Precocious Puberty
Conditions
Brief summary
The purpose of the study is to assess the efficacy of triptorelin 11.25 mg pamoate in the delay of premature onset of puberty in girls less than 9 years and boys less than 10 years. This is measured by assessing the proportion of children who have a suppressed Luteinizing Hormone (LH) response to Gonadotropin Releasing Hormone (GnRH) test performed 3 months after injection with triptorelin 11.25 mg.
Interventions
DRUGTriptorelin pamoate 11.25mg (Decapeptyl® SR)
One intra muscular injection at day 1 and month 3.
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
in the screening phase: * Onset of sex characteristics (Tanner method) breast development in girls or testicular enlargement in boys before the age of 8 years in girls and 9 years in boys. * Weight ≥ 20 kg. Inclusion Criteria in the treatment phase: * Proven central precocious puberty defined as onset of sex characteristics development (according to Tanner method) diagnosed before the age of 8 years in girls and 9 years in boys. * Age at evaluation less than 9 years for girls and 10 years for boys. * A pubertal response of LH to GnRH test in both sexes (stimulated LH ≥ 5 IU/l). * Difference Bone age (BA) (according to Greulich et Pyle method) - Chronological age (CA) \> 1 year. * Testosterone level ≥ 0.5 ng/ml in boys.
Exclusion criteria
* Patient with a peripheral precocious puberty: extrapituitary secretion of gonadotropins or gonadotropin-independent gonadal or adrenal sex steroids secretion. * Patient with a cerebral tumour requiring a neurosurgery or cerebral irradiation. * Patient with a Body Weight ≥ 125% of the ideal weight for the height and age (growth curves). * The patient has received a previous treatment with a GnRH analogue, or medroxyprogesterone or cyproterone acetate.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | 3 months after the first injection of triptorelin pamoate 11.25 mg |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Follicle Stimulating Hormone (FSH) Level Following GnRH Test | Screening, month 3 and 6 | — |
| Basal FSH Level | Month 0, 1, 2, 3, 4, 5, and 6 | — |
| Basal LH Level | Month 0, 1, 2, 3, 4, 5 and 6 | — |
| Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Month 0, 1, 2, 3, 4, 5 and 6 | — |
| Testosterone Level | Month 0, 3 and 6 | — |
| Number of Girls With Inhibin B Levels < 6 pg/ml | Month 0, 3 and 6 | — |
| Number of Participants Whose Intravenous (i.v.) GnRH-stimulated LH Response Was ≤3 IU/L | Month 6 | — |
| Height Standard Deviation Score (SDS) | Month 0, 3 and 6 | Standard deviation (SD) is a standard term used in growth studies and represents Standard Deviations calculated as the patient value minus the mean divided by the standard deviation. Standard Deviation Scores vary depending on the age and sex of the child. |
| Body Mass Index (BMI) SDS | Month 0, 3 and 6 | — |
| Change From Baseline in Growth Velocity (GV) SDS at Month 6 | Baseline and month 6 | Change from baseline of GV was calculated as: GV at month 6 - GV at baseline. GV SDS was calculated using SAS algorithm. Growth velocity during the study was calculated using the two height measures as: GV = (Height at baseline - Height at screening)\*365/delay between two height measures. |
| Difference Between Bone Age and Chronological Age | Month 0 and 6 | Bone age was defined according to Greulich and Pyle method. Chronological age was calculated using the date of birth. |
| Uterine Length | Month 0, 3 and 6 | — |
| Triptorelin Plasma Levels | Month 1, 2, 3, 4, 5 and 6 | — |
| Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Between screening and month 6 | Pubertal stage (graded from 1 to 5 for penis and breast development, graded from 1 to 6 for pubic hair development) according to the Tanner method was collected. A low stage (i.e. 1) corresponds to a pre-pubertal stage and a high stage (i.e. 5 or 6) to an adult stage. Any increase of grade was defined as 'increased' and no change in grade or a reduced grade was defined as 'stabilised or reduced'. |
Countries
France
Participant flow
Recruitment details
62 participants were screened, of which 37 met the study's entry criteria and received at least one dose of investigational medicinal product. 25 participants failed screening. Participants were recruited from October 2007 at 18 Hospital clinics across France.
