HumRes62751
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SNCTP000005397
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BASEC2022-01546
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NCT05144256
Double-blind, multicenter study versus placebo, on Mitapivat in patients aged 1 to < 18 years with pyruvate kinase deficiency and regularly transfused, followed by an open-label treatment period of 5 years.
Zusammenfassung der Studie
This study concerns patients aged 1 to < 18 years with PK deficiency who are regularly transfused. The primary objective is to evaluate the efficacy of the active experimental drug (mitapivat) compared to the placebo on reducing the transfusion requirement of patients. This study also aims to assess the safety of mitapivat, its effect on metabolism and iron overload, and the impact on patients' quality of life. The study will be conducted over a period of approximately 5.9 years. The study includes 2 parts, with the first part (Part 1) conducted in blind, 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 24 weeks. The purpose of the optimization period is to determine the dose of mitapivat (or the corresponding placebo) that seems best suited to the patient. Patients who complete Part 1 of the study will have the opportunity to continue 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 routine medical care, but they may be performed more frequently. Blood samples for laboratory analyses will be collected at each visit.
(BASEC)
Untersuchte Intervention
Pyruvate kinase deficiency
(BASEC)
Untersuchte Krankheit(en)
Patients aged 1 to < 18 years with pyruvate kinase deficiency and who are regularly transfused.
(BASEC)
Kriterien zur Teilnahme
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 patient's assent, if applicable, must have signed an informed consent. Must have confirmation from 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. Must have 6 to 26 transfusion episodes in the 52 weeks prior to providing informed consent/assent. Must provide complete information on transfusion history in the 52 weeks prior to providing informed consent/assent. Administration of folic acid supplementation as part of routine clinical care for at least 21 days prior to administration of the first dose of the study drug, to continue 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 refrain from any sexual activity that could induce pregnancy in their usual lifestyle; or 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 the 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 the gradual dose reduction) for men. The second form of contraception may include an acceptable barrier method. (BASEC)
Ausschlusskriterien
Pregnant or breastfeeding patients. 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 and/or clinically significant prolongation of the QT interval in the 6 months prior to obtaining informed consent/assent. Hepatobiliary disorders. Renal dysfunction, defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2. Fasting triglycerides > 440 mg/dl (5 mmol/l). Patients with a high likelihood of exposure or family history of hepatitis B or C, who then test positive for hepatitis B antigen or hepatitis C virus antibodies with signs of active infection by hepatitis B or C virus. Patients with a high likelihood of exposure to HIV or family history of HIV who then test positive for anti-HIV-1 or anti-HIV-2 antibodies. History of major surgical intervention (including splenectomy) ≤ 6 months prior to providing informed consent/assent and/or planned to undergo major surgical intervention during the selection period or double-blind period. Current or past participation (within 90 days prior to the first dose of the study drug or within a time equivalent to 5 half-lives of the study drug, whichever is longer) in any other clinical study involving an investigational drug or 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 time equivalent to 5 half-lives (whichever is longer) prior to randomization. Receiving products that are strong inhibitors of cytochrome P450 (CYP)3A4/5 that have not been discontinued for ≥ 5 days or a time equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been discontinued for ≥ 28 days or a time equivalent to 5 half-lives (whichever is longer) prior to randomization. Administration of anabolic steroids, including testosterone preparations that have not been discontinued 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 prior 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 patient's assent, if applicable, must have signed an informed consent. Must have confirmation from 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. Must have 6 to 26 transfusion episodes in the 52 weeks prior to providing informed consent/assent. Must provide complete information on transfusion history in the 52 weeks prior to providing informed consent/assent. Administration of folic acid supplementation as part of routine clinical care for at least 21 days prior to administration of the first dose of the study drug, to continue 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 refrain from any sexual activity that could induce pregnancy in their usual lifestyle; or 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 the 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 the gradual dose reduction) for men. The second form of contraception may include an acceptable barrier method. (BASEC)
