Clinical trial NCT04770779: A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)
Official title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Mitapivat in Subjects With Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE-T)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Transfusion-dependent Alpha-Thalassemia
Transfusion-dependent Beta-Thalassemia
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-02-25
Enrollment: 258
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: The primary objective of this study was to compare the effect of mitapivat versus placebo on transfusion burden in participants with α- or β-transfusion-dependent thalassemia.

Detailed description: The mitapivat group included 171 participants. The placebo group included 87 participants.

Eligibility criteria: Inclusion Criteria:

* Greater than or equal to (≥)18 years of age at the time of providing informed consent;
* Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis;
* Considered transfusion-dependent, defined as 6 to 20 red blood cells (RBC) units transfused and ≤6-week transfusion-free period during the 24-week period before randomization;
* If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
* Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use two forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
* Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

Exclusion Criteria:

* Pregnant, breastfeeding, or parturient;
* Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C);
* Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
* Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization;
* Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization;
* History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
* History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent;
* Hepatobiliary disorders;
* Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 meter (m)\^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
* Nonfasting triglycerides \>440 milligrams per deciliter (mg/dL) (5 millimoles per liter \[mmol/L\]);
* Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
* Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
* Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
* History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study;
* Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;
* Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization;
* Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥12 weeks before randomization;
* Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Federal Food, Drug, and Cosmetic (FD\&C) Blue #2\]);
* Any medical, hematological, 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 excluded 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).

Primary outcomes:
measure: Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
timeFrame: Double-blind Period: Baseline through Week 48
Secondary outcomes:
measure: Double-blind Period: Percentage of Participants Who Achieved TRR2
timeFrame: Double-blind period: Baseline through Week 48
measure: Double-blind Period: Percentage of Participants Who Achieved TRR3
timeFrame: Double-blind period: Baseline up to Week 13 through Week 48
measure: Double-blind Period: Percentage of Participants Who Achieved TRR4
timeFrame: Double-blind period: Baseline up to Week 13 through Week 48
measure: Double-blind Period: Percent Change From Baseline in Transfused RBC Units
timeFrame: Double-blind Period: Baseline, Week 13 through Week 48
measure: Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence
timeFrame: Double-blind Period: Baseline through Week 48
measure: Double-blind Period: Change From Baseline in Iron Levels
timeFrame: Double-blind Period: Baseline through Week 48
measure: Double-blind Period: Change From Baseline in Serum Ferritin Levels
timeFrame: Double-blind Period: Baseline through Week 48
measure: Double-blind Period: Change From Baseline in Total Iron Binding Capacity
timeFrame: Double-blind Period: Baseline through Week 48
measure: Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels
timeFrame: Double-blind Period: Baseline through Week 48
measure: Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
timeFrame: Double-blind Period: From first dose of study drug up to week 48
measure: Open-label Extension Period: Number of Participants With TEAEs, Serious TEAEs, Related TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to 3
timeFrame: Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)
measure: Double-blind Period: Plasma Concentrations of Mitapivat
timeFrame: Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
measure: Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat
timeFrame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
measure: Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat
timeFrame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
measure: Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat
timeFrame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
measure: Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat
timeFrame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
measure: Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
timeFrame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
measure: Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP)
timeFrame: Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
measure: Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)
timeFrame: Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: La Jolla
country: United States
facility: San Diego Hospital, UC San Diego Health
state: California
city: Oakland
country: United States
facility: Children's Hospital Oakland
state: California
city: Palo Alto
country: United States
facility: Stanford Medicine
state: California
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Penn Medicine - University of Pennsylvania Health System
state: Pennsylvania
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance, University of Washington
state: Washington
city: Ribeirão Preto
country: Brazil
facility: Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
city: São Paulo
country: Brazil
facility: GSH Banco de Sangue de São Paulo
city: Kyustendil
country: Bulgaria
facility: MHAT "Dr. Nikola Vasiliev" AD
city: Pleven
country: Bulgaria
facility: UMHAT "Dr. Georgi Stranski" Pleven
city: Plovdiv
country: Bulgaria
facility: UMHAT "Sveti Georgi" EAD
city: Sofia
country: Bulgaria
facility: SHATHD Sofia
city: Stara Zagora
country: Bulgaria
facility: UMHAT "Prof. Dr. Stoyan Kirkovich"
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Toronto
country: Canada
facility: Toronto General Hospital, University Health Network
state: Ontario
city: Hovedstaden
country: Denmark
facility: Rigshospitalet
city: Créteil
country: France
facility: CHU Hôpital Henri Mondor
city: Lyon
country: France
facility: Hôpital Edouard Herriot, CHU de Lyon
city: Marseille
country: France
facility: CHU Hôpital de la Timone
city: Paris
country: France
facility: Hôpital Necker Enfants Malades
city: Berlin
country: Germany
facility: Charité - UB - CVK - Medizinische Klinik
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Achaia
country: Greece
facility: University General Hospital of Patras
city: Athens
country: Greece
facility: Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
city: Athina
country: Greece
facility: Laiko General Hospital
city: Ioannina
country: Greece
facility: University Hospital of Ioannina
city: Thessaloníki
country: Greece
facility: Ippokrateio General Hospital
city: Brindisi
country: Italy
facility: Ospedale "A. Perrino" - Brindisi
city: Cagliari
country: Italy
facility: Ospedale Pediatrico Microcitemico
city: Ferrara
country: Italy
facility: Ospedale Sant'Anna
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Modena
country: Italy
facility: A.O.U Di Modena
city: Napoli
country: Italy
facility: AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
city: Orbassano
country: Italy
facility: A.O.U. San Luigi Gonzaga
city: Beyrouth
country: Lebanon
facility: Chronic Care Center
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah Johor Bahru
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth, Kota Kinabalu
city: Kota Setar
country: Malaysia
facility: Hospital Sultanah Bahiyah
city: Kuala Lumpur
country: Malaysia
facility: Hospital Tunku Azizah
city: Kuantan
country: Malaysia
facility: Hospital Tengku Ampuan Afzan
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
city: Pandan Indah
country: Malaysia
facility: Hospital Ampang
city: Pulau Pinang
country: Malaysia
facility: Hospital Pulau Pinang
city: Amsterdam
country: Netherlands
facility: Amsterdam Universitair Medisch Centrum, Locatie AMC
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Westzeedijk 353
country: Netherlands
facility: Erasmus MC
city: Riyadh
country: Saudi Arabia
facility: King Abdullah International Medical Research Center
city: Riyadh
country: Saudi Arabia
facility: King Khalid University Hospital
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Murcia
country: Spain
facility: Hospital Universitario Virgen Arrixaca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Bangkok
country: Thailand
facility: Phramongkutklao Hospital
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital
city: Bangkok
country: Thailand
facility: Faculty of Medicine Siriraj Hospital
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
city: Mueang Khon Kaen
country: Thailand
facility: Srinagarind Hospital, Khon Kaen University
city: Mueang Phitsanulok
country: Thailand
facility: Naresuan University Hospital
city: Pathum Wan
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Adana
country: Turkey
facility: Acibadem Adana Hospital
city: Antalya
country: Turkey
facility: Akdeniz University Faculty of Medicine
city: Balcali
country: Turkey
facility: Çukurova University
city: Bornova
country: Turkey
facility: Ege University Faculty of Medicine
city: Fatih
country: Turkey
facility: Istanbul University Faculty of Medicine
city: Mersin
country: Turkey
facility: Hacettepe University
city: Abu Dhabi
country: United Arab Emirates
facility: Burjeel Medical City
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References: