| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Achondroplasia in Children |
|
| E.1.1.1 | Medical condition in easily understood language |
| Disproportionate short stature with rhizomelia (shortened proximal limbs). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000452 |
| E.1.2 | Term | Achondroplasia |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of long-term administration of daily doses of oral infigratinib in subjects with ACH.
To evaluate the efficacy of long-term administration of daily doses of oral infigratinib in subjects with ACH as assessed as changes over time in standing height Z-score. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate changes in other indicators of growth and development in subjects with ACH receiving long-term treatment with oral infigratinib, such as:
○ Change over time in height velocity (HV) Z-score in relation to ACH and non-ACH growth charts.
○ Changes over time in other anthropometric parameters after administration of oral infigratinib.
○ Age at puberty onset and progression of pubertal development.
To evaluate changes over time in ACH disease burden with long-term administration of oral doses of infigratinib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Rollover Subjects
1. Pediatric subjects with ACH who have completed study activities in a previous QED-sponsored interventional study with infigratinib.
2. Subjects and parent(s) or legally authorized representatives (LARs) are willing and able to comply with study visits and study procedures.
3. In girls ≥10 years of age or girls of any age who have experienced menarche, having a negative pregnancy test.
4. If sexually active, subject must be willing to use a highly effective method of contraception while taking study drug and for 1 month after the last dose of study drug.
5. The PI, or a person designated by the PI, will obtain written informed consent from each subject’s Legally Authorised Representative and the subject’s assent, when applicable, before any study-specific activity is performed.
Inclusion Criteria for Treatment Naïve Subjects
1. Subject must be 3 to <18 years of age (inclusive) at screening and have growth potential (as defined by HV ≥1.5 cm/year, Tanner stage ≤4 of pubertal development, and bone age of ≤13 years in females and ≤15 years in males.
2. Subjects and parent(s) or LARs are willing and able to comply with study visits and study procedures.
3. Subjects are able to swallow oral medication.
4. Subjects who have a diagnosis of ACH, documented clinically and confirmed by genetic testing.
5. Subjects have at least a 6-month period of growth assessment in the PROPEL study (Protocol QBGJ398-001) before study entry.
6. In girls ≥10 years of age or girls of any age who have experienced menarche, having a negative pregnancy test.
7. If sexually active, subject must be willing to use a highly effective method of contraception while taking study drug and for 1 month after the last dose of study drug.
8. The PI, or a person designated by the PI, will obtain written informed consent from each subject’s Legally Authorised Representative and the subject’s assent, when applicable, before any study-specific activity is performed. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria for Rollover Subjects
1. Subject has concurrent circumstance, disease, or condition that, in the view of the PI and/or sponsor, would interfere with study participation or safety evaluations.
2. Subjects who developed a medical condition that will require the initiation of treatment with a prohibited medication.
3. Subjects that prematurely discontinued a prior QED-sponsored interventional study with infigratinib.
4. Subjects that have reached final height or near final height (as defined by HV <1.5cm/year and Tanner stage ≥4).
Exclusion Criteria for Treatment Naïve Subjects
Medical Conditions
1. Subjects who have hypochondroplasia or short stature condition other than ACH (eg, trisomy 21, pseudoachondroplasia, psychosocial short stature).
2. Subjects who have significant concurrent disease or condition that, in the view of the PI and/or sponsor, would represent an increased risk to the subject or would interfere with study participation or safety evaluations, including but not limited to cardiac or vascular disease; hyperthyroidism; abnormal thyroid levels or recently diagnosed hypothyroidism that has not been stable on therapy for at least 3 months; uncontrolled diabetes mellitus (hemoglobin A1c [HbA1c] >9%); adrenal insufficiency; autoimmune inflammatory disease; inflammatory bowel disease; diagnosis of severe sleep apnea that will require surgery or the initiation of continuous positive airway pressure (CPAP) machine use. Subjects with previously diagnosed obstructive sleep apnea (OSA) who are already using a CPAP machine at Screening and whose OSA is stable are eligible provided they continue to be compliant with CPAP use.
3. Subjects who have a history and/or current evidence of extensive ectopic tissue calcification.
4. Subjects who have a history of malignancy.
5. Subjects who are currently receiving treatment with agents that are known strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 or medications that alter the pH of the gastrointestinal tract, including antacids, H2 antagonists (eg, ranitidine), and proton-pump inhibitors (eg, omeprazole); or enzyme-inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone.
6. Subjects who have current evidence of endocrine alterations of calcium/phosphorus homeostasis (Vitamin D supplementation or Vitamin D treatment for Vitamin D insufficiency or deficiency with normal calcium and phosphorus levels is allowed).
7. Subjects who have received 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).
8. Subjects who have received treatment with growth hormone, insulin-like growth factor 1 (IGF 1), anabolic steroids or any investigational or approved drug for the treatment of ACH in the previous 6 months. Subjects that received the last dose of any of these growth-promoting agents ≥6 months before screening are eligible.
9. Subjects who have significant abnormality in screening laboratory results, including but not limited to the following:
a. Hemoglobin <10.0 g/dL.
b. Total bilirubin >1.5× upper limit of normal (ULN).
c. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) >2× ULN.
d. Glomerular filtration rate <60 mL/min/1.73m2 calculated using the Schwartz formula.
Other Exclusions
10. Subjects who have an allergy to any components of the study drug.
11. Subjects who have had a fracture within 6 months of screening.
12. Subjects who are eligible to enroll in any other ongoing QED-sponsored interventional study with infigratinib. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety evaluations including incidence, type, severity, and causality of adverse events (AEs), serious adverse events (SAEs), laboratory test results (urinalysis, chemistry, hematology), and clinically significant changes in vital signs, physical examinations, ophthalmic and dental evaluations, and imaging (x-rays, dual x-ray absorptiometry [DXA] scan).
• Changes over time in height Z-score in relation to ACH and non-ACH growth charts.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every year throughout the duration of the study. |
|
| E.5.2 | Secondary end point(s) |
• Change over time in HV Z-score in relation to ACH and non-ACH growth charts.
• Changes over time in body proportions that may include, but may not be limited to, upper to lower body segment ratio, upper arm to forearm length ratio, upper leg to lower leg length ratio, arm span to standing height ratio, and head circumference to standing height ratio.
• Change over time in weight Z-score and body mass index (BMI).
• Age of puberty onset and time to Tanner stage ≥4.
Changes over time in disease-specific complications that may include (but are not limited to):
○ Number of episodes of otitis media per year.
○ Number of episodes and/or severity of sleep apnea.
○ Changes over time in range of motion (hip, knee and elbow).
○ Changes over time in skeletal abnormalities of the lower extremities and spine (ie, tibial bowing, interpedicular narrowing, lumbar hyperlordosis, etc.).
○ Quality of life [QoL] as assessed by Pediatric Quality of Life Inventory (PedsQL [generic core scale short form, child and parent reports]). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every year throughout the duration of the study.
For the complete list please refer to the protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| United States |
| France |
| United Kingdom |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last visit of the last subject (LVLS) in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
Print
