A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

May 20, 2022 updated by: Agios Pharmaceuticals, Inc.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency

Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Brazil
      • São Paulo, Brazil
        • Hospital Central da Faculdade de Medicina USP Cidade Universitaria
  • Canada
      • Hamilton, Canada, L8S 4LB
        • McMaster University - Health Sciences Centre
      • Toronto, Canada, M5G 2C4
        • Toronto General Hospital, University Health Network
  • Czechia
      • Prague, Czechia
        • Institute of Hematology and Blood Transfusion
  • Denmark
      • Herlev, Denmark, 2730
        • University of Copenhagen, Herlev Hospital
  • France
      • Amiens, France, 80054
        • CHU Amiens Picardie
      • Bordeaux, France
        • Hôpital Saint-André
      • Créteil, France, 94010
        • Hopital Henri-Mondor
      • Marseille, Cedex 5, France, 13385
        • Hopital De La Timone
      • Toulouse, France
        • Institut Claudius Regaud
  • Germany
      • Berlin, Germany
        • Charité University Medicine
      • Würzburg, Germany, 97080
        • Universitätsklinikum Würzburg
  • Italy
      • Genova, Italy, 16128
        • Ospedale Galliera
      • Milano, Italy, 20122
        • Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
      • Napoli, Italy, 80138
        • AOU Policlinico, Università della Campania "Luigi Vanvitelli"
  • Japan
      • Kyoto, Japan
        • Kyoto Katsura Hospital
      • Mie, Japan
        • Agios Investigative Site
      • Osaka, Japan, 534-0021
        • Osaka City General Hospital
      • Osaka, Japan
        • Kansai Medical University, Department of Pediatrics, Hirakata Hospital
      • Tokyo, Japan
        • Toho University Omori Medical Center
    • Miyagi
      • Sendai-City, Miyagi, Japan
        • Tohoku University Hospital
  • Korea, Republic of
      • Daegu 705-703, Korea, Republic of, 42415
        • Yeungnam University Hospital
  • Netherlands
      • Utrecht, Netherlands, 3584
        • Universitair Medisch Centrum Utrecht
  • Spain
      • Barcelona, Spain, 08035
        • Hospital U. Vall d'Hebron Servicio de Hematología Clínica
      • El Palmar, Spain, 30120
        • Hospital Clinico Universitario Virgen de la Arricaxa
      • Madrid, Spain, 28046
        • Hospital Universitario La Paz
  • Switzerland
      • Lausanne, Switzerland, 1011
        • Centre Hospitalier Universitaire Vaudois (CHUV)
  • Thailand
      • Bangkok, Thailand, 10700
        • Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
  • Turkey
      • Ankara, Turkey
        • Hacettepe University
  • United Kingdom
      • Cambridge, United Kingdom, 94609
        • Addenbrooke's Hospital
      • Liverpool, United Kingdom, L7 8XP
        • The Royal Liverpool and Broadgreen University
      • London, United Kingdom, W12 0NN
        • Imperial College Healthcare NHS Trust, Hammersmith Hospital
      • London, United Kingdom, W12 0NN
        • University College London
      • Manchester, United Kingdom, M13 9WL
        • Manchester Royal Infirmary
  • United States
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • University of Arkansas for Medical Sciences
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University
    • Indiana
      • Indianapolis, Indiana, United States, 46260
        • Indiana Hemophilia and Thrombosis Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States, 02115
        • The Children's Hospital Corporation d/b/a Boston's Children Hospital
    • Michigan
      • Detroit, Michigan, United States, 48304
        • Wayne State University School of Medicine, Children's Hospital of Michigan
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • Duke University
      • Greenville, North Carolina, United States, 27858
        • East Carolina University
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital Medical Center
    • Texas
      • Houston, Texas, United States, 77030
        • Houston Methodist Research Institute
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Primary Children's Hospital Univ. of Utah
    • Washington
      • Seattle, Washington, United States, 98109
        • Seattle Cancer Care Alliance

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Informed consent;
  • Male or female, aged 18 years or older;
  • Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
  • Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
  • Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;
  • Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation.
  • Adequate organ function;
  • Women of reproductive potential, have a negative serum pregnancy test;
  • 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 treatment for women and 90 days for men following the last dose of study treatment;
  • Willing to comply with all study procedures for the duration of the study;

Exclusion Criteria:

  • Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;
  • Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data;
  • Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent;
  • Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;
  • Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;
  • Prior treatment with a pyruvate kinase activator;
  • Prior bone marrow or stem cell transplant;
  • Currently pregnant or breastfeeding;
  • History of major surgery within 6 months of signing informed consent;
  • Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment;
  • Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment;
  • History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
  • History of allergy to AG-348 or its excipients;
  • Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.
Drug: Placebo
Placebo matching AG-348 tablets, administered to maintain the blind.
Experimental: AG-348, 5 mg
Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Drug: AG-348
AG-348 tablets.
Experimental: AG-348, 20 mg
Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Drug: AG-348
AG-348 tablets.
Experimental: AG-348, 50 mg
Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Drug: AG-348
AG-348 tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Time Frame: Baseline, Weeks 16, 20, 24
Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Weeks 16, 20, 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
Time Frame: Baseline, Weeks 16, 20, 24
This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Weeks 16, 20, 24
Maximum Change From Baseline in Hb Concentration
Time Frame: Baseline, up to Week 24
This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, up to Week 24
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
Time Frame: Baseline, up to Week 24
This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, up to Week 24
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
Time Frame: Baseline, Weeks 16, 20, 24
The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Weeks 16, 20, 24
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
Time Frame: Baseline, Weeks 16, 20, 24
The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Weeks 16, 20, 24
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
Time Frame: Baseline, Weeks 16, 20, 24
The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Weeks 16, 20, 24
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
Time Frame: Baseline, Weeks 16, 20, 24
The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Weeks 16, 20, 24
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
Time Frame: Baseline, Week 24
The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Week 24
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
Time Frame: Baseline, Week 24
The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Baseline, Week 24
Percentage of Participants With Adverse Events
Time Frame: From signing of informed consent form to the end of study, including follow-up (up to Day 197)
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
From signing of informed consent form to the end of study, including follow-up (up to Day 197)
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Maximum Plasma Concentration (Cmax) for AG-348
Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Time to Cmax (Tmax) for AG-348
Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Time to Last Measurable Concentration (Tlast) for AG-348
Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Time Frame: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.
From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Time Frame: Baseline, Week 24
Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants.
Baseline, Week 24

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants With Adverse Events of Special Interest (AESI)
Time Frame: Through 4 weeks after last dose (approximately Week 31)
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AESI can be serious or non-serious.
Through 4 weeks after last dose (approximately Week 31)
Change From Baseline in Bone Mineral Density Z-Score at Week 24
Time Frame: Baseline, Week 24
Baseline, Week 24
Change From Baseline in Bone Mineral Density T-Score at Week 24
Time Frame: Baseline, Week 24
Baseline, Week 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Agios Pharmaceuticals, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 9, 2018

Primary Completion (Actual)

October 9, 2020

Study Completion (Actual)

October 9, 2020

Study Registration Dates

First Submitted

May 24, 2018

First Submitted That Met QC Criteria

June 5, 2018

First Posted (Actual)

June 7, 2018

Study Record Updates

Last Update Posted (Actual)

May 24, 2022

Last Update Submitted That Met QC Criteria

May 20, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AG348-C-006

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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