HumRes62555
|
SNCTP000005355
|
BASEC2022-01423
|
NCT05175105
Double-blind, multicenter study versus placebo, on Mitapivat in patients aged 1 to < 18 years with pyruvate kinase deficiency and not regularly transfused, followed by an open-label treatment period of 5 years.
Descrizione riassuntiva dello studio
This study concerns patients aged 1 to < 18 years with PK deficiency who are not regularly transfused. The primary objective is to evaluate the efficacy of the active experimental drug (mitapivat) compared to the placebo on the increase of hemoglobin concentrations. This study also aims to evaluate the safety of mitapivat, its effect on hemolysis, erythropoietic activity, iron metabolism, and its overload. The study will be conducted over a period of approximately 5.7 years. The study includes 2 parts, with the first part (Part 1) conducted in a blind manner, meaning neither the patient, nor the study physician, nor the center staff, nor the sponsor will know if the patient is receiving the active drug (mitapivat) or the placebo. During this Part 1, there will be a dose determination period ("optimization period") of 8 weeks followed by a fixed-dose period of 12 weeks. The purpose of the optimization period is to determine the dose of mitapivat (or the corresponding placebo) that seems to best suit the patient. Patients who complete Part 1 of the study will have the opportunity to continue the study in Part 2, in which patients will receive mitapivat for a duration of up to 5 years. However, in order to maintain the blind of Part 1, patients who continue in Part 2 will receive both mitapivat and placebo for 8 weeks before receiving only mitapivat. The dose of mitapivat or placebo will be determined based on the patient's age and weight and will be administered twice daily either in the form of tablets or granules depending on age. Tests and procedures will be performed at each study visit, some of which are part of usual medical care, but they may be performed more frequently. Blood samples for laboratory analyses will be taken at each visit.
(BASEC)
Intervento studiato
Pyruvate kinase deficiency
(BASEC)
Malattie studiate
pyruvate kinase deficiency and not regularly transfused
(BASEC)
Criteri di partecipazione
Aged 1 to < 18 years. Patients aged 12 to 24 months must weigh at least 7 kg and the patient, or the legal representative of the patient, the parent(s) or legal guardian, and the assent of the patient, if applicable, must have signed an informed consent. Confirmation by a clinical laboratory of a PK deficiency, defined as the documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation, as determined by genotyping performed by the central genotyping laboratory of the study. No more than 5 red blood cell (RBC) transfusions within a 52-week period prior to providing informed consent/assent and no red blood cell transfusions ≤ 12 weeks prior to administration of the first dose of the study drug. Hemoglobin concentration ≤ 10 g/dl for patients aged 12 to < 18 years or ≤ 9 g/dl for patients aged 1 to < 12 years during the selection period. The hemoglobin concentration must be based on an average of at least 2 measurements of Hb concentration (separated by ≥ 7 days) collected during the selection period. Administration of a folic acid supplement as part of routine clinical care for at least 21 days prior to administration of the first dose of the study drug, to be continued during participation in the study. Female subjects who have reached menarche and/or breast development at Tanner stage 2, as well as male patients whose partners have had their first menstruation, must agree to use 2 forms of contraception, of which 1 must be considered highly effective, from the time of informed consent/assent throughout the study, and for 28 days after the last dose of the study drug (including the time needed for gradual dose reduction) for women who have reached menarche and 90 days after the last dose of the study drug (including the time needed for gradual dose reduction) for men. The second form of contraception may include an acceptable barrier method. (BASEC)
Criteri di esclusione
Pregnant or breastfeeding patient. Homozygous for the R479H mutation or having 2 non-missense mutations without the presence of another missense mutation in the PKLR gene as determined by genotyping performed by the central genotyping laboratory of the study. History of malignant tumor. History of active and/or uncontrolled heart or lung disease or clinically significant prolongation of the QT interval in the 6 months prior to obtaining informed consent/assent. Hepatobiliary disorders. Renal dysfunction, defined by an estimated glomerular filtration rate < 60 ml/min/1.73 m2. Fasting triglycerides > 440 mg/dl. Patients with a high probability of exposure or family history of hepatitis B or hepatitis C, who are then positive for hepatitis B antigen or antibodies to hepatitis C virus with signs of active infection by hepatitis B or hepatitis C virus. Patients with a high probability of exposure to HIV or family history of HIV who are then positive for anti-HIV-1 or anti-HIV-2 antibodies. History of major surgical intervention (including splenectomy) ≤ 6 months prior to giving informed consent/assent and/or planning to undergo major surgical intervention during the selection period or the double-blind period. Current or past participation (within 90 days prior to the first dose of the study drug or within a timeframe equivalent to 5 half-lives of the study drug, depending on the longer period) in any other clinical study involving a study drug or experimental device. Previous bone marrow or stem cell transplantation. Current treatment with hematopoietic stimulating agents; the last dose must have been administered at least 28 days or within a timeframe equivalent to 5 half-lives (depending on the longer period) prior to randomization. Receiving