Clinical trial NCT05144256: 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: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Pediatric Pyruvate Kinase Deficiency
Pediatric Hemolytic Anemia
Keywords: Anemia
Hematologic Diseases
Metabolic Diseases
Mitapivat
AG-348
ACTIVATE-KidsT
PK Deficiency
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-12-03
Enrollment: 49
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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;
* Nonfasting triglycerides \>440 milligrams per deciliter (mg/dL) (5 millimoles per liter \[mmol/L\]);
* Active uncontrolled infection requiring systemic antimicrobial therapy;
* Participants with known active hepatitis B or hepatitis C virus infection;
* Participants with known human immunodeficiency virus (HIV) infection;
* 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 exposure to gene therapy, or 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, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Food, Drug, and Cosmetics blue dye number 2 (FD\&C Blue #2)\], Opadry® II White \[hypromellose, titanium dioxide, lactose monohydrate, and triacetin\], 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; also included are:

  * Participants who are institutionalized by regulatory or court order.
  * Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).
* Receiving a pyruvate kinase activator that has not been stopped for ≥52 weeks before providing informed consent/assent.

Primary outcomes:
measure: Percentage of Participants Achieving Transfusion Reduction Response (TRR)
timeFrame: Week 9 to Week 32
Secondary outcomes:
measure: Percentage of Participants With Transfusion-free Response
timeFrame: Week 9 to Week 32
measure: Change in the Number of Transfusion Episodes
timeFrame: Week 9 to Week 32
measure: Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume
timeFrame: Week 9 to Week 32
measure: Percentage of Participants With Normal Hemoglobin (Hb) Response
timeFrame: Week 9 to Week 32
measure: Change From Baseline in Estradiol Concentration
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Estrone Concentration
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Total Testosterone Concentration
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Free Testosterone Concentration in Participants ≥7 Years of Age or Tanner Stage ≥2 (Whichever Occurs First)
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Sexual Maturity Rating with Tanner Stage
timeFrame: Baseline up to Week 298
measure: Percentage Number of Female Participants With Development of Ovarian Cysts
timeFrame: Baseline up to Week 298
measure: Change From Baseline in the Size of Ovarian Cysts in Female Participants
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Height-for-age Z-score
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Weight-for-age Z-score
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Body Mass Index (BMI)-for-age Z-score
timeFrame: Baseline up to Week 298
measure: Change From Baseline in Bone Mineral Density (BMD) Z-score
timeFrame: Baseline up to Week 298
measure: Change from Baseline in Serum Iron Concentration
timeFrame: Baseline up to Week 292
measure: Change from Baseline in Serum Ferritin Concentration
timeFrame: Baseline up to Week 292
measure: Change from Baseline in Total Iron-binding Capacity
timeFrame: Baseline up to Week 292
measure: Change from Baseline in Transferrin/Transferrin Saturation
timeFrame: Baseline up to Week 292
measure: Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
timeFrame: Baseline up to Week 292
measure: Change from Baseline in PedsQL Generic Core Scale (GCS)
timeFrame: Baseline up to Week 292
measure: Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat
timeFrame: Weeks 2, 8, 12, and 16
measure: Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat
timeFrame: Weeks 2, 8, 12, and 16
measure: Concentration at Steady State (Css) of Mitapivat
timeFrame: Week 16: 6 and 8 hours postdose
measure: Trough Concentration (Ctrough) of Mitapivat
timeFrame: Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Palo Alto
country: United States
facility: Stanford Medicine
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Emory
state: Georgia
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Las Vegas
country: United States
facility: Cure 4 the Kids Foundation, A Division of Roseman University of Health Sciences
state: Nevada
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Ottawa
country: Canada
facility: Comprehensive Hemophilia Care Clinic at CHEO (Children's Hospital Eastern Ontario)
state: Ontario
city: Olomouc
country: Czechia
facility: Fakultní Nemocnice Olomouc
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
state: Midtjylland
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Berlin
country: Germany
facility: Charite - UB - CVK - Medizinische Klinik
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
city: Lausanne
country: Switzerland
facility: CHUV University Hospital of Lausanne
state: Bern
city: Izmir
country: Turkey
facility: Ege University Faculty of Medicine
state: Adana
city: Ankara
country: Turkey
facility: Hacettepe University
city: İstanbul
country: Turkey
facility: İstanbul Üniversitesi Tıp Fakültesi [Istanbul University Faculty of Medicine] Çocuk Sağlığı Enstitüsü [Institute of Child Health]
city: London
country: United Kingdom
facility: King's College Hospital NHS
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References: