A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Pyruvate Kinase Deficiency, Anemia, Hemolytic
About this trial
This is an interventional treatment trial for Pyruvate Kinase Deficiency
Eligibility Criteria
Inclusion Criteria:
- Informed consent;
- Male or female, aged 18 years or older;
- Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
- Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
- Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;
- Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation.
- Adequate organ function;
- Women of reproductive potential, have a negative serum pregnancy test;
- For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent 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 giving informed consent, during the study, and for 28 days following the last dose of study treatment for women and 90 days for men following the last dose of study treatment;
- Willing to comply with all study procedures for the duration of the study;
Exclusion Criteria:
- Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;
- Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data;
- Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent;
- Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;
- Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;
- Prior treatment with a pyruvate kinase activator;
- Prior bone marrow or stem cell transplant;
- Currently pregnant or breastfeeding;
- History of major surgery within 6 months of signing informed consent;
- Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment;
- Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment;
- History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
- History of allergy to AG-348 or its excipients;
- Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.
Sites / Locations
- University of Arkansas for Medical Sciences
- Emory University
- Indiana Hemophilia and Thrombosis Center
- Massachusetts General Hospital
- The Children's Hospital Corporation d/b/a Boston's Children Hospital
- Wayne State University School of Medicine, Children's Hospital of Michigan
- Duke University
- East Carolina University
- Cincinnati Children's Hospital Medical Center
- Houston Methodist Research Institute
- Primary Children's Hospital Univ. of Utah
- Seattle Cancer Care Alliance
- Hospital Central da Faculdade de Medicina USP Cidade Universitaria
- McMaster University - Health Sciences Centre
- Toronto General Hospital, University Health Network
- Institute of Hematology and Blood Transfusion
- University of Copenhagen, Herlev Hospital
- CHU Amiens Picardie
- Hopital Saint-Andre
- Hôpital Henri-Mondor
- Hôpital de la Timone
- Institut Claudius Regaud
- Charite University Medicine
- Universitätsklinikum Würzburg
- Ospedale Galliera
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
- AOU Policlinico, Università della Campania "Luigi Vanvitelli"
- Tohoku University Hospital
- Kyoto Katsura Hospital
- Agios Investigative Site
- Osaka City General Hospital
- Kansai Medical University, Department of Pediatrics, Hirakata Hospital
- Toho University Omori Medical Center
- Yeungnam University Hospital
- Universitair Medisch Centrum Utrecht
- Hospital U. Vall d'Hebron Servicio de Hematología Clínica
- Hospital Clinico Universitario Virgen de la Arricaxa
- Hospital Universitario La Paz
- Centre Hospitalier Universitaire Vaudois (CHUV)
- Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
- Hacettepe University
- Addenbrooke's Hospital
- The Royal Liverpool and Broadgreen University
- Imperial College Healthcare NHS Trust, Hammersmith Hospital
- University College London
- Manchester Royal Infirmary
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Placebo Comparator
Experimental
Experimental
Experimental
Placebo
AG-348, 5 mg
AG-348, 20 mg
AG-348, 50 mg
Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.
Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.