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
Overview
- Phase
- Phase 3
- Intervention
- Mitapivat
- Conditions
- Pediatric Pyruvate Kinase Deficiency
- Sponsor
- Agios Pharmaceuticals, Inc.
- Enrollment
- 49
- Locations
- 40
- Primary Endpoint
- Percentage of Participants Achieving Transfusion Reduction Response (TRR)
- Status
- Active, Not Recruiting
- Last Updated
- 8 days ago
Overview
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 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;
- •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 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
Mitapivat
For participants randomized to receive mitapivat, dosing occurs orally twice daily (BID), and is based on age and weight. Dosing is optimized through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. Following titration, participants remain on their individually optimized dose during the remainder of the Double-blind (DB) Period for 24 weeks. After the DB period, participants will enter an Open-label Extension (OLE) Period. To preserve blinding of treatment allocation, participants will continue mitapivat at their optimized dose and undergo mock titration with placebo for 8 weeks. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).
Intervention: Mitapivat
Mitapivat
For participants randomized to receive mitapivat, dosing occurs orally twice daily (BID), and is based on age and weight. Dosing is optimized through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. Following titration, participants remain on their individually optimized dose during the remainder of the Double-blind (DB) Period for 24 weeks. After the DB period, participants will enter an Open-label Extension (OLE) Period. To preserve blinding of treatment allocation, participants will continue mitapivat at their optimized dose and undergo mock titration with placebo for 8 weeks. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).
Intervention: Mitapivat-matching placebo
Placebo
For participants randomized to receive matched placebo, dosing is identical to that described above for mitapivat. Following the initial dose titration period, participants remain on their individually optimized dose during the remainder of the DB period for 32 weeks. After the DB period, participants will enter an OLE period. To preserve blinding of treatment allocation, participants will continue placebo at their optimized dose and undergo mitapivat dose optimization through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8 of the OLE Period, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).
Intervention: Mitapivat
Placebo
For participants randomized to receive matched placebo, dosing is identical to that described above for mitapivat. Following the initial dose titration period, participants remain on their individually optimized dose during the remainder of the DB period for 32 weeks. After the DB period, participants will enter an OLE period. To preserve blinding of treatment allocation, participants will continue placebo at their optimized dose and undergo mitapivat dose optimization through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8 of the OLE Period, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).
Intervention: Mitapivat-matching placebo
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Change from Baseline in Transferrin/Transferrin Saturation(Baseline up to Week 292)
- Percentage of Participants With Transfusion-free Response(Week 9 to Week 32)
- Change From Baseline in Total Testosterone Concentration(Baseline up to Week 298)
- Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age(Baseline up to Week 298)
- Change From Baseline in Weight-for-age Z-score(Baseline up to Week 298)
- Change From Baseline in Bone Mineral Density (BMD) Z-score(Baseline up to Week 298)
- Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume(Week 9 to Week 32)
- Percentage of Participants With Normal Hemoglobin (Hb) Response(Week 9 to Week 32)
- Change From Baseline in Estradiol Concentration(Baseline up to Week 298)
- Change From Baseline in Body Mass Index (BMI)-for-age Z-score(Baseline up to Week 298)
- Change from Baseline in Serum Ferritin Concentration(Baseline up to Week 292)
- Change in the Number of Transfusion Episodes(Week 9 to Week 32)
- Percentage Number of Female Participants With Development of Ovarian Cysts(Baseline up to Week 298)
- Change From Baseline in the Size of Ovarian Cysts in Female Participants(Baseline up to Week 298)
- Change From Baseline in Height-for-age Z-score(Baseline up to Week 298)
- Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale(Baseline up to Week 292)
- Change From Baseline in Estrone Concentration(Baseline up to Week 298)
- Change From Baseline in Sexual Maturity Rating with Tanner Stage(Baseline up to Week 298)
- Change from Baseline in Total Iron-binding Capacity(Baseline up to Week 292)
- Change from Baseline in PedsQL Generic Core Scale (GCS)(Baseline up to Week 292)
- Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat(Weeks 2, 8, 12, and 16)
- Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat(Weeks 2, 8, 12, and 16)
- Concentration at Steady State (Css) of Mitapivat(Week 16: 6 and 8 hours postdose)
- Change From Baseline in Free Testosterone Concentration in Participants ≥7 Years of Age or Tanner Stage ≥2 (Whichever Occurs First)(Baseline up to Week 298)
- Change from Baseline in Serum Iron Concentration(Baseline up to Week 292)
- Trough Concentration (Ctrough) of Mitapivat(Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose)