Clinical trial NCT00001521: Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Congenital Adrenal Hyperplasia (CAH)
Keywords: Congenital Adrenal Hyperplasia (CAH)
Intervention
Children
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 1999-11-04
Enrollment: 66
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: * INCLUSION CRITERIA:

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.

EXCLUSION CRITERIA:

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).

Primary outcomes:
measure: Adult Height Relative to General Population
timeFrame: Followed to attainment of adult height, average of 11 years from date of randomization
Secondary outcomes:
measure: Adult Height Relative to Mid-parental Height
timeFrame: Followed to attainment of adult height, average of 11 years from date of randomization
measure: Predicted Adult Height
timeFrame: At date of randomization and at pubertal onset (average of seven years from date of randomization)
measure: Predicted Adult Height Change
timeFrame: 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)
measure: Number of Years Bone Age Remained Unchanged
timeFrame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
measure: Change in Body Mass Index (BMI)
timeFrame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
measure: Body Mass Index (BMI)
timeFrame: Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
measure: Average Annual Growth Velocity
timeFrame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
measure: Dose of Oral Hydrocortisone
timeFrame: 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)
measure: Average Daily Dose of Oral Hydrocortisone
timeFrame: 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)
measure: Percent of Visits With 17-hydroxyprogesterone in the Optimal Range (<1,200 ng/dL)
timeFrame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
measure: Percent of Visits With Androstenedione in Normal Range
timeFrame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
measure: Average Testosterone
timeFrame: From date of randomization to pubertal onset visit (which on average was seven years) and pubertal onset to final visit (average was 4 years)
measure: Number of Participants With Onset of Early Central Puberty
timeFrame: Measured from date of randomization to onset of early central puberty
measure: Average Age at Menarche
timeFrame: Followed from date of randomization to onset of menarche
measure: Number of Female Participants With Normal Menstrual Cyclicity at Final Visit
timeFrame: Measured at single time point at final visit, average of 11 years from date of randomization
measure: Number of Participants With Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) > 2.5
timeFrame: Final visit, average of 11 years from date of randomization
measure: Average (Median) Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
timeFrame: Measured at single time point at final visit, average of 11 years from date of randomization
measure: Number of Male Participants With Testicular Adrenal Rest Tumors (TART)
timeFrame: Pubertal onset visit (average of seven years from date of randomization) and at final visit (average of 11 years from date of randomization)
measure: Anterior Posterior Spine Bone Mineral Density (BMD) at Final Visit
timeFrame: Final visit, average of 11 years from date of randomization
measure: Femoral Neck Bone Mineral Density (BMD) at Final Visit
timeFrame: Final visit, average of 11 years from date of randomization
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Deborah P Merke, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. 2024 Dec 3:dgae824. doi: 10.1210/clinem/dgae824. Online ahead of print.