Clinical Trials Register

Summary
EudraCT Number:	2021-000212-34
Sponsor's Protocol Code Number:	AG348-C-018
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2021-000212-34

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE-T)

A.4.1

Sponsor's protocol code number

AG348-C-018

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04770779

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Agios Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Agios Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Agios Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Scientific Communications
B.5.3	Address:
B.5.3.1	Street Address	88 Sidney Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02139-4169
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 844 633 2332
B.5.6	E-mail	medinfo@agios.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mitapivat, Mitapivat sulfate, PYRUKYND
D.3.2	Product code	AG-348
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mitapivat
D.3.9.1	CAS number	2151847-10-6
D.3.9.2	Current sponsor code	AG-348 sulfate hydrate
D.3.9.3	Other descriptive name	AGI-1480, AGX-0841, AG-348, AG-348 hemisulfate
D.3.9.4	EV Substance Code	SUB181978
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Transfusion-Dependent Alpha- or Beta-Thalassemia

E.1.1.1

Medical condition in easily understood language

Thalassemia-genetic blood disorder where not enough hemoglobin is
produced.2Types-α &β
Transfusion-dependent thalassemias-Patients who do require regular transfusions.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.0
E.1.2	Level	LLT
E.1.2	Classification code	10081904
E.1.2	Term	Transfusion dependent thalassemia
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To compare the effect of mitapivat versus placebo on transfusion burden in subjects
with α- or β-transfusion dependent thalassemia (TDT)

E.2.2

Secondary objectives of the trial

• To compare the durability of the effect of mitapivat versus placebo on transfusion burden
• To evaluate the effect of mitapivat versus placebo on additional measures of transfusion burden
• To evaluate the effect of mitapivat versus placebo on iron metabolism
• To evaluate the safety of mitapivat
• To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ≥18 years of age at the time of providing informed consent.
2. Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, HbE/β-thalassemia, or α-thalassemia/HbH disease) based on DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, DNA analysis can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test, results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used.
3. Transfusion dependent, defined as 6 to 20 RBC units transfused and a ≤6-week transfusion-free period during the 24-week period before randomization.
4. If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization.
5. 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 2 forms of contraception, 1 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.
6. Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

E.4

Principal exclusion criteria

1. Pregnant, breastfeeding or parturient.
2. Documented history of homozygous or heterozygous HbS or HbC.
3. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
4. Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization.
5. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization.
6. History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ.
7. History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, including but not limited to:
a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia
b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
c. Heart rate–corrected QT interval using Fridericia’s method ≥450 milliseconds (males) or ≥470 milliseconds (females), except for right or left bundle branch block
d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50%
e. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated
8. Hepatobiliary disorders, including but not limited to:
a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis
b. Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not exclusionary)
c. History of drug-induced cholestatic hepatitis
d. Aspartate aminotransferase >2.5 × upper limit of normal (ULN); unless due to hemolysis and hepatic iron deposition) and alanine aminotransferase >2.5 × ULN (unless due to hepatic iron deposition)
9. Estimated glomerular filtration rate <45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
10. Nonfasting triglycerides >440 mg/dL (5 mmol/L).
11. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered ≥7 days before randomization.
12. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen.
13. Positive test for HIV-1 Ab or HIV-2 Ab.
14. History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study.
15. Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational treatment, whichever is longer) in any other clinical study involving an investigational treatment or device.
16. Receiving strong cytochrome P450 (CYP)3A4/5 inhibitors that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a time frame equivalent to 5 half-lives (whichever is longer), before randomization.
17. 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.
18. 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]).
19. 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:
• Subjects who are institutionalized by regulatory or court order
• Subjects 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)

E.5 End points

E.5.1

Primary end point(s)

• Transfusion reduction response (TRR), defined as a ≥50% reduction in transfused red blood cell (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

Please refer to the schedule of assessment

E.5.2

Secondary end point(s)

• ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with baseline (TRR3)
• ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with baseline (TRR2)
• ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with baseline (TRR4)
• Change from baseline in transfused RBC units from Week 13 through Week 48
• Transfusion independence, defined as transfusion-free for ≥8 consecutive weeks through Week 48
• Change from baseline in iron, serum ferritin, total iron binding capacity, and transferrin saturation through Week 48
• Type, severity, and relationship of adverse events (AEs) and serious adverse events
• Plasma or blood concentrations and pharmacokinetic parameters of mitapivat and pharmacodynamic parameters, including adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG)

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the schedule of assessment

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Targeted genotyping, exploratory analysis of biomarkers

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Egypt

Malaysia

Taiwan

Australia

Brazil

Canada

Lebanon

Saudi Arabia

Thailand

Turkey

United Kingdom

United States

Bulgaria

Denmark

France

Germany

Greece

Italy

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

234

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

240

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-04-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-01

P. End of Trial
P.	End of Trial Status	Ongoing

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