Central Precocious Puberty
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to assess long-term safety and efficacy of leuprorelin in the treatment of Central Precocious Puberty (CPP).
Detailed description
The drug in this study is called leuprorelin. It is administered as a 1 month subcutaneous depot injection. Leuprorelin is used to treat children who have CPP. This study will look at whether leuprorelin can stop early puberty in pre-pubertal children. The study will enroll approximately 300 participants. Participants with body weight \>=20 kg will receive the recommended dose of leuprorelin 3.75 mg subcutaneous injection every 4 weeks for 96 weeks. Participants with body weight \<20 kg will receive recommended dose of 1.88 mg subcutaneous injection every 4 weeks for 96 weeks. This trial will be conducted in China. The overall time to participate in this study is 104 weeks. Participants will make 11 visits to the clinic, and will be followed-up by the physician on a long-term basis until stable puberty is reached.
Interventions
DRUGLeuprorelin
Suspension for injection.
Sponsors
Takeda
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 9 Years
Healthy volunteers
No
Inclusion criteria
1. In the opinion of the investigator, the participant and/or parent(s) or legal guardian are capable of understanding and complying with protocol requirements. 2. The participant or the participant's parent(s) or legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Has onset of appearance of secondary sexual characteristic earlier than age 8.0 years in girls or earlier than 9.0 years in boys and the symptom is persistent, and has confirmed diagnosis of CPP. 4. Has basal luteinizing hormone (LH) level greater than (\>) 5.0 international units per liter (IU/L) or peak LH \>3.3 IU/L with LH/follicle-stimulating factor (FSH) \>0.6 in stimulation test. 5. Has evidence of gonadal development evaluated by ultrasonography: ovarian volume \>=1 milliliter (mL) with multiple follicles \>=4 millimeter (mm) in any ovary or uterine enlargement in females or testicular volume \>=4 mL in males. 6. Has advanced bone age (BA) \>=1 year and BA is less than or equal to (\<=) 11.5 years in females or \<=12.5 years in males OR predicted adult height \<150 centimeter (cm) in females or \<160 cm in males OR standard deviation score (SDS) \<-2 standard deviations (SD) OR rapid growth defined as growth of BA /growth of chronologic age \>1. BA is determined by Greulich and Pyle standards or Tanner-Whitehouse 3 (TW3) standards at screening. 7. Has anticipated treatment duration of at least 2 year in investigator's judgment. 8. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 90 days after last dose. 9. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study. 10. The female participant who, at the discretion of the investigator, is deemed to be of child bearing potential must provide negative urine pregnancy text at Day -1 or Day 1 prior to drug administration.
Exclusion criteria
1. Has received any investigational compound within 30 days prior to Screening. 2. Has received gonadotropin-releasing hormone analog (GnRHa) treatment in a previous clinical study or as a therapeutic agent. 3. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (example \[eg\], spouse, parent, child, sibling) or may consent under duress. 4. Has any findings in his/her medical history, physical examination, or safety clinical laboratory tests giving reasonable suspicion of underlying disease that might interfere with the conduct of the trial. 5. Has any concomitant medical condition that, in the opinion of the investigator, may expose a participant to an unacceptable level of safety risk or that affects participant compliance. 6. Has any screening abnormal laboratory value that suggests a clinically significant underlying disease or condition that may prevent the participant from entering the study; or the participant has: creatinine \>=1.5 milligram per deciliter (mg/dL), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>2 times the upper limit of normal (ULN), or total bilirubin \>2.0 mg/dL, with AST/ALT elevated above the limits of normal values. 7. Has a history or clinical manifestations of significant adrenal or thyroid diseases or intracranial tumor OR has a history of malignant disease. 8. Has a history of hypersensitivity or allergies to leuprorelin, or related compounds including any excipients of the compound. 9. Has a diagnosis of peripheral precocious puberty. 10. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening Visit. 11. Participant or parent(s), at the discretion of the investigator, is unlikely to comply with the protocol or is unsuitable for any of other reason. 12. If female, the participant is of childbearing potential (eg, not sterilized). 13. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period. 14. If male, the participant intends to donate sperm during the course of this study or for 90 days thereafter. 15. Has participated in another clinical study and/or has received any investigational compound within 30 days prior to Screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | Day 1 up to Week 100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Regression or no Progression in Tanner Staging at Week 96 | Week 96 | Tanner assessment score was used to document the stage of development of puberty through the assessment of secondary sexual characteristics. Female pubertal development staged by pubic hair development and breast size; male pubertal development staged by size of the genitalia and development of pubic hair. Rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size). Regression or no progression was defined as negative change (improvement) or no change in Tanner score at Week 96 compared to baseline. |
Countries
China
Participant flow
Recruitment details
Participants took part in the study at 11 investigative sites in China from 07 August 2015 to 23 November 2018.
