Congenital Adrenal Hyperplasia
Conditions
Keywords
CAH, Adrenal Disorder, Congenital Adrenal Hyperplasia
Brief summary
An investigation of the ability of Tildacerfont to reduce supraphysiologic glucocorticoid dosing in classic Congenital adrenal hyperplasia (CAH) subjects up to 76 weeks of treatment. Optional open label extension up to 240 weeks.
Detailed description
This is a study that evaluated the ability of tildacerfont to reduce the glucocorticoid steroid dose used by adult subjects with CAH. The first 24-weeks were a double-blind, placebo controlled, comparison of tildacerfont vs placebo. The following 52-weeks allowed all subjects to move to open label tildacerfont to continue to reduce steroid dose where appropriate, and observe long term safety. Subjects were offered a long term open label extension up to 240 weeks.
Interventions
Tablet, administered daily
Sponsors
Spruce Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-Blind for first 24 weeks, then open label
Intervention model description
Subjects will be randomized in a 1:1 manner to either Tildacerfont or Placebo for 24 weeks followed by 52 weeks open label Tildacerfont
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects ≥18 years old at screening 2. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase deficiency based on genetic mutation in CYP21A2 and/or documented (at any time) elevated 17-hydroxyprogesterone (17-OHP) and currently treated with hydrocortisone (HC), HC acetate, prednisone, prednisolone, methylprednisolone, dexamethasone (or a combination of the aforementioned glucocorticoid \[GCs\]) 3. Has lower limit of detection ≤ androstenedione (A4) ≤ 2.5x upper limit of normal (ULN) at screening measured before a morning GC dose 4. Has been on a stable, supraphysiologic dose of GC replacement (defined as ≥30 mg/day and ≤60 mg/day in HCe) for ≥1 month before screening 5. For subjects with the salt-wasting form of CAH, subject has been on a stable dose of mineralocorticoid replacement for ≥1 month 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
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, any of its excipients, or any other CRF1 receptor antagonist 4. Shows clinical signs or symptoms of adrenal insufficiency 5. 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: 1. An ongoing malignancy or \<3 years of remission history from any malignancy, other than successfully treated localized skin cancer 2. eGFR of \<45 mL/min/1.73 m2 3. Current or history of liver disease (with the exception of Gilbert's syndrome) 4. 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 5. Active hepatitis B, hepatitis C, or HIV at screening 6. Subjects who plan to undergo bariatric surgery during the study are excluded 7. Any other condition that would impact subject safety or confound interpretation of study results 6. Psychiatric conditions, including but not limited to bipolar disorder, schizophrenia, or schizoaffective disorders that are not effectively controlled on medication and may have an adverse impact on study compliance. Symptoms including hallucinations, delusions, and psychosis are exclusionary. Additionally: Increased risk of suicide based on the Investigator's judgment or the results of the C-SSRS conducted at screening and baseline (eg, C-SSRS Type 3, 4, or 5 ideation within the past 6 months or any suicidal behavior within the past 12 months) b. Hospital Anxiety and Depression Scale (HADS) score \>12 for either depression or anxiety at screening or baseline 7. Has clinically significant abnormal ECG or clinical laboratory results. Abnormal results that must be reviewed and discussed with the Medical Monitor to determine eligibility for this study include but are not limited to: 1. Any clinically meaningful abnormal ECG results, including QTcF \>450 ms for male participants or \>470 ms for female participants 2. ALT \>2x ULN 3. Total bilirubin \>1.5x ULN 4. Total bile acids \>5x ULN 8. Routinely works overnight shifts 9. 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 10. Females who are pregnant or nursing 11. Use of any other investigational drug from 30 days or 5 half-lives (whichever is longer) before screening to the end of the study 12. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before the start of the Treatment Period to the end of the study: 1. Rosiglitazone, aromatase inhibitors, testosterone, growth hormones, or any other medication or supplement that could impact subject safety or confound interpretation of study results 2. The drugs which are: i. Moderate to strong inhibitors and/or inducers of CYP3A4 ii. Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (except hormonal contraception containing ≤35 μg ethinyl estradiol) iii. Sensitive substrates or narrow-therapeutic-range substrates of BCRP (except those that can be administered QD in the morning, separated by approximately 10 hours from evening administration of study drug) 13. Donation or receipt of blood from 90 days before Screening to the end of the study; donation or receipt of platelets, white blood cells, or plasma from 30 days before Screening to the end of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Daily GC Dose in Subjects With Classic CAH Over the 24-week, Double Blind, Placebo-Controlled Treatment Period | 24 Weeks | Absolute change from baseline (Day 1) in GC dose in HCe at Week 24. The analysis of absolute change in total daily GC dose in HCe will include data from Weeks 3, 6, 12, 18 and 24 in a mixed model |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH | 24 weeks | Proportion of subjects with GC dose ≤11mg/m2/day in HCe and A4 ≤1.2x baseline or A4 ≤ ULN at Week 24 |
| Effectiveness in Reducing Cardiovascular Risk in Subjects With CAH | 24 Weeks | Proportion of subjects with improvement in at least one cardiovascular risk factor at Week 24 |
Countries
Australia, Brazil, Canada, Estonia, Germany, Italy, Latvia, Lithuania, Poland, Romania, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study randomized approximately 100 participants with classic congenital adrenal hyperplasia (CAH) currently receiving glucocorticoid (GC) at a supraphysiologic dose
Pre-assignment details
An optional Screening visit to capture information within 45 days of Day 1 in this study may have been used to determine eligibility and fulfill screening requirements for this study. A 6- or 12 week GC Conversion Period (Week -12 to either Week -6 or Week -2 \[±3 days\]) for participants on dexamethasone at the initial Screening Visit who agreed to convert to a non-dexamethasone regimen as determined by their physician.
