Congenital Adrenal Hyperplasia (CAH)Phase 3NCT00001521
Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia
A Phase 3 study testing Fludrocortisone, Hydrocortisone and Letrozole in people with Congenital Adrenal Hyperplasia (CAH), run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.
Trial summary
This study was developed to determine if a combination of four drugs (flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone) can normalize growth in children with congenital adrenal hyperplasia. Read more about this study
- Who is it for?
- Ages 2 to 18 years
- Conditions the study is for
- Congenital Adrenal Hyperplasia (CAH)
- What is being tested?
- Fludrocortisone, Hydrocortisone and Letrozole
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 66 participants
- Where
- 1 siteUnited States
- Study dates
- 8 Jun 1995to 1 Apr 2024
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Subjects will be boys with bone ages 2 to 13 years and girls with bone ages 2 to 11 years with CAH due to classic 21-hydroxylase deficiency.
- Subjects must either not yet have undergone pubertal activation of the hypothalamic-pituitary-gonadal axis, or, if pubertal activation has occurred, must be receiving a GnRH agonist to suppress secondary central precocious puberty.
- Children with a bone age of 1 to 2 years may enroll in the protocol for optimization of conventional therapy, but will not be randomized to a study arm until the bone age reaches 2.
Who cannot join
- Children who have concurrent illnesses requiring glucocorticoid treatment (such as severe asthma), or requiring drugs that markedly alter hydrocortisone metabolism (such as anticonvulsants), and children who cannot be brought into reasonable control with conventional treatment (an unusual occurrence).
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: An Open, Randomized, Long-Term Clinical Trial of Flutamide, Testolactone, and Reduced Hydrocortisone Dose vs. Conventional Treatment of Children With Congenital Adrenal Hyperplasia
This study was developed to determine if a combination of four drugs (flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone) can normalize growth in children with congenital adrenal hyperplasia.
The study will take 60 children, boys and girls, and divide them into 2 groups based on the medications given. Group one will receive the new four-drug combination. Group two will receive the standard treatment for congenital adrenal hyperplasia (hydrocortisone and fludrocortisone).
Read more
The boys in group one will take the medication until the age of 14 at which time they will stop taking the four-drug combination and begin receiving the standard treatment for congenital adrenal hyperplasia. Girls in group one will take the four-drug combination until the age of 13, at which time they will stop and begin receiving the standard treatment for congenital adrenal hyperplasia plus flutamide. Flutamide will be given to the girls until two years after their first menstrual period or until adult height.
All of the children will be followed until they reach their final adult height. The effectiveness of the treatment will be determined by measuring the patient's adult height.
Read the detailed description
To test the hypothesis that the regimen of flutamide (an antiandrogen), testolactone or letrozole (an inhibitor of androgen-to-estrogen conversion), and reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia, and can avoid the complications of supraphysiologic glucocorticoid dosage, 60 children with this disorder will be randomized to receive either the above regimen or conventional treatment until they have reached age 13 years in a girl or age 14 in a boy. After these ages boys will receive the conventional treatment and girls will receive conventional treatment plus flutamide. In girls, flutamide will be continued until 6 months after menarche. All children will be followed until they have attained final adult height. The principal outcome measure will be adult height.
- Conditions
- Congenital Adrenal Hyperplasia (CAH)
- Being tested
- Fludrocortisone, Hydrocortisone, Letrozole, Flutamide, Testolactone
- Keywords
- Congenital Adrenal Hyperplasia (CAH), Intervention, Children
- 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.
FludrocortisoneDrug
Mineralocorticoid needed to replace aldosterone deficiency. Patients will continue to receive an optimal fludrocortisone dose
HydrocortisoneDrug
Glucocorticoid needed to replace cortisol deficiency. Reduced hydrocortisone dose might normalize the growth and adult stature of children with congenital adrenal hyperplasia
LetrozoleDrug
Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.
