A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)

Transfusion-dependent Beta-Thalassemia Clinical Trial

— ENERGIZE-T  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04770779
• Other study ID #: AG348-C-018
• Secondary ID: 2021-000212-34
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 30, 2021
• Est. completion date: June 2029

Study information

• Verified date: June 2024
• Source: Agios Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary purpose of this study is to compare the effect of mitapivat versus placebo on transfusion burden in participants with transfusion-dependent alpha- or beta-thalassemia (TDT).

Description:

The mitapivat group will include approximately 160 participants. The placebo group will include approximately 80 participants.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 258
• Est. completion date: June 2029
• Est. primary completion date: April 11, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Documented diagnosis of thalassemia (ß-thalassemia with or without a-globin gene mutations, hemoglobin E (HbE)/ß-thalassemia, or a-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis;

• Considered transfusion-dependent, defined as 6 to 20 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 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).

Related Conditions & MeSH terms

• alpha-Thalassemia
• beta-Thalassemia
• Thalassemia
• Transfusion-dependent Alpha-Thalassemia
• Transfusion-dependent Beta-Thalassemia

Intervention

Drug:
• Placebo Matching Mitapivat
Tablets
• Mitapivat
Tablets

Locations

Country	Name	City	State
Brazil	Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP	Ribeirão Preto
Brazil	GSH Banco de Sangue de São Paulo	São Paulo
Bulgaria	MHAT "Dr. Nikola Vasiliev" AD	Kyustendil
Bulgaria	UMHAT "Dr. Georgi Stranski" Pleven	Pleven
Bulgaria	UMHAT "Sveti Georgi" EAD	Plovdiv
Bulgaria	SHATHD Sofia	Sofia
Bulgaria	UMHAT "Prof. Dr. Stoyan Kirkovich"	Stara Zagora
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Toronto General Hospital, University Health Network	Toronto	Ontario
Denmark	Rigshospitalet	Hovedstaden
France	CHU Hôpital Henri Mondor	Créteil
France	Hôpital Edouard Herriot, CHU de Lyon	Lyon
France	CHU Hôpital de la Timone	Marseille
France	Hôpital Necker Enfants Malades	Paris
Germany	Charité - UB - CVK - Medizinische Klinik	Berlin
Germany	Universitätsklinikum Essen	Essen
Germany	Universitätsklinikum Leipzig	Leipzig
Greece	University General Hospital of Patras	Achaia
Greece	Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School	Athens
Greece	Laiko General Hospital	Athina
Greece	University Hospital of Ioannina	Ioannina
Greece	Ippokrateio General Hospital	Thessaloníki
Italy	Ospedale "A. Perrino" - Brindisi	Brindisi
Italy	Ospedale Pediatrico Microcitemico	Cagliari
Italy	Ospedale Sant'Anna	Ferrara
Italy	Ente Ospedaliero Ospedali Galliera	Genova
Italy	Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico	Milano
Italy	A.O.U Di Modena	Modena
Italy	AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli	Napoli
Italy	A.O.U. San Luigi Gonzaga	Orbassano
Lebanon	Chronic Care Center	Beyrouth
Malaysia	Hospital Sultanah Aminah Johor Bahru	Johor Bahru
Malaysia	Hospital Queen Elizabeth, Kota Kinabalu	Kota Kinabalu
Malaysia	Hospital Sultanah Bahiyah	Kota Setar
Malaysia	Hospital Tunku Azizah	Kuala Lumpur
Malaysia	Hospital Tengku Ampuan Afzan	Kuantan
Malaysia	Hospital Umum Sarawak	Kuching
Malaysia	Hospital Ampang	Pandan Indah
Malaysia	Hospital Pulau Pinang	Pulau Pinang
Netherlands	Amsterdam Universitair Medisch Centrum, Locatie AMC	Amsterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Netherlands	Erasmus MC	Westzeedijk 353
Saudi Arabia	King Abdulaziz Hospital - Al Ahsa	Al-Ahsa
Saudi Arabia	King Abdullah International Medical Research Center	Riyadh
Saudi Arabia	King Khalid University Hospital	Riyadh
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen Arrixaca	Murcia
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	National Taiwan University Hospital	Taipei
Thailand	Faculty of Medicine Siriraj Hospital	Bangkok
Thailand	Phramongkutklao Hospital	Bangkok
Thailand	Ramathibodi Hospital	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Srinagarind Hospital, Khon Kaen University	Mueang Khon Kaen
