Congenital Adrenal HyperplasiaPhase 2ARCHNCT03548246
Androgen Reduction in Congenital Adrenal Hyperplasia
A Phase 2 study testing Abiraterone acetate, Hydrocortisone and Fludrocortisone in people with Congenital Adrenal Hyperplasia, run by University of Texas Southwestern Medical Center at 4 sites in United States.
Trial summary
Children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency tend to have elevated circulating levels of androgens, which can accelerate skeletal maturation and adversely impact adult height. Read more about this study
- Who is it for?
- Ages 2 to 9 years
- Conditions the study is for
- Congenital Adrenal Hyperplasia
- What is being tested?
- Abiraterone acetate, Hydrocortisone and Fludrocortisone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 4 sitesUnited States
- Study dates
- Jan 2023to Jan 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 9 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Pre-pubescent girls (age 2 years [12 kg] to 8 years inclusive; skeletal age ≤9 years) or boys (age 2 years [12 kg] to 9 years inclusive; skeletal age ≤10 years).
- Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B, or by clinical course.
- Requirement for standard of care fludrocortisone (any dose) and ≥10 mg/m2/day of hydrocortisone for at least 1 month prior to the study consent.
- Morning serum androstenedione concentrations >1.5 x ULN after 7 days of dosing with doses of hydrocortisone required for physiologic replacement.
- Informed consent .
Who cannot join
- Evidence of central puberty: Tanner Stage >2 for breast development in girls or testicular volume >4 mL in boys, or random LH >0.3 mIU/mL.
- Current or history of hepatitis from any etiology.
- Abnormal liver function tests (transaminases>3X ULN).
- Abnormal renal function tests (BUN or creatinine >1.5 ULN).
- Significant anemia (hemoglobin < 12 g/dl).
- Clinically significant ECG abnormality
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- A history of a malabsorption syndrome.
- Evidence of active malignancy.
- Co-existent disease that may interfere with linear growth or that requires concomitant therapy that is likely to interfere with study procedures or results.
- Treatment with potentially hepatotoxic medications, CYP2D6, strong inhibitors or inducers of CYP3A4
- Treatment with medications to affect puberty or synthesis of sex steroids, including gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor blockers
- Treatment with growth hormone
- Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its excipients.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
University of Michigan
Ann Arbor, Michigan, 48109
National Institutes of Health
Bethesda, Maryland, 20892
Children's Medical Center
Dallas, Texas, 75235
Children's Hospital of Los Angeles
Los Angeles, California, 90027
About this study
Official title: A Phase 1-2 Multi-Center Study to Assess the Efficacy and Safety of Abiraterone Acetate as Adjunctive Therapy in Pre-Pubescent Children With Classic 21-Hydroxylase Deficiency
Children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency tend to have elevated circulating levels of androgens, which can accelerate skeletal maturation and adversely impact adult height. Additionally, these children require supraphysiologic doses of hydrocortisone to suppress secretion of adrenal androgen precursors, and this treatment can retard linear growth. This study seeks to use oral abiraterone acetate (Zytiga)as an adjunct to approved CAH therapy (oral hydrocortisone and fludrocortisone) for pre-pubescent children with classic 21-hydroxylase deficiency in order to reduce daily requirement of hydrocortisone.
Read the detailed description
Congenital adrenal hyperplasia (CAH) is an inherited inability to synthesize cortisol in the adrenal gland. More than 90% of cases are cause by deficiency of steroid 21-hydroxylase (CYP21, also termed CYP21A2, P450c21), which is a cytochrome P450 enzyme located in the endoplasmic reticulum. It catalyzes conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, a precursor for cortisol, and progesterone to deoxycorticosterone, a precursor for aldosterone. Aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, shock and if untreated, death in the first few weeks of life. Because patients cannot synthesize cortisol efficiently, the adrenal cortex is stimulated by corticotropin (ACTH) and overproduces cortisol precursors. Some of these precursors are diverted to sex hormone biosynthesis, which may cause signs of androgen excess including ambiguous genitalia in newborn females, rapid postnatal growth in both sexes, and accelerated skeletal maturation and decreased adult height. Patients require supraphysiologic replacement doses of glucocorticoids to suppress the adrenocorticotropic hormone (ACTH)-driven adrenal androgen synthesis. Excessive glucocorticoids are associated with excessive weight gain and slowing of linear growth. It would be desirable in pre-pubertal children to decrease the exposure to excess glucocorticoids while avoiding the adverse effects of inappropriate exposure to androgens. Abiraterone acetate is a prodrug of abiraterone, an irreversible inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), a key enzyme required for testosterone synthesis. This agent indeed suppresses adrenal androgen secretion in adult women. This Phase 2 will determine if, over 24 months, this treatment retards bone age advancement and thus improves adult height prognosis. The present study is the first clinical trial to explore the utility of abiraterone acetate as a means for decreasing daily requirements for glucocorticoids in pre-pubertal children with 21-hydroxylase deficiency.
