Nevanimibe HCl for the Treatment of Classic CAH

• Sponsor: Millendo Therapeutics US, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03669549
• Collaborator: (none)
• Enrollment: 15
• Locations: 11
• Arm: 1
• Actual Duration (Months): 24
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a multicenter, intra-subject dose-titration open-label study of nevanimibe hydrochloride (HCl) for the treatment of classic congenital adrenal hyperplasia (CAH). Following a Screening Period of approximately 2-14 weeks, eligible subjects will enter a Baseline Period of approximately 2-8 weeks and then a 16-week Treatment Period. It is anticipated that the overall duration of the study per subject will range from 24-42 weeks.

Condition or Disease	Intervention/Treatment	Phase
Congenital Adrenal Hyperplasia	Drug: Nevanimibe hydrochloride	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for the Treatment of Classic Congenital Adrenal Hyperplasia
• Actual Study Start Date: Jul 11, 2018
• Actual Primary Completion Date: Jun 3, 2020
• Actual Study Completion Date: Jul 12, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nevanimibe hydrochloride Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID	Drug: Nevanimibe hydrochloride; During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects Achieving Serum 17-OHP Targets [Through Day 113]

   The primary efficacy endpoint was the overall response rate within each cohort, defined as the percentage of patients achieving serum 17-OHP targets as follows: Men and postmenopausal women: 17-OHP ≤ 2x ULN Premenopausal women: Follicular phase: 17-OHP ≤ 2x follicular phase ULN Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN - follicular phase ULN))

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency and/or historical documentation of elevated 17-OHP

• 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 screening and throughout the treatment period of the study

Exclusion Criteria:

• Nonclassic CAH

• Other causes of adrenal insufficiency

• HIV, hepatitis B, or hepatitis C

• AST or ALT >2x ULN, bilirubin or serum creatinine >1.5x ULN

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Ribeirão Preto, Medicine Faculty (Faculdade de Medicina) of Ribeirão Preto	Ribeirão Preto		Brazil	14051-140
2	Universidade Federal de São Paulo, Escola Paulista de Medicina	São Paulo		Brazil	04037-002
3	Hospital das Clínicas da FMUSP - Prédio do Instituto Central	São Paulo		Brazil	05403-900
4	Institute of Endocrinology	Praha 1		Czechia
5	Hospital Pitié-Salpetrière	Paris		France
6	Bnai Zion Medical Center	Haifa		Israel
7	Beilinson Hospital	Petach Tikva		Israel
8	Tel-Aviv-Sourasky Medical Center	Tel Aviv		Israel
9	Hospital General Universitario Gregorio Marañón	Madrid		Spain
10	Hospital Universitario Virgen del Rocío	Sevilla		Spain
11	University Hospital La Fe	Valencia		Spain

Sponsors and Collaborators

• Millendo Therapeutics US, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 31, 2019
• Statistical Analysis Plan - May 13, 2020

More Information

Publications

None provided.

• Responsible Party: Millendo Therapeutics US, Inc.
• ClinicalTrials.gov Identifier: NCT03669549
• Other Study ID Numbers: ATR-101-202
• First Posted: Sep 13, 2018
• Last Update Posted: Mar 4, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millendo Therapeutics US, Inc.: CAH; nevanimibe
• Additional relevant MeSH terms: Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Hyperplasia

Study Results

Participant Flow

Recruitment Details	Global Amendment 1: Approximately 20-24 adults with a documented history of classic CAH will be enrolled Global Amendment 2: Approximately 20-24 evaluable adults with a documented history of classic CAH will be enrolled 20-24 patients planned, 15 patients analyzed
Pre-assignment Detail	Screening Period of 2-14 weeks After signing informed consent, patients with classic CAH entered the Screening Period to assess preliminary eligibility for the study based on the inclusion and exclusion criteria. In addition, pertinent information was collected such as past medical history, demographic data, and prior and current medications.

Arm/Group Title	Nevanimibe HCl
Arm/Group Description	Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.
Period Title: Overall Study
STARTED	15
COMPLETED	9
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Nevanimibe HCl
Arm/Group Description	Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.3 (11.0)
Sex: Female, Male (Count of Participants)
Female	8 53.3%
Male	7 46.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	15 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Czechia	2 13.3%
Brazil	1 6.7%
Israel	4 26.7%
France	2 13.3%
Spain	6 40%
Baseline serum 17-hydroxyprogesterone (ng/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/dL]	10644.1 (10618.3)

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects Achieving Serum 17-OHP Targets
Description	The primary efficacy endpoint was the overall response rate within each cohort, defined as the percentage of patients achieving serum 17-OHP targets as follows: Men and postmenopausal women: 17-OHP ≤ 2x ULN Premenopausal women: Follicular phase: 17-OHP ≤ 2x follicular phase ULN Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN - follicular phase ULN))
Time Frame	Through Day 113

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nevanimibe HCl
Arm/Group Description	Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.
Measure Participants	15
Number [percent]	7.1