Ausschlusskriterien
Pregnant or breastfeeding patients. 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 and/or clinically significant prolongation of the QT interval in the 6 months prior to obtaining informed consent/assent. Hepatobiliary disorders. Renal dysfunction, defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2. Fasting triglycerides > 440 mg/dl (5 mmol/l). Patients with a high likelihood of exposure or family history of hepatitis B or C, who then test positive for hepatitis B antigen or hepatitis C virus antibodies with signs of active infection by hepatitis B or C virus. Patients with a high likelihood of exposure to HIV or family history of HIV who then test positive for anti-HIV-1 or anti-HIV-2 antibodies. History of major surgical intervention (including splenectomy) ≤ 6 months prior to providing informed consent/assent and/or planned to undergo major surgical intervention during the selection period or double-blind period. Current or past participation (within 90 days prior to the first dose of the study drug or within a time equivalent to 5 half-lives of the study drug, whichever is longer) in any other clinical study involving an investigational drug or 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 time equivalent to 5 half-lives (whichever is longer) prior to randomization. Receiving products that are strong inhibitors of cytochrome P450 (CYP)3A4/5 that have not been discontinued for ≥ 5 days or a time equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been discontinued for ≥ 28 days or a time equivalent to 5 half-lives (whichever is longer) prior to randomization. Administration of anabolic steroids, including testosterone preparations that have not been discontinued 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 prior 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)
Studienstandort
Lausanne
(BASEC)
Canada, Czechia, Denmark, Germany, Netherlands, Spain, Switzerland, Turkey (T�rkiye), United Kingdom, United States (ICTRP)
Sponsor
Verena Perneczky Fortrea Switzerland AG c/o Regus Badenerstr. 47 8004 Zürich Tel: +41 44-561-5354 Email: SwissRepresentative@fortrea.com
(BASEC)
Kontakt für weitere Auskünfte zur Studie
Kontaktperson Schweiz
PD Dr Raffaele RENELLA
+41-21-314-05-03
Raffaele.Renella@clutterchuv.chCHUV
(BASEC)
Allgemeine Auskünfte
Agios Pharmaceuticals, Inc.
(ICTRP)
Wissenschaftliche Auskünfte
Agios Pharmaceuticals, Inc.
(ICTRP)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Ethikkommission Waadt
(BASEC)
Datum der Bewilligung durch die Ethikkommission
06.03.2023
(BASEC)
ICTRP Studien-ID
NCT05144256 (ICTRP)
Offizieller Titel (Genehmigt von der Ethikkommission)
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 AG348-C-022 (BASEC)
Wissenschaftlicher Titel
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 (ICTRP)
Öffentlicher Titel
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 (ICTRP)
Untersuchte Krankheit(en)
Pediatric Pyruvate Kinase DeficiencyPediatric Hemolytic Anemia (ICTRP)
Untersuchte Intervention
Drug: MitapivatDrug: Mitapivat-matching placebo (ICTRP)
Studientyp
Interventional (ICTRP)
Studiendesign
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Ein-/Ausschlusskriterien
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 >2.5upper 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)
nicht verfügbar
Primäre und sekundäre Endpunkte
Percentage of Participants Achieving Transfusion Reduction Response (TRR) (ICTRP)
Percentage of Participants With Transfusion-free Response;Change in the Number of Transfusion Episodes;Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume;Percentage of Participants With Normal Hemoglobin (Hb) Response;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;Percentage 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;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)
Registrierungsdatum
22.11.2021 (ICTRP)
Einschluss des ersten Teilnehmers
nicht verfügbar
Sekundäre Sponsoren
nicht verfügbar
Weitere Kontakte
Medical Affairs, Agios Pharmaceuticals, Inc. (ICTRP)
Sekundäre IDs
2021-003265-36, 2024-515024-37-00, AG348-C-022 (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar
Weitere Informationen zur Studie
https://clinicaltrials.gov/study/NCT05144256 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar