Evaluation of CRN04894 Safety, Efficacy, and Pharmacokinetics in Congenital Adrenal Hyperplasia: A 12-Week, Phase 2 Open-Label, Sequential Dose Cohort Study
- Trial ID
- 2023-503488-40-00
- Protocol
- CRN04894-03
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of CRN04894 in participants with **Congenital Adrenal Hyperplasia**. Additionally, the primary efficacy objective is to assess the efficacy of CRN04894 by measuring the change from baseline in serum **androstenedione** (A4) levels. This is clinically relevant as it aims to determine the potential of CRN04894 to manage hormone levels in this condition, which is crucial for improving patient outcomes.
The secondary efficacy objective is to evaluate the efficacy of CRN04894 by measuring the change from baseline in serum **17-hydroxyprogesterone** (17-OHP) levels. This secondary measure provides further insight into the drug's impact on hormone regulation, which is important for comprehensive management of the disease.
Participants
The clinical trial involves a total of **21 participants** diagnosed with **congenital adrenal hyperplasia**. The study population includes both male and female subjects, with an age range of 18 to 75 years, although participants as young as 16 years may be included in the United States. Participants are required to have a confirmed diagnosis of classic 21-hydroxylase deficiency and must be on a stable regimen of glucocorticoid replacement therapy. The trial population was selected based on specific inclusion criteria, ensuring compliance with glucocorticoid and, if applicable, mineralocorticoid replacement regimens. Additionally, participants on estrogen therapy must have maintained a stable dose for at least three months prior to screening. The study does not exclude vulnerable populations, indicating a diverse participant group. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, efficacy, and pharmacokinetics of CRN04894 in participants with **congenital adrenal hyperplasia**. This is a 12-week, Phase 2, open-label, sequential dose cohort study. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as age and stable glucocorticoid replacement therapy. Participants will be required to have a confirmed diagnosis of classic 21-hydroxylase deficiency and must be on a stable regimen of glucocorticoid replacement.
The trial will include multiple follow-up visits to monitor the safety and efficacy of the treatment. The primary safety endpoints will focus on the incidence of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and any adverse events leading to discontinuation. The primary efficacy endpoint will be the change from baseline in morning serum androstenedione (A4) at Week 12. Secondary efficacy endpoints will include changes in serum 17-OHP levels.
Participants will be involved in the study for a maximum of 12 weeks, with the possibility of early termination if significant adverse events occur or if the participant fails to comply with the study protocol. The trial is expected to conclude by April 2025, with recruitment having started in September 2023. The study will ensure that all participants are monitored closely throughout the trial duration to ensure their safety and the integrity of the data collected.
Treatment
The clinical trial involves the administration of **CRN04894**, an **ACTH receptor antagonist**, as the primary experimental medication. CRN04894 is provided in tablet form and is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 160 mg over the treatment period. The treatment duration is set for 84 days. This medication is not a pediatric formulation and is chemically synthesized. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to the experimental medication, the trial includes several non-experimental treatments. **Methylprednisolone acetate** combined with **lidocaine hydrochloride monohydrate** is administered as a solution for injection. This synthetic glucocorticoid is used at a maximum daily dose of 120 mg, with a total maximum dose of 120 mg over the treatment period of 84 days. The administration route is via injection, and it is not a pediatric formulation.
**Abiraterone acetate** is another non-experimental treatment used in the study. It is administered orally in a pharmaceutical form identified as PHF00082MIG. The maximum daily dose is 60 mg, with a total maximum dose of 60 mg over the 84-day treatment period. This naturally occurring glucocorticoid is chemically synthesized and not intended for pediatric use.
**Fludrocortisone** is included as a mineralocorticoid treatment, administered orally. The maximum daily dose is 0.2 mg, with a total maximum dose of 0.3 mg over the treatment period. The pharmaceutical form is PHF00245MIG, and it is not a pediatric formulation. This treatment is chemically synthesized.
Lastly, **hydrocortisone**, a synthetic form of endogenously produced cortisol, is administered orally. The maximum daily dose is 30 mg, with a total maximum dose of 40 mg over the 84-day treatment period. The pharmaceutical form is PHF00099MIG, and it is not a pediatric formulation. This treatment is also chemically synthesized.
