Achondroplasia
Conditions
Keywords
skeletal dysplasia, endochondral ossification, achondroplasia, ACH, Shortened proximal limbs, fibroblast growth factor receptor 3, FGFR3, disproportionate short stature, quality of life, dwarfism, bone diseases, musculoskeletal diseases, osteochondrodysplasia, functional abilities, annualized growth velocity, annualized height velocity, growth, growth disorder, congenital, AHV, AGV, infant and toddler, endochondral bone formation
Brief summary
This is a Phase 2, multicenter, randomized, placebo-controlled study to evaluate the safety and efficacy of infigratinib in participants \< 3 years old with ACH. The purposes of the SAD and Phase 2 portions are to identify and confirm the dose of infigratinib to be used in the Phase 2b portion, based on safety and PK. The purpose of the Phase 2b, placebo-controlled portion is to evaluate the safety and efficacy of infigratinib in children \< 3 years old with ACH at the selected dose.
Detailed description
PROPEL Infant & Toddler (I&T) is a Phase 2, multicenter, randomized, placebo-controlled study that comprises 4 portions: the single ascending dose (SAD) portion (open-label), the Phase 2 portion (open-label), the Phase 2b portion (placebo-controlled), and an Extension Portion (open-label). The study will evaluate children with ACH \< 3 years old being administered oral infigratinib.
Interventions
DRUGInfigratinib is provided as a single dose of minitablets for oral administration
* The initial cohort dose of infigratinib will begin at the protocol-specified starting dose, with subsequent cohort escalation based on protocol specific criteria. * The dose and number of minitablets will be calculated based on individual participant age and weight.
DRUGInfigratinib is provided as sprinkle capsules for daily oral administration
* The cohort dose of infigratinib will be the dose identified in the Single Ascending Dose portion for the age group. * The dose and number of sprinkle capsules/day will be calculated based on individual participant age and weight. Doses will be adjusted based on age and weight changes approximately every 3 months.
DRUGInfigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration
* The cohort dose of infigratinib or placebo will be the dose confirmed in the Phase 2 portion for the age group. * The dose and number of sprinkle capsules/day will be calculated based on individual participant age and weight. Doses will be adjusted based on age and weight changes approximately every 3 months.
Sponsors
QED Therapeutics, a BridgeBio company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
This study comprises 4 portions: a Single Ascending Dose (SAD) portion and open-label Phase 2 portion to evaluate safety and PK and select a dose level for Phase 2b; a placebo-controlled Phase 2b portion, to assess safety and efficacy at the selected dose level; and an open-label extension portion to evaluate safety and efficacy in children \< 3 years old who have completed the Phase 2 or Phase 2b portion of the study.
Eligibility
Sex/Gender
ALL
Age
0 Years to 32 Months
Healthy volunteers
No
Inclusion criteria
* Diagnosis of ACH confirmed by genetic testing. If prospective participants had prior genetic testing, the diagnosis must be confirmed by a report from a certified laboratory, documenting the specific mutation. * Age 0 to 32 months (2 years and 8 months) at screening. * Signed informed consent, which must be obtained from each participant's parent(s) or legal guardian. * Parent(s)/Guardian(s) willing and able to attend all study visits and comply with all study requirements. * Parent(s)/Guardian(s) willing and able to comply with the routine care of the study participants according to local guidance for the management of infants and young children with ACH. * Able to swallow age-appropriate oral medication. * In participants \<1 year old, be compliant with recommended vitamin D supplementation of 5 10 μg/day or higher (or as recommended by country specific guidelines).
Exclusion criteria
* Participants who have hypochondroplasia or diagnosis of genetic condition other than ACH, or any clinical condition that can affect growth. * Gestational age at birth \<37 weeks and/or birth weight \<2500 grams. * Gastroesophageal reflux disease requiring prolonged treatment (\>1 week) with prohibited medications. * Evidence of cervicomedullary compression, as defined by an Achondroplasia Foramen Magnum Score (AFMS) 4, symptomatic or asymptomatic, diagnosed during MRI done at screening or a previous MRI done at any time if the participant had not undergone decompression surgery. * History of fracture of a long bone or spine within 6 months prior to screening. * Any other significant concurrent disease or condition that, in the view of the investigator and/or sponsor, would confound assessment of efficacy or safety of infigratinib and/or would require treatment with a prohibited medication (per protocol), and/or would place the participant at high risk for poor treatment compliance or for failure to complete the study. * Having received or planning to receive treatment with any other investigational or approved product for the treatment of ACH or short stature, including (but not limited to) r-hGH, IGF-1, CNP analog, FGF ligand trap, or treatment targeting FGFR inhibition at any time. * Regular long-term (\>3 weeks; more than twice/year) treatment with supraphysiologic doses of glucocorticoid therapy (ie, \>15 mg/m2/day of hydrocortisone or equivalent) or treatment with glucocorticoids at anti-inflammatory doses (for over 3 weeks within 6 months of the screening visit. NOTE: Low-dose topical, inhaled, or intranasal corticosteroids are acceptable. * Significant abnormality in screening laboratory results, * Allergy or hypersensitivity to any components of the study drug.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Single Ascending Dose Portion: Identify the dose of infigratinib to be used in each age cohort of the Phase 2 potion of the study (by assessing safety and PK of infigratinib and its active metabolites) | 2 weeks |
