A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

December 14, 2021 updated by: Agios Pharmaceuticals, Inc.

An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency

Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348 was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their optimized dose from Part 1.

Study Overview

Status

Completed

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

27

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

      • Toronto, Canada, M5G 2C4
        • Toronto General Hospital, University Health Network
      • Herlev, Denmark, 2730
        • University of Copenhagen, Herlev Hospital
      • Créteil, France, 94010
        • Hôpital Universitaire Henri Mondor
      • Marseille, Cedex 5, France, 13385
        • Hopital de la Timone
      • Dublin, Ireland
        • St James's Hospital Department of Haematology
      • Milano, Italy, 20122
        • Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
      • Napoli, Italy, 80138
        • AOU Policlinico, Università della Campania "Luigi Vanvitelli"
      • Napoli, Italy, 80131
        • AORN Cardarelli
      • Napoli, Italy, 80131
        • Ospedale Galliera
      • Utrecht, Netherlands, 3584
        • Universitair Medisch Centrum Utrecht
      • Bangkok, Thailand, 10700
        • Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University
      • Cambridge, United Kingdom, CB2 0QQ
        • Addenbrooke's Hospital
      • London, United Kingdom, WC1E 6BT
        • University College London
      • London, United Kingdom, W12 0NN
        • Imperial College Healthcare NHS Trust, Hammersmith Hospital
      • Manchester, United Kingdom, M13 9WL
        • Manchester Royal Infirmary
    • California
      • Oakland, California, United States, 94609
        • UCSF Benioff Children's Hospital
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Massachusetts General Hospital
    • 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

16 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 or older;
  • Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR) gene, of which at least 1 is a missense mutation;
  • History of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent;
  • Complete records of transfusion history for the 52 weeks prior to the date of informed consent, including all transfusion dates, number of blood units transfused for all the transfusions, and Hb concentrations within 1 week prior to transfusion for at least 80% of the transfusions;
  • Have received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation;
  • Have adequate organ function;
  • Negative serum pregnancy test for women of reproductive potential;
  • For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential: be abstinent 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 AG-348;
  • Willing to comply with all study procedures, in particular the individual transfusion trigger (TT) calculated based on 52 weeks of transfusion history, 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 participate in the study, and/or that could confound the interpretation of the study data;
  • History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to date of informed consent;
  • 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. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted;
  • Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug;
  • 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 CYP3A4, 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 5 times their half-lives (whichever is longer) prior to start of study drug;
  • Currently receiving hematopoietic stimulating agents (eg, erythropoietins [EPOs], granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study drug;
  • 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;
  • Allergy to AG-348 or its excipients;
  • Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to the first dose of study drug.

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: AG-348
Participants received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimized dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2.

Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance.

Part 2 (Fixed Dose Period): Optimized dose determined in Part 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2
Time Frame: From Part 2, Day 1 to Part 2 Week 24
Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardized to 24 weeks compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardized to 24 weeks.
From Part 2, Day 1 to Part 2 Week 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annualized Number of RBC Units Transfused During the Study
Time Frame: Part 1 Day 1 to Part 2 Week 24
The annualized total number of RBC units transfused during the entire study (both Part 1 and Part 2) is reported. It was calculated as the total number of RBC units transfused up to the end of Fixed Dose Period divided by the total number of days from the first dose date until the end date of Fixed Dose Period × 52.
Part 1 Day 1 to Part 2 Week 24
Number of Transfusion Episodes in Part 2
Time Frame: From Part 2 Day 1 to Part 2 Week 24
This is the number of transfusion episodes in Part 2. The number of transfusion episodes were standardized to 24 weeks. Transfusions received over up to 3 consecutive days were counted as 1 episode.
From Part 2 Day 1 to Part 2 Week 24
Percentage of Transfusion-Free Participants in Part 2
Time Frame: From Part 2 Day 1 to Part 2 Week 24
Transfusion-free responders were the participants who were transfusion-free in Part 2.
From Part 2 Day 1 to Part 2 Week 24
Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2
Time Frame: From Part 2 Day 1 to Part 2 Week 24
This is the percentage of participants who achieved hemoglobin (Hb) concentrations in the normal range at least once, 8 weeks or more after a transfusion in Part 2.
From Part 2 Day 1 to Part 2 Week 24
Percentage of Participants With Adverse Events
Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. 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.
Through 4 weeks after last dose (approximately Part 2, Week 31)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)
Time Frame: From Part 1 Day 1 to end of Part 2, including follow-up (Day 197)
An AE is 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.
From Part 1 Day 1 to end of Part 2, including follow-up (Day 197)
Bone Mineral Density Z-Score
Time Frame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24
Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24
Bone Mineral Density T-Score
Time Frame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24
Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

Collaborators and Investigators

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

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.

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)

June 26, 2018

Primary Completion (Actual)

November 12, 2020

Study Completion (Actual)

November 12, 2020

Study Registration Dates

First Submitted

March 26, 2018

First Submitted That Met QC Criteria

June 6, 2018

First Posted (Actual)

June 18, 2018

Study Record Updates

Last Update Posted (Actual)

January 4, 2022

Last Update Submitted That Met QC Criteria

December 14, 2021

Last Verified

December 1, 2021

More Information

Terms related to this study

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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