Participants by arm
| Arm | Count |
|---|---|
| Tildacerfont Group Tildacerfont 200 mg administered daily via oral tablet for 24 weeks; followed by open label tildacerfont 200 mg for 52 weeks | 48 |
| Placebo Placebo administered daily via oral tablet for 24 weeks; followed by open label tildacerfont 200 mg for 52 weeks | 52 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 1 | 0 |
| Double-blind Treatment Period | Lost to Follow-up | 1 | 0 |
| Double-blind Treatment Period | Protocol Violation | 1 | 0 |
| Double-blind Treatment Period | Withdrawal by Subject | 1 | 2 |
| Open-Label Treatment Period | Adverse Event | 0 | 1 |
| Open-Label Treatment Period | Other | 0 | 1 |
| Open-Label Treatment Period | Physician Decision | 1 | 0 |
| Open-Label Treatment Period | Study Terminated | 15 | 19 |
| Open-Label Treatment Period | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Total | Placebo | Tildacerfont Group |
|---|---|---|---|
| 17-hydroxyprogesterone (17-OHP) | 5649.8 ng/dL STANDARD_DEVIATION 7195.84 | 5656.6 ng/dL STANDARD_DEVIATION 6995.03 | 5642.5 ng/dL STANDARD_DEVIATION 7481.57 |
| Adrenocorticotropic hormone, corticotropin (ACTH) | 167.94 pg/mL STANDARD_DEVIATION 257.663 | 159.77 pg/mL STANDARD_DEVIATION 190.594 | 176.79 pg/mL STANDARD_DEVIATION 316.658 |
| Age, Continuous | 32.5 years STANDARD_DEVIATION 11.77 | 32.0 years STANDARD_DEVIATION 12.08 | 33.0 years STANDARD_DEVIATION 11.52 |
| Androstenedione (A4) | 224.6 ng/dL STANDARD_DEVIATION 224.24 | 222.2 ng/dL STANDARD_DEVIATION 203.28 | 227.2 ng/dL STANDARD_DEVIATION 247.1 |
| BMI | 31.51 kg/m^2 STANDARD_DEVIATION 8.059 | 32.03 kg/m^2 STANDARD_DEVIATION 8.301 | 30.95 kg/m^2 STANDARD_DEVIATION 7.837 |
| Females with Child-Bearing Potential | 48 Participants | 26 Participants | 22 Participants |
| Height | 161.55 cm STANDARD_DEVIATION 10.227 | 160.87 cm STANDARD_DEVIATION 10.348 | 162.29 cm STANDARD_DEVIATION 10.151 |
| Homeostatic model assessment of insulin resistance (HOMA-IR) | 3.32 units on a scale STANDARD_DEVIATION 2.583 | 3.22 units on a scale STANDARD_DEVIATION 2.297 | 3.42 units on a scale STANDARD_DEVIATION 2.885 |
| Hospital Anxiety and Depression Scale (HADs) Total Score | 7.2 units on a scale STANDARD_DEVIATION 5.52 | 6.2 units on a scale STANDARD_DEVIATION 4.9 | 8.1 units on a scale STANDARD_DEVIATION 6.01 |
| Number of Cardiovascular Risk Factors 0 | 2 participants | 2 participants | 0 participants |
| Number of Cardiovascular Risk Factors 1 | 8 participants | 1 participants | 7 participants |
| Number of Cardiovascular Risk Factors 2 | 18 participants | 12 participants | 6 participants |
| Number of Cardiovascular Risk Factors >2 | 72 participants | 37 participants | 35 participants |
| Race/Ethnicity, Customized Asian | 14 Participants | 8 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 Participants | 6 Participants | 7 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 85 Participants | 44 Participants | 41 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 81 Participants | 43 Participants | 38 Participants |
| Sex: Female, Male Female | 53 Participants | 28 Participants | 25 Participants |
| Sex: Female, Male Male | 47 Participants | 24 Participants | 23 Participants |
| Testicular adrenal rest tumor (TART) Volume | 2.1485 mL STANDARD_DEVIATION 2.22651 | 2.2170 mL STANDARD_DEVIATION 2.32177 | 2.1056 mL STANDARD_DEVIATION 2.32648 |
| Testosterone | 234.5 ng/dL STANDARD_DEVIATION 249.5 | 215.1 ng/dL STANDARD_DEVIATION 231.74 | 256.1 ng/dL STANDARD_DEVIATION 268.67 |
