A Study to Assess the Efficacy, Safety and Pharmacokinetics of Debio 4326 in Pediatric Participants Receiving Gonadotropin-Releasing Hormone Agonist Therapy for Central Precocious Puberty

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of Debio 4326 in suppressing serum luteinizing hormone (LH) to prepubertal levels 52 weeks after the first Debio 4326 injection in pediatric participants receiving gonadotropin-releasing hormone agonist (GnRHa) therapy for central precocious puberty (CPP).

Official Title
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An Open-Label, Single-Arm, Multi-Center, Phase 3 Study on the Efficacy, Safety, and Pharmacokinetics of Debio 4326, a Triptorelin 12-month Formulation, in Pediatric Participants Who Are Receiving Gonadotropin-Releasing Hormone Agonist Therapy for Central Precocious Puberty

Conditions
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Central Precocious Puberty

Intervention / Treatment
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* Drug: Debio 4326


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of central precocious puberty and currently receiving GnRHa therapy. Onset of development of sex characteristics (i.e., breast development in girls or testicular enlargement in boys according to the Tanner method) before the age of 8 years in girls and 9 years in boys. Initially, only participants aged (a) 5 to 8 years inclusive (i.e., <9 years) are eligible. The Sponsor will determine based on the recommendation of the DMC following the interim analysis whether participants aged 2 to 4 years inclusive (i.e., <5 years) and/or 9 to 10 years inclusive (i.e., <11 years) may be recruited. Participant to receive at least 1 year of GnRHa therapy from study treatment start. Start of initial GnRHa therapy no later than 18 months after onset of the first signs of Central precocious puberty (CPP). Difference between bone age (Greulich and Pyle method) and chronological age of ≥1 year based on historical values at the initiation of the GnRHa therapy. Pubertal-type LH response following a GnRH/GnRHa stimulation test, or random non-stimulated serum (if considered local standard of care), based on historical values prior to the initiation of GnRHa therapy. Clinical evidence of puberty, defined as Tanner Staging ≥2 for breast development for girls and testicular volume ≥4 mL (cc) for boys, prior to the initiation of GnRHa therapy. Exclusion Criteria: Gonadotropin-independent (peripheral) precocious puberty: gonadotropin-independent gonadal or adrenal sex steroid secretion. Non-progressing, isolated premature thelarche prior to the initial GnRHa therapy. Presence of an unstable intracranial tumor or an intracranial tumor potentially requiring neurosurgery or cerebral irradiation. Participants with hamartomas not requiring surgery are eligible. Any other condition or chronic illness possibly interfering with growth (e.g., renal failure, diabetes, moderate to severe scoliosis, previously treated intracranial tumor). Other than GnRHa therapy, any ongoing treatment with a potential effect on serum levels of gonadotropins or sex steroids, or possibly interfering with growth. Prior or current therapy with medroxyprogesterone acetate, growth hormone, or Insulin-like growth factor-1 (IGF-1). Diagnosis of short stature, i.e., more than 2.25 standard deviations (SD) below the mean height-for-age. Known history of seizures, epilepsy, and/or central nervous system disorders that may have been associated with seizures or convulsions. Prior (within 2 months of study treatment start) or current use of medications that have been associated with seizures or convulsions. Use of anticoagulants (heparin or coumarin derivatives).