Participants by arm
| Arm | Count |
|---|---|
| Triptorelin Pamoate 11.25 mg 11.25 mg triptorelin pamoate via intramuscular injection at baseline and month 3. | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 2 |
Baseline characteristics
| Characteristic | Triptorelin Pamoate 11.25 mg |
|---|---|
| Age, Categorical <=18 years | 37 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 8.2 years STANDARD_DEVIATION 1.1 |
| Region of Enrollment France | 37 participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 1 Participants |
| Weight | 32.76 Kg STANDARD_DEVIATION 7.36 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 37 |
| serious Total, serious adverse events | 1 / 37 |
Outcome results
Primary
Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L
Time frame: 3 months after the first injection of triptorelin pamoate 11.25 mg
Population: Analyses performed on:~* Intention to Treat (ITT): all patients having received ≥1 injection. Any subject with missing data is considered a non-responder.~* Modified ITT (mITT): all ITT patients with ≥ Month 3 post-baseline assessment of primary efficacy criterion.~* Per Protocol (PP): all mITT patients without major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | Yes [ITT (n=37)] | 31 participants |
| Triptorelin Pamoate 11.25 mg | Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | No [ITT (n=37)] | 6 participants |
| Triptorelin Pamoate 11.25 mg | Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | Yes [mITT (n=34)] | 31 participants |
| Triptorelin Pamoate 11.25 mg | Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | No [mITT (n=34)] | 3 participants |
| Triptorelin Pamoate 11.25 mg | Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | Yes [PP (n=32)] | 30 participants |
| Triptorelin Pamoate 11.25 mg | Number of Participants With a GnRH-stimulated LH Level ≤3 IU/L | No [PP (n=32)] | 2 participants |
Secondary
Basal FSH Level
Time frame: Month 0, 1, 2, 3, 4, 5, and 6
Population: Analysis was performed on the ITT population. 2 participants had missing data at month 1, 3, 4 and 6. 1 and 3 participants had missing data at month 2 and month 5 respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 0 (screening, n=37) | 4.13 IU/L | Standard Deviation 2.65 |
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 1 (n=35) | 0.67 IU/L | Standard Deviation 0.53 |
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 2 (n=36) | 1.07 IU/L | Standard Deviation 0.82 |
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 3 (n=35) | 1.11 IU/L | Standard Deviation 0.73 |
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 4 (n=35) | 0.78 IU/L | Standard Deviation 0.39 |
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 5 (n=34) | 1.41 IU/L | Standard Deviation 2.09 |
| Triptorelin Pamoate 11.25 mg | Basal FSH Level | Month 6 (n=35) | 1.36 IU/L | Standard Deviation 1.24 |
Secondary
Basal LH Level
Time frame: Month 0, 1, 2, 3, 4, 5 and 6
Population: Analysis was performed on ITT population. 2 participants had missing data at month 1, 3, 4 and 6. 1 and 3 participants had missing data at month 2 and month 5 respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 4 (n=35) | 0.43 IU/L | Standard Deviation 0.23 |
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 0 (screening, n=37) | 1.49 IU/L | Standard Deviation 1.78 |
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 1 (n=35) | 0.42 IU/L | Standard Deviation 0.22 |
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 2 (n=36) | 0.42 IU/L | Standard Deviation 0.31 |
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 3 (n=35) | 0.43 IU/L | Standard Deviation 0.27 |
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 5 (n=34) | 0.48 IU/L | Standard Deviation 0.7 |
| Triptorelin Pamoate 11.25 mg | Basal LH Level | Month 6 (n=35) | 0.44 IU/L | Standard Deviation 0.42 |
Secondary
Body Mass Index (BMI) SDS
Time frame: Month 0, 3 and 6
Population: Analysis was performed on the ITT population. 1 and 2 participants had missing data at month 0 and month 6 respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Body Mass Index (BMI) SDS | Month 0 (baseline, n=36) | 0.58 SD score | Standard Deviation 0.85 |
| Triptorelin Pamoate 11.25 mg | Body Mass Index (BMI) SDS | Month 3 (n=37) | 0.64 SD score | Standard Deviation 0.89 |
| Triptorelin Pamoate 11.25 mg | Body Mass Index (BMI) SDS | Month 6 (n=35) | 0.60 SD score | Standard Deviation 0.78 |
Secondary
Change From Baseline in Growth Velocity (GV) SDS at Month 6
Change from baseline of GV was calculated as: GV at month 6 - GV at baseline. GV SDS was calculated using SAS algorithm. Growth velocity during the study was calculated using the two height measures as: GV = (Height at baseline - Height at screening)\*365/delay between two height measures.