FlutamideDrug
Non steroidal anti-androgen that prevents the action of androgens by blocking receptor sites in target tissue. It may also produce changes in testosterone and estradiol
TestolactoneDrug
Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.
| Study group | Role | What they receive |
|---|---|---|
| Investigational therapy | Experimental | Children with congenital adrenal hyperplasia (CAH) and bone ages of 2-13 years in boys and 2-11 years in girls were randomized to receive antiandrogen (flutamide 10mg/kg/day orally), aromatase inhibitor (testolactone - 20mg/ kg/day orally OR letrozole - 1.5mg/m^2 body surface area orally), low-dose hydrocortisone (6-8 mg/m^2/day orally), and fludrocortisone (100-200 mcg/day, depending on lab evaluation, orally). Participants received the four-drug regimen until the age of 13 in the girls and 14 in the boys and then were switched to standard therapy. Female participants on investigational drugs were continued on flutamide until attainment of final adult height or two years post menarche. Participants who experienced early puberty received GnRH agonist therapy: depot leuprolide 7.5-15 mg/kg monthly intramuscularly or deslorelin 4 mcg/kg/day (adjusted based on weight and response) subcutaneously. Receives: Drug: Fludrocortisone; Drug: Hydrocortisone; Drug: Letrozole; Drug: Flutamide; Drug: Testolactone |
| Standard therapy | Experimental | Children with congenital adrenal hyperplasia (CAH) and bone ages of 2-13 years in boys and 2-11 years in girls received standard therapy/conventional treatment (with hydrocortisone and fludrocortisone). Participants received hydrocortisone approximately 10-15 mg/m^2/day orally, not exceeding 25mg/m^2/day, and fludrocortisone 100-200 mcg/day orally depending on lab evaluation. Participants who experienced early puberty received GnRH agonist therapy: depot leuprolide 7.5-15 mg/kg monthly intramuscularly or deslorelin 4 mcg/kg/day (adjusted based on weight and response) subcutaneously. Receives: Drug: Fludrocortisone; Drug: Hydrocortisone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Adult Height Relative to General Population
Adult height expressed in standard deviation score (SDS) units relative to the general population, with attainment of adult height defined as incremental growth < 1.5 cm over 12 months. Adult height SDS was based on National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, National Center for Health Statistics) data at 20 years old.
Measured: Followed to attainment of adult height, average of 11 years from date of randomization
Secondary outcomes (20)
Adult Height Relative to Mid-parental Height
Adult height expressed in standard deviation score (SDS) units relative to the mid-parental height for the general population. Adult height is defined as incremental growth < 1.5 cm over 12 months. Adult height SDS was based on National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, National Center for Health Statistics) data at 20 years old. Mid-parental height was calculated based on reported parental heights calculated as (father's height (cm) + mother's height (cm))/ 2 ± 6.5 (cm).
Measured: Followed to attainment of adult height, average of 11 years from date of randomization
Predicted Adult Height
Predicted adult height was calculated using the bone age at the baseline visit or the first available bone age, using the Bayley-Pinneau method. Predicted adult height was calculated as the standard deviation score (SDS) units relative to the general population based on the National Health and Nutrition Examination Survey data (Centers for Disease Control and Prevention (CDC), National Center for Health Statistics) at 20 years old. Baseline was defined as time of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys).
