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A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Regularly Transfused, Followed by a 5-Year Extension Period (ACTIVATE-KidsT)

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ClinicalTrials.gov Identifier: NCT05144256
Recruitment Status : Recruiting
First Posted : December 3, 2021
Last Update Posted : June 29, 2022
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE November 22, 2021
First Posted Date  ICMJE December 3, 2021
Last Update Posted Date June 29, 2022
Actual Study Start Date  ICMJE June 8, 2022
Estimated Primary Completion Date November 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 22, 2021)
Percentage of Participants Achieving Transfusion Reduction Response (TRR) [ Time Frame: Week 9 to Week 32 ]
TRR is defined as ≥33% reduction in total red blood cell (RBC) transfusion volume from Week 9 through Week 32 of the double-blind period, normalized by weight and actual study drug duration compared with the historical transfusion volume, standardized by weight, and to 24 weeks.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2021)
  • Percentage of Participants With Transfusion-free Response [ Time Frame: Week 9 to Week 32 ]
    Transfusion-free response is defined as achievement of 0 transfusions administered from Week 9 through Week 32 of the double-blind period.
  • Change in the Number of Transfusion Episodes [ Time Frame: Week 9 to Week 32 ]
    The change in the number of transfusion episodes from Week 9 through Week 32 of the double-blind period compared with the historical number of transfusion episodes standardized to 24 weeks.
  • Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume [ Time Frame: Week 9 to Week 32 ]
    The percentage change in weight-normalized and study treatment duration-normalized total transfusion volume from Week 9 through Week 32 of the double-blind period will be compared with the historical transfusion volume standardized by weight and to 24 weeks.
  • Percentage of Participants With Normal Hemoglobin (Hb) Response [ Time Frame: Week 9 to Week 32 ]
    Normal Hb response is defined as achievement of Hb concentrations in the normal range at least once, 8 weeks or more after a transfusion during Week 9 through Week 32 of the double-blind period.
  • Change From Baseline in Estradiol Concentration [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Estrone Concentration [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Total Testosterone Concentration [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Free Testosterone Concentration in Participants ≥7 Years of Age or Tanner Stage ≥2 (Whichever Occurs First) [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Sexual Maturity Rating with Tanner Stage [ Time Frame: Baseline up to Week 298 ]
    Tanner Stage 1 corresponds to the prepubertal form, with progression to Tanner Stage 5, the final adult form.
  • Percentage Number of Female Participants With Development of Ovarian Cysts [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in the Size of Ovarian Cysts in Female Participants [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Height-for-age Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Weight-for-age Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Body Mass Index (BMI)-for-age Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Bone Mineral Density (BMD) Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change from Baseline in Serum Iron Concentration [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Serum Ferritin Concentration [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Total Iron-binding Capacity [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Transferrin/Transferrin Saturation [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score [ Time Frame: Baseline up to Week 292 ]
    The PKDD is a 7-item measure of the core signs and symptoms of pyruvate kinase deficiency (PK deficiency). The PKDD has been validated in adults with PK deficiency; the scoring algorithm for the pediatric version of the PKDD will be developed as part of the in-trial psychometric validation of the instrument.
  • Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score [ Time Frame: Baseline up to Week 292 ]
    The PKDIA for pediatric participants is a 4-item patient-reported outcome measure of the common impacts of PK deficiency on activities of daily living. The PKDIA has been validated in adults with PK deficiency; the scoring algorithm for the pediatric version of the PKDIA will be developed as part of the in-trial psychometric validation of the instrument.
  • Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat [ Time Frame: Weeks 2, 8, 12, and 16 ]
  • Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat [ Time Frame: Weeks 2, 8, 12, and 16 ]
  • Concentration at Steady State (Css) of Mitapivat [ Time Frame: Week 16: 6 and 8 hours postdose ]
  • Trough Concentration (Ctrough) of Mitapivat [ Time Frame: Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2021)
  • Percentage of Participants With Transfusion-free Response [ Time Frame: Week 9 to Week 32 ]
    Transfusion-free response is defined as achievement of 0 transfusions administered from Week 9 through Week 32 of the double-blind period.
