Puberty, Precocious
Conditions
Keywords
Testotoxicosis, Familial Male-limited Precocious Puberty (FMPP)
Brief summary
The primary objective of this study is to investigate whether bicalutamide given in combination with anastrozole once daily for 12 months is effective in treating testotoxicosis in boys. Testotoxicosis is a condition that causes early puberty in boys including growth in height, and development of muscles and sexual organs .
Interventions
DRUGBicalutamide
oral
DRUGAnastrozole
oral
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
2 Years to 13 Years
Healthy volunteers
No
Inclusion criteria
* Provision of written informed consent of parent/legal guardian and subject assent (as needed by local requirements) * Male aged 2 years and over * Diagnosis of testotoxicosis based on the following: * Clinical features of Progressive sexual precocity documented by Tanner staging and evidence of symmetrical testicular enlargement * Clinical features of significantly advanced bone age (defined as bone age of at least 12 months beyond chronological age) * Pubertal levels of serum testosterone * Prepubertal levels of serum gonadotropins * Lack of an increase in serum gonadotropin levels following GnRH stimulation * Other pathology excluded by: * Undetectable plasma b human chorionic gonadotropin (bHCG). Samples with values below the LOQ will be reported as \<10 IU/L which in the clinical setting equate to 'undetectable'. * Normal levels of 17-hydroxyprogesterone (17-OHP) * Normal levels of dehydroepiandrosterone sulphate (DHEAS) * Naive to anti androgen receptor therapy: (Note: Ketoconazole and Spironolactone are considered acceptable as is prior use of anastrozole or other aromatase inhibitors) * A documented reliable height measurement taken \> 6 months prior to study enrollment. Additionally for subjects who have previously received ketoconazole or spironolactone treatment, a documented reliable height measurement taken immediately prior to beginning this treatment. (Note: for subjects who received such previous treatment only a single assessment is needed if it was taken immediately prior to beginning treatment and \> 6 months prior to study entry) * Subjects should be free of endocrine or other effects of previous treatment for testotoxicosis prior to study entry: to ensure this there should be 15 days or 4 drug half lives (whichever is the longer) washout period from prior medication for testotoxicosis.
Exclusion criteria
* Evidence of central precocious puberty as demonstrated by GnRH stimulation test * Serum concentration of total or direct bilirubin, GGT, AST or ALT greater than 1.5 times the upper limit of normal for age * Serum concentration of creatinine greater than 1.5 times the upper limit of normal for age * Any concomitant medical condition that, in the opinion of the investigator, may expose a subject to an unacceptable level of safety risk or that affects subject compliance * Known hypersensitivity to any of the study medications * Participation in a clinical study at the time of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Growth Rate (cm/Year) | Assessed after 12 months treatment | Change in growth rate after 12 months relative to the growth rate during the ≥6 month pre-study period, based on raw height data (cm/year). |
| Change in Growth Rate (SD Units) | Assessed after 12 months treatment | Change in growth rate after 12 months relative to the growth rate during the ≥6 month pre-study period, calculated after adjustment for the chronological age of the patient (expressed as a standard deviation \[SD\] score). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Age Maturation Rate (cm/Year) | Assessed after 6 and 12 months treatment | Radiographs were used to assess the bone age at ≥6 months pre-study, baseline, 6 and 12 months. The rate of change in bone age at baseline was calculated from a radiograph taken at least 6 months prior to study enrolment. The change in bone maturation after 6 months of treatment was calculated relative to the rate of change in bone age during the ≥ 6 months pre-study period. |
| Change in Bone Age to Chronological Age Ratio | Assessed after 6 and 12 months of treatment | Change in bone age to chronological age ratio after 6 and 12 months treatment relative to the baseline ratio for all patients. |
| Change in Growth Rate (cm/Year) | Assessed after 6 months treatment | Change in growth rate after 6 months of treatment relative to the growth rate during the ≥6 months pre-study period. |
