Congenital Adrenal Hyperplasia
Conditions
Brief 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. 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. In this Phase 1 study, the investigators will determine the minimum effective dose of abiraterone acetate that normalizes androstenedione levels during the 7-day Treatment Period.
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. In this Phase 1 study, the investigators will determine the minimum effective dose of abiraterone acetate that normalizes androstenedione levels during the 7-day Treatment Period.
Interventions
DRUGAbiraterone acetate
This is a dose escalation study. Up to 3 successive cohorts of 8 subjects each will receive 7 days of 1, 2 or 4 mg/kg/d of abiraterone acetate, until 7/8 subjects have met the desired endpoint.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Michigan
Children's Hospital Los Angeles
University of Texas Southwestern Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 9 Years
Healthy volunteers
No
Inclusion criteria
1. Pre-pubescent girls (age 2 years \[12 kg minimum\] to 8 years inclusive; skeletal age \<10 years) or boys (age 2 years \[12 kg\] to 9 years inclusive; skeletal age \<11 years). 2. Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B or clinical course (e.g., adrenal crisis with documented hyperkalemia and hyponatremia, at diagnosis or during a later evaluation; ambiguous genitalia in females). Documentation of one or both parents' genotypes may be required to confirm the subject's genotype. 3. 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. 4. Morning serum androstenedione concentrations \>1.5 x Upper limit normal (ULN) after 7 days of dosing with doses of hydrocortisone required for physiologic replacement. 5. At least one parent (or other legally acceptable representative) must sign the informed consent form before the performance of any study procedures, but both parents must sign if both have parental rights. Children who are capable of providing assent (typically 10 years of age and older) must sign an assent form before the performance of any study procedures
Exclusion criteria
1. Evidence of central puberty: Tanner Stage \>2 for breast development in girls or testicular volume \>4 mL in boys, or random luteinizing hormone (LH) \>0.3 milli-international units (mIU)/mL. Subjects with pubic and/or axillary hair as the only sign of puberty onset will be allowed. 2. Current or history of hepatitis from any etiology, including history of active viral hepatitis A, B, or C. 3. Patients with baseline hepatic impairment are excluded from this trial. To be eligible for this protocol, patients must meet all of the following criteria: AST, ALT and Total bilirubin \< ULN Albumin \> lower limits of normal (LLN) No evidence of ascites No evidence of encephalopathy 4. Abnormalities of liver function developing during the study 5. Abnormal renal function tests, defined as blood urea nitrogen (BUN) or creatinine \>1.5 ULN for age. 6. Significant anemia (hemoglobin \< 12 g/dl). If documented to be due to iron deficiency, subjects may be rescreened 3 months after this has been treated. 7. Clinically significant abnormality in the 12-lead electrocardiogram (ECG) 8. A history of a malabsorption syndrome. 9. Evidence of active malignancy. 10. Serious or uncontrolled co-existent disease, including active or uncontrolled infection. Subjects may be rescreened after resolution of any such condition. 11. Concurrent medical condition or disease other than 21-hydroxylase deficiency that may interfere with linear growth or that requires concomitant therapy that is likely to interfere with study procedures or results. 12. Asthma or other condition requiring treatment with systemic corticosteroids within the past 3 months. Asthma treatment with inhaled corticosteroids is permitted. 13. Treatment with potentially hepatotoxic medications (statins); strong inhibitors of CYP3A4 (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), or CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). CYP2C8 substrates (rosiglitazone, pioglitazone, rapaglinide) and CYP2D6 substrates (dextromethorphan, thioridazine) should be avoided 14. Treatment with medications to affect puberty or synthesis of sex steroids, including gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor blockers (e.g., flutamide, spironolactone). However, a gonadotropin releasing hormone agonist may be started during the study for treatment-emergent central puberty without disqualifying the subject 15. Treatment with growth hormone at enrollment or during the course of the study. 16. Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its excipients (refer to United States Prescribing Information). 17. Has received an investigational drug within 4 weeks of the planned first dose of study drug or is currently enrolled in an investigational interventional study. 18. Any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments. 19. Presence or history of cataracts.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalization of Serum Androstenedione Level | 7 days | The original primary endpoint was the dose of abiraterone acetate that normalized androstenedione to age-appropriate levels in 7/8 subjects after 7 days of treatment. However, an insufficient number of participants was enrolled to evaluate the primary endpoint. Therefore, we have instead presented the number of participants at each dose level who did normalize androstenedione to age-appropriate levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 17-hydroxyprogestoerone Levels | 7 days | Final lab results at Screening and V6. This outcome is not pre-specified in the protocol and was inadvertently added at the time of registration. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) of Abiraterone | 7 days | Sparse pharmacokinetic (PK) will be derived from peak and trough abiraterone levels. |
| Peak Plasma Concentration (Cmax) | 7 days | Sparse pharmacokinetic (PK) will be derived from peak and trough abiraterone levels. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Dihydrotestosterone Levels | 7 days | Final lab results at Screening and V6. This was erroneously listed as a secondary outcome in PRS. We have changed the outcome measure type to Other pre-specified. . |
| Number of Adverse Events | 7 days | Safety monitoring in Phase 1 will include liver function tests (AST, Alanine Aminotransferease (ALT), bilirubin) and possible mineralocorticoid effects (blood pressure, plasma renin). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abiraterone acetate 1 mg/kg/d Abiraterone acetate will be administered orally at a daily dose of 1 mg/kg for 7 days in addition to the standard of care treatment of hydrocortisone and fludrocortisone.