products that are strong inhibitors of cytochrome P450 (CYP)3A4/5 that have not been stopped for ≥ 5 days or a timeframe equivalent to 5 half-lives (depending on the longer period), or strong inducers of CYP3A4 that have not been stopped for ≥ 28 days or a timeframe equivalent to 5 half-lives (depending on the longer period), prior to randomization. Administration of anabolic steroids, including testosterone preparations that have not been stopped for at least 28 days prior to randomization. Known allergy to mitapivat or its excipients (microcrystalline cellulose, sodium croscarmellose, sodium stearyl fumarate, mannitol, and magnesium stearate). Any medical, hematological, psychological, or behavioral condition or any previous or current treatment that, in the opinion of the investigator, could confer an unacceptable risk to participation in the study and/or could bias the interpretation of the study data. (BASEC)
Aged 1 to < 18 years. Patients aged 12 to 24 months must weigh at least 7 kg and the patient, or the legal representative of the patient, the parent(s) or legal guardian, and the assent of the patient, if applicable, must have signed an informed consent. Confirmation by a clinical laboratory of a PK deficiency, defined as the documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation, as determined by genotyping performed by the central genotyping laboratory of the study. No more than 5 red blood cell (RBC) transfusions within a 52-week period prior to providing informed consent/assent and no red blood cell transfusions ≤ 12 weeks prior to administration of the first dose of the study drug. Hemoglobin concentration ≤ 10 g/dl for patients aged 12 to < 18 years or ≤ 9 g/dl for patients aged 1 to < 12 years during the selection period. The hemoglobin concentration must be based on an average of at least 2 measurements of Hb concentration (separated by ≥ 7 days) collected during the selection period. Administration of a folic acid supplement as part of routine clinical care for at least 21 days prior to administration of the first dose of the study drug, to be continued during participation in the study. Female subjects who have reached menarche and/or breast development at Tanner stage 2, as well as male patients whose partners have had their first menstruation, must agree to use 2 forms of contraception, of which 1 must be considered highly effective, from the time of informed consent/assent throughout the study, and for 28 days after the last dose of the study drug (including the time needed for gradual dose reduction) for women who have reached menarche and 90 days after the last dose of the study drug (including the time needed for gradual dose reduction) for men. The second form of contraception may include an acceptable barrier method. (BASEC)
Criteri di esclusione
Pregnant or breastfeeding patient. Homozygous for the R479H mutation or having 2 non-missense mutations without the presence of another missense mutation in the PKLR gene as determined by genotyping performed by the central genotyping laboratory of the study. History of malignant tumor. History of active and/or uncontrolled heart or lung disease or clinically significant prolongation of the QT interval in the 6 months prior to obtaining informed consent/assent. Hepatobiliary disorders. Renal dysfunction, defined by an estimated glomerular filtration rate < 60 ml/min/1.73 m2. Fasting triglycerides > 440 mg/dl. Patients with a high probability of exposure or family history of hepatitis B or hepatitis C, who are then positive for hepatitis B antigen or antibodies to hepatitis C virus with signs of active infection by hepatitis B or hepatitis C virus. Patients with a high probability of exposure to HIV or family history of HIV who are then positive for anti-HIV-1 or anti-HIV-2 antibodies. History of major surgical intervention (including splenectomy) ≤ 6 months prior to giving informed consent/assent and/or planning to undergo major surgical intervention during the selection period or the double-blind period. Current or past participation (within 90 days prior to the first dose of the study drug or within a timeframe equivalent to 5 half-lives of the study drug, depending on the longer period) in any other clinical study involving a study drug or experimental device. Previous bone marrow or stem cell transplantation. Current treatment with hematopoietic stimulating agents; the last dose must have been administered at least 28 days or within a timeframe equivalent to 5 half-lives (depending on the longer period) prior to randomization. Receiving products that are strong inhibitors of cytochrome P450 (CYP)3A4/5 that have not been stopped for ≥ 5 days or a timeframe equivalent to 5 half-lives (depending on the longer period), or strong inducers of CYP3A4 that have not been stopped for ≥ 28 days or a timeframe equivalent to 5 half-lives (depending on the longer period), prior to randomization. Administration of anabolic steroids, including testosterone preparations that have not been stopped for at least 28 days prior to randomization. Known allergy to mitapivat or its excipients (microcrystalline cellulose, sodium croscarmellose, sodium stearyl fumarate, mannitol, and magnesium stearate). Any medical, hematological, psychological, or behavioral condition or any previous or current treatment that, in the opinion of the investigator, could confer an unacceptable risk to participation in the study and/or could bias the interpretation of the study data. (BASEC)
Luogo dello studio
Losanna
(BASEC)
Canada, France, Germany, Israel, Italy, Netherlands, Spain, Switzerland, United States (ICTRP)
Sponsor
Agios
(BASEC)
Contatto per ulteriori informazioni sullo studio
Persona di contatto in Svizzera
Pr Renella Raffaele
+41 (0)21 314 14 33
Raffaele.Renella@clutterchuv.chCHU Vaudois
(BASEC)
Informazioni generali
Agios Pharmaceuticals, Inc.
