E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Classic Congenital Adrenal Hyperplasia |
|
E.1.1.1 | Medical condition in easily understood language |
CAH is a serious, chronically debilitating, and life-threatening genetic disorder characterized by impaired adrenal synthesis of cortisol and overproduction of adrenal androgens |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010323 |
E.1.2 | Term | Congenital adrenal hyperplasia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of tildacerfont in reducing A4 in subjects with CAH over 12 weeks |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of tildacerfont in reducing key hormones in subjects with CAH over 12 weeks |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male and female subjects 18 to 55 years old, inclusive
2.Has a documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency based on genetic mutation in CYP21A2 and/or elevated 17-OHP
3.Has A4 >1.5x ULN and ACTH >2x ULN at both screening and Week 4 (measured before any AM GC dose)
4.Has been on a stable dose of GC replacement ≥15 mg/day and ≤50 mg/day in HCe that does not vary in total daily dose from day to day for ≥3 months before screening without any evidence of non-adherence to the GC regimen during this period (stress dosing is allowed)
5.For subjects with the salt-wasting form of CAH, subject has been on a stable dose of mineralocorticoid replacement for ≥3 months before screening
6.Agrees to follow contraception guidelines. Male subjects must also agree to refrain from donating sperm throughout the treatment period and for 90 days after the last dose of study drug.
7. Is able to understand all study procedures and risks involved and provides written informed consent indicating willingness to comply with all aspects of the protocol |
|
E.4 | Principal exclusion criteria |
1.Has a known or suspected diagnosis of any other known form of classic CAH (not due to 21-hydroxylase deficiency)
2.Has a history that includes bilateral adrenalectomy or hypopituitarism
3.Has a history of allergy or hypersensitivity to tildacerfont or any other CRF1 receptor antagonist
4.Current treatment with dexamethasone as GC therapy for CAH
a.Prior treatment with dexamethasone is allowed as long as the transition to an alternative GC regimen (eg, HC, prednisone, or prednisolone) has resulted in a stable dose of GC replacement for ≥3 months before screening.
5.Is not adherent to GC or study drug dosing regimen during the Run-in Period (defined as taking <80% of expected doses as directed; stress dosing of GCs is allowed)
6.Shows clinical signs or symptoms of adrenal insufficiency
7.Has had a clinically significant unstable medical condition, medically significant illness, or chronic disease occurring within 30 days of screening, including but not limited to:
a. An ongoing malignancy or <3 years of remission history from any malignancy, other than successfully treated localized skin cancer
b. Presence of clinically significant renal disease, as evidenced by an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2
c. Current or chronic history of liver disease (including nonalcoholic steatohepatitis and female subjects with a history of intrahepatic cholestasis of pregnancy) or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)
d.History of alcohol or substance abuse within the last year, or any significant history of alcohol or substance abuse that would likely prevent the subject from reliably participating in the study, based on the opinion of the Investigator
e.Active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening
8.Had or has a clinically significant psychiatric disorder, including the following:
a.Evidence of major depressive episode, bipolar disorder, schizophrenia, schizoaffective disorder, major depressive disorder with psychotic features, or any other psychotic disorder within the preceding 6 months
b.Increased risk of suicide based on the Investigator’s judgment or the results of the Columbia–Suicide Severity Rating Scale (C-SSRS) conducted at screening and Week 6 (eg, C-SSRS Type 3, 4, or 5 ideation within the past 6 months or any suicidal behavior within the past 12 months)
c.HADS score >12 for either depression or anxiety at screening or Week 6
9. Has clinically significant abnormal electrocardiogram (ECG) or clinical laboratory results.
10. Routinely works overnight shifts
11. Subjects with travel plans/work schedules that result in significant and frequent changes in time zones (>2 hours) will require Medical Monitor approval for enrollment
12.Females who are pregnant or nursing
13.Use of any other investigational drug from 30 days or 5 half-lives (whichever is longer) before screening to the end of the study
14. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before Day 1 to the end of the study:
• Rosiglitazone, aromatase inhibitors, testosterone, or growth hormones
• The drugs listed in Section 13.1, which are:
o Strong inhibitors and/or inducers of CYP3A4 (with the exception of GCs and birth control medications)
o Medications metabolized by CYP3A4, 2B6, 2C8, 2C9, and/or 2C19 or known to be substrates of the transporters P-gp, BCRP, or OATP that are also sensitive substrates or substrates with narrow therapeutic ranges
15.Use of any anticoagulants or antiplatelet therapies within 30 days before screening
16.Has a history of an active bleeding disorder
17.Donation of blood from 60 days before Day 1 to the end of the study; or donation of platelets, white blood cells, or plasma from 15 days before Day 1 to the end of the study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Percentage change in A4 from Baseline to Week 18 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects blood will be collected at scheduled clinic visits at screening, during the run-in period Day 1 and Week 4, and during treatment period at Week 6, 10, 14, 18. |
|
E.5.2 | Secondary end point(s) |
Percentage change from Baseline to Week 18 in the following:
• 17-OHP
• ACTH
Proportion of subjects who achieve the following at Week 18:
• A4 ≤ ULN
• 17-OHP ≤ 4x ULN
• ACTH ≤ ULN |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Subjects blood will be collected at scheduled clinic visits at screening, during the run-in period Day 1 and Week 4, and during treatment period at week 6, 10,14, 18. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Denmark |
France |
Germany |
Netherlands |
Poland |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
A subject is considered to have completed study treatment if the subject has completed all visits through Week 58 of the Treatment Period. A subject is considered to have completed the study if the subject has completed all phases of the study, including the final follow-up visit. The end of the study is defined as the date of the last follow-up visit of the last subject in the study |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |