Phase 2b, Randomized, Double-Blind, Placebo-Controlled Clinical Trial, Preceded by a Single Ascending Dose Portion and a Phase 2 Open-Label Portion, to Evaluate the Safety and Efficacy of Oral Infigratinib in Infants and Young Children With Achondroplasia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 77
- 试验地点
- 12
- 主要终点
- 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)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 0 Years 至 32 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
Phase 2B Cohort 1 infigratinib (2 to less than 3 years old)
Randomized Safety and Efficacy Portion
干预措施: Infigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration (Drug)
SAD Cohort 1 infigratinib (2 to less than 3 years old)
Single Ascending Dose Escalation and PK Portion
干预措施: Infigratinib is provided as a single dose of minitablets for oral administration (Drug)
Phase 2B Cohort 3 Placebo (0 to less than 6 months old)
Randomized Safety and Efficacy study
干预措施: Infigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2B Cohort 2 infigratinib (6 months to less than 2 years old)
Randomized Safety and Efficacy Portion
干预措施: Infigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration (Drug)
Open- label Extension infigratinib (0 months to 3 years [+6 months old])
Open-label extension portion continuing to assess safety and efficacy in children until they reach 3 years old (+6 months)
干预措施: Infigratinib is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2B Cohort 3 infigratinib (0 to less than 6 months old)
Randomized Safety and Efficacy Portion
干预措施: Infigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2 Cohort 1 infigratinib (2 to less than 3 years old)
Open-label Safety and PK Portion
干预措施: Infigratinib is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2 Cohort 3 infigratinib (6 months to less than 1 year old)
Open-label Safety and PK Portion
干预措施: Infigratinib is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2 Cohort 4 infigratinib (0 to less than 6 months)
Open-label Safety and PK Portion
干预措施: Infigratinib is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2B Cohort 1 Placebo (2 to less than 3 years old)
Randomized Safety and Efficacy study
干预措施: Infigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration (Drug)
Phase 2 Cohort 2 infigratinib (1 to less than 2 years old)
Open-label Safety and PK Portion
干预措施: Infigratinib is provided as sprinkle capsules for daily oral administration (Drug)
SAD Cohort 2 infigratinib (1 to less than 2 years old)
Single Ascending Dose Escalation and PK Portion
干预措施: Infigratinib is provided as a single dose of minitablets for oral administration (Drug)
SAD Cohort 3 infigratinib (6 months to less than 1 year old)
Single Ascending Dose Escalation and PK Portion
干预措施: Infigratinib is provided as a single dose of minitablets for oral administration (Drug)
SAD Cohort 4 infigratinib (0 to less than 6 months old)
Single Ascending Dose Escalation and PK Portion
干预措施: Infigratinib is provided as a single dose of minitablets for oral administration (Drug)
Phase 2B Cohort 2 placebo (6 months to less than 2 years old)
Randomized Safety and Efficacy study
干预措施: Infigratinib or placebo comparator is provided as sprinkle capsules for daily oral administration (Drug)
结局指标
主要结局
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)
时间窗: 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).
时间窗: 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)
时间窗: 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)
时间窗: 3 years and 6 months
次要结局
- 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 growth (by assessing change from BL in Weight-for-Length Z-score at Week 52)(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 2b: Bone morphology (as assessed using x-rays)(52 weeks)
- 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: 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 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: 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)
- 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))