Efficacy
The efficacy of CRN04894 in the treatment of **Congenital Adrenal Hyperplasia** will be assessed through a primary efficacy endpoint, which is the change from baseline in morning serum androstenedione (A4) levels at Week 12. This measurement will be conducted before 11:00 AM to ensure consistency and accuracy. Additionally, a secondary efficacy endpoint will evaluate the change from baseline in morning serum 17-hydroxyprogesterone (17-OHP) levels at the same time point, Week 12.
The collection and analysis of these efficacy parameters will be performed using validated laboratory tests to ensure the reliability of the data. The schedule for these assessments is structured to capture the necessary data at baseline and at the end of the 12-week treatment period. The trial is designed to provide a comprehensive evaluation of the efficacy of CRN04894 in achieving the desired hormonal balance in participants with Congenital Adrenal Hyperplasia.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants ≥18 to 75 years of age at the time of signing the Informed Consent Form (ICF). Participants ≥16 years of age may be included in sites located in the United States (US)
- Classic 21-hydroxylase deficiency confirmed by the Investigator and approved by the Medical Monitor.
- On a stable (defined as no dose change of >5 mg/day hydrocortisone equivalent (see Section 12.5) within 6 months prior to Screening) regimen of glucocorticoid replacement (eg, hydrocortisone, prednisolone, prednisone, methylprednisolone).
- Compliance, as judged per investigator discretion, with glucocorticoid replacement and mineralocorticoid replacement (if applicable) regimen documented during the Screening Period
- Minimum total daily dose of ≥15 mg hydrocortisone (or equivalent)
- If on estrogen therapy (any route), dose must be stable for at least 3 months prior to Screening.
Exclusion Criteria
- Diagnosis of any other form of CAH other than classic 21-hydroxylase deficiency
- Dexamethasone or oral betamethasone use within 30 days of Screening
- History of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic glucocorticoid therapy
- Night shift workers or any other reason for abnormal sleep/wake cycles
- Clinically significant medical condition or abnormal laboratory tests, as judged by the Investigator, other than CAH
- History of major surgery/surgical therapy for any cause within 4 weeks prior to Screening
- Diabetes mellitus treated with insulin for less than 6 weeks prior to Screening, or with change in total daily insulin dose by >15% within 6 weeks prior to Screening
- Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) ≥8.5%(≥69 mmol/mL), or estimated HbA1c based on fructosamine if HbA1c is not evaluable (eg, due to hemoglobinopathies)
- Participants with hypothyroidism who are not receiving adequate hormone replacement therapy based on thyroid hormone levels measured at the time of Screening, as determined by the Investigator
- History of unstable angina or acute myocardial infarction within 12 weeks prior to Screening or other clinically significant cardiac disease at the time of Screening as judged by the Investigator
- Concomitant mental condition rendering him/her unable to understand the nature, scope, and possible consequences of the study, and/or evidence of poor compliance with medical instructions
- History of cancer excluding cured/treated dermal squamous or basal cell carcinoma or cervical carcinoma in situ
- Women who are pregnant or lactating or, if of childbearing potential, who are unwilling to use highly effective contraception as described in this study. Male participants who are unwilling to use highly effective contraception as described in this study.
- Known history of illicit drug or alcohol abuse within the last year
- Use of antiandrogen therapy in the past 3 months (eg, spironolactone, finasteride, cyproterone acetate, flutamide)
- Use of testosterone, androgen-containing supplements, aromatase inhibitors, or growth hormone
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 29 Sept 2023 | 3 |
 Italy | Not Recruiting | 29 Sept 2023 | 9 |
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 |
|---|---|---|---|---|---|---|
METHYLPREDNISOLONE | Other | PHF00243MIG | SOLUTION FOR INJECTION | 120 | 84 | SCP65085035 |
PREDNISOLONE | Other | PHF00082MIG | ORAL | 60 | 84 | SCP15687495 |
FLUDROCORTISONE | Other | PHF00245MIG | ORAL | 0.2 | 84 | SCP231617 |
HYDROCORTISONE | Other | PHF00099MIG | ORAL | 30 | 84 | SCP29190199 |