A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
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ClinicalTrials.gov Identifier: NCT03559699 |
Recruitment Status :
Completed
First Posted : June 18, 2018
Last Update Posted : December 8, 2020
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Pyruvate Kinase Deficiency Anemia, Hemolytic | Drug: AG-348 | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 27 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency |
Actual Study Start Date : | May 25, 2018 |
Actual Primary Completion Date : | November 12, 2020 |
Actual Study Completion Date : | November 12, 2020 |

Arm | Intervention/treatment |
---|---|
Experimental: Part 1: Dose Optimization AG-348
Part 1 (Dose Optimization Period): Participants will receive AG-348 for up to 16 weeks. Part 2 (Fixed Dose Period): Participants will receive their optimized dose of AG-348 as determined by the individual participant's transfusion cycle and response to AG-348 in Part 1. |
Drug: AG-348
Part 1 (Dose Optimization Period): All participants will begin by receiving 5 milligrams (mg) orally, twice a day. Each participant's dose of AG-348 may be increased to 20 mg twice a day or 50 mg twice a day depending on their response to AG-348 and their tolerance. Part 2 (Fixed Dose Period): Last dose received in Part 1, twice a day. |
- Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2 [ Time Frame: From Part 2, Day 1 to the end of the study (Part 2, Week 24) ]
- Number of RBC Units Transfused During the Study [ Time Frame: From Part 1, Day 1 to the end of the study (Part 2, Week 24) ]
- Number of Transfusion Episodes in Part 2 [ Time Frame: Part 2, Day 1 to the end of study (Part 2, Week 24) ]
- Percentage of Transfusion-Free Participants in Part 2 [ Time Frame: Part 2, Day 1 to the end of study (Part 2, Week 24) ]
- Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2 [ Time Frame: Part 2, Day 1 to the end of study (Part 2, Week 24) ]
- Bone Mineral Density T-Score [ Time Frame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24 ]
- Bone Mineral Density Z-Score [ Time Frame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24 ]
- Percentage of Participants Experiencing an Adverse Event [ Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31) ]
- Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI) [ Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31) ]

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03559699

Study Chair: | Medical Affairs | Agios Pharmaceuticals, Inc. |
Responsible Party: | Agios Pharmaceuticals, Inc. |
ClinicalTrials.gov Identifier: | NCT03559699 |
Other Study ID Numbers: |
AG348-C-007 |
First Posted: | June 18, 2018 Key Record Dates |
Last Update Posted: | December 8, 2020 |
Last Verified: | December 2020 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Anemia, Hemolytic, Congenital Nonspherocytic Anemia, Hemolytic Pyruvate Metabolism, Inborn Errors Anemia, Hemolytic, Congenital Anemia |
Hematologic Diseases Genetic Diseases, Inborn Carbohydrate Metabolism, Inborn Errors Metabolism, Inborn Errors Metabolic Diseases |