Efficacy and Safety Evaluation of Infigratinib in Pediatric Patients with Hypochondroplasia: A Phase 2/3 Multicenter, Open-Label and Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** and **safety** of infigratinib in pediatric participants with **hypochondroplasia** (HCH) who have short stature. In Phase 2, the study aims to obtain preliminary evidence of the efficacy of infigratinib in children aged 5 to 11 years and assess its safety and tolerability. In Phase 3, the focus is on evaluating the efficacy of infigratinib in a broader age range of 3 to less than 18 years, targeting those with short stature and potential for growth. This is clinically relevant as it addresses the need for effective treatment options in managing growth deficiencies associated with HCH.

Secondary objectives include:

• Phase 3: Evaluating changes in other key indicators of growth and body proportions.
• Phase 2: Assessing changes in cognitive functions.
• Phase 2: Evaluating changes in other indicators of growth and body proportions.
• Phase 2: Evaluating the pharmacokinetic (PK) profile of infigratinib and its active metabolites in children with HCH after oral administration.
• Phase 2: Evaluating CXM, an indicator of bone growth.

The clinical trial involves a total of **107 participants** diagnosed with **hypochondroplasia**, a condition characterized by disproportionate short stature. The study population includes both male and female pediatric participants, specifically those aged 3 to less than 18 years, with a focus on those aged 5 to 11 years for the Phase 2 portion. Participants were selected based on their completion of at least 26 weeks in a prior observational study and their ability to comply with study procedures. The trial includes individuals who are ambulatory and able to stand without assistance, and who can swallow oral medication. Participants are required to have a negative pregnancy test if applicable and must agree to use effective contraception if sexually active. The study population is considered vulnerable, given the pediatric nature of the participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **infigratinib** in pediatric participants with **hypochondroplasia**. This study is structured as a Phase 2/3 trial, beginning with an open-label phase followed by a double-blind, randomized, placebo-controlled phase. The trial aims to gather preliminary evidence of efficacy in children aged 5 to 11 years during Phase 2 and to further assess efficacy in participants aged 3 to less than 18 years during Phase 3. The trial is expected to conclude by December 31, 2028, with recruitment starting on May 30, 2025.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of **hypochondroplasia**, and ability to swallow oral medication. The trial will include regular follow-up visits to monitor safety and efficacy, with the primary endpoint being the change in height velocity from baseline. Secondary endpoints include changes in height Z-score and body segment ratio. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.

The expected duration of participant involvement is up to 104 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. Participants will be randomly assigned to receive either **infigratinib** in capsule form or a placebo, both administered orally. The study will ensure that all participants and their guardians provide informed consent and agree to comply with the study's requirements, including the use of contraception for sexually active participants. The trial's design and procedures are intended to rigorously evaluate the potential benefits and risks of **infigratinib** in treating **hypochondroplasia** in a pediatric population.

The clinical trial involves the administration of **Infigratinib**, a chemical compound with the active substance name **Infigratinib**. It is provided in the form of a **capsule** and is intended for **oral** administration. The dosage is specified as 0.25 mg/kg, with a maximum daily dose of 0.25 mg/kg. The treatment period is set for a maximum of 104 weeks. The formulation is suitable for pediatric use, and the product is manufactured by QED Therapeutics. The chemical structure of Infigratinib is also known by its synonyms, BGJ398 and BBP-831.

The study also includes a **placebo** as a comparator treatment. The placebo is presented in the form of a **tablet** and is also administered **orally**. The placebo is chemically inert and is used to evaluate the efficacy and safety of Infigratinib by providing a control group for comparison. The dosage and treatment period for the placebo are identical to those of Infigratinib, with a maximum daily dose of 0.25 mg/kg and a treatment duration of up to 104 weeks.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the efficacy and safety of Infigratinib in children with hypochondroplasia, with the placebo serving as a control to validate the results obtained from the experimental treatment group.

The efficacy of **infigratinib** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change from baseline in height velocity (HV), annualized to centimeters per year, during Phase 2, and the change from baseline to Week 52 in annualized height velocity (AHV) compared to placebo during Phase 3. Secondary endpoints will evaluate the change from baseline to Week 52 in height Z-score, in relation to hypochondroplasia (HCH) tables, and the change in the upper to lower body segment ratio, both compared to placebo.

Measurements for these endpoints will be collected at specified timepoints, including baseline and Week 52, using standardized and validated methods. The trial will involve pediatric participants aged 3 to less than 18 years with HCH who have short stature and potential for growth. The study will be conducted in a double-blind, randomized, placebo-controlled manner to ensure the reliability and validity of the efficacy assessments. The data collected will be analyzed to determine the efficacy of infigratinib in improving growth parameters in the target population.