| Time Since Congenital adrenal hyperplasia (CAH) Diagnosis | 29.5 years STANDARD_DEVIATION 12.37 | 28.0 years STANDARD_DEVIATION 12.99 | 31.2 years STANDARD_DEVIATION 11.58 |
| Type of CAH Diagnosis Salt-wasting | 71 Participants | 35 Participants | 36 Participants |
| Type of CAH Diagnosis Simple Virilizing | 29 Participants | 17 Participants | 12 Participants |
| Waist Circumference | 98.56 cm STANDARD_DEVIATION 18.357 | 100.07 cm STANDARD_DEVIATION 19.128 | 96.90 cm STANDARD_DEVIATION 17.518 |
| Weight | 82.05 kg STANDARD_DEVIATION 21.871 | 82.50 kg STANDARD_DEVIATION 22.004 | 81.56 kg STANDARD_DEVIATION 21.948 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 52 | 0 / 92 |
| other Total, other adverse events | 11 / 48 | 16 / 52 | 77 / 92 |
| serious Total, serious adverse events | 0 / 48 | 0 / 52 | 2 / 92 |
Outcome results
Primary
Change in Total Daily GC Dose in Subjects With Classic CAH Over the 24-week, Double Blind, Placebo-Controlled Treatment Period
Absolute change from baseline (Day 1) in GC dose in HCe at Week 24. The analysis of absolute change in total daily GC dose in HCe will include data from Weeks 3, 6, 12, 18 and 24 in a mixed model
Time frame: 24 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tildacerfont Group | Change in Total Daily GC Dose in Subjects With Classic CAH Over the 24-week, Double Blind, Placebo-Controlled Treatment Period | -5.0 mg | Standard Deviation 8.91 |
| Placebo | Change in Total Daily GC Dose in Subjects With Classic CAH Over the 24-week, Double Blind, Placebo-Controlled Treatment Period | -4.3 mg | Standard Deviation 9.75 |
Secondary
Effectiveness in Reducing Cardiovascular Risk in Subjects With CAH
Proportion of subjects with improvement in at least one cardiovascular risk factor at Week 24
Time frame: 24 Weeks
Population: Responders are subjects with improvement in ≥ 1 baseline cardiovascular risk factor at Week 24.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildacerfont Group | Effectiveness in Reducing Cardiovascular Risk in Subjects With CAH | 26 Participants |
| Placebo | Effectiveness in Reducing Cardiovascular Risk in Subjects With CAH | 19 Participants |
Secondary
Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH
Proportion of subjects with GC dose ≤11mg/m2/day in HCe and A4 ≤1.2x baseline or A4 ≤ ULN at Week 24
Time frame: 24 weeks
Population: Responders are subjects with glucocorticoid dose ≤11 mg/m2/day in HCe and A4 ≤ 1.2x Baseline or A4 ≤ ULN at Week 24.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildacerfont Group | Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH | 4 Participants |
| Placebo | Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH | 5 Participants |
Secondary
Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH
Proportion of subjects with baseline GC dose ≤ 35mg HCe who achieve GC dose ≤11 mg/m2/day in HCe and A4 ≤ 1.2x baseline or ≤ ULN at Week 24
Time frame: 24 Weeks
Population: Responders are subjects with baseline glucocorticoid dose ≤ 35 mg HCe and glucocorticoid dose ≤11 mg/m2/day in HCe and A4 ≤ 1.2x Baseline or A4 ≤ ULN at Week 24.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildacerfont Group | Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH | 2 Participants |
| Placebo | Effect of Tildacrfont in Reducing GC Use to Near-physiologic Levels While Maintaining Androgen Control in Subjects With CAH | 4 Participants |