Time frame: Baseline and month 6
Population: Analysis was performed on the ITT population. If GV at screening was missing, the value was derived from data recorded between 5 to 19 months ago otherwise GV at screening was considered missing. 9 participants had missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Change From Baseline in Growth Velocity (GV) SDS at Month 6 | -1.95 SD score | Standard Deviation 2.07 |
Secondary
Change From Screening in Pubertal Stage (Tanner Method) at Month 6
Pubertal stage (graded from 1 to 5 for penis and breast development, graded from 1 to 6 for pubic hair development) according to the Tanner method was collected. A low stage (i.e. 1) corresponds to a pre-pubertal stage and a high stage (i.e. 5 or 6) to an adult stage. Any increase of grade was defined as 'increased' and no change in grade or a reduced grade was defined as 'stabilised or reduced'.
Time frame: Between screening and month 6
Population: Analysis was performed on the ITT population. 2 participants had missing data for pubic hair stage and breast stage.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Pubic hair stage stabilised or reduced (n=35) | 30 participants |
| Triptorelin Pamoate 11.25 mg | Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Pubic hair stage increased (n=35) | 5 participants |
| Triptorelin Pamoate 11.25 mg | Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Breast stage stabilised or reduced (n=34) | 32 participants |
| Triptorelin Pamoate 11.25 mg | Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Breast stage increased (n=34) | 2 participants |
| Triptorelin Pamoate 11.25 mg | Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Penis stage stabilised or reduced (n=1) | 1 participants |
| Triptorelin Pamoate 11.25 mg | Change From Screening in Pubertal Stage (Tanner Method) at Month 6 | Penis stage increased (n=1) | 0 participants |
Secondary
Difference Between Bone Age and Chronological Age
Bone age was defined according to Greulich and Pyle method. Chronological age was calculated using the date of birth.
Time frame: Month 0 and 6
Population: Analysis was performed on the ITT population. 33 participants were assessed. 4 participants had missing data at month 6.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Difference Between Bone Age and Chronological Age | Month 0 (screening, n=37) | 2.09 years | Standard Deviation 0.91 |
| Triptorelin Pamoate 11.25 mg | Difference Between Bone Age and Chronological Age | Month 6 (n=33) | 2.02 years | Standard Deviation 0.88 |
Secondary
Follicle Stimulating Hormone (FSH) Level Following GnRH Test
Time frame: Screening, month 3 and 6
Population: Analysis was performed on the ITT population. 3 participants and 2 participants had missing data at month 3 and month 6 respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Follicle Stimulating Hormone (FSH) Level Following GnRH Test | Screening (n=37) | 11.84 IU/L | Standard Deviation 3.23 |
| Triptorelin Pamoate 11.25 mg | Follicle Stimulating Hormone (FSH) Level Following GnRH Test | Month 3 (n=34) | 2.26 IU/L | Standard Deviation 2.5 |
| Triptorelin Pamoate 11.25 mg | Follicle Stimulating Hormone (FSH) Level Following GnRH Test | Month 6 (n=35) | 2.34 IU/L | Standard Deviation 1.65 |
Secondary
Height Standard Deviation Score (SDS)
Standard deviation (SD) is a standard term used in growth studies and represents Standard Deviations calculated as the patient value minus the mean divided by the standard deviation. Standard Deviation Scores vary depending on the age and sex of the child.
