Clinical trial NCT03853798: Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007
Official title: An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pyruvate Kinase Deficiency
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-02-26
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open-label, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with AG-348 in participants who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.


Eligibility criteria: Inclusion Criteria:

* Be willing and able to comply with study visits and procedures;
* Have signed written informed consent prior to participating in this extension study;
* Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit;
* Cohorts 2 and 3: Have demonstrated clinical benefit from AG-348 treatment in the antecedent study, in the opinion of the Investigator;
* For women of reproductive potential, have a negative pregnancy test during screening;
* 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 drug for women and 90 days following the last dose of study drug for men.

Exclusion Criteria:

* Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG- 348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the participant to complete study visits and procedures.
* Are currently pregnant or breastfeeding.
* Have a splenectomy scheduled during the study treatment period.
* Meet the withdrawal criteria of his/her antecedent AG-348 study during screening of this extension study.
* Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4 that have not been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug on this extension study.
* Have received anabolic steroids, including testosterone preparations, within 28 days prior to start of study drug on this extension study.
* Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this extension study.
* Have exposure to any investigational drug other than AG-348, device, or procedure within 3 months prior to start of study drug on this extension study.

Primary outcomes:
measure: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From baseline to safety follow-up (up to 198 weeks)
measure: Number of Participants with AEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation
timeFrame: From baseline to safety follow-up (up to 198 weeks)
Secondary outcomes:
measure: Percentage of Participants Achieving a Hemoglobin (Hb) Response in Participants Who Previously Received Placebo in Study AG348-C-006
timeFrame: Weeks 16, 20, 24
measure: Area Under the Concentration-Time Curve (AUC) of AG-348 in Participants Who Previously Received Placebo in Study AG348-C-006
timeFrame: Week 12: pre-dose, post-dose at 30 minutes, 1 hour (h), 2 h, 4 h, 8 h
measure: Maximum Observed Concentration of AG-348 in Participants Who Previously Received Placebo in Study AG348-C-006
timeFrame: Week 12: pre-dose, post-dose at 30 minutes, 1 h, 2 h, 4 h, 8 h
measure: Change from Baseline in Hb Concentration
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Bilirubin
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Lactate Dehydrogenase (LDH)
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Haptoglobin Levels
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Reticulocyte Percentages
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Number of Transfusion Events
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)
timeFrame: From baseline up to Week 193 (Day 1)
measure: Change from Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)
timeFrame: From baseline up to Week 193 (Day 1)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital, Oakland
state: California
city: Atlanta
country: United States
facility: Emory-Children's Center
state: Georgia
city: Indianapolis
country: United States
facility: Indiana Hemophilia & Thrombosis Center Inc.
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University School of Medicine
state: Michigan
city: Durham
country: United States
facility: Duke University Medical Center
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: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: São Paulo
country: Brazil
facility: UNICAMP - Hemocentro
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Herlev
country: Denmark
facility: Herlev University Hospital
city: Bordeaux
country: France
facility: CHU Hopitaux de Bordeaux - Hôpital Saint-André
city: Créteil
country: France
facility: CHU Hôpital Henri Mondor
city: Marseille
country: France
facility: Hospital La Timone
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse - Oncopole
city: Berlin
country: Germany
facility: Charite - UB - CVK - Medizinische Klinik
city: Würzburg
country: Germany
facility: Universitätsklinik Würzburg
city: Dublin 8
country: Ireland
facility: St James's Hospital
city: Genova
country: Italy
facility: Ospedale Galliera
city: Milano
country: Italy
facility: Osp Maggiore Policlinico Milano
city: Napoli
country: Italy
facility: AORN Cardarelli
city: Napoli
country: Italy
facility: Università della Campania "Luigi Vanvitelli"
city: Tsu-shi
country: Japan
facility: Mie University Hospital
state: Mie
city: Sendai
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Kyoto
country: Japan
facility: Kyoto Katsura Hospital
city: Osaka
country: Japan
facility: Kansai Medical University, Dep. of Pediatrics, Hirakata Hospital
city: Tokyo
country: Japan
facility: Toho University Omori Medical Center
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Hospital
city: Utrecht
country: Netherlands
facility: Van Creveldkliniek
city: Barcelona
country: Spain
facility: Hospital. U. Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Murcia
country: Spain
facility: Htal Clínico Universitario Virgen de la Arrixaca.
city: Vaud (Lausanne)
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Bangkok
country: Thailand
facility: Faculty of Medicine Siriraj Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Faculty of Medicine
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: University College London
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References:
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.