  • Change in the Number of Transfusion Episodes [ Time Frame: Week 9 to Week 32 ]
    The change in the number of transfusion episodes from Week 9 through Week 32 of the double-blind period compared with the historical number of transfusion episodes standardized to 24 weeks.
  • Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume [ Time Frame: Week 9 to Week 32 ]
    The percentage change in weight-normalized and study treatment duration-normalized total transfusion volume from Week 9 through Week 32 of the double-blind period will be compared with the historical transfusion volume standardized by weight and to 24 weeks.
  • Percentage of Participants With Normal Hemoglobin (Hb) Response [ Time Frame: Week 9 to Week 32 ]
    Normal Hb response is defined as achievement of Hb concentrations in the normal range at least once, 8 weeks or more after a transfusion during Week 9 through Week 32 of the double-blind period.
  • Change From Baseline in Sex Hormones [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Sexual Maturity Rating with Tanner Stage [ Time Frame: Baseline up to Week 298 ]
    Tanner Stage 1 corresponds to the prepubertal form, with progression to Tanner Stage 5, the final adult form.
  • Development and Assessment of Ovarian Cysts (in Female Participants Only) [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Height-for-age Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Weight-for-age Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Body Mass Index (BMI)-for-age Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change From Baseline in Bone Mineral Density (BMD) Z-score [ Time Frame: Baseline up to Week 298 ]
  • Change from Baseline in Serum Iron Concentration [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Serum Ferritin Concentration [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Total Iron-binding Capacity [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Transferrin/Transferrin Saturation [ Time Frame: Baseline up to Week 292 ]
  • Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score [ Time Frame: Baseline up to Week 292 ]
    The PKDD is a 7-item measure of the core signs and symptoms associated with PK deficiency.
  • Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score [ Time Frame: Baseline up to Week 292 ]
    The PKDIA for pediatric participants is a 4-item patient-reported outcome measure of the common impacts of PK deficiency on activities of daily living.
  • Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat [ Time Frame: Randomization and after 2, 8, 12, and 16 weeks of treatment ]
  • Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat [ Time Frame: Randomization and after 2, 8, 12 and 16 weeks of treatment ]
  • Concentration at Steady State (Css) of Mitapivat [ Time Frame: Week 16: 6 hours (hr) and 8 hr postdose ]
  • Trough Concentration (Ctrough) of Mitapivat [ Time Frame: Week 8: ≤30 minutes (min) predose; Week 12: ≤30 min predose ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Regularly Transfused, Followed by a 5-Year Extension Period
Official Title  ICMJE A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Subjects With Pyruvate Kinase Deficiency Who Are Regularly Transfused, Followed by a 5-Year Open-label Extension Period
Brief Summary ACTIVATE-KidsT (AG348-C-022) is a multicenter study designed to evaluate the efficacy and safety of treatment with mitapivat compared with placebo in pediatric participants with pyruvate kinase deficiency (PK deficiency) who are regularly receiving blood transfusions. Participants will be randomized 2:1 to receive either mitapivat or matching placebo. Randomization will be stratified by age (1 to < 6 years, 6 to < 12 years, 12 to < 18 years) and splenectomy status. Participants will be dosed by age and weight during a double-blind period consisting of an 8-week dose titration period followed by a 24-week fixed-dose period. Participants who complete the double-blind period will be eligible to receive mitapivat for up to 5 years in the open-label extension (OLE) period.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Pediatric Pyruvate Kinase Deficiency
  • Pediatric Hemolytic Anemia
Intervention  ICMJE
  • Drug: Mitapivat
    Tablets or granules
    Other Names:
    • AG-348
    • AG-348 sulfate hydrate
    • Mitapivat sulfate
  • Drug: Mitapivat-matching placebo
    Tablets or granules
Study Arms  ICMJE
  • Experimental: Mitapivat
    Double-Blind Period: Participants will receive mitapivat orally, at doses based on age and weight, for 8 weeks in the dose titration period and for 24 weeks in the fixed-dose period.