Measured: At date of randomization and at pubertal onset (average of seven years from date of randomization)
Predicted Adult Height Change
Changes in predicted adult height from baseline to pubertal onset, pubertal onset to final visit, and baseline to final visit. Adult height standard deviation score (SDS) was based on National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, National Center for Health Statistics) data at 20 years old. Predicted adult height at baseline was calculated using the bone age at the baseline visit or the first available bone age according to the Bayley-Pinneau method. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years), pubertal onset to final visit (average was 4 years), and date of randomization to final visit (average of 11 years)
Number of Years Bone Age Remained Unchanged
Number of prepubertal and pubertal years bone age remained unchanged. Baseline bone age was calculated using the bone age at the baseline visit or the first available bone age according to the Bayley-Pinneau method. Change in bone age from baseline to pubertal onset and pubertal onset to final visit was measured in years. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Change in Body Mass Index (BMI)
Changes in body mass index (BMI) were evaluated from baseline to puberty onset and puberty onset to final visit. BMI calculation was based on average of three early morning height measurements by stadiometer and weight measurement by scale for each timepoints. BMI was calculated as the standard deviation score (SDS) units relative to the general population based on the National Health and Nutrition Examination Survey data (Centers for Disease Control and Prevention (CDC), National Center for Health Statistics) at 20 years old. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was time at attainment of adult height, defined as incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Body Mass Index (BMI)
Body mass index (BMI) was calculated based on average of three early morning height measurements by stadiometer and weight measurement by scale. BMI was calculated as the standard deviation score (SDS) units relative to the general population based on the National Health and Nutrition Examination Survey data (Centers for Disease Control and Prevention (CDC), National Center for Health Statistics) at 20 years old. Measures evaluated at pubertal onset and at final visit. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
Average Annual Growth Velocity
Average annual growth (height) velocity, measured as the change in height over time relative to the population mean and adjusted for age and sex. Measured during the study period from baseline visit to pubertal onset visit (visits occurring approximately every 6 months) and from pubertal onset to adult height. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Dose of Oral Hydrocortisone
Dose of oral hydrocortisone participant was taking adjusted for body surface area. Dose was recorded at baseline (first visit), pubertal onset, and at adult height (final visit). Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: At date of randomization, pubertal onset (average of seven years from date of randomization), and at final visit (average of 11 years from date of randomization)
Average Daily Dose of Oral Hydrocortisone
Average daily dose of oral hydrocortisone adjusted for body surface area. Dose was measured by developmental periods and for differences between sexes. Doses recorded at every visit, approximately every 6 months. Average dose measured from baseline to pubertal onset, from pubertal onset visit to adult height (final visit), and from baseline to adult height. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years), pubertal onset to final visit (average was 4 years), and date of randomization to final visit (average of 11 years)
Percent of Visits With 17-hydroxyprogesterone in the Optimal Range (<1,200 ng/dL)
Percentage of visits where early morning (pre-medication) 17-hydroxyprogesterone measurements fell within the optimal range (<1,200 ng/dL) during the study period from baseline to pubertal onset and pubertal onset visit to final visit, with visits occurring approximately every 6 months. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Percent of Visits With Androstenedione in Normal Range
Percentage of visits where early morning (pre-medication) androstenedione measurements fell within the normal range based on age and sex-specific ranges during the study period. Measurements done from baseline to pubertal onset visit, and from pubertal onset visit to adult height (final visit), with visits occurring approximately every 6 months. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Average Testosterone
Average testosterone based on early morning (pre-medication) testosterone levels measured for participants approximately every six months. Average testosterone measured from baseline to pubertal onset and from pubertal onset visit to adult height (final visit) by sex. Baseline was defined as date of randomization. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Number of Participants With Onset of Early Central Puberty
Number of participants with onset of early central puberty, defined as testicular volume ≥ 4 mL in males before age 10, and breast Tanner stage 2 in females before age 9.
Measured: Measured from date of randomization to onset of early central puberty
Average Age at Menarche
Average age at menarche (years) in female participants only.
Measured: Followed from date of randomization to onset of menarche
Number of Female Participants With Normal Menstrual Cyclicity at Final Visit
Number of female participants with normal menstrual cyclicity at final visit. Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: Measured at single time point at final visit, average of 11 years from date of randomization
Number of Participants With Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) > 2.5
Number of participants with Insulin resistance based on Homeostasis model assessment of insulin resistance (HOMA-IR) > 2.5 at the final visit. Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: Final visit, average of 11 years from date of randomization
Average (Median) Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
Homeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, measured as insulin (μU/mL) × glucose (mmol/L)/22.5 at final visit. HOMA-IR value ≤ 2.5 is considered normal. HOMA-RI value > 2.5 is considered abnormal. Higher HOMA-IR value indicates greater insulin resistance. Final visit was attainment of adult, defined as height with incremental growth <1.5 cm over 12 months.
