A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for the Treatment of Classic Congenital Adrenal Hyperplasia

Phase 1

Conditions: Classic Congenital Adrenal Hyperplasia
MedDRA version: 20.0Level: LLTClassification code 10010323Term: Congenital adrenal hyperplasiaSystem Organ Class: 100000004850
Therapeutic area: Diseases [C] - Hormonal diseases [C19]

Registration Number: EUCTR2017-004878-34-ES

Lead Sponsor: Millendo Therapeutics US, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 24

Inclusion Criteria

• Men and women 18 to 80 years of age (inclusive) at the time of informed consent.
• Documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency based on either or both of the following criteria:
1.Documented genetic mutation in the CYP21A2 enzyme consistent with a diagnosis of classic CAH
2.Historical documentation of elevated 17-OHP (e.g., in infancy or following a cosyntropin/ACTH stimulation test)
• Serum 17-OHP = 4x ULN during the Baseline Period
- Premenopausal women in the follicular phase of the menstrual cycle must have serum 17 OHP = 4x follicular phase ULN
- Premenopausal women in the luteal phase of the menstrual cycle must have serum 17 OHP = (4x follicular phase ULN + (luteal phase ULN – follicular phase ULN))
• Chronic glucocorticoid replacement therapy for at least 6 consecutive months prior to Screening
• Stable glucocorticoid and mineralocorticoid regimen for at least 4 weeks prior to the Screening (S1), Baseline (B1), and Enrollment (T1) Visits
• For subjects who undergo maintenance glucocorticoid dose adjustment between Screening and Enrollment, stable serum 17-OHP levels (adjusted as needed for menstrual cycle phase) prior to Enrollment, defined as the most recent 2 values being within 30% of each other (calculated as 100 × (1 – (smaller value/larger value)))
• Female subjects of childbearing potential must consent to use two medically acceptable methods of contraception, excluding depot progesterone, throughout the study period and for 30 days after the last dose of study treatment during any sexual intercourse with a fertile male partner
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 4

Exclusion Criteria

• Nonclassic CAH
• Other causes of adrenal insufficiency such as Addison’s disease or adrenalectomy, or classic CAH with serum 17-OHP < 4x ULN and daily maintenance glucocorticoid dose in the adrenal insufficiency range (e.g., = 8-10 mg hydrocortisone/m2 body surface area per day)
• Surgery within the previous three months prior to screening or planned surgery during study participation. Minor procedures are permitted (e.g., removal of skin tags or other minor dermatological procedures)
• History of active cancer requiring medical or surgical therapy within the past 6 months (with the exception of successfully treated non-metastatic basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix)
• Female subjects must not be currently pregnant or breastfeeding or have conceived or given birth within 3 months of Screening
• Abnormal laboratory tests at Screening:
1. ALT or AST > 2x ULN
2. Bilirubin > 1.5x ULN
3. Serum creatinine > 1.5x ULN
• Positive screen for HIV, hepatitis B surface antigen or hepatitis C antibody at Screening
• An average QTcF value of > 470 msec at Screening
• Current or ongoing use of any prohibited concomitant medications (Section 5.8)
• History of substance abuse within the past 1 year prior to informed consent
• Positive toxicology screening test for substances of abuse, other than marijuana
• Known allergy to nevanimibe HCl (formerly known as ATR-101)
• Participation in any study of an investigational drug within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to Screening
• Any other medical or psychiatric condition that, in the opinion of the Investigator, is likely to confound the interpretation of the study results or prevent the subject from understanding the requirements of or successfully completing the study (e.g., myocardial infarction (MI) or cerebrovascular accident/transient ischemic attack (CVA/TIA) within the past 6 months)

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy and safety of orally administered nevanimibe HCl for the treatment of classic CAH;Secondary Objective: • To assess the changes in adrenal cortical steroids and steroid intermediates <br>• To determine the pharmacokinetic (PK) parameters of nevanimibe and its major metabolite(s)<br>• To assess the PK/pharmacodynamic (PD) relationships of nevanimibe and its major metabolite(s);Primary end point(s): The primary efficacy endpoint is the overall response rate within each cohort, defined as the percentage of subjects achieving serum 17-OHP targets as follows:<br>• Men and postmenopausal women: 17-OHP = 2x ULN<br>• Premenopausal women:<br>- Follicular phase: 17-OHP = 2x follicular phase ULN<br>- Luteal phase: 17-OHP = (2x follicular phase ULN + (luteal phase ULN – follicular phase ULN));Timepoint(s) of evaluation of this end point: Timepoint of evaluation of the primary end Point: T2, T3, T4, T5

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Safety Endpoints: Safety endpoints include the incidence of treatment-emergent AEs and SAEs, as well as the values and changes from baseline in clinical laboratory tests, vital signs, PEs and ECG parameters. There are no prespecified targets for the safety endpoints.<br><br>The PK and PD endpoints include the following:<br>•The Cmax, Tmax, AUC0-4 and other PK parameters of nevanimibe and its major metabolite(s) (as appropriate and as the data allow)<br>•The relationship between the Cmax and AUC0-4 of nevanimibe and its major metabolite(s) in relation to the change in 17-OHP levels (as appropriate and as the data allow)<br>Additional PK and PD endpoints may be described in the SAP.;Timepoint(s) of evaluation of this end point: Timepoint of evaluation of the safety end Point: every 4 weeks during study participation<br><br>Timepoint of evaluation of the PK and PD end Point: T1, T2, T3, T4, T5

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