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Debio 4326<br>Participants will receive the first injection of Debio 4326, on Day 1 in Part A followed by a second injection 52 weeks later in Part B of the study. | Drug: Debio 4326<br>* Administered as an intramuscular (IM) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of Participants With Suppression of Gonadotropin-Releasing Hormone Agonist Stimulated Serum Luteinizing Hormone (LH) to Less Than or Equal to (≤)5 International Units per Liter (IU/L) |  | Week 52 in Part A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Adverse Events of Special Interest (AESIs) and Serious TEAEs |  | Up to 104 weeks | 
| Parts A and B: Number of Participants with Clinically Significant Abnormalities in Vital Signs |  | Up to 104 weeks | 
| Parts A and B: Change From Baseline in Body Weight |  | Up to 104 weeks | 
| Parts A and B: Change From Baseline in Body Mass Index |  | Up to 104 weeks | 
| Parts A and B: Number of Participants With Erythema, Swelling, and Induration at the Injection Site Immediately and 2 Hours After Each Debio 4326 Injection as per Investigator's Assessment |  | Up to 2 hours post-dose on Day 1 in both Parts A and B | 
| Parts A and B: Number of Participants With Pain at the Injection Site Immediately and 2 Hours After Each Debio 4326 Injection as per Participant's Assessment Using the Wong-Baker FACES® Pain Rating Scale |  | Up to 2 hours post-dose on Day 1 in both Parts A and B | 
| Parts A and B: Percentage of Participants Who do not Exhibit the Acute-on-Chronic (AOC) Phenomenon |  | Up to 48 hours post-dose on Day 3 in both Parts A and B | 
| Parts A and B: Percentage of Participants With Stimulated Serum LH ≤5 IU/L |  | Up to Week 52 in both Parts A and B | 
| Parts A and B: Percentage of Participants With Stimulated Serum LH ≤4 IU/L |  | Up to Week 52 in both Parts A and B | 
| Parts A and B: Number of Participants With Change in Hormone Levels | The following hormones will be assessed: basal LH, follicle-stimulating hormone (FSH), estradiol, testosterone, GnRHa-stimulated LH, and GnRHa-stimulated FSH. | Up to Week 52 in both Parts A and B | 
| Parts A and B: Percentage of Girls With Prepubertal Serum Estradiol <20 pg/mL (<73 pmol/L) |  | Up to Week 52 in both Parts A and B | 
| Parts A and B: Percentage of Boys With Testosterone <30 ng/dL (<1.0 nmol/L) |  | Up to Week 52 in both Parts A and B | 
| Parts A and B: Change From Baseline in Height-for-Age Z Score |  | Baseline, up to Week 52 in both Parts A and B | 
| Parts A and B: Number of Participants With Change From Baseline in Growth Velocity |  | Up to Week 52 in both Parts A and B | 
| Percentage of Participants in Whom the Bone Age/Chronological Age Did Not Rise Relative to Baseline |  | Part A: Baseline, up to Week 52 in both Parts A and B | 
| Parts A and B: Percentage of Participants Who Achieve Stabilization of Sexual Maturation (Regression or Stabilization Compared to Baseline by Tanner Staging) |  | Baseline, Weeks 26 and 52 in both Parts A and B | 
| Parts A and B: Percentage of Girls With Regression of Uterine Length (Using Transabdominal Ultrasound) |  | Weeks 26 and 52 in both Parts A and B | 
| Parts A and B: Percentage of Boys With Absence of Progression of Testis Volumes (Clinical Assessment With Orchidometer) |  | Weeks 26 and 52 in both Parts A and B | 
| Parts A and B: Plasma Concentration of Triptorelin | The pharmacokinetics (PK) of triptorelin will be evaluated in plasma. | Pre-dose and at multiple timepoints post-dose up to 52 weeks in Part A and 64 weeks in Part B | 
| Percentage of Participants With Stimulated Serum LH Levels Greater Than (>)5 IU/L at Post Treatment Visit (PTV) | This outcome measure will be analyzed only in participants who stop all hormonal treatment with any GnRHa at end of treatment (EOT). | 64 weeks after the last Debio 4326 injection in Part A or B | 
| Part B: Accumulation Ratio on Maximum Serum Concentration (RacCmax) |  | At multiple timepoints post-dose up to 48 hours (Day 2) in Part B | 
| Part B: Accumulation Ratio on Serum Concentration at the End of the Dosing Interval (RacCtrough) |  | At multiple timepoints post-dose up to 52 weeks in Part B |