Measured: Measured at single time point at final visit, average of 11 years from date of randomization
Number of Male Participants With Testicular Adrenal Rest Tumors (TART)
Number of male participants with testicular adrenal rest tumors (TART), measured by scrotal ultrasound, at pubertal onset visit and final visit. Pubertal onset was defined as when patients entered puberty (Tanner 2 breast in females, testicle size ≥ 4 mL in males) or completed therapy with either aromatase inhibitor and/or GnRHa (age 13 years in girls and 14 years in boys). Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
Anterior Posterior Spine Bone Mineral Density (BMD) at Final Visit
Anterior posterior spine bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA) scan at final visit. The instrument specific comparisons (in standard deviations) were made to the average peak bone mass of a normal population, i.e. to the average bone mass of persons of the same age and sex as the patient. Final visit is defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: Final visit, average of 11 years from date of randomization
Femoral Neck Bone Mineral Density (BMD) at Final Visit
Femoral neck bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA) scan at final visit. The instrument specific comparisons (in standard deviations) were made to the average peak bone mass of a normal population, i.e. to the average bone mass of persons of the same age and sex as the patient. Final visit was defined as attainment of adult height with incremental growth < 1.5 cm over 12 months.
Measured: Final visit, average of 11 years from date of randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 1999 (estimated)
- Study start8 Jun 1995
- Primary completion1 Apr 2024
- Study completion1 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Congenital Adrenal Hyperplasia (CAH)Studies of the same condition, open and under way.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 66 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Deborah P Merke, M.D., Principal investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001521
- Sponsor's protocol ID
- 960033
- Other IDs
- 96-CH-0033
- Status last verified
- 8 May 2024
- First submitted
- 3 Nov 1999
- Last updated
- 12 Jun 2025
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Data is being used for secondary analyses.
Publications
Merke DP, Mallappa A, Parker M, Sukin C, Kulkarni SE, Keil MF, Van Ryzin C, Hill SC, Reynolds JC, Cutler GB Jr, Sinaii N. Adult Height Following Prepubertal Treatment With Antiandrogen, Aromatase Inhibitor, and Reduced Hydrocortisone in CAH. J Clin Endocrinol Metab. 2025 Jun 17;110(7):e2171-e2182. doi: 10.1210/clinem/dgae824.
PubMed 39672600
Study at a glance
From the registry record, last updated by the sponsor on 12 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open, Randomized, Long-Term Clinical Trial of Flutamide, Testolactone, and Reduced Hydrocortisone Dose vs. Conventional Treatment of Children With Congenital Adrenal Hyperplasia
- ClinicalTrials.gov ID
- NCT00001521
- Acronym / sponsor ID
- 960033
- Conditions
- Congenital Adrenal Hyperplasia (CAH)
- Keywords
- Congenital Adrenal Hyperplasia (CAH), Intervention, Children
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 66 participants (actual)
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)US National Institutes of Health
- Study start
- 8 Jun 1995 (actual)
- Primary completion
- 1 Apr 2024 (actual)
- Study completion
- 1 Apr 2024 (actual)
- First posted
- 4 Nov 1999 (estimated)
- Results
- Posted 12 Jun 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study was developed to determine if a combination of four drugs (flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone) can normalize growth in children with congenital adrenal hyperplasia.
The study will take 60 children, boys and girls, and divide them into 2 groups based on the medications given. Group one will receive the new four-drug combination. Group two will receive the standard treatment for congenital adrenal hyperplasia (hydrocortisone and fludrocortisone).
The boys in group one will take the medication until the age of 14 at which time they will stop taking the four-drug combination and begin receiving the standard treatment for congenital adrenal hyperplasia. Girls in group one will take the four-drug combination until the age of 13, at which time they will stop and begin receiving the standard treatment for congenital adrenal hyperplasia plus flutamide. Flutamide will be given to the girls until two years after their first menstrual period or until adult height.
