Clinical trial NCT03548220: A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pyruvate Kinase Deficiency
Anemia, Hemolytic
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-06-07
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.


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.

Primary outcomes:
measure: Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
timeFrame: Baseline, Weeks 16, 20, 24
Secondary outcomes:
measure: Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
timeFrame: Baseline, Weeks 16, 20, 24
measure: Maximum Change From Baseline in Hb Concentration
timeFrame: Baseline, up to Week 24
measure: Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
timeFrame: Baseline, up to Week 24
measure: Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
timeFrame: Baseline, Weeks 16, 20, 24
measure: Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
timeFrame: Baseline, Weeks 16, 20, 24
measure: Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
timeFrame: Baseline, Weeks 16, 20, 24
measure: Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
timeFrame: Baseline, Weeks 16, 20, 24
measure: Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With Adverse Events
timeFrame: From signing of informed consent form to the end of study, including follow-up (up to Day 197)
measure: Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
timeFrame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
measure: Maximum Plasma Concentration (Cmax) for AG-348
timeFrame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
measure: Time to Cmax (Tmax) for AG-348
timeFrame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
measure: Time to Last Measurable Concentration (Tlast) for AG-348
timeFrame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
measure: Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
timeFrame: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
measure: Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
timeFrame: Baseline, Week 24
Other outcomes:
measure: Percentage of Participants With Adverse Events of Special Interest (AESI)
timeFrame: Through 4 weeks after last dose (approximately Week 31)
measure: Change From Baseline in Bone Mineral Density Z-Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Bone Mineral Density T-Score at Week 24
timeFrame: Baseline, Week 24
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana Hemophilia and Thrombosis Center
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: The Children's Hospital Corporation d/b/a Boston's Children Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University School of Medicine, Children's Hospital of Michigan
state: Michigan
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Houston Methodist Research Institute
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital Univ. of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: São Paulo
country: Brazil
facility: Hospital Central da Faculdade de Medicina USP Cidade Universitaria
city: Hamilton
country: Canada
facility: McMaster University - Health Sciences Centre
city: Toronto
country: Canada
facility: Toronto General Hospital, University Health Network
city: Prague
country: Czechia
facility: Institute of Hematology and Blood Transfusion
city: Herlev
country: Denmark
facility: University of Copenhagen, Herlev Hospital
city: Amiens
country: France
facility: CHU Amiens Picardie
city: Bordeaux
country: France
facility: Hopital Saint-Andre
city: Créteil
country: France
facility: Hôpital Henri-Mondor
city: Marseille, Cedex 5
country: France
facility: Hôpital de la Timone
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Berlin
country: Germany
facility: Charite University Medicine
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Genova
country: Italy
facility: Ospedale Galliera
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: AOU Policlinico, Università della Campania "Luigi Vanvitelli"
city: Sendai-City
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Kyoto
country: Japan
facility: Kyoto Katsura Hospital
city: Mie
country: Japan
facility: Agios Investigative Site
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Osaka
country: Japan
facility: Kansai Medical University, Department of Pediatrics, Hirakata Hospital
city: Tokyo
country: Japan
facility: Toho University Omori Medical Center
city: Daegu 705-703
country: Korea, Republic of
facility: Yeungnam University Hospital
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Barcelona
country: Spain
facility: Hospital U. Vall d'Hebron Servicio de Hematología Clínica
city: El Palmar
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arricaxa
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Bangkok
country: Thailand
facility: Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
city: Ankara
country: Turkey
facility: Hacettepe University
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Liverpool
country: United Kingdom
facility: The Royal Liverpool and Broadgreen University
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References:
citation: Al-Samkari H, Galacteros F, Glenthoj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, van Beers EJ; ACTIVATE Investigators. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. N Engl J Med. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634.
citation: Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.