Thailand	Naresuan University Hospital	Mueang Phitsanulok
Thailand	King Chulalongkorn Memorial Hospital	Pathum Wan
Turkey	Acibadem Adana Hospital	Adana
Turkey	Akdeniz University Faculty of Medicine	Antalya
Turkey	Çukurova University	Balcali
Turkey	Ege University Faculty of Medicine	Bornova
Turkey	Istanbul University Faculty of Medicine	Fatih
Turkey	Hacettepe University	Mersin
United Arab Emirates	Burjeel Medical City	Abu Dhabi
United Kingdom	Imperial College Healthcare NHS Trust - Hammersmith Hospital	London
United Kingdom	University College London	London
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Dana Faber Cancer Institute	Boston	Massachusetts
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	San Diego Hospital, UC San Diego Health	La Jolla	California
United States	Weill Cornell Medical Center	New York	New York
United States	Children's Hospital Oakland	Oakland	California
United States	Stanford Medicine	Palo Alto	California
United States	Penn Medicine - University of Pennsylvania Health System	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Seattle Cancer Care Alliance, University of Washington	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Agios Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Brazil,  Bulgaria,  Canada,  Denmark,  France,  Germany,  Greece,  Italy,  Lebanon,  Malaysia,  Netherlands,  Saudi Arabia,  Spain,  Taiwan,  Thailand,  Turkey,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Transfusion Reduction Response (TRR)	TRR is defined as =50% reduction in transfused red blood cells (RBC) units with a reduction of =2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline.	Baseline up to Week 48
Secondary	Percentage of Participants With =33% Reduction in Transfused RBC Units From Week 13 Through Week 48 Compared With Baseline		Baseline, Week 13 up to Week 48
Secondary	Percentage of Participants With =50% Reduction in Transfused RBC Units in Any Consecutive 24-week Period Through Week 48 Compared With Baseline		Baseline up to Week 48
Secondary	Percentage of Participants With =50% Reduction in Transfused RBC Units From Week 13 Through Week 48 Compared With Baseline		Baseline, Week 13 up to Week 48
Secondary	Change From Baseline in Transfused RBC Units From Week 13 Through Week 48		Baseline, Week 13 up to Week 48
Secondary	Percentage of Participants With Transfusion-Independence	Transfusion-independence is defined as transfusion-free for =8 consecutive weeks through Week 48.	Up to Week 48
Secondary	Change From Baseline in Iron Through Week 48		Baseline, Week 48
Secondary	Change From Baseline in Serum Ferritin Through Week 48		Baseline, Week 48
Secondary	Change From Baseline in Total Iron Binding Capacity Through Week 48		Baseline, Week 48
Secondary	Change From Baseline in Transferrin Saturation Through Week 48		Baseline, Week 48
Secondary	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)		Up to Week 317
Secondary	Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs), Graded by Severity	AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03) from Grades 1 to 4 where Grade 1 is mild and Grade 4 is life-threatening.	Up to Week 317
Secondary	Percentage of Participants with Adverse Events (AEs) Considered by the Investigator to be Related to Study Drug		Up to Week 317
Secondary	Percentage of Participants with Serious Adverse Events (SAEs) Considered by the Investigator to be Related to Study Drug		Up to Week 317
Secondary	Plasma or Blood Concentrations Over Time for Mitapivat		Pre-dose Week 12; pre-dose Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Secondary	Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Mitapivat		Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Secondary	Maximum Plasma Concentration (Cmax) of Mitapivat		Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Secondary	Time of Maximum Plasma Concentration (Tmax) of Mitapivat		Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Secondary	Blood Concentration of Adenosine Triphosphate (ATP)		Pre-dose Day 1; pre-dose Week 12; pre-dose Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Secondary	Blood Concentration of 2,3 - diphosphoglycerate (2,3-DPG)		Pre-dose Day 1; pre-dose Week 12; pre-dose Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36