| Change in Predicted Adult Height (PAH) | Assessed after 12 months treatment | Radiographs are used to assess the bone age, the change in predicted adult height (PAH) is calculated from the bone age using the Bayley and Pinneau Method. The change in PAH is be calculated by subtracting the PAH at baseline from the PAH at 12 months. |
| Change in Average Testicular Volume | Assessed after 6 and 12 months of treatment | Testicular volume of both testes was measured using either ultrasound or an orchidometer. Testicular volume was measured at baseline and at 6 and 12 months. The change in testicular volume from baseline was calculated for the left and right testicle as well as the average across both testes by subtracting the baseline volume from the volumes at 6 and 12 months within each patient. |
| Number of Patients With Height Between 5th and 95th Percentile | Assessed after 3, 6, 9 and 12 months of treatment | The number of patients whose height lies between the 5th and 95th percentiles (using the percentile tables on the WHO database) for chronological age at the 12 month assessment. |
| Change in Growth Rate (SD Units) | Assessed after 6 months treatment | Change in growth rate after 6 months of treatment relative to the growth rate during the ≥6 months pre-study period. |
Countries
Canada, France, India, Russia, United Kingdom, United States
Participant flow
Recruitment details
The first patient was enrolled on 22 November 2004 and the last patient completed the 12 months visit on 7 May 2008. Patients were allocated treatment at 9 centres in 3 countries: India, the UK and the USA. Care for two patients, transferred from one US to a new approved US centre, therefore, patients were treated at 10 centres in total
Pre-assignment details
Of the 24 patients enrolled, 10 failed eligibility criteria and were classed as screening failures while the remaining 14 patients were allocated treatment.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Bicalutamide With Anastrozole Patients with testotoxicosis (familial male-limited precocious puberty) were given study drugs (bicalutamide in combination with anastrozole) orally once-daily for 12 months. The dosing of bicalutamide and anastrozole was independently tailored for each patient. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Open Label Bicalutamide With Anastrozole |
|---|---|
| Age, Continuous | 3.5 Years |
| Race/Ethnicity, Customized Ethnic group African/American | 1 Participants |
| Race/Ethnicity, Customized Ethnic group Asian | 3 Participants |
| Race/Ethnicity, Customized Ethnic group Hispanic/Latino | 1 Participants |
| Race/Ethnicity, Customized Ethnic group Not Applicable | 9 Participants |
| Race/Ethnicity, Customized Race Black | 1 Participants |
| Race/Ethnicity, Customized Race Caucasian | 12 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 13 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Change in Growth Rate (cm/Year)
Change in growth rate after 12 months relative to the growth rate during the ≥6 month pre-study period, based on raw height data (cm/year).
Time frame: Assessed after 12 months treatment
Population: All treated (AT) set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Growth Rate (cm/Year) | -1.62 cm/year | Standard Deviation 5.13 |
Comparison: The primary efficacy parameter, change in growth rate (cm/year) after 12 months relative to the baseline growth rate was analysed using a one sample t-test. A 95% 2-sided confidence interval was calculated for the mean change in growth rate.p-value: 0.27895% CI: [-4.72, 1.48]t-test, 2 sided
Primary
Change in Growth Rate (SD Units)
Change in growth rate after 12 months relative to the growth rate during the ≥6 month pre-study period, calculated after adjustment for the chronological age of the patient (expressed as a standard deviation \[SD\] score).
Time frame: Assessed after 12 months treatment
Population: All treated (AT) set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Growth Rate (SD Units) | -0.07 SD units | Standard Deviation 1.78 |
Comparison: The primary efficacy parameter, change in growth rate (SD units) after 12 months relative to the baseline growth rate was analysed using a one sample t-test. A 95% 2-sided confidence interval was calculated for the mean change in growth rate.p-value: 0.88295% CI: [-1.15, 1]t-test, 2 sided
Secondary
Change in Average Testicular Volume
Testicular volume of both testes was measured using either ultrasound or an orchidometer. Testicular volume was measured at baseline and at 6 and 12 months. The change in testicular volume from baseline was calculated for the left and right testicle as well as the average across both testes by subtracting the baseline volume from the volumes at 6 and 12 months within each patient.
