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to mimic the appearance of the dazucorilant softgel capsule but does not contain any active substance. The use of a placebo allows for the assessment of the true efficacy and safety profile of dazucorilant by providing a baseline for comparison. The placebo is administered following the same oral route and dosing schedule as the active medication to maintain the study's blinding integrity.
Efficacy
The efficacy of **dazucorilant** in patients with Amyotrophic Lateral Sclerosis (ALS) will be assessed through a series of predefined endpoints in a Phase 2, multicenter, randomized, double-blind, placebo-controlled study. The primary efficacy endpoint is the change from baseline to Week 24 in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score. This scale is a validated tool used to measure the functional status of patients with ALS, providing a comprehensive assessment of disease progression.
Secondary efficacy endpoints include changes from baseline to Week 24 in muscle strength, assessed using a hand-held dynamometer, and changes in percent slow vital capacity and EQ-5D-5L scores. Additionally, time to death, time to respiratory support greater than 22 hours per day for 7 days, and the combined assessment of function and survival (CAFS) will be evaluated. Plasma samples for pharmacokinetic analysis will be obtained from a subset of approximately 20% of patients at the Week 3 visit to report the dazucorilant area under the curve (AUC) and maximum concentration (Cmax).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female patients ≥18 years of age with ALS as defined by Gold Coast criteria
- Patients with sporadic or familial ALS. In Part 1 patients must have a risk of ALS progression characterized by an ENCALS risk profile score ≥ -6 and ≤ -3. In Part 2 patients must have a risk of ALS progression characterized by a TRICALS risk profile score ≥ -7 and ≤ -3.
- Regulatory-authority-approved therapies for the treatment of ALS are permitted. If taking riluzole, edaravone, and/or sodium phenylbutyrate and taurursodiol, must have been on a stable dose of riluzole for ≥30 days, edaravone for ≥60 days and/or sodium phenylbutyrate and taurursodiol maintenance dosage ≥30 days prior to Screening. Sodium phenylbutyrate and taurursodiol are not permitted for patients enrolled in Part 2 of the study.
- Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
- Able to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, and other study evaluations and procedures.
- Provide written informed consent for participation in the study. If the patient is willing to sign the ICF but cannot physically sign it, an impartial witness must sign the ICF. Patients who are unable to come to the site in-person following informed consent for initial study participation may subsequently be consented remotely if allowed by local regulations/IRBs.
- Male patients and female patients of childbearing potential must agree to use a protocol-specified method of contraception from screening and during the study until 28 days after last dose of study drug
- Part 2 only: Patients with a pathogenic mutation in superoxide dismutase 1 (SOD1) must not be receiving treatment with tofersen or eligible for treatment with tofersen if available. Patients who have received prior treatment with tofersen and discontinued due to safety and/or efficacy reasons prior to Screening are eligible.
- Part 2 only: Use of ultra high-dose methylcobalamin for the treatment of ALS is permitted provided the patient has been on a stable dose for ≥ 11 weeks prior to the Day 1 visit.
Exclusion Criteria
- History of a clinically significant non-ALS neurologic disorder, including, but not limited to, muscular dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, Alzheimer’s disease, cervical spondylosis, Parkinson’s disease, Lewy body dementia, vascular dementia, Huntington’s disease, epilepsy, stroke, multiple sclerosis, multifocal motor neuropathy, diabetic neuropathy, brain tumor, or brain infection/abscess.
- Inability to swallow capsules.
- Blood platelet count <150,000/mm3.
- Renal impairment indicated by eGFR ≤30 mL/min/1.73m2. Part 2 only: Patients with a recent history of acute kidney injury should have returned to their baseline renal function (ie, eGFR prior to acute kidney injury) prior to enrollment.
- Human immunodeficiency virus (HIV) or current chronic/active infection with hepatitis C virus or hepatitis B virus including patients with chronic or active hepatitis B as diagnosed by serologic tests. Part 2 only: Known history of HIV or chronic/active infection with hepatitis C or hepatitis B virus; testing does not need to be performed if infection status is unknown.
