ACTIVATE-KidsT: 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
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| 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 24 weeks in the fixed-dose period. |
Drug: Mitapivat
Tablets or granules
Other Names:
|
| 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. |
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 OLE period will receive both mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment. |
Drug: Mitapivat
Tablets or granules
Other Names:
Drug: Mitapivat-matching placebo
Tablets or granules
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants Achieving Transfusion Reduction Response (TRR) [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 Outcome Measures
- Percentage of Participants With Transfusion-free Response [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 [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 [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 [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 [Baseline up to Week 298]
- Change From Baseline in Estrone Concentration [Baseline up to Week 298]
- Change From Baseline in Total Testosterone Concentration [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) [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 Sexual Maturity Rating with Tanner Stage [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 [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 Weight-for-age Z-score [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 Bone Mineral Density (BMD) Z-score [Baseline up to Week 298]
- Change from Baseline in Serum Iron Concentration [Baseline up to Week 292]
- Change from Baseline in Serum Ferritin Concentration [Baseline up to Week 292]
- Change from Baseline in Total Iron-binding Capacity [Baseline up to Week 292]
- Change from Baseline in Transferrin/Transferrin Saturation [Baseline up to Week 292]
- Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score [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 [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 [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]
- Trough Concentration (Ctrough) of Mitapivat [Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose]
Eligibility Criteria
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;
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Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh a minimum of 7 kilograms (kg);
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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;
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Six to 26 transfusion episodes in the 52-week period before providing informed consent/assent;
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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;
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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;
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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:
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Pregnant or breastfeeding;
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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;
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History of malignancy;
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History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent;
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Hepatobiliary disorders including, but not limited to:
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Liver disease with histopathological evidence of cirrhosis or severe fibrosis;
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Clinically symptomatic cholelithiasis or cholecystitis (participants with prior cholecystectomy are eligible);
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History of drug-induced cholestatic hepatitis;
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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);
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Renal dysfunction as defined by an estimated glomerular filtration rate <60 milliliters per minute (mL/min)/1.73 m^2;
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Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
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Active uncontrolled infection requiring systemic antimicrobial therapy;
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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;
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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;
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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;
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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;
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Prior bone marrow or stem cell transplantation;
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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;
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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;
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Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization;
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Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate);
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Phoenix Children's Hospital | Phoenix | Arizona | United States | 85016 |
| 2 | Cure 4 the Kids Foundation, A Division of Roseman University of Health Sciences | Las Vegas | Nevada | United States | 89135 |
| 3 | Hospital Universitario Vall d'Hebron | Barcelona | Spain | 08035 | |
| 4 | Hospital Clinico Universitario Virgen de la Arrixaca | Madrid | Spain | 30120 |
Sponsors and Collaborators
- Agios Pharmaceuticals, Inc.
Investigators
- Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AG348-C-022
- 2021-003265-36