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    Summary
    EudraCT Number:2023-001104-33
    Sponsor's Protocol Code Number:AT0071002
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2023-12-22
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2023-001104-33
    A.3Full title of the trial
    A Sequential, Two-Part Study to Evaluate the Clinical Benefit, Safety, Pharmacokinetics, and Pharmacodynamics of AT-007 in Pediatric Patients with Classic Galactosemia (CG)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Sequential, Two-Part Study to Evaluate the Clinical Benefit, Safety, Pharmacokinetics, and Pharmacodynamics of AT-007 in Pediatric Patients with Classic Galactosemia (CG)
    A.4.1Sponsor's protocol code numberAT0071002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04902781
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/487/2023
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorApplied 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 supportApplied Therapeutics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationApplied Therapeutics Inc.
    B.5.2Functional name of contact pointChief medical officer
    B.5.3 Address:
    B.5.3.1Street Address545 Fifth Avenue, Suite 1400
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.6E-mailrperfetti@appliedtherapeutics.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/22/2642
    D.3 Description of the IMP
    D.3.1Product nameGovorestat
    D.3.2Product code AT-007
    D.3.4Pharmaceutical form Oral suspension
    D.3.4.1Specific paediatric formulation No
    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 INNGovorestat
    D.3.9.1CAS number 2170729-29-8
    D.3.9.2Current sponsor codeAT-007
    D.3.9.4EV Substance CodeSUB213868
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral suspension
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Galactosemia
    E.1.1.1Medical condition in easily understood language
    Galactosemia
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10017610
    E.1.2Term Galactosemia
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical benefit of long-term orally-administered AT-007 (govorestat) on how pediatric patients with Classic Galactosemia (CG) feel and function as a composite sum of change on speech and language skills, behavior and daily living skills (as measured Oral and Written Language Scales [OWLS-II] and Behavior Assessment System for Children 3rd Edition [BASC-3] tests)
    E.2.2Secondary objectives of the trial
    Evaluate the following parameters of orally-administered AT-007 in paediatric patinets with CG:
    -The efficacy in reducing the pharmacodynamic biomarker, galactitol.
    - The efficacy of long-term in preventing or ameliorating behavioral and developmental symptoms as measured by the BASC test; speech and language symptoms as measured by the OWLS test; impairment in cognitive function via National Institutes of Health (NIH) Toolbox Cognition Battery; movement disorders of the upper limbs as assessed by the Archimedes Spiral Drawing Test and 9-Hole Pegboard test; impairment in gross and fine motor function as assessed by Standing Balance test and the Scale for the Assessment and Rating of Ataxia (SARA).
    -The efficacy of long-term in preventing early-onset and/or progression of cataracts.
    -The clinical benefit of long-term on sexual maturation and ovarian function in pediatric female patients with CG.
    -The safety of AT-007.
    -The PK parameters of multiple doses of AT-007.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or non-pregnant, non-lactating female patient aged ≥2 to <18 years.
    2. CG diagnosis confirmed by evidence of absent or significantly decreased (<1%) GALT activity in RBCs, or a historical record of diagnosis of CG (medical record or written communication by health care professional containing gene analysis and/or GALT enzyme activity).
    3. No clinically significant abnormal laboratory value as determined by the Investigator during screening.
    4. Patient’s vital signs (measured after 5 minutes rest in a seated position) at screening must be within the normal ranges for the specific age, as determined by the Investigator.
    5. Patient may be on concomitant medications and dietary supplements; however, they must be on stable doses for at least 1 month prior to screening, unless approved by the Investigator.
    6. Patient may have long-term complications of galactosemia, including mild neurological deficits such as ataxia, tremor, dysmetria and dystonia, mild cognitive impairment, and mild language difficulty, and primary ovarian insufficiency, that, in the opinion of the Investigator, do not interfere with the patient’s ability to participate in the study.
    7. Patient need to be on a galactose restricted diet for ≥90 days prior to their enrollment in the study and remain and throughout the study.
    8. Screening 12-lead ECG with normal sinus rhythm without pathological Q wave or clinically significant ST/T wave changes.
    9. Willing and able to be confined to the clinical research unit (CRU) as required by the protocol.
    10. Parent(s)/LAR(s) willing and able to consent voluntarily for patient to participate in this study by providing written informed consent prior to the start of any study-specific procedures (also, patient assent, if applicable).
    E.4Principal exclusion criteria
    1. History or presence of clinically significant hematopoietic, hepatic (i.e. ALT or AST or total bilirubin > 1.5 x ULN), endocrine, metabolic, pulmonary, neurological, psychiatric, immunological, dermatological, or gastrointestinal diseases; conditions capable of altering the absorption, metabolism, or elimination of drugs; or conditions that constitute a risk factor when taking the study drug and/or impact the conduct or results of the study.
    2. Evidence of diagnosis of any type of galactosemia other than CG. Subjects with Duarte variant galactosemia are not eligible.
    3. Severe cognitive impairment defined as:
    a. Bayley Scales of Infant and Toddler Development (Bayley-4) Development Quotient < 50, or Vineland Adaptive Behavior Scales (Vineland-3) Comprehensive Interview Form Standard Score < 50 for age 24 to ≤30-month old
    b. Wechsler Preschool and Primary Scale of Intelligence (WPPSI) Full Scale Intelligence Quotient (FSIQ) score < 50, or Vineland-3 Comprehensive Interview Form Standard Score < 50 for age >30 months to < 7 years old (y.o)
    c. Wechsler Intelligence Scale for Children (WISC) FSIQ score < 50, or Vineland-3 Comprehensive Interview Form Standard Score < 50 for age 7 to < 17 y.o
    d. Wechsler Adult Intelligence Scale (WAIS) FSIQ score < 50, or Vineland-3 Comprehensive Interview Form Standard Score < 50 for age 17 y.o.
