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A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Not Regularly Transfused, Followed by a 5-Year Extension Period (ACTIVATE-Kids)

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ClinicalTrials.gov Identifier: NCT05175105
Recruitment Status : Recruiting
First Posted : January 3, 2022
Last Update Posted : November 15, 2022
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Brief Summary:
Study ACTIVATE-Kids (AG348-C-023) will evaluate the efficacy and safety of orally administered mitapivat as compared with placebo in pediatric participants with pyruvate kinase deficiency (PKD) who are not 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). Participants will be dosed by age and weight during a double-blind period consisting of an 8-week dose titration period followed by a 12-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.

Condition or disease Intervention/treatment Phase
Pediatric Pyruvate Kinase Deficiency Pediatric Hemolytic Anemia Drug: Mitapivat Drug: Mitapivat-matching placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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 Not Regularly Transfused, Followed by a 5-Year Open-label Extension Period
Actual Study Start Date : June 6, 2022
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : October 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 12 weeks in the fixed-dose period.
Drug: Mitapivat
Tablets or granules
Other Names:
  • AG-348
  • AG-348 sulfate hydrate
  • Mitapivat sulfate

Placebo Comparator: Placebo
Double-Blind Period: Participants will receive mitapivat-matching placebo orally for 8 weeks in the dose titration period and for 12 weeks in the fixed-dose period.
Drug: Mitapivat-matching placebo
Tablets or granules

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 open-label extension period will receive both mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment.
Drug: Mitapivat
Tablets or granules
Other Names:
  • AG-348
  • AG-348 sulfate hydrate
  • Mitapivat sulfate

Drug: Mitapivat-matching placebo
Tablets or granules




Primary Outcome Measures :
  1. Percentage of Participants Achieving a Hemoglobin (Hb) Response [ Time Frame: Baseline up to Week 20 ]
    Hb response is defined as a ≥1.5 grams per deciliter (g/dL) (0.93 millimoles per liter [mmol/L]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 12, 16, and 20 during the double-blind period. The individual participant's baseline Hb concentration is defined as the average of all available Hb concentrations collected for that participant during the screening period up to the first dose of study drug.


Secondary Outcome Measures :
  1. Average Change From Baseline in Hb Concentration at Weeks 12, 16, and 20 [ Time Frame: Baseline, Weeks 12, 16, and 20 ]
  2. Maximum Change in Hb Concentration From Baseline During the Double-blind Period [ Time Frame: Baseline up to Week 20 ]
  3. Change From Baseline in Estradiol Concentration [ Time Frame: Baseline up to Week 286 ]
  4. Change From Baseline in Estrone Concentration [ Time Frame: Baseline up to Week 286 ]
  5. Change From Baseline in Total Testosterone Concentration [ Time Frame: Baseline up to Week 286 ]
  6. 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 286 ]
  7. Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age [ Time Frame: Baseline up to Week 286 ]
  8. Change From Baseline in Sexual Maturity Rating with Tanner Stage [ Time Frame: Baseline up to Week 286 ]
    Tanner Stage 1 corresponds to the prepubertal form, with progression to Tanner Stage 5, the final adult form.

  9. Number of Female Participants With Development of Ovarian Cysts [ Time Frame: Baseline up to Week 286 ]
  10. Change From Baseline in the Size of Ovarian Cysts in Female Participants [ Time Frame: Baseline up to Week 286 ]
  11. Change From Baseline in Height-for-age Z-score [ Time Frame: Baseline up to Week 286 ]
  12. Change From Baseline in Weight-for-age Z-score [ Time Frame: Baseline up to Week 286 ]
  13. Change From Baseline in Body Mass Index (BMI)-for-age Z-score [ Time Frame: Baseline up to Week 286 ]
  14. Change From Baseline in Bone Mineral Density (BMD) Z-score [ Time Frame: Baseline up to Week 286 ]
  15. Average Change From Baseline in Indirect Bilirubin Concentration at Weeks 12, 16, and 20 [ Time Frame: Baseline, Weeks 12, 16, and 20 ]
  16. Average Change From Baseline in Lactose Dehydrogenase (LDH) Concentration at Weeks 12, 16, and 20 [ Time Frame: Baseline, Weeks 12, 16, and 20 ]
  17. Change From Baseline in Haptoglobin Concentration at Week 20 [ Time Frame: Baseline, Week 20 ]
  18. Change From Baseline in Reticulocytes [ Time Frame: Baseline up to Week 286 ]
  19. Change From Baseline in Serum Iron Concentration [ Time Frame: Baseline up to Week 280 ]
  20. Change From Baseline in Serum Ferritin Concentration [ Time Frame: Baseline up to Week 280 ]
  21. Change From Baseline in Total Iron-binding Capacity [ Time Frame: Baseline up to Week 280 ]
  22. Change From Baseline in Transferrin/Transferrin Saturation [ Time Frame: Baseline up to Week 280 ]
  23. Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score [ Time Frame: Baseline up to Week 294 ]
    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.

  24. Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score [ Time Frame: Baseline up to Week 294 ]
    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.

  25. Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat [ Time Frame: Weeks 2, 8, 12, and 16 ]
  26. 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 ]
  27. Concentration at Steady State (Css) of Mitapivat [ Time Frame: Week 16: 6 and 8 hours postdose ]
  28. Trough Concentration (Ctrough) of Mitapivat [ Time Frame: Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose ]


Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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;
  • No more than 5 red blood cell (RBC) transfusions in the 52-week period before providing informed consent/assent and no RBC transfusions ≤12 weeks before administration of the first dose of study drug;
  • Hemoglobin concentration ≤10 grams per deciliter (g/dL) for participants 12 to <18 years of age or ≤9 g/dL for participants 1 to <12 years of age during the screening period. Hb concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the screening period;
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05175105


Contacts
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Contact: Agios Medical Affairs 833-228-8474 medinfo@agios.com

Locations
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United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Canada, Quebec
Centre hospitalier Universitaire de Sainte-Justine Recruiting
Montreal, Quebec, Canada, QC H3T 1C5
France
Hôpital Pellegrin Recruiting
Bordeaux, Aquitaine, France, 33000
Israel
Carmel Medical Center Recruiting
Haifa, Hefa, Israel, 34362
Spain
Hospital Universitario Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Hospital Universitario Infantil Nino Jesus Recruiting
Madrid, Spain, 28009
Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
Investigators
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Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.
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Responsible Party: Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT05175105    
Other Study ID Numbers: AG348-C-023
2021-003333-11 ( EudraCT Number )
First Posted: January 3, 2022    Key Record Dates
Last Update Posted: November 15, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Agios Pharmaceuticals, Inc.:
Anemia
Hematologic Diseases
Metabolic Diseases
Mitapivat
AG-348
ACTIVATE-Kids
PK Deficiency
Additional relevant MeSH terms:
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Anemia, Hemolytic
Anemia, Hemolytic, Congenital Nonspherocytic
Pyruvate Metabolism, Inborn Errors
Anemia
Hematologic Diseases
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases