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
Overview
- Phase
- Phase 3
- Intervention
- Mitapivat-matching placebo
- Conditions
- Pediatric Pyruvate Kinase Deficiency
- Sponsor
- Agios Pharmaceuticals, Inc.
- Enrollment
- 30
- Locations
- 31
- Primary Endpoint
- Percentage of Participants Achieving a Hemoglobin (Hb) Response
- Status
- Active, Not Recruiting
- Last Updated
- 8 days ago
Overview
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.
Investigators
Eligibility 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 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). 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;
Arms & Interventions
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.
Intervention: Mitapivat-matching placebo
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 first receive blinded mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment before being transitioned to only receive active, open-label drug (mitapivat).
Intervention: Mitapivat-matching placebo
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.
Intervention: Mitapivat
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 first receive blinded mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment before being transitioned to only receive active, open-label drug (mitapivat).
Intervention: Mitapivat
Outcomes
Primary Outcomes
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 Outcomes
- Change From Baseline in Serum Ferritin Concentration(Baseline up to Week 280)
- Change From Baseline in the Size of Ovarian Cysts in Female Participants(Baseline up to Week 286)
- Change From Baseline in Bone Mineral Density (BMD) Z-score(Baseline up to Week 286)
- Change From Baseline in Free Testosterone Concentration in Participants ≥7 Years of Age or Tanner Stage ≥2 (Whichever Occurs First)(Baseline up to Week 286)
- Average Change From Baseline in Hb Concentration at Weeks 12, 16, and 20(Baseline, Weeks 12, 16, and 20)
- Change From Baseline in Estradiol Concentration(Baseline up to Week 286)
- Change From Baseline in Total Testosterone Concentration(Baseline up to Week 286)
- Change From Baseline in Transferrin/Transferrin Saturation(Baseline up to Week 280)
- Change From Baseline in Sexual Maturity Rating with Tanner Stage(Baseline up to Week 286)
- Change From Baseline in Weight-for-age Z-score(Baseline up to Week 286)
- Change From Baseline in Body Mass Index (BMI)-for-age Z-score(Baseline up to Week 286)
- Maximal Change in Hb Concentration From Baseline During the Double-blind Period(Baseline up to Week 20)
- Change From Baseline in Estrone Concentration(Baseline up to Week 286)
- Average Change From Baseline in Lactose Dehydrogenase (LDH) Concentration at Weeks 12, 16, and 20(Baseline, Weeks 12, 16, and 20)
- Change From Baseline in Haptoglobin Concentration at Week 16(Baseline, Week 16)
- Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale(Baseline up to Week 280)
- Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age(Baseline up to Week 286)
- Number of Female Participants With Development of Ovarian Cysts(Baseline up to Week 286)
- Change From Baseline in Height-for-age Z-score(Baseline up to Week 286)
- Change From Baseline in Serum Iron Concentration(Baseline up to Week 280)
- Change From Baseline in Total Iron-binding Capacity(Baseline up to Week 280)
- Change from Baseline in PedsQL Generic Core Scale (GCS)(Baseline up to Week 280)
- Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat(Weeks 2, 8, 12, and 16)
- Average Change From Baseline in Indirect Bilirubin Concentration at Weeks 12, 16, and 20(Baseline, Weeks 12, 16, and 20)
- Change From Baseline in Reticulocytes(Baseline up to Week 286)
- Concentration at Steady State (Css) of Mitapivat(Week 16: 6 and 8 hours postdose)
- Trough Concentration (Ctrough) of Mitapivat(Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose)
- Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat(Weeks 2, 8, 12, and 16)