| Phase 2 Portion: Confirm the doses to be used in each age cohort in the Phase 2b portion of the study (by assessing safety and PK of infigratinib and its active metabolites). | 52 weeks |
| Phase 2b Portion: Evaluate the safety and efficacy of infigratinib in infants and children < 3 years old with ACH (by assessing AE's & SAE's) | 52 weeks |
| Extension Portion: Evaluate the safety and efficacy of infigratinib in participants who completed the Phase 2 or Phase 2b portion of the study until they have reached 3 years old (+6 months) (by assessing AE's and SAE's) | 3 years and 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Phase 2: Evaluate the safety of oral daily doses of infigratinib (by assessing AEs and SAEs) | 52 weeks |
| Phase 2: Evaluate changes in indicators of growth (by assessing change from BL in body length z-score at Week 52 in relation to ACH tables) | 52 weeks |
| Phase 2: Evaluate changes in indicators of body proportions (by assessing change from BL to Week 52 in upper-to-lower body segment ratio and head circumference/body length ratio) | 52 weeks |
| Phase 2: Change from BL in Health-related Quality of Life (HRQoL) (as assessed by Infant and Toddler Quality of Life Inventory [ITQoL] tool) | 52 weeks |
| Phase 2: Milestone Development of motor skills (assessed with development milestone charts) | 52 weeks |
| Phase 2: Milestone Development of language skills (assessed with development milestone charts) | 52 weeks |
| Phase 2: Milestone Development of personal-social skills (assessed with development milestone charts) | 52 weeks |
| Phase 2: Skull and brain morphology (as assessed using MRI) | 52 weeks |
| Phase 2: Age at closure of cranial structures (as assessed by physical examination) | 52 weeks |
| Phase 2: Age at closure of fontanelles (as assessed by physical examination) | 52 weeks |
| Phase 2: Incidence of surgical interventions (i.e., cervical decompression, adenotonsillectomy etc) | 52 weeks |
| Phase 2: Incidence and severity of sleep apnea (as assessed by polysomnography) | 52 weeks |
| Phase 2: Bone morphology (as assessed using x-rays) | 52 weeks |
| Phase 2b: Evaluate the pharmacokinetic (PK) profile of infigratinib and its metabolites (by assessing the PK of infigratinib and its active metabolites) | 52 weeks |
| Phase 2b: Change from BL in Health-related Quality of Life (HRQoL) (as assessed by Infant and Toddler Quality of Life Inventory [ITQoL] tool) | 52 weeks |
| Phase 2b: Evaluate the safety of oral daily doses of infigratinib (by assessing AEs and SAEs) | 52 weeks |
| Phase 2b: Evaluate changes in indicators of growth (by assessing change from BL in body length z-score at Week 52 in relation to ACH tables) | 52 weeks |
| Phase 2b: Evaluate changes in indicators of growth (by assessing AHV at Week 52 in relation to ACH tables) | 52 weeks |
| Phase 2b: Evaluate changes in indicators of growth (by assessing AHV Z-score at Week 52 in relation to ACH tables) | 52 weeks |
| Phase 2b: Evaluate changes in indicators of body proportions (by assessing change from BL to Week 52 in upper-to-lower body segment ratio and head circumference/body length ratio) | 52 weeks |
| Phase 2b: Evaluate changes in indicators of growth (by assessing change from BL in Weight-for-Length Z-score at Week 52) | 52 weeks |
| Phase 2b: Milestone Development of motor skills (assessed with development milestone charts) | 52 weeks |
| Phase 2b: Milestone development of language skills (assessed with development milestone charts) | 52 weeks |
| Phase 2b: Milestone development of personal-social skills (assessed with development milestone charts) | 52 weeks |
| Phase 2b: Skull and brain morphology (as assessed using MRI) | 52 weeks |
| Phase 2b: Age at closure of cranial structures (as assessed by physical examination) | 52 weeks |
| Phase 2b: Age at closure of fontanelles (as assessed by physical examination) | 52 weeks |
| Phase 2b: Incidence of surgical interventions (i.e., cervical decompression, adenotonsillectomy etc) | 52 weeks |
| Phase 2b: Incidence and severity of sleep apnea (as assessed by polysomnography) | 52 weeks |
| Phase 2b: Bone morphology (as assessed using x-rays) | 52 weeks |
| Extension Phase: Evaluate the safety of oral daily doses of infigratinib (by assessing AEs and SAEs) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Change from BL in body length Z-score | Until they have reached 3 years old (+6 months) |
| Extension Phase: Change from BL in upper to lower body segment ratio (cm) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Change from BL in head circumference body length ratio | Until they have reached 3 years old (+6 months) |
| Extension Phase: Milestone development of social/emotional skills (assessed with development milestone charts) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Milestone development of language communication skills (assessed with development milestone charts) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Milestone development of cognitive skills (assessed with development milestone charts) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Milestone development of movement/physical development skills (assessed with development milestone charts) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Age at closure of cranial structures (as assessed by physical examination) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Age at closure of fontanelles (as assessed by physical examination) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Incidence of surgical interventions (i.e., cervical decompression, adenotonsillectomy etc) | Until they have reached 3 years old (+6 months) |
| Extension Phase: Bone morphology (as assessed using x-rays) | Until they have reached 3 years old (+6 months) |
Countries
Australia, Canada, Norway, Singapore, Spain, United Kingdom, United States
Contacts
CONTACTQED Therapeutics Inc.
Outcome results
None listed