Time frame: Assessed after 6 and 12 months of treatment
Population: All treated (AT) set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Average Testicular Volume | After 6 months treatment | 1.46 mL | Standard Deviation 2.29 |
| Open Label Bicalutamide With Anastrozole | Change in Average Testicular Volume | After 12 months treatment | 2.69 mL | Standard Deviation 2.51 |
Secondary
Change in Bone Age Maturation Rate (cm/Year)
Radiographs were used to assess the bone age at ≥6 months pre-study, baseline, 6 and 12 months. The rate of change in bone age at baseline was calculated from a radiograph taken at least 6 months prior to study enrolment. The change in bone maturation after 6 months of treatment was calculated relative to the rate of change in bone age during the ≥ 6 months pre-study period.
Time frame: Assessed after 6 and 12 months treatment
Population: Calculated on All treated analysis set for those patients who had a 6-month pre study radiograph.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Bone Age Maturation Rate (cm/Year) | After 6 months treatment | -2.03 cm/year | Standard Deviation 0.38 |
| Open Label Bicalutamide With Anastrozole | Change in Bone Age Maturation Rate (cm/Year) | After 12 months treatment | -2.29 cm/year | Standard Deviation 0.51 |
Secondary
Change in Bone Age to Chronological Age Ratio
Change in bone age to chronological age ratio after 6 and 12 months treatment relative to the baseline ratio for all patients.
Time frame: Assessed after 6 and 12 months of treatment
Population: All treated (AT) set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Bone Age to Chronological Age Ratio | After 6 months treatment | -0.09 Ratio | Standard Deviation 0.14 |
| Open Label Bicalutamide With Anastrozole | Change in Bone Age to Chronological Age Ratio | After 12 months treatment | -0.24 Ratio | Standard Deviation 0.18 |
Secondary
Change in Growth Rate (cm/Year)
Change in growth rate after 6 months of treatment relative to the growth rate during the ≥6 months pre-study period.
Time frame: Assessed after 6 months treatment
Population: All treated (AT) set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Growth Rate (cm/Year) | -0.70 cm/year | Standard Deviation 5.77 |
Secondary
Change in Growth Rate (SD Units)
Change in growth rate after 6 months of treatment relative to the growth rate during the ≥6 months pre-study period.
Time frame: Assessed after 6 months treatment
Population: All treated (AT) set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Growth Rate (SD Units) | -0.14 SD units | Standard Deviation 1.67 |
Secondary
Change in Predicted Adult Height (PAH)
Radiographs are used to assess the bone age, the change in predicted adult height (PAH) is calculated from the bone age using the Bayley and Pinneau Method. The change in PAH is be calculated by subtracting the PAH at baseline from the PAH at 12 months.
Time frame: Assessed after 12 months treatment
Population: Calculated on All treated analysis set, however, if bone age is less than 6 years or bone age is less than 7 years and bone age\>=(chronological age-1) then PAH cannot be calculated using the Bayley and Pinneau method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Change in Predicted Adult Height (PAH) | 6.21 cm | Standard Deviation 3.93 |
Secondary
Number of Patients With Height Between 5th and 95th Percentile
The number of patients whose height lies between the 5th and 95th percentiles (using the percentile tables on the WHO database) for chronological age at the 12 month assessment.
Time frame: Assessed after 3, 6, 9 and 12 months of treatment
Population: All treated (AT) set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open Label Bicalutamide With Anastrozole | Number of Patients With Height Between 5th and 95th Percentile | After 3 months treatment | 3 Participants |
| Open Label Bicalutamide With Anastrozole | Number of Patients With Height Between 5th and 95th Percentile | After 6 months treatment | 3 Participants |
| Open Label Bicalutamide With Anastrozole | Number of Patients With Height Between 5th and 95th Percentile | After 9 months treatment | 3 Participants |
| Open Label Bicalutamide With Anastrozole | Number of Patients With Height Between 5th and 95th Percentile | After 12 months treatment | 3 Participants |