Clinical trial NCT05175105: 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
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
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-Kids
PK Deficiency
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2022-01-03
Enrollment: 30
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: 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.


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;
* 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 a Hemoglobin (Hb) Response
timeFrame: Baseline up to Week 20
Secondary outcomes:
measure: Average Change From Baseline in Hb Concentration at Weeks 12, 16, and 20
timeFrame: Baseline, Weeks 12, 16, and 20
measure: Maximal Change in Hb Concentration From Baseline During the Double-blind Period
timeFrame: Baseline up to Week 20
measure: Change From Baseline in Estradiol Concentration
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Estrone Concentration
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Total Testosterone Concentration
timeFrame: Baseline up to Week 286
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 286
measure: Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Sexual Maturity Rating with Tanner Stage
timeFrame: Baseline up to Week 286
measure: Number of Female Participants With Development of Ovarian Cysts
timeFrame: Baseline up to Week 286
measure: Change From Baseline in the Size of Ovarian Cysts in Female Participants
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Height-for-age Z-score
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Weight-for-age Z-score
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Body Mass Index (BMI)-for-age Z-score
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Bone Mineral Density (BMD) Z-score
timeFrame: Baseline up to Week 286
measure: Average Change From Baseline in Indirect Bilirubin Concentration at Weeks 12, 16, and 20
timeFrame: Baseline, Weeks 12, 16, and 20
measure: Average Change From Baseline in Lactose Dehydrogenase (LDH) Concentration at Weeks 12, 16, and 20
timeFrame: Baseline, Weeks 12, 16, and 20
measure: Change From Baseline in Haptoglobin Concentration at Week 16
timeFrame: Baseline, Week 16
measure: Change From Baseline in Reticulocytes
timeFrame: Baseline up to Week 286
measure: Change From Baseline in Serum Iron Concentration
timeFrame: Baseline up to Week 280
measure: Change From Baseline in Serum Ferritin Concentration
timeFrame: Baseline up to Week 280
measure: Change From Baseline in Total Iron-binding Capacity
timeFrame: Baseline up to Week 280
measure: Change From Baseline in Transferrin/Transferrin Saturation
timeFrame: Baseline up to Week 280
measure: Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
timeFrame: Baseline up to Week 280
measure: Change from Baseline in PedsQL Generic Core Scale (GCS)
timeFrame: Baseline up to Week 280
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: Palo Alto
country: United States
facility: Stanford Medicine
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Emory
state: Georgia
city: Chicago
country: United States
facility: UChicago Medicine
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St Jude's Children's Research Hospital
state: Tennessee
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: Montreal
country: Canada
facility: Centre hospitalier Universitaire de Sainte-Justine
state: Quebec
city: Bordeaux
country: France
facility: Hôpital Pellegrin
state: Aquitaine
city: Wurzburg
country: Germany
facility: Universitatsklinikum Wurzburg
state: Bayern
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 Universitario Infantil Nino Jesus
city: Lausanne
country: Switzerland
facility: CHUV University Hospital of Lausanne
state: Bern
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References: