A Study to Evaluate the Efficacy and Safety of Infigratinib in Children and Adolescents With Achondroplasia

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of infigratinib in children and adolescents with achondroplasia (ACH) who have completed at least 26 weeks of participation in the QED-sponsored study PROPEL (QBGJ398-001).

Official Title
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A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Infigratinib in Children 3 to <18 Years of Age With Achondroplasia: PROPEL 3

Conditions
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Achondroplasia

Intervention / Treatment
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* Drug: Infigratinib 0.25 mg/kg/day
* Drug: Placebo Comparator 0.25 mg/kg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria: Subject must be 3 to <18 years of age at screening with growth potential defined as annualized height velocity of >1.5 cm/year over a period of at least 6 months, pubertal Tanner stage ≤4, and bone age ≤13 years in females and ≤15 years in males. Type of Subject and Disease Characteristics Subjects who have a diagnosis of ACH that has been documented clinically and confirmed by genetic testing. Subjects must have completed at least 26 weeks in the PROPEL (QBGJ398-001) study before study entry. Subjects are able to swallow oral medication. Subjects and parent(s), legal guardian(s), or caregivers are willing and able to comply with study visits and study procedures. Subjects are ambulatory and able to stand without assistance. Sex and Contraceptive/Barrier Requirements Negative pregnancy test in girls ≥10 years of age or girls of any age who have experienced menarche. If sexually active, subjects must be willing to use a highly effective method of contraception while taking study drug and for 3 months after the last dose of study drug. Informed Consent Signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol, must be obtained for each subject from their parent(s) or legal guardian and signed informed consent/assent must be obtained from the subject (when applicable) Exclusion Criteria: Exclusion Criteria Medical Conditions Subjects who have hypochondroplasia or short stature condition other than ACH. Significant concurrent disease or condition that, in the view of the investigator and/or sponsor, would confound assessment of efficacy or safety of infigratinib. Current evidence of clinically significant corneal or retinal disorder/keratopathy confirmed by ophthalmic examination. Concurrent circumstance, disease or condition that, in the view of the investigator and/or sponsor, would interfere with study participation or safety evaluations and/or would require treatment with a prohibited medication, and/or would place the subject at high risk for poor treatment compliance or for not completing the study. History and/or current evidence of extensive ectopic tissue calcification. History of malignancy. Prior/Concomitant Therapy Having received or planning to receive treatment with any other investigational or approved product for the treatment of ACH or short stature. Regular long-term treatment (≥3 weeks) with supraphysiologic doses of glucocorticoid therapy (ie, >15 mg/m2/day of hydrocortisone or equivalence) or treatment with glucocorticoids at anti-inflammatory doses for over 3 weeks within 6 months of the screening visit (low-dose ongoing inhaled steroid for asthma is acceptable). Previous limb-lengthening surgery at any time or planned/expected to have limb-lengthening surgery or guided growth surgery during the study period. Guided growth surgery with plates removed at least 12 months prior to screening is allowed. Currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 or prolonged treatment (>1 week) with medications that alter the pH of the gastrointestinal tract or antiepileptic drugs that are CYP3A4 and/or P-gp inducers, including carbamazepine, phenytoin, phenobarbital, and primidone. Current evidence of endocrine alterations of calcium/phosphorus homeostasis. Diagnostic assessments Subjects who have significant abnormality in screening laboratory results. Other Exclusions Having had a fracture of the long bones (ie, extremities) or spine within 12 months prior to screening. Pregnant or breastfeeding at the screening visit or planning to become pregnant (self or partner) at any time during the study. Allergy or hypersensitivity to any components of the study drug.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infigratinib 0.25 mg/kg/day<br>Infigratinib at 2, 3.5, 5, 7, 10 mg | Drug: Infigratinib 0.25 mg/kg/day<br>* Daily doses of oral Infigratinib (sprinkle capsules) at 2, 3.5, 5, 7, 10 mg<br>|
| Placebo Comparator: Placebo 0.25 mg/kg/day<br>Placebo Comparator at 2, 3.5, 5, 7, 10 mg | Drug: Placebo Comparator 0.25 mg/kg/day<br>* Daily doses of oral Placebo Comparator (sprinkle capsules) at 2, 3.5, 5, 7, 10 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline (BL) in annualized height velocity (cm/year) |  | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from BL in height Z-score (in relation to ACH tables) |  | Week 52 | 
| Change from BL in upper to lower body segment ratio |  | Week 52 | 
| Change from BL in height Z-score (in relation to non-ACH tables) |  | Week 52 | 
| Annualized height velocity (cm/year) |  | Week 52 | 
| Absolute and change from baseline in upper arm to forearm length ratio (cm) |  | Week 52 | 
| Absolute and change from baseline in upper leg to lower leg length ratio (cm) |  | Week 52 | 
| Absolute and change from baseline in arm span (cm) to standing height ratio |  | Week 52 | 
| Absolute and change from baseline in head circumference (cm) to standing height ratio |  | Week 52 | 
| Absolute value and change in body mass index |  | Week 52 | 
| Incidence of adverse events |  | Week 52 | 
| Change from BL in annualized height velocity (cm/year) in children 5 years old and older, compared to placebo |  | Week 52 | 
| Change from BL in the Physical Functioning dimension of the Pediatric Quality of Life Generic Core Scale Short Form | Scale scores 0-100. Higher score=better Health-Related Quality of Life | Week 52 | 
| Change in psychomotor function assessed by age-appropriate computerized tests (Detection Test), compared to placebo | Lower score=better performance. Range values=2-6 | Week 52 | 
| Change from BL in attention assessed by age-appropriate computerized tests (Identification Test) | Lower score=better performance. Range values=2-6 | Week 52 | 
| Change from BL in visual learning assessed by age-appropriate computerized tests (One Card Learning Test) | Higher score=better performance. Range values=0-1.6 | Week 52 | 
| Change from BL in working memory assessed by age-appropriate computerized tests (One Back Test) | Lower score=better performance. Range values=2-6 | Week 52 | 
| Pharmacokinetic profile of infigratinib by assessment of maximum concentration (Cmax) |  | Week 52 | 
| Pharmacokinetic profile of infigratinib by assessment of time-to-maximum concentration (Tmax) |  | Week 52 | 
| Change from BL in collagen X marker concentration (ug/L) |  | Week 52 | 
| Evaluate the acceptability and palatability of infigratinib using a 5-point hedonic scale |  | Week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skeletal dysplasia, Endochondral ossification, Quality of life in achondroplasia, Fibroblast growth factor receptor 3, FGFR3, Endochondral bone formation, Short-limb disproportionate dwarfism, Dwarfism, Bone disease, Functionality in achondroplasia, Musculoskeletal diseases, Osteochondrodysplasia, Genetic diseases, Long-term treatment, Growth, Annualized height velocity