Pre-assignment details
Chinese participants with central precocious puberty (CPP) were enrolled to receive leuprorelin as per body weight.
Participants by arm
| Arm | Count |
|---|---|
| Leuprorelin Participants with body weight greater than or equal to (\>=) 20 kilogram (kg) received the recommended initial dose of leuprorelin 3.75 milligram (mg), injection, subcutaneously, once every 4 weeks for 96 weeks. Participants with body weight less than (\<) 20 kg received leuprorelin 1.88 mg, injection, subcutaneously, once every 4 weeks for 96 weeks. The dose was adjusted based on participant's condition and investigator's judgment in alignment with the product label in China. | 307 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 6 |
| Overall Study | Pretreatment Event (PTE) or AE | 3 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Leuprorelin |
|---|---|
| Age at date of diagnosis of CPP | 7.95 years STANDARD_DEVIATION 0.982 |
| Age, Continuous | 8.03 years STANDARD_DEVIATION 0.935 |
| Bone Age/Chronological Age | 1.26 ratio STANDARD_DEVIATION 0.139 |
| Bone Mineral Density | 0.4791 gram per square centimeter (g/cm^2) STANDARD_DEVIATION 0.2142 |
| Height | 133.68 centimeter (cm) STANDARD_DEVIATION 7.108 |
| Peak Stimulated Follicle-stimulating Hormone (FSH) | 14.992 U/L STANDARD_DEVIATION 6.7343 |
| Peak Stimulated Luteinizing Hormone (LH) | 20.664 unit per liter (U/L) STANDARD_DEVIATION 18.1982 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 307 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment China | 307 Participants |
| Sex: Female, Male Female | 305 Participants |
| Sex: Female, Male Male | 2 Participants |
| Tanner Staging Evaluation: Breast (Female) and Genitals (Male) Stage 1 | 3 Participants |
| Tanner Staging Evaluation: Breast (Female) and Genitals (Male) Stage 2 | 172 Participants |
| Tanner Staging Evaluation: Breast (Female) and Genitals (Male) Stage 3 | 120 Participants |
| Tanner Staging Evaluation: Breast (Female) and Genitals (Male) Stage 4 | 11 Participants |
| Tanner Staging Evaluation: Breast (Female) and Genitals (Male) Stage 5 | 1 Participants |
| Tanner Staging Evaluation: Pubic Hair Stage 1 | 266 Participants |
| Tanner Staging Evaluation: Pubic Hair Stage 2 | 31 Participants |
| Tanner Staging Evaluation: Pubic Hair Stage 3 | 9 Participants |
| Tanner Staging Evaluation: Pubic Hair Stage 4 | 0 Participants |
| Tanner Staging Evaluation: Pubic Hair Stage 5 | 1 Participants |
| Weight | 30.44 kilogram (kg) STANDARD_DEVIATION 5.346 |
| Weight Categories <20 kg | 5 Participants |
| Weight Categories >=20 kg | 302 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 307 |
| other Total, other adverse events | 189 / 307 |
| serious Total, serious adverse events | 12 / 307 |
Outcome results
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time frame: Day 1 up to Week 100
Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Leuprorelin | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 252 participants |
Secondary
Percentage of Participants With Regression or no Progression in Tanner Staging at Week 96
Tanner assessment score was used to document the stage of development of puberty through the assessment of secondary sexual characteristics. Female pubertal development staged by pubic hair development and breast size; male pubertal development staged by size of the genitalia and development of pubic hair. Rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size). Regression or no progression was defined as negative change (improvement) or no change in Tanner score at Week 96 compared to baseline.
Time frame: Week 96
Population: The full analysis set included all enrolled participants who received at least 1 dose of study drug. The full analysis set where data at specified time points was available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Leuprorelin | Percentage of Participants With Regression or no Progression in Tanner Staging at Week 96 | Female | 83.5 percentage of participants |
| Leuprorelin | Percentage of Participants With Regression or no Progression in Tanner Staging at Week 96 | Male | 0 percentage of participants |