All of the children will be followed until they reach their final adult height. The effectiveness of the treatment will be determined by measuring the patient's adult height.
Detailed description
To test the hypothesis that the regimen of flutamide (an antiandrogen), testolactone or letrozole (an inhibitor of androgen-to-estrogen conversion), and reduced hydrocortisone dose can normalize the growth and adult stature of children with congenital adrenal hyperplasia, and can avoid the complications of supraphysiologic glucocorticoid dosage, 60 children with this disorder will be randomized to receive either the above regimen or conventional treatment until they have reached age 13 years in a girl or age 14 in a boy. After these ages boys will receive the conventional treatment and girls will receive conventional treatment plus flutamide. In girls, flutamide will be continued until 6 months after menarche. All children will be followed until they have attained final adult height. The principal outcome measure will be adult height.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Investigational therapy | Experimental | Drug: Fludrocortisone, Drug: Hydrocortisone, Drug: Letrozole, Drug: Flutamide, Drug: TestolactoneChildren with congenital adrenal hyperplasia (CAH) and bone ages of 2-13 years in boys and 2-11 years in girls were randomized to receive antiandrogen (flutamide 10mg/kg/day orally), aromatase inhibitor (testolactone - 20mg/ kg/day orally OR letrozole - 1.5mg/m^2 body surface area orally), low-dose hydrocortisone (6-8 mg/m^2/day orally), and fludrocortisone (100-200 mcg/day, depending on lab evaluation, orally). Participants received the four-drug regimen until the age of 13 in the girls and 14 in the boys and then were switched to standard therapy. Female participants on investigational drugs were continued on flutamide until attainment of final adult height or two years post menarche. Participants who experienced early puberty received GnRH agonist therapy: depot leuprolide 7.5-15 mg/kg monthly intramuscularly or deslorelin 4 mcg/kg/day (adjusted based on weight and response) subcutaneously. |
| Standard therapy | Experimental | Drug: Fludrocortisone, Drug: HydrocortisoneChildren with congenital adrenal hyperplasia (CAH) and bone ages of 2-13 years in boys and 2-11 years in girls received standard therapy/conventional treatment (with hydrocortisone and fludrocortisone). Participants received hydrocortisone approximately 10-15 mg/m^2/day orally, not exceeding 25mg/m^2/day, and fludrocortisone 100-200 mcg/day orally depending on lab evaluation. Participants who experienced early puberty received GnRH agonist therapy: depot leuprolide 7.5-15 mg/kg monthly intramuscularly or deslorelin 4 mcg/kg/day (adjusted based on weight and response) subcutaneously. |
Who may qualify
- Ages
- 2 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- Subjects will be boys with bone ages 2 to 13 years and girls with bone ages 2 to 11 years with CAH due to classic 21-hydroxylase deficiency.
- Subjects must either not yet have undergone pubertal activation of the hypothalamic-pituitary-gonadal axis, or, if pubertal activation has occurred, must be receiving a GnRH agonist to suppress secondary central precocious puberty.
- Children with a bone age of 1 to 2 years may enroll in the protocol for optimization of conventional therapy, but will not be randomized to a study arm until the bone age reaches 2.
Key exclusion criteria (1 listed)
- Children who have concurrent illnesses requiring glucocorticoid treatment (such as severe asthma), or requiring drugs that markedly alter hydrocortisone metabolism (such as anticonvulsants), and children who cannot be brought into reasonable control with conventional treatment (an unusual occurrence).
