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    Summary
    EudraCT Number:2019-002954-21
    Sponsor's Protocol Code Number:QBGJ398-201
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-05-13
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-002954-21
    A.3Full title of the trial
    Phase 2, Open-Label, Dose-Escalation and Dose-Expansion Study of Infigratinib, an FGFR 1-3-Selective Tyrosine Kinase Inhibitor, in Children with Achondroplasia: PROPEL 2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate Infigratinib in children with Achondroplasia
    A.3.2Name or abbreviated title of the trial where available
    PROPEL 2
    A.4.1Sponsor's protocol code numberQBGJ398-201
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorQED Therapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportQED Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQED Therapeutics
    B.5.2Functional name of contact pointDaniela Rogoff
    B.5.3 Address:
    B.5.3.1Street Address8000 Marina Blvd, Suite 400
    B.5.3.2Town/ cityBrisbane
    B.5.3.3Post codeCA 94005
    B.5.3.4CountryUnited States
    B.5.4Telephone number0012144066898
    B.5.6E-mailDaniela.Rogoff@qedtx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameInfigratinib phosphate
    D.3.2Product code BGJ398 (also known as BBP-831)
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNINFIGRATINIB
    D.3.9.1CAS number 872511-34
    D.3.9.2Current sponsor codeBGJ398 (also known as BBP-831)
    D.3.9.4EV Substance CodeSUB186757
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.1 to 1.0
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Achondroplasia in Children
    E.1.1.1Medical condition in easily understood language
    disproportionate short stature with shortened limbs
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000452
    E.1.2Term Achondroplasia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Dose Escalation: Primary Objective:
    To identify a dose of oral infigratinib, based on safety and efficacy evaluations, for children with achondroplasia (ACH) to be used for further study.

    Dose Expansion: Primary Objective:
    To provide preliminary evidence of efficacy of oral infigratinib for the treatment of ACH, as assessed by change from baseline in height velocity in children with ACH.

    PK Substudy: Primary Objective:
    To evaluate the pharmacokinetic (PK) profile of infigratinib and major active metabolites in children with ACH after administration of oral infigratinib.
    E.2.2Secondary objectives of the trial
    Dose Escalation, Expansion, and PK Substudy Secondary Objectives
    • To evaluate the safety and tolerability of oral infigratinib in children with ACH.
    • To evaluate changes from baseline in anthropometric parameters after administration of oral infigratinib.
    • To evaluate the pharmacokinetic and pharmacodynamic (PK/PD) profile of infigratinib in children with ACH after administration of oral infigratinib.

    Exploratory Objective
    • To evaluate changes in ACH disease burden
    • To evaluate changes in biomarkers of infigratinib activity
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent by subject or parent(s) or legally authorized representative (LAR) and signed informed assent by the subject (when applicable).
    - 3 to 11 years of age (inclusive) at screening. The PK Substudy will only enroll subjects ≥8 years old.
    - Diagnosis of ACH, documented clinically and confirmed by genetic testing.
    - If a girl ≥10 years of age, negative pregnancy test.
    -.If sexually active, willing to use a highly effective method of contraception while taking study drug and for 3 months after the last dose of study drug.
    - Subjects and parent(s) or LAR are willing and able to comply with study visits and study procedures.
    - Able to swallow oral medication.
    - Willing to stop consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges, or products containing juice of these fruits while participating in the study; and have not consumed these within 7 days before the first dose of study drug.
    E.4Principal exclusion criteria
    1. Hypochondroplasia or short stature condition other than ACH (eg, trisomy 21, pseudoachondroplasia, psychosocial short stature).
    2. In females, having had their menarche.
    3. Height < −2 or > +2 standard deviations for age and sex based on reference tables on growth in children with ACH (Horton 1978).
    4. Annualized height velocity ≤1.5 cm/year over a period ≥6 months prior to screening.
    5. Significant concurrent disease or condition that, in the view of the Investigator and/or Sponsor, would confound assessment of efficacy or safety of infigratinib, 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; insulin-requiring diabetes mellitus; adrenal insufficiency; autoimmune inflammatory disease; inflammatory bowel disease; presence of a functioning ventriculoperitoneal shunt; or diagnosis of severe sleep apnea (pre existing or done at screening based on the sleep
    study) requiring surgery or continuous positive airway pressure (CPAP) machine.
    6. 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. AST/SGOT or ALT/SGPT >2× ULN.
    d. Calculated or measured creatinine clearance of <60 mL/min.
    7. Current evidence of corneal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, or keratoconjunctivitis, confirmed by ophthalmic examination.
    8. History and/or current evidence of extensive ectopic tissue calcification.
    9. History of malignancy.
    10. Currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration. Subjects are not permitted to receive vitamin D analogues for the treatment of vitamin D deficiency or to initiate multivitamin supplementation containing any form of vitamin D (Over-the-counter [OTC] multivitamin supplements containing vitamin D that were initiated ≥3 months before screening are allowed at the same dose). Subjects receiving medications that alter the pH of the gastrointestinal tract, including antacids, H2 antagonists (eg, ranitidine), and proton-pump inhibitors (eg, omeprazole); or enzyme-inducing antiepileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone will be excluded.
    11. Current evidence of endocrine alterations of calcium/phosphorus homeostasis:
    a. Inorganic phosphorus outside of normal limits.
    b. Total serum calcium (can be corrected) outside of normal limits.
    12. Allergy to any components of the study drug.
    13. Treatment with growth hormone, insulin-like growth factor 1 (IGF1), or anabolic steroids in the previous 6 months or long-term treatment (>3 months) at any time.
    14. Treatment with a C-type natriuretic peptide (CNP) analog, fibroblast growth factor (FGF) ligand trap, or treatment targeting FGFR inhibition at any time.
    15. 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).
    16. Treatment with any other investigational product or investigational medical device for the treatment of ACH or short stature.
    17. Previous limb-lengthening surgery or guided growth surgery.
    18. Fracture within 6 months of screening (due to potential effects on bone biomarkers and bone morphology).
    E.5 End points
    E.5.1Primary end point(s)
    Dose Escalation: Primary Endpoint
    • Treatment-emergent adverse events (TEAEs) that lead to dose decrease or discontinuation.
    • Change from baseline in height velocity (annualized to cm/year). (Baseline is defined as the annualized height velocity obtained from a minimum of 6 months of observation in the PROPEL study.)