    Intervention: Drug: Mitapivat
  • Placebo Comparator: Placebo
    Double-Blind Period: Participants will receive mitapivat-matching placebo orally for 8 weeks in the dose titration period and for 24 weeks in the fixed-dose period.
    Intervention: Drug: Mitapivat-matching placebo
  • Experimental: Mitapivat (OLE period)
    Participants who have completed the double-blind period will be eligible to receive mitapivat for up to 5 years in the OLE period. Participants entering the OLE period will receive both mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment.
    Interventions:
    • Drug: Mitapivat
    • Drug: Mitapivat-matching placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 22, 2021)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 1, 2029
Estimated Primary Completion Date November 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent from the participant, or the participant's legally authorized representative, parent(s), or legal guardian, and the participant's assent, where applicable (informed consent/assent) must be obtained before any study-related procedures are conducted, and participants must be willing to comply with all study procedures for the duration of the study;
  • Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh a minimum of 7 kilograms (kg);
  • Clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined as documented presence of at least 2 mutant alleles in the pyruvate kinase L/R (PKLR) gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory;
  • Six to 26 transfusion episodes in the 52-week period before providing informed consent/assent;
  • Have complete records of transfusion history for the 52 weeks before providing informed consent/assent, defined as having all the following available: (1) all the transfusion dates, (2) the RBC transfusion volume (milliliters and/or number of units) for all the transfusions, and (3) hemoglobin concentrations within 1 week before transfusion for at least 80% of the transfusions;
  • Receiving folic acid supplementation as part of routine clinical care for at least 21 days before administration of the first dose of study drug, to be continued during study participation;
  • Female participants who have attained menarche and/or breast development in Tanner Stage 2, as well as male participants with partners who have attained menarche, must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of informed consent/assent, throughout the study, and for 28 days after the last dose of study drug (including the time required to dose taper) for female participants who have attained menarche and 90 days after the last dose of study drug (including the time required to dose taper) for male participants. The second form of contraception can include an acceptable barrier method.

Exclusion Criteria:

  • Pregnant or breastfeeding;
  • Homozygous for the R479H mutation or have 2 nonmissense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory;
  • History of malignancy;
  • History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent;
  • Hepatobiliary disorders including, but not limited to:

    • Liver disease with histopathological evidence of cirrhosis or severe fibrosis;
    • Clinically symptomatic cholelithiasis or cholecystitis (participants with prior cholecystectomy are eligible);
    • History of drug-induced cholestatic hepatitis;
    • Aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition);
  • Renal dysfunction as defined by an estimated glomerular filtration rate <60 milliliters per minute (mL/min)/1.73 m^2;
  • Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
  • Active uncontrolled infection requiring systemic antimicrobial therapy;
  • Participants with a high likelihood of exposure to, or parental history of, hepatitis B or hepatitis C who subsequently test positive for hepatitis B antigen or hepatitis C virus antibody with signs of active hepatitis B or hepatitis C virus infection;
  • Participants with a high likelihood of exposure to, or parental history of, human immunodeficiency virus (HIV) who subsequently test positive for HIV-1 or -2 antibodies;
  • History of major surgery (including splenectomy) ≤6 months before providing informed consent/assent and/or planning on undergoing a major surgical procedure during the screening or double-blind period;
  • Current enrollment or past participation (within 90 days before the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device;
  • Prior bone marrow or stem cell transplantation;
  • Currently receiving hematopoietic stimulating agents; the last dose must have been administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before randomization;
  • Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), before randomization;
  • Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization;
  • Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate);
  • Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Agios Medical Affairs 833-228-8474 medinfo@agios.com
Listed Location Countries  ICMJE Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05144256
Other Study ID Numbers  ICMJE AG348-C-022
2021-003265-36 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Agios Pharmaceuticals, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Agios Pharmaceuticals, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.
PRS Account Agios Pharmaceuticals, Inc.
Verification Date June 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP