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    Summary
    EudraCT Number:2019-001838-34
    Sponsor's Protocol Code Number:GBT440-029
    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:2019-08-12
    Trial results View 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 number2019-001838-34
    A.3Full title of the trial
    A Phase 2, Open Label, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Voxelotor in Patients with Sickle Cell Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multiple dose escalation study to evaluate the effectiveness of Voxelotor in Patients with Sickle Cell Disease
    A.4.1Sponsor's protocol code numberGBT440-029
    A.5.4Other Identifiers
    Name:IND numberNumber:121,691
    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 SponsorGlobal Blood 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 supportGlobal Blood Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlobal Blood Therapeutics, Inc.
    B.5.2Functional name of contact pointShaimaa Shafie
    B.5.3 Address:
    B.5.3.1Street Address181 Oyster Point Blvd
    B.5.3.2Town/ citySouth San Francisco, CA
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number001650822 8731
    B.5.6E-mailsshafie@gbt.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/3/16/1769 - EMA/OD/187/16
    D.3 Description of the IMP
    D.3.1Product nameVoxelotor 500 mg
    D.3.2Product code GBT440
    D.3.4Pharmaceutical form Tablet
    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 INNVOXELOTOR
    D.3.9.1CAS number 1446321-46-5
    D.3.9.2Current sponsor codeGBT440
    D.3.9.4EV Substance CodeSUB190711
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1500 to 3000
    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
    Sickle Cell Disease
    E.1.1.1Medical condition in easily understood language
    Sickle Cell Disease is a chronic, inherited blood disorder that impacts haemoglobin, a protein found in red blood cells (RBCs) that carries oxygen throughout the body.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10040644
    E.1.2Term Sickle cell disease
    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 tolerability and safety of voxelotor at daily doses of >1500 mg (2000 mg to 3000 mg) in participants with sickle cell disease (SCD)
    E.2.2Secondary objectives of the trial
    Secondary Objectives:

    - To evaluate the change in Hb and hemolysis measures
    - To evaluate the incidence rate of vaso-occlusive crises (VOCs)

    Exploratory Objectives:

    - To evaluate the pharmacodynamic (PD) properties (effect on Hb-oxygen equilibrium curve [OEC]) as measured by P50 and P20
    - To assess voxelotor pharmacokinetics (PK) as evaluated by population PK analysis and % Hb occupancy
    - To evaluate the PK-PD relationship of voxelotor at daily doses of >1500 mg
    - To evaluate the effects of voxelotor on Clinical Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants who meet all the following criteria will be eligible for enrollment in the study:

    1. Male or female with sickle cell disease

    2. Documentation of SCD genotype HbSS or HbSB0

    3. Age 18 to < 60 years, inclusive

    4. Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL during Screening, and considered stable and close to baseline by the investigator

    5. For participants taking hydroxyurea (HU), the dose in mg/kg must be stable for at least 90 days prior to signing the informed consent form (ICF) and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator.

    6. Participants, who if female and of child bearing potential, agree to use highly effective methods of contraception or practicing abstinence from study start to 30 days after the last dose of study drug, and who if male, agree to use barrier methods of contraception or practice abstinence from study start to 30 days after the last dose of study drug.

    7. Participant has provided documented informed consent
    E.4Principal exclusion criteria
    Participants meeting any of the following exclusion criteria will not be eligible for study enrollment:

    1. More than 10 vaso-occlusive crises (VOCs) within 12 months of screening that required a hospital, emergency room, or clinic visit

    2. Female participant who is breast feeding or pregnant

    3. Receiving regularly scheduled blood (red blood cell [RBC]) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received an RBC transfusion for any reason within 60 days of signing the ICF or at any time during the screening period

    4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 30 days prior to dosing (ie, a vaso-occlusive event cannot be within 30 days prior to dosing)

    5. Screening laboratory test of alanine aminotransferase (ALT) > 4 × upper level of normal (ULN)

    6. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy, including acute bacterial infection requiring antibiotics

    7. Known to be COVID-19 positive from within 3 weeks of screening through Day 1

    8. Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive

    9. Severe renal dysfunction (estimated glomerular filtration rate [GFR] < 50 mL/min/1.73 m2 at the Screening visit; calculated by the local laboratory to assess safety) or is on chronic dialysis

    10. History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy)

    11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:
    a. Unstable angina pectoris or myocardial infarction or elective coronary intervention
    b. Congestive heart failure requiring hospitalization
    c. Uncontrolled clinically significant arrhythmias
    d. Pulmonary hypertension

    12. Criteria related to ECG parameters:
    a. PR interval > 220 msec in any participant
    b. QRS interval > 120 msec or QT interval corrected using Fridericia’s formula (QTcF) > 480 msec (both genders) in participants without bundle branch block
    c. QRS interval > 120 msec in participants with newly (within 3 months) emerged bundle branch block
    d. A participant with stable bundle branch block with or without stable cardiac disease may be enrolled; QRS interval > 120 msec and QTcF interval > 480 msec are acceptable in these participants.

    13. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable)

    14. Participated in another clinical trial of an investigational agent or medical device within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent or medical device

    15. Inadequate venous access as determined by the Investigator/site staff

    16. Medical, psychological, or behavioral conditions, which, in the opinion of the investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent

    17. Received erythropoietin or other hematopoietic growth factor treatment within 28 days of signing ICF or is anticipated to require such agents during the study

    18. Ongoing or recent (within 2 years) substance abuse

    19. Known allergy to voxelotor

    20. Use of herbal medications (eg, St. John’s Wort), sensitive cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic index, strong CYP3A4 inhibitors, fluconazole, or moderate or strong CYP3A4 inducers.
    E.5 End points
    E.5.1Primary end point(s)
    Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Any new or worsening events which occurs after first dose or through 28 days after study drug discontinuation
    E.5.2Secondary end point(s)
    Secondary Endpoints:

    The secondary endpoints are:
    • Change in Hb and clinical measures of hemolysis (unconjugated bilirubin, % reticulocyte, absolute reticulocyte, and LDH) from Baseline
    • Proportion of participants with an Hb increase > 1 g/dL compared to Baseline
    • Incidence rate of VOCs

    Exploratory Endpoints:

    The exploratory endpoints are:
    • P50 and P20 at 8 hours and 24 hours postdose
    • PK of voxelotor as assessed by population PK analysis using nonlinear mixed-effect modeling
    • % Hb occupancy at 8 hours and 24 hours postdose
    • CGI-C
    • PGI-C
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the timepoints for the evaluation of the Secondary Endpoints and Exploratory Endpoints, please refer to the Schedule of assessment Appendix A- E in the GBT440-029 Study Protocol Amendment 2.0, dated 05 October 2020
    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 No
    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
    Multiple Dose Escalation Study
    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.8.2.4Number of treatment arms in the trial2
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 years1
    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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    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)
    Upon completion of dosing for individual participants or after study termination, eligible participants will be given the option to enroll in an open-label extension study.
    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 Decision2019-09-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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