- Women who are pregnant, planning to become pregnant, or are breastfeeding. Women of childbearing potential who are unwilling or unable to use a highly effective method of contraception from screening through the duration of treatment and up to 28 days after last dose of study drug.
- Known liver impairment (Child-Pugh Class A, B, or C).
- History of Class III/IV heart failure (per New York Heart Association).
- At the time of Screening, any use of non-invasive ventilation (NIV), e.g., continuous positive airway pressure [CPAP], noninvasive bi-level positive airway pressure [NPPV] or noninvasive volume ventilation [NVV] for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation.
- Cancer that is currently being treated (except adequately controlled basal cell carcinoma or squamous cell carcinoma of the skin, stage I endometrial cancer, or carcinoma in situ of the cervix or breast) or a history of cancer with an expected survival < 2 years.
- History of any other clinically significant cardiovascular, renal, hepatic, endocrine, metabolic, respiratory, gastrointestinal (GI), bleeding, autoimmune, neurological, psychiatric disorder, or unstable medical condition (other than ALS), as judged by the Investigator.
- History and/or symptoms of adrenal insufficiency.
- Abnormal liver function defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × upper limit of normal (ULN).
- QTcF interval based on the mean of 2 ECGs of >450 ms, for men and >470 ms for women.
- History of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long-QT syndrome).
- Positive nasopharyngeal PCR test for SARS-CoV-2 on Day -1 or within 8 weeks prior to Screening.
- Ongoing use of any strong CYP3A4 inhibitor/inducer, or any medication with a narrow therapeutic index that is predominantly metabolized by CYP2C8 or is a substrate of breast cancer resistance protein (BCRP) or P-glycoprotein 1 (P gp) that cannot be adequately dose adjusted.
- Taking, or have taken, any strong CYP3A inducer within 30 days (or 5 half-lives if longer) before Screening, or any strong CYP3A inhibitor within 14 days before Screening.
- Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.
- Received any live or attenuated vaccine within 30 days, before the first dose of study drug.
- Taking, or have taken, any systemic, inhaled, or potent dermatologic topical corticosteroids (Class I to III) within a period equivalent to 5 half-lives of the corticosteroid used prior to first dose of study drug. Patients who have stopped glucocorticoid use should have an alternative option if their condition deteriorates during the study.
- Participation in a clinical trial for ALS involving small molecules within 30 days of the Screening, or treatment with another investigational drug (including through compassionate use programs), biological agent, or device within 30 days or 5 half-lives of study agent, whichever is longer. No prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed at any time in the patient’s history.
- Unstable or poorly controlled comorbid disease process of any organ system currently requiring active treatment or likely to require treatment adjustment during the study.
- Previous exposure or treatment with glucocorticoid receptor modulators or antagonists.
- History of hypersensitivity or severe reaction to the study drug’s excipients.
- In the Investigator’s opinion, should not participate in the study or may not be capable of providing informed consent or following the study schedule. This includes, but is not limited to, presence of unstable psychiatric disease, cognitive impairment, dementia, or substance abuse within 2 years prior to Screening.
- Is a family member of one of the Sponsor’s employees, the Investigator, or the site staff working directly on the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 14 Nov 2022 | 12 |
 France | Not Recruiting | 14 Nov 2022 | 41 |
 Germany | Recruiting | 14 Nov 2022 | 59 |
 Ireland | Not Recruiting | 14 Nov 2022 | 7 |
 The Netherlands | Recruiting | 14 Nov 2022 | — |
 Poland | Not Recruiting | 14 Nov 2022 | 67 |
 Spain | Not Recruiting | 14 Nov 2022 | 36 |
| Netherlands | — | — | 18 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo to Dazucorilant softgel capsule | Placebo | N/A | — | — | — | N/A |
CORT113176 | Test | CAPSULE, SOFT | ORAL | 300 | 156 | PRD11343314 |
CORT113176 | Test | CAPSULE, HARD | ORAL | 300 | 156 | PRD12054875 |