Clinical trial NCT04770753: A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT)
Official title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Mitapivat in Subjects With Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non-Transfusion-dependent Alpha-Thalassemia
Non-Transfusion-dependent Beta-Thalassemia
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-02-25
Enrollment: 194
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 purpose of this study was to compare the effect of mitapivat versus placebo on hemolytic anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).

Detailed description: The mitapivat group included 130 participants whereas the placebo group had 64 participants.

Eligibility criteria: Inclusion Criteria:

* 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 Hb electrophoresis, Hb high-performance liquid chromatography (HPLC)), and/or deoxyribonucleic acid (DNA) analysis;
* Hb concentration ≤10.0 grams per deciliter (g/dL) (100.0 grams per liter \[g/L\]), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period;
* Non-transfusion-dependent, defined as ≤5 red blood cell (RBC) units during the 24-week period before randomization; and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions during the Screening Period;
* If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
* Women of child-bearing potential (WOCBP) must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 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 (HbS) or hemoglobin C (HbC);
* 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 ≥18 weeks before randomization;
* Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization;
* History of malignancy, (active or treated) ≤5 years before providing informed consent;
* History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
* Hepatobiliary disorders;
* Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 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) ≤16 weeks 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 ≥10 weeks before randomization;
* Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD\&C Blue #2\]);
* 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 Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline
timeFrame: Double-Blind Period: Baseline up to Week 12 through Week 24
Secondary outcomes:
measure: Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24
timeFrame: Double-Blind Period: Baseline, Week 12 through Week 24
measure: Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24
timeFrame: Double-Blind Period: Baseline, Week 12 through Week 24
measure: Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline
timeFrame: Double-Blind Period: Baseline up to Week 12 through Week 24
measure: Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Change From Baseline in Haptoglobin at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Change From Baseline in Reticulocytes at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Change From Baseline in Erythropoietin at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24
timeFrame: Double-Blind Period: At Weeks 12, 16, 20, and 24
measure: Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24
timeFrame: Double-Blind Period: At Weeks 12, 16, 20, and 24
measure: Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
measure: Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24
timeFrame: Double-Blind Period: Baseline, Week 24
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 the time of signing informed consent to Week 24
measure: Double-Blind Period: Plasma Concentration of Mitapivat
timeFrame: Double-Blind Period: Pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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 20
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 at Week 20
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 at Week 20
measure: Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat
timeFrame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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 at Week 20
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, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
measure: Open-Label Extension Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to Grade 3
timeFrame: Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: San Diego Hospital, UC San Diego Health
state: California
city: Palo Alto
country: United States
facility: Stanford Medicine
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
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: Caxias Do Sul
country: Brazil
facility: Universidade de Caxias do Sul
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
city: Rio De Janeiro
country: Brazil
facility: HEMORIO Instituto Nacional de Hematologia
city: Santo André
country: Brazil
facility: Praxis Pesquisa Medica
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
city: São Paulo
country: Brazil
facility: GSH Banco de Sangue de São Paulo
city: Kyustendil
country: Bulgaria
facility: MHAT "Dr. Nikola Vasiliev" AD
city: Sofia
country: Bulgaria
facility: SHATHD Sofia
city: Toronto
country: Canada
facility: Toronto General Hospital, University Health Network
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Créteil
country: France
facility: CHU Hôpital Henri Mondor
city: Lyon
country: France
facility: Hopital Edouard Herriot, CHU de Lyon
city: Athens
country: Greece
facility: Laiko General Hospital
city: Athens
country: Greece
facility: Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
city: Rio
country: Greece
facility: University General Hospital of Patras
city: Thessaloniki
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 Ca' Granda Ospedale Maggiore Policlinico
city: Modena
country: Italy
facility: A.O.U Di Modena
city: Napoli
country: Italy
facility: A.O.R.N. "A. Cardarelli"
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: Alor Setar
country: Malaysia
facility: Hospital Sultanah Bahiyah
city: Ampang
country: Malaysia
facility: Hospital Ampang
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah Johor Bahru
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth, Kota Kinabalu
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: Pulau Pinang
country: Malaysia
facility: Hospital Pulau Pinang
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Al-Mubarraz
country: Saudi Arabia
facility: King Abdulaziz Hospital - Al Ahsa
city: Riyadh
country: Saudi Arabia
facility: King Abdullah International Medical Research Center
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: Taichung
country: Taiwan
facility: China Medical University, Taiwan
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: 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: Dubai
country: United Arab Emirates
facility: Thalassemia Centre Dubai
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital
state: CAM
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary, Manchester University NHS Foundation Trust
state: LAN
city: London
country: United Kingdom
facility: University College London
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References: