Interventional Study of Infigratinib in Children < 3 Years Old With Achondroplasia (ACH)

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Infigratinib 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.
• Препарат Infigratinib 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.
• Препарат Infigratinib 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.
• Препарат Infigratinib is provided as sprinkle capsules for daily oral administration
  * The dose of infigratinib will be the dose confirmed in the Phase 2 portion and used in the Phase 2b 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 for the first year and every 6 months thereafter.

Первичные конечные точки

• 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) [Срок оценки: 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). [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 3 years and 6 months]

Вторичные конечные точки (12)

• Phase 2: Evaluate the safety of oral daily doses of infigratinib (by assessing AEs and SAEs) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 52 weeks]
• Phase 2: Milestone Development of motor skills (assessed with development milestone charts) [Срок оценки: 52 weeks]
• Phase 2: Milestone Development of language skills (assessed with development milestone charts) [Срок оценки: 52 weeks]
• Phase 2: Milestone Development of personal-social skills (assessed with development milestone charts) [Срок оценки: 52 weeks]
• Phase 2: Skull and brain morphology (as assessed using MRI) [Срок оценки: 52 weeks]
• Phase 2: Age at closure of cranial structures (as assessed by physical examination) [Срок оценки: 52 weeks]
• Phase 2: Age at closure of fontanelles (as assessed by physical examination) [Срок оценки: 52 weeks]
• Phase 2: Incidence of surgical interventions (i.e., cervical decompression, adenotonsillectomy etc) [Срок оценки: 52 weeks]
• Phase 2: Incidence and severity of sleep apnea (as assessed by polysomnography) [Срок оценки: 52 weeks]

Критерии участия

Критерии включения

• 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).

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 3 центра

• UCSF Benioff Children's Hospital — Oakland
• Johns Hopkins University — Baltimore
• University of Wisconsin Madison - Waisman Center Bone Dysplasia Clinic — Madison

Великобритания · 3 центра

• NHS Greater Glasgow and Clyde — Glasgow
• Manchester University NHS Foundation Trust — Manchester
• Sheffield Children's NHS Foundation Trust — Sheffield

Канада · 2 центра

• Children's Hospital of Eastern Ontario Research Institute — Ottawa
• Université de Montréal - Centre Hospitalier Universitaire Sainte-Justine — Montreal

Австралия · 1 центр

• Murdoch Children's Research Institute — Parkville

Норвегия · 1 центр

• Paediatric Clinical Research Unit at Oslo University Hospital — Oslo

Сингапур · 1 центр

• KK Women's and Children's Hospital — Singapore

Испания · 1 центр

• Unidad de Cirugía Artroscópica (UCA) — Vitoria-Gasteiz

Идентификаторы

NCT: NCT07169279 · QBGJ398-204

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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