Time frame: Month 0, 3 and 6
Population: Analysis was performed on the ITT population. 2 participants had missing data at month 6.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Height Standard Deviation Score (SDS) | Month 0 (baseline, n=37) | 1.25 SD score | Standard Deviation 1.14 |
| Triptorelin Pamoate 11.25 mg | Height Standard Deviation Score (SDS) | Month 3 (n=37) | 1.32 SD score | Standard Deviation 1.16 |
| Triptorelin Pamoate 11.25 mg | Height Standard Deviation Score (SDS) | Month 6 (n=35) | 1.32 SD score | Standard Deviation 1.16 |
Secondary
Number of Girls With Inhibin B Levels < 6 pg/ml
Time frame: Month 0, 3 and 6
Population: Analysis was performed on female patients in the ITT population. 2 participants had missing data at month 3 and month 6.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Number of Girls With Inhibin B Levels < 6 pg/ml | Yes - month 0 (screening, n=36) | 18 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Inhibin B Levels < 6 pg/ml | No - month 0 (screening, n=36) | 18 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Inhibin B Levels < 6 pg/ml | Yes - month 3 (n=34) | 33 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Inhibin B Levels < 6 pg/ml | No - month 3 (n=34) | 1 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Inhibin B Levels < 6 pg/ml | Yes - month 6 (n=34) | 32 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Inhibin B Levels < 6 pg/ml | No - month 6 (n=34) | 2 participants |
Secondary
Number of Girls With Oestradiol Levels ≤ 20 pg/ml
Time frame: Month 0, 1, 2, 3, 4, 5 and 6
Population: Analysis was performed on female patients in the ITT population. 2 participants had missing data at month 1, 3, 4 and 6. 1 participant and 3 participants had missing data at month 2 and 5 respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 0 (n=36) | 22 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 0 (n=36) | 14 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 1 (n=34) | 34 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 1 (n=34) | 0 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 2 (n=35) | 34 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 2 (n=35) | 1 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 3 (n=34) | 33 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 3 (n=34) | 1 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 4 (n=34) | 34 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 4 (n=34) | 0 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 5 (n=33) | 33 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 5 (n=33) | 0 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | Yes - month 6 (n=34) | 33 participants |
| Triptorelin Pamoate 11.25 mg | Number of Girls With Oestradiol Levels ≤ 20 pg/ml | No - month 6 (n=34) | 1 participants |
Secondary
Number of Participants Whose Intravenous (i.v.) GnRH-stimulated LH Response Was ≤3 IU/L
Time frame: Month 6
Population: Analysis was performed on Intention to Treat population (ITT) defined as all participants having received at least one injection of 11.25 mg triptorelin pamoate. n indicates the number of patients who had an assessment at the visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Number of Participants Whose Intravenous (i.v.) GnRH-stimulated LH Response Was ≤3 IU/L | Yes (n=37) | 32 participants |
| Triptorelin Pamoate 11.25 mg | Number of Participants Whose Intravenous (i.v.) GnRH-stimulated LH Response Was ≤3 IU/L | No (n=37) | 5 participants |
Secondary
Testosterone Level
Time frame: Month 0, 3 and 6
Population: Testosterone level from the male patient in the ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Testosterone Level | Month 0 (screening) | 2.0 ng/ml |
| Triptorelin Pamoate 11.25 mg | Testosterone Level | Month 3 | 0.12 ng/ml |
| Triptorelin Pamoate 11.25 mg | Testosterone Level | Month 6 | 0.16 ng/ml |
Secondary
Triptorelin Plasma Levels
Time frame: Month 1, 2, 3, 4, 5 and 6
Population: Analysis was performed on the Pharmacokinetics (PK) Valid population defined as all participants who received at least one injection of 11.25 mg triptorelin pamoate and had at least one PK assessment. 2 participants had data missing at month 1,3 and 6. 1, 3 and 4 participants had data missing at month 2, 4 and 5 respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Triptorelin Plasma Levels | Month 1 (n=35) | 0.187 ng/mL | Standard Deviation 0.115 |
| Triptorelin Pamoate 11.25 mg | Triptorelin Plasma Levels | Month 2 (n=36) | 0.048 ng/mL | Standard Deviation 0.023 |
| Triptorelin Pamoate 11.25 mg | Triptorelin Plasma Levels | Month 3 (n=35) | 0.034 ng/mL | Standard Deviation 0.018 |
| Triptorelin Pamoate 11.25 mg | Triptorelin Plasma Levels | Month 4 (n=34) | 0.201 ng/mL | Standard Deviation 0.12 |
| Triptorelin Pamoate 11.25 mg | Triptorelin Plasma Levels | Month 5 (n=33) | 0.045 ng/mL | Standard Deviation 0.023 |
| Triptorelin Pamoate 11.25 mg | Triptorelin Plasma Levels | Month 6 (n=35) | 0.030 ng/mL | Standard Deviation 0.017 |
Secondary
Uterine Length
Time frame: Month 0, 3 and 6
Population: Analysis was performed on female patients in the ITT population. 2 participants had missing data at month 3 and 6.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate 11.25 mg | Uterine Length | Month 0 (screening, n=35) | 37.6 mm | Standard Deviation 10.6 |
| Triptorelin Pamoate 11.25 mg | Uterine Length | Month 3 (n=34) | 37.4 mm | Standard Deviation 8.2 |
| Triptorelin Pamoate 11.25 mg | Uterine Length | Month 6 (n=34) | 36.8 mm | Standard Deviation 6.9 |