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 |
|---|---|---|
| FludrocortisoneMineralocorticoid needed to replace aldosterone deficiency. Patients will continue to receive an optimal fludrocortisone dose | Drug | Investigational therapy, Standard therapy |
| HydrocortisoneGlucocorticoid needed to replace cortisol deficiency. Reduced hydrocortisone dose might normalize the growth and adult stature of children with congenital adrenal hyperplasia | Drug | Investigational therapy, Standard therapy |
| LetrozoleAromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. | Drug | Investigational therapy |
| FlutamideNon steroidal anti-androgen that prevents the action of androgens by blocking receptor sites in target tissue. It may also produce changes in testosterone and estradiol | Drug | Investigational therapy |
| TestolactoneAromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. | Drug | Investigational therapy |
Primary outcome
Adult Height Relative to General Population
Time frame: Followed to attainment of adult height, average of 11 years from date of randomization
Adult height expressed in standard deviation score (SDS) units relative to the general population, with attainment of adult height defined as incremental growth < 1.5 cm over 12 months. Adult height SDS was based on National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, National Center for Health Statistics) data at 20 years old.
20 secondary outcomes
Adult Height Relative to Mid-parental Height
Time frame: Followed to attainment of adult height, average of 11 years from date of randomization
Predicted Adult Height
Time frame: At date of randomization and at pubertal onset (average of seven years from date of randomization)
Predicted Adult Height Change
Time frame: From date of randomization to pubertal onset visit (which on average was seven years), pubertal onset to final visit (average was 4 years), and date of randomization to final visit (average of 11 years)
Number of Years Bone Age Remained Unchanged
Time frame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Change in Body Mass Index (BMI)
Time frame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Body Mass Index (BMI)
Time frame: Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
Average Annual Growth Velocity
Time frame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Dose of Oral Hydrocortisone
Time frame: At date of randomization, pubertal onset (average of seven years from date of randomization), and at final visit (average of 11 years from date of randomization)
Average Daily Dose of Oral Hydrocortisone
Time frame: From date of randomization to pubertal onset visit (which on average was seven years), pubertal onset to final visit (average was 4 years), and date of randomization to final visit (average of 11 years)
Percent of Visits With 17-hydroxyprogesterone in the Optimal Range (<1,200 ng/dL)
Time frame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Percent of Visits With Androstenedione in Normal Range
Time frame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Average Testosterone
Time frame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
Number of Participants With Onset of Early Central Puberty
Time frame: Measured from date of randomization to onset of early central puberty
Average Age at Menarche
Time frame: Followed from date of randomization to onset of menarche
Number of Female Participants With Normal Menstrual Cyclicity at Final Visit
Time frame: Measured at single time point at final visit, average of 11 years from date of randomization
Number of Participants With Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) > 2.5
Time frame: Final visit, average of 11 years from date of randomization
Average (Median) Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
Time frame: Measured at single time point at final visit, average of 11 years from date of randomization
Number of Male Participants With Testicular Adrenal Rest Tumors (TART)
Time frame: Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
Anterior Posterior Spine Bone Mineral Density (BMD) at Final Visit
Time frame: Final visit, average of 11 years from date of randomization
Femoral Neck Bone Mineral Density (BMD) at Final Visit
Time frame: Final visit, average of 11 years from date of randomization
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jun 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 39672600Merke DP, Mallappa A, Parker M, Sukin C, Kulkarni SE, Keil MF, Van Ryzin C, Hill SC, Reynolds JC, Cutler GB Jr, Sinaii N. Adult Height Following Prepubertal Treatment With Antiandrogen, Aromatase Inhibitor, and Reduced Hydrocortisone in CAH. J Clin Endocrinol Metab. 2025 Jun 17;110(7):e2171-e2182. doi: 10.1210/clinem/dgae824.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No. Data is being used for secondary analyses.
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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.
Deborah P Merke, M.D. principal investigator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Fludrocortisone, Hydrocortisone and Letrozole in people with Congenital Adrenal Hyperplasia (CAH), run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site 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 3 inclusion and 1 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: finished, as of the sponsor's last update on 12 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jun 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Adult Height Relative to General Population (time frame: Followed to attainment of adult height, average of 11 years from date of randomization). 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 NCT00001521, 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 12 Jun 2025.