- Conditions
- Congenital Adrenal Hyperplasia
- Being tested
- Abiraterone acetate, Placebo, Hydrocortisone, Fludrocortisone
- Medical subject headings
- Adrenal Hyperplasia, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Abiraterone acetateDrug
Also called Zytiga
Daily oral abiraterone acetate for 2 years. The dose will be specified based on pharmacodynamic data from Phase 1.
PlaceboDrug
Daily placebo for 2 years.
HydrocortisoneDrug
Hydrocortisone will be administered at a starting dose of 7-9 mg/M2/d and adjusted as necessary based on 17-hydroxyprogesterone and ACTH levels.
FludrocortisoneDrug
Fludrocortisone will be administered at the dose the subject was taking a study entry and adjusted as necessary to keep plasma renin in the high normal range.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Daily placebo, plus usual maintenance treatment with hydrocortisone and fludrocortisone. Receives: Drug: Placebo; Drug: Hydrocortisone; Drug: Fludrocortisone |
| Abiraterone acetate | Experimental | Abiraterone acetate administered daily in dose determined in Phase 1, plus usual maintenance treatment with hydrocortisone and fludrocortisone.. Receives: Drug: Abiraterone acetate; Drug: Hydrocortisone; Drug: Fludrocortisone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Bone age advancement
Advancement from baseline in radiographically determined skeletal maturation
Measured: 104 weeks
Secondary outcomes (5)
Weight
Change from baseline, determined every 6 months.
Measured: 104 weeks
Body mass index Z-score
Change from baseline, determined every 6 months.
Measured: 104 weeks
Predicted adult height
Derived from height and radiographically determined skeletal maturation, determined every 6 months
Measured: 104 weeks
Hydrocortisone dose required to normalize androstenedione levels
Hydrocortisone dose (measured as milligrams per meter squared body surface area, per day) will be adjusted in a blinded manner every 3 months by the treating physician to maintain serum androstenedione in the normal range, with increases as necessary to maintain ACTH < 5 times the upper limit of the reference range.
Measured: 104 weeks
Number of adverse events
Measured: 104 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jun 2018
- Study startJan 2023 (estimated)
- Primary completionJan 2026 (estimated)
- Study completionJan 2026 (estimated)
Why it stopped: This study plan has halted and was withdrawn from the IRB.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Congenital Adrenal HyperplasiaStudies of the same condition, open and under way.
- More trials run by University of Texas Southwestern Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health Clinical Center (CC), University of Michigan, Children's Hospital Los Angeles, Feinstein Institute for Medical Research
- Responsible party
- Principal investigator, Perrin C White, MD, University of Texas Southwestern Medical Center
- Investigators
- Perrin C White, MD, Principal investigator, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03548246
- Sponsor's protocol ID
- 042015-068
- Acronym
- ARCH
- Status last verified
- Jan 2023
- First submitted
- 24 Apr 2015
- Last updated
- 1 Feb 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014 Aug;99(8):2763-70. doi: 10.1210/jc.2014-1258. Epub 2014 Apr 29.
PubMed 24780050
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1-2 Multi-Center Study to Assess the Efficacy and Safety of Abiraterone Acetate as Adjunctive Therapy in Pre-Pubescent Children With Classic 21-Hydroxylase Deficiency
- ClinicalTrials.gov ID
- NCT03548246
- Acronym / sponsor ID
- ARCH / 042015-068
- Conditions
- Congenital Adrenal Hyperplasia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: This study plan has halted and was withdrawn from the IRB.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of Texas Southwestern Medical CenterUniversity, hospital or other
- Collaborators
- National Institutes of Health Clinical Center (CC), University of Michigan, Children's Hospital Los Angeles, Feinstein Institute for Medical Research
- Study start
- Jan 2023 (estimated)
- Primary completion
- Jan 2026 (estimated)
- Study completion
- Jan 2026 (estimated)
- First posted
- 7 Jun 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency tend to have elevated circulating levels of androgens, which can accelerate skeletal maturation and adversely impact adult height. Additionally, these children require supraphysiologic doses of hydrocortisone to suppress secretion of adrenal androgen precursors, and this treatment can retard linear growth. This study seeks to use oral abiraterone acetate (Zytiga)as an adjunct to approved CAH therapy (oral hydrocortisone and fludrocortisone) for pre-pubescent children with classic 21-hydroxylase deficiency in order to reduce daily requirement of hydrocortisone.