    4. Complications of CG resulting in disability that, in the opinion of the Investigator (PI), may prevent the patient from completing all study requirements.
    5. Impaired renal function or estimated glomerular filtration rate < 90 mL/min/1.73 m2 (Schwartz Formula).
    6. History or presence of significant cardiovascular disorders including myocardial infarction, stroke, left ventricular hypertrophy, atrial fibrillation, valvular heart disease, or uncontrolled hypertension (sitting blood pressure >140/90 mmHg in children ≥13 to <18 y.o; >120/80 in children ≥7 to ≤12 y.o; >110/80 in children aged ≥2 to ≤6 y.o).
    7. Clinically significant overweight or Body Mass Index > 97th percentile for the specific age.
    8. Clinically significant underweight (in the opinion of the PI) and BMI < 3rd percentile for the specific age and gender.
    9. Positive test for hepatitis B (HBV) surface antigen, hepatitis C (HCV) antibody, or human immunodeficiency virus (HIV) at screening or previous treatment for HBV, HCV, or HIV infection.
    10. Abnormal findings on the screening 12-lead ECG, such as ST/T wave changes of ischemia, pathological Q wave changes, or any rhythm other than normal sinus rhythm.
    11. Evidence of significant active hematological disease and/or cumulative blood donation of 1 unit (500 mL) or more including blood drawn during clinical studies in the last 90 days.
    12. Pregnant, lactating, or not using/not willing to use appropriate means of contraception.
    13. Any prior history of substance abuse or treatment for such.
    14. History of clinically significant drug hypersensitivity reactions.
    15. Immediate family members of Investigators and site personnel directly affiliated with this study (defined as a child or sibling, whether biological or legally adopted).
    16. Any significant health problems unrelated to CG or any other condition that, in the opinion of the PI, precludes the patient from following and completing the protocol.
    17. Unwilling to comply with a galactose-restricted diet.
    18. Positive urine screen for drugs of abuse unless clinically indicated.
    19. Participation in another clinical trial of a different IMP (randomized patients only) within 5 half-lives prior to the first dose of IMP.
    20. Use of any OTC medication ≤7 days prior to the first dose of IMP through the last dose of IMP without evaluation and approval by the PI.
    21. Use of any prescription medication, except that allowed per protocol, from 14 days prior to the first dose of IMP through the last dose of IMP without evaluation and approval by the PI.
    22. Treatment with any sensitive substrates of BCRP or potent inhibitors of BCRP ≤5 half-lives prior to the first dose of IMP through the last dose of IMP.
    23. Treatment with sensitive substrates of OAT1 and OAT3 ≤5 half-lives prior to the first dose of IMP through the last dose of IMP.
    24. Treatment with sensitive substrates of CYP3A4, or CYP2B6, or CYP2C19, or CYP1A2 ≤5 half-lives prior to the first dose of IMP through the last dose of IMP.
    25. Treatment with the specific nephrotoxic drugs < 5 half-lives prior to the first dose of IMP through the last dose of IMP (details available in the protocol).
    26. Consumption of beverages or foods that contain alcohol, high levels of sorbitol, grapefruit, poppy seeds, broccoli, Brussels sprouts, pomegranate, star fruit, char-grilled meat, or caffeine/xanthine from 48 hours prior to the first dose of IMP through the last dose of IMP.
    27. Treatment with medications potentially associated with transaminase elevations, such as mirtazapine ≤5 half-lives prior to the first dose of IMP through the last dose of IMP.
    E.5 End points
    E.5.1Primary end point(s)
    Changes in the following 4 domains from baseline to Month 6 and every 6 months thereafter (i.e., changes from baseline to Month 12, Month 18, etc.)
    − Speech and Language (OWLS-II, both Expressive Language (also termed Oral Expression test) and Receptive Language (also termed Listening Comprehension) domains)
    − BASC-3 Behavioral Symptoms index (includes atypicality, withdrawal, attention) and BASC-3 Daily Living domain
    − Sensitivity analyses were performed including manual dexterity (9-Hole Pegboard Test) and cognitive function (NIH Toolbox Cognition Battery)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to Month 6, Month 12 and Month 18.
    E.5.2Secondary end point(s)
    - Changes in each of the individual domains/tests noted above as components of the primary endpoint (including individual components of the BASC test), and the components of the primary endpoint sensitivity analyses (Cognition and 9-Hole Pegboard Test [9HPT])
    - Changes in gross motor skills, as measured by NIH Toolbox Motor Battery Standing Balance test
    - Changes in plasma galactitol from baseline
    - Changes in tremor assessed by the Archimedes Spiral Drawing Test
    - Changes in gross and fine motor function as assessed by SARA
    - Changes in onset and severity/progression of cataracts using the Lens Opacities Classification System III (LOCS III)
    - Changes in sexual maturation and ovarian function in female patients (based on follicle stimulating hormone [FSH], luteinizing hormone [LH], estradiol, Tanner stage milestones, and clinical endocrinology examination)
    - PK parameters
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to Month 6, Month 12 and Month 18.
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    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 study will be considered completed as soon as substantial evidence of clinical benefit (or futility) is established and all patients have had the end of study (EOS) Visit at approximately 28 days after the last dose.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years2
    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: 47
    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: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 17
    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 under-age incapable of giving consent personally.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 47
    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)
    None.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation University of Colorado School of Medicine, Children’s Hospital Colorado
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Rare Disease Research
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Michigan Medicine, University of Michigan
    G.4.3.4Network Country United States
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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