Adverse Events

Time Frame	From the time of informed consent through treatment period and until 30 days after the last dose of study drug
Arm/Group Title	Nevanimibe HCl Dose Level: <500 mg BID		Nevanimibe HCl Dose Level:500 to <1000 mg BID		Nevanimibe HCl Dose Level: 1000 to <1500 mg BID		Nevanimibe HCl Dose Level: 1500 to <2000 mg BID		Nevanimibe HCl Dose Level:2000 mg BID
Arm/Group Description	Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.		Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.		Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.		Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.		Ascending dose level of oral nevanimibe hydrochloride beginning with 500 mg BID up to 2000 mg BID Nevanimibe hydrochloride: During the 16-week treatment period, all subjects will begin dosing with nevanimibe HCl 500 mg BID and be dose titrated to 1000 mg BID, 1500 mg BID, and 2000 mg BID as needed based on serum 17-OHP assessments every 4 weeks.
All Cause Mortality
	Nevanimibe HCl Dose Level: <500 mg BID		Nevanimibe HCl Dose Level:500 to <1000 mg BID		Nevanimibe HCl Dose Level: 1000 to <1500 mg BID		Nevanimibe HCl Dose Level: 1500 to <2000 mg BID		Nevanimibe HCl Dose Level:2000 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/5 (0%)		0/14 (0%)		0/9 (0%)		0/9 (0%)
Serious Adverse Events
	Nevanimibe HCl Dose Level: <500 mg BID		Nevanimibe HCl Dose Level:500 to <1000 mg BID		Nevanimibe HCl Dose Level: 1000 to <1500 mg BID		Nevanimibe HCl Dose Level: 1500 to <2000 mg BID		Nevanimibe HCl Dose Level:2000 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/5 (0%)		1/14 (7.1%)		0/9 (0%)		0/9 (0%)
Infections and infestations
Uroinfection	0/14 (0%)	0	0/5 (0%)	0	1/14 (7.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Nevanimibe HCl Dose Level: <500 mg BID		Nevanimibe HCl Dose Level:500 to <1000 mg BID		Nevanimibe HCl Dose Level: 1000 to <1500 mg BID		Nevanimibe HCl Dose Level: 1500 to <2000 mg BID		Nevanimibe HCl Dose Level:2000 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/14 (21.4%)		5/5 (100%)		8/14 (57.1%)		7/9 (77.8%)		5/9 (55.6%)
Eye disorders
Dry eye	0/14 (0%)	0	2/5 (40%)	2	0/14 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Gastrointestinal disorders
Abdominal discomfort, Diarrhoea, Dyspepsia, Flatulence, Gingival bleeding, Nausea	0/14 (0%)	0	2/5 (40%)	2	2/14 (14.3%)	2	4/9 (44.4%)	4	2/9 (22.2%)	2
General disorders
Asthenia, Chest pain, Fatigue, Noncardiac chest pain, Pyrexia	0/14 (0%)	0	2/5 (40%)	2	1/14 (7.1%)	1	0/9 (0%)	0	2/9 (22.2%)	2
Immune system disorders
Drug hypersensitivity	1/14 (7.1%)	1	0/5 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Infections and infestations
Cystitis, Nasopharyngitis, Urinary tract infection	0/14 (0%)	0	0/5 (0%)	0	2/14 (14.3%)	2	0/9 (0%)	0	1/9 (11.1%)	1
Injury, poisoning and procedural complications
Toxicity to various agents	0/14 (0%)	0	0/5 (0%)	0	0/14 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Investigations
Blood glucose increased	0/14 (0%)	0	0/5 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Metabolism and nutrition disorders
Decreased appetite	0/14 (0%)	0	0/5 (0%)	0	1/14 (7.1%)	1	1/9 (11.1%)	1	0/9 (0%)	0
Nervous system disorders
Disturbance in attention, Headache, Syncope	0/14 (0%)	0	0/5 (0%)	0	2/14 (14.3%)	2	1/9 (11.1%)	1	0/9 (0%)	0
Psychiatric disorders
Insomnia, Panic attack	0/14 (0%)	0	0/5 (0%)	0	0/14 (0%)	0	2/9 (22.2%)	2	0/9 (0%)	0
Renal and urinary disorders
Dysuria, Hypertonic bladder, Micturition urgency, Pollakiuria	0/14 (0%)	0	3/5 (60%)	3	3/14 (21.4%)	3	1/9 (11.1%)	1	0/9 (0%)	0
Reproductive system and breast disorders
Vaginal hemorrhage	0/14 (0%)	0	0/5 (0%)	0	0/14 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough, Oropharyngeal pain	0/14 (0%)	0	2/5 (40%)	2	0/14 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Skin and subcutaneous tissue disorders
Acne, Eczema, Pruritus, Rash, Urticaria	2/14 (14.3%)	2	3/5 (60%)	3	2/14 (14.3%)	2	0/9 (0%)	0	0/9 (0%)	0

Limitations/Caveats

Nevanimibe hydrochloride administered orally at doses of 500-2000 mg BID for up to 16 weeks in the first 10 evaluable patients did not result in sufficient efficacy. The Sponsor has decided to refrain from further development at this time.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.