(ICTRP)
Informazioni scientifiche
Agios Pharmaceuticals, Inc.
(ICTRP)
Nome del comitato etico approvante (per studi multicentrici solo il comitato principale)
Commissione d'etica Vaud
(BASEC)
Data di approvazione del comitato etico
09.02.2023
(BASEC)
ID di studio ICTRP
NCT05175105 (ICTRP)
Titolo ufficiale (approvato dal comitato etico)
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 AG348-C-023 (BASEC)
Titolo accademico
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 (ICTRP)
Titolo pubblico
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 (ICTRP)
Malattie studiate
Pediatric Pyruvate Kinase DeficiencyPediatric Hemolytic Anemia (ICTRP)
Intervento studiato
Drug: MitapivatDrug: Mitapivat-matching placebo (ICTRP)
Tipo di studio
Interventional (ICTRP)
Disegno dello studio
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Criteri di inclusione/esclusione
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 >2.5upper limit of normal (ULN) (unless due to
hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5ULN
(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. (ICTRP)
non disponibile
Endpoint primari e secondari
Percentage of Participants Achieving a Hemoglobin (Hb) Response (ICTRP)
Average Change From Baseline in Hb Concentration at Weeks 12, 16, and 20;Maximal Change in Hb Concentration From Baseline During the Double-blind Period;Change From Baseline in Estradiol Concentration;Change From Baseline in Estrone Concentration;Change From Baseline in Total Testosterone Concentration;Change From Baseline in Free Testosterone Concentration in Participants =7 Years of Age or Tanner Stage =2 (Whichever Occurs First);Change From Baseline in Luteinizing Hormone Concentration in Participants =6 Years of Age;Change From Baseline in Sexual Maturity Rating with Tanner Stage;Number of Female Participants With Development of Ovarian Cysts;Change From Baseline in the Size of Ovarian Cysts in Female Participants;Change From Baseline in Height-for-age Z-score;Change From Baseline in Weight-for-age Z-score;Change From Baseline in Body Mass Index (BMI)-for-age Z-score;Change From Baseline in Bone Mineral Density (BMD) Z-score;Average Change From Baseline in Indirect Bilirubin Concentration at Weeks 12, 16, and 20;Average Change From Baseline in Lactose Dehydrogenase (LDH) Concentration at Weeks 12, 16, and 20;Change From Baseline in Haptoglobin Concentration at Week 16;Change From Baseline in Reticulocytes;Change From Baseline in Serum Iron Concentration;Change From Baseline in Serum Ferritin Concentration;Change From Baseline in Total Iron-binding Capacity;Change From Baseline in Transferrin/Transferrin Saturation;Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale;Change from Baseline in PedsQL Generic Core Scale (GCS);Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat;Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat;Concentration at Steady State (Css) of Mitapivat;Trough Concentration (Ctrough) of Mitapivat (ICTRP)
Data di registrazione
22.11.2021 (ICTRP)
Inclusione del primo partecipante
non disponibile
Sponsor secondari
non disponibile
Contatti aggiuntivi
Medical Affairs, Agios Pharmaceuticals, Inc. (ICTRP)
ID secondari
2021-003333-11, AG348-C-023 (ICTRP)
Risultati-Dati individuali dei partecipanti
non disponibile
Ulteriori informazioni sullo studio
https://clinicaltrials.gov/ct2/show/NCT05175105 (ICTRP)
Risultati dello studio
Riepilogo dei risultati
non disponibile
Link ai risultati nel registro primario
non disponibile