Detailed description
Congenital adrenal hyperplasia (CAH) is an inherited inability to synthesize cortisol in the adrenal gland. More than 90% of cases are cause by deficiency of steroid 21-hydroxylase (CYP21, also termed CYP21A2, P450c21), which is a cytochrome P450 enzyme located in the endoplasmic reticulum. It catalyzes conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, a precursor for cortisol, and progesterone to deoxycorticosterone, a precursor for aldosterone. Aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, shock and if untreated, death in the first few weeks of life. Because patients cannot synthesize cortisol efficiently, the adrenal cortex is stimulated by corticotropin (ACTH) and overproduces cortisol precursors. Some of these precursors are diverted to sex hormone biosynthesis, which may cause signs of androgen excess including ambiguous genitalia in newborn females, rapid postnatal growth in both sexes, and accelerated skeletal maturation and decreased adult height. Patients require supraphysiologic replacement doses of glucocorticoids to suppress the adrenocorticotropic hormone (ACTH)-driven adrenal androgen synthesis. Excessive glucocorticoids are associated with excessive weight gain and slowing of linear growth. It would be desirable in pre-pubertal children to decrease the exposure to excess glucocorticoids while avoiding the adverse effects of inappropriate exposure to androgens. Abiraterone acetate is a prodrug of abiraterone, an irreversible inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), a key enzyme required for testosterone synthesis. This agent indeed suppresses adrenal androgen secretion in adult women. This Phase 2 will determine if, over 24 months, this treatment retards bone age advancement and thus improves adult height prognosis. The present study is the first clinical trial to explore the utility of abiraterone acetate as a means for decreasing daily requirements for glucocorticoids in pre-pubertal children with 21-hydroxylase deficiency.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebo, Drug: Hydrocortisone, Drug: FludrocortisoneDaily placebo, plus usual maintenance treatment with hydrocortisone and fludrocortisone. |
| Abiraterone acetate | Experimental | Drug: Abiraterone acetate, Drug: Hydrocortisone, Drug: FludrocortisoneAbiraterone acetate administered daily in dose determined in Phase 1, plus usual maintenance treatment with hydrocortisone and fludrocortisone.. |
Who may qualify
- Ages
- 2 to 9 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- Pre-pubescent girls (age 2 years [12 kg] to 8 years inclusive; skeletal age ≤9 years) or boys (age 2 years [12 kg] to 9 years inclusive; skeletal age ≤10 years).
- Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B, or by clinical course.
- Requirement for standard of care fludrocortisone (any dose) and ≥10 mg/m2/day of hydrocortisone for at least 1 month prior to the study consent.
- Morning serum androstenedione concentrations >1.5 x ULN after 7 days of dosing with doses of hydrocortisone required for physiologic replacement.
- Informed consent .
Key exclusion criteria (13 listed)
- Evidence of central puberty: Tanner Stage >2 for breast development in girls or testicular volume >4 mL in boys, or random LH >0.3 mIU/mL.
- Current or history of hepatitis from any etiology.
- Abnormal liver function tests (transaminases>3X ULN).
- Abnormal renal function tests (BUN or creatinine >1.5 ULN).
- Significant anemia (hemoglobin < 12 g/dl).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Abiraterone acetateAlso: ZytigaDaily oral abiraterone acetate for 2 years. The dose will be specified based on pharmacodynamic data from Phase 1. | Drug | Abiraterone acetate |
| PlaceboDaily placebo for 2 years. | Drug | Placebo |
| HydrocortisoneHydrocortisone will be administered at a starting dose of 7-9 mg/M2/d and adjusted as necessary based on 17-hydroxyprogesterone and ACTH levels. | Drug | Abiraterone acetate, Placebo |
| FludrocortisoneFludrocortisone will be administered at the dose the subject was taking a study entry and adjusted as necessary to keep plasma renin in the high normal range. | Drug | Abiraterone acetate, Placebo |
Primary outcome
Bone age advancement
Time frame: 104 weeks
Advancement from baseline in radiographically determined skeletal maturation
5 secondary outcomes
Weight
Time frame: 104 weeks
Body mass index Z-score
Time frame: 104 weeks
Predicted adult height
Time frame: 104 weeks
Hydrocortisone dose required to normalize androstenedione levels
Time frame: 104 weeks
Number of adverse events
Time frame: 104 weeks
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2023.
- Background: PubMed 24780050Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014 Aug;99(8):2763-70. doi: 10.1210/jc.2014-1258. Epub 2014 Apr 29.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Perrin C White, MD principal investigator
University of Texas Southwestern Medical Center
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Abiraterone acetate, Hydrocortisone and Fludrocortisone in people with Congenital Adrenal Hyperplasia, run by University of Texas Southwestern Medical Center at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 1 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Bone age advancement (time frame: 104 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03548246, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2023.