Trial · Interventional
CompletedPhase 3Results postedRegistry dataThis trial does not test a peptide that PepBank tracks.
United States
1 trial · 1 completed · 1 with posted results
Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia
NCT000015218 Jun 1995 to 1 Apr 2024
Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.
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.
Experimental
Investigational therapy
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.
Experimental
Standard therapy
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.
Outcomes the sponsor listed as primary.
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.
Adult Height Relative to Mid-parental Height
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 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).
Predicted Adult Height
Time frame · At date of randomization and at pubertal onset (average of seven years from date of randomization)
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).
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
Number of Participants With Onset of Early Central Puberty
Time frame · Measured from date of randomization to 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.
Average Age at Menarche
Time frame · Followed from date of randomization to onset of menarche
Average age at menarche (years) in female participants only.
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 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.
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
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.
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
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.
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)
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.
Anterior Posterior Spine Bone Mineral Density (BMD) at Final Visit
Time frame · Final visit, average of 11 years from date of randomization
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.
Femoral Neck 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) 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.
Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | -0.34 | 0.93 |
| Standard Therapy | -0.6 | 0.89 |
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | -0.45 | 0.85 |
| Standard Therapy | -0.83 | 0.78 |
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | -2.0 | 1.5 |
| Standard Therapy | -2.1 | 1.5 |
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | 1.93 | 1.29 |
| Standard Therapy | 1.10 | 1.32 |
| Group | Value (Years) | Spread |
|---|---|---|
| Investigational Therapy | 3.86 | 2.13 |
| Standard Therapy | 2.78 | 2.43 |
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | 0.12 | 0.7 |
| Standard Therapy | 0.36 | 0.79 |
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | 1.07 | 1.30 |
| Standard Therapy | 1.09 | 0.93 |
| Group | Value (Standard Deviation Score (SDS) units) | Spread |
|---|---|---|
| Investigational Therapy | -1.01 | 1.84 |
| Standard Therapy | -0.34 | 2.18 |
| Group | Deaths | Serious events | Other events |
|---|---|---|---|
| Investigational TherapyChildren 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. | 0 / 31 | 3 / 31 | 31 / 31 |
| Standard TherapyChildren 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. | 0 / 35 | 10 / 35 | 31 / 35 |
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