Abiraterone acetate: This is a dose escalation study. Up to 3 successive cohorts of 8 subjects each will receive 7 days of 1, 2 or 4 mg/kg/d of abiraterone acetate, until 7/8 subjects have met the desired endpoint. | 2 |
| Abiraterone acetate 2 mg/kg/d If the 1 mg/kg/d dosing does not result in androstenedione level normalization, abiraterone acetate will be administered orally at a daily dose of 2 mg/kg for 7 days in addition to the standard of care treatment of hydrocortisone and fludrocortisone.
Abiraterone acetate: This is a dose escalation study. Up to 3 successive cohorts of 8 subjects each will receive 7 days of 1, 2 or 4 mg/kg/d of abiraterone acetate, until 7/8 subjects have met the desired endpoint. | 2 |
| Abiraterone acetate 4 mg/kg/d If the 2 mg/kg/d dosing does not result in androstenedione level normalization, abiraterone acetate will be administered orally at a daily dose of 4 mg/kg for 7 days in addition to the standard of care treatment of hydrocortisone and fludrocortisone.
Abiraterone acetate: This is a dose escalation study. Up to 3 successive cohorts of 8 subjects each will receive 7 days of 1, 2 or 4 mg/kg/d of abiraterone acetate, until 7/8 subjects have met the desired endpoint. | 0 |
| Total | 4 |
Baseline characteristics
| Characteristic | Abiraterone acetate 1 mg/kg/d | Abiraterone acetate 2 mg/kg/d | Abiraterone acetate 4 mg/kg/d | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 5 years | 7 years | — | 6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Region of Enrollment United States | 2 participants | 2 participants | — | 4 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 0 |
| other Total, other adverse events | 2 / 2 | 1 / 2 | 0 / 0 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 0 |
Outcome results
Primary
Normalization of Serum Androstenedione Level
The original primary endpoint was the dose of abiraterone acetate that normalized androstenedione to age-appropriate levels in 7/8 subjects after 7 days of treatment. However, an insufficient number of participants was enrolled to evaluate the primary endpoint. Therefore, we have instead presented the number of participants at each dose level who did normalize androstenedione to age-appropriate levels.
Time frame: 7 days
Population: No subjects enrolled at 4 mg/kg/d
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abiraterone acetate 1 mg/kg/d | Normalization of Serum Androstenedione Level | 0 Participants |
| Abiraterone acetate 2 mg/kg/d | Normalization of Serum Androstenedione Level | 1 Participants |
| Abiraterone acetate 4 mg/kg/d | Normalization of Serum Androstenedione Level | 0 Participants |
Secondary
17-hydroxyprogestoerone Levels
Final lab results at Screening and V6. This outcome is not pre-specified in the protocol and was inadvertently added at the time of registration.
Time frame: 7 days
Population: Due to early termination of this study and incomplete enrollment, the collected data are incomplete and limited. These collected samples will never be analyzed in the future. Due to quality issues with the resulting of 17-hydroxyprogestoerone, there is one per-protocol patient to report this result on.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abiraterone acetate 1 mg/kg/d | 17-hydroxyprogestoerone Levels | -2790 ng/dL |
Secondary
Area Under the Plasma Concentration Versus Time Curve (AUC) of Abiraterone
Sparse pharmacokinetic (PK) will be derived from peak and trough abiraterone levels.
Time frame: 7 days
Population: The values for this outcome measurement were not collected and we have no data relating to PK to report because the collected samples were not processed for this outcome measure and will never be processed in the future as well.
Secondary
Peak Plasma Concentration (Cmax)
Sparse pharmacokinetic (PK) will be derived from peak and trough abiraterone levels.
Time frame: 7 days
Population: The values for this outcome measurement were not collected and we have no data relating to PK to report because the collected samples were not processed for this outcome measure and will never be processed in the future as well.
Other Pre-specified
Dihydrotestosterone Levels
Final lab results at Screening and V6. This was erroneously listed as a secondary outcome in PRS. We have changed the outcome measure type to Other pre-specified. .
Time frame: 7 days
Population: Due to early termination of this study and incomplete enrollment, the collected data are incomplete and limited, it is not considered valid to perform this outcome measure assessment and therefore unable to analyze and report it.
Other Pre-specified
Number of Adverse Events
Safety monitoring in Phase 1 will include liver function tests (AST, Alanine Aminotransferease (ALT), bilirubin) and possible mineralocorticoid effects (blood pressure, plasma renin).
Time frame: 7 days
Population: No participants enrolled at the 4 mg/kg/d level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abiraterone acetate 1 mg/kg/d | Number of Adverse Events | 6 events |
| Abiraterone acetate 2 mg/kg/d | Number of Adverse Events | 1 events |