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

• ClinicalTrials.gov Identifier: NCT03559699
• Recruitment Status: Recruiting
• First Posted: June 18, 2018
• Last Update Posted: September 17, 2019
• Sponsor: Agios Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Agios Pharmaceuticals, Inc.

Study Description

Brief Summary:

Study AG348-C-007 is a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, subjects with pyruvate kinase deficiency (PKD), who are regularly receiving blood transfusions. The study is comprised of two parts. During the Part 1 Dose Optimization Period of the study, all participants will start on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose will be optimized individually, up to a maximum dose of 50 milligrams (mg), twice daily. During the Part 2 Fixed-Dose Period, participants will receive AG-348 at their optimized dose from Part 1.

Condition or disease	Intervention/treatment	Phase
Pyruvate Kinase Deficiency; Anemia, Hemolytic	Drug: AG-348	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• 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
• Estimated Primary Completion Date: January 2021
• Estimated Study Completion Date: January 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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) ]

Secondary Outcome Measures :

1. 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) ]
2. Number of Transfusion Episodes in Part 2 [ Time Frame: Part 2, Day 1 to the end of study (Part 2, Week 24) ]
3. Percentage of Transfusion-Free Participants in Part 2 [ Time Frame: Part 2, Day 1 to the end of study (Part 2, Week 24) ]
4. 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) ]
5. Bone Mineral Density T-Score [ Time Frame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24 ]
6. Bone Mineral Density Z-Score [ Time Frame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24 ]
7. Percentage of Participants Experiencing an Adverse Event [ Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31) ]
8. Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI) [ Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31) ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Medical Affairs; 833-228-8474; medinfo@agios.com

  Show 23 Study Locations

Sponsors and Collaborators

Agios Pharmaceuticals, Inc.

Investigators

• Study Chair: Medical Affairs; Agios Pharmaceuticals, Inc.

More Information

• Responsible Party: Agios Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03559699 History of Changes
• Other Study ID Numbers: AG348-C-007
• First Posted: June 18, 2018
• Last Update Posted: September 17, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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