    Dose Expansion: Primary Endpoint
    • Change from baseline in height velocity (annualized to cm/year).

    PK Substudy: Primary Endpoint:
    • PK parameters of infigratinib and major active metabolites (eg, Cmax, Clast, Tmax, AUC24, T1/2, AUCinf, CL/F, Vz/F, and Racc)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The evaluation is scheduled at 6, and 18 months for dose escalation, and 12 months for dose expansion.
    E.5.2Secondary end point(s)
    Dose Escalation, Dose Expansion, and PK Substudy
    Secondary Endpoints
    • Safety evaluations by incidence, type, severity, and causality of adverse events (AEs), serious adverse events (SAEs), laboratory test results (urinalysis, chemistry, hematology), clinically significant changes in vital signs, physical examination (including ophthalmic and dental evaluation), electrocardiograms, and imaging.
    • Absolute height velocity (annualized to cm/year), expressed numerically and as Z-score in relation to non-ACH tables.
    • Change from baseline in height velocity (annualized to cm/year) (for PK Substudy only).
    • Absolute (expressed as absolute value and Z-score in relation to ACH and non-ACH standardized pediatric growth curves) and change from baseline in anthropometric parameters, including body proportions. Anthropometric measurements may include, but may not be limited to, standing height, sitting height, weight, head circumference, upper and lower arm length, thigh length, knee height, and arm span. Body proportion measurement ratios 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.
    • PK parameters (eg, Cmax and Tmax)
    • Changes in PD parameters (biomarkers of bone turnover that may include type X collagen degradation fragment, collagen X marker [CXM]) (not applicable for the PK Substudy).

    Exploratory Endpoint
    • Changes in disease-specific complications, such as changes in mobility (assessed by elbow, hip, and knee range of motion), changes in the number of episodes of otitis media per year, changes in number of episodes and/or severity of sleep apnea, and changes in quality of life [QoL] as assessed by PedsQL (generic core scale short form, child and parent reports).
    ○ Baseline for range of motion and PedsQL will correspond to the values obtained at the baseline visit.
    ○ Baseline for the number of episodes of otitis media will be the number of episodes recorded during the PROPEL study [expressed as episodes/year].
    ○ Baseline f or sleep apnea, will correspond to the polysomnogram performed at screening [to rule out severe sleep apnea].)
    • Phosphorylation change in extracellular signal-regulated kinases 1 and 2 (ERK1/2), signal transducers and activators of transcription (STATs) in blood cells
    E.5.2.1Timepoint(s) of evaluation of this end point
    The evaluation is scheduled at 6, and 18 months for dose escalation, and 12 months for dose expansion.

    For the complete list please refers to the protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    cohort dose escalation and dose expansion study, PK substudy
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    France
    Spain
    United Kingdom
    United States
    E.8.7Trial 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 trial is defined with LVLS.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 78
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 78
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects below the age limit to provide consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 39
    F.4.2.2In the whole clinical trial 78
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will have the opportunity to continue treatment in a long term open label extension study, under a different protocol
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-31
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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