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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03559699
Recruitment Status : Recruiting
First Posted : June 18, 2018
Last Update Posted : July 19, 2018
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Brief Summary:
Study AG348-C-007 is a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in approximately 15-20 adult participants 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 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 : April 2021
Estimated Study Completion Date : May 2021

Arm Intervention/treatment
Experimental: Part 1: Dose Optimization AG-348

Part 1 (Dose Optimization Period): Participants will receive AG-348 for approximately 16 to 24 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.

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) levels 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) ]

Information from the National Library of Medicine

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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 levels within 1 week prior to transfusion for at least 80% of the transfusions;
  • 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 effective forms of contraception from the time of giving informed consent, during the study, and for 30 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 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 60 days prior to the Screening Visit;
  • 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 providing 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 times their half-life prior to start of study drug dosing (Day 1 of Part 1);
  • History of allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, or rash of erythema multiforme type or Stevens-Johnson syndrome, or other serious clinical manifestations;
  • History of hypersensitivity to AG-348 or its excipients.

Information from the National Library of Medicine

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 identifier (NCT number): NCT03559699

Contact: Medical Affairs 833-228-8474

United States, California
UCSF Benioff Children's Hospital Not yet recruiting
Oakland, California, United States, 94609
Stanford University Not yet recruiting
Palo Alto, California, United States, 94304
United States, Georgia
Emory University Not yet recruiting
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Toronto General Hospital, University Health Network Not yet recruiting
Toronto, Canada, M5G 2C4
University of Copenhagen, Herlev Hospital Recruiting
Herlev, Denmark, 2730
CHU Amiens Picardie Not yet recruiting
Amiens, France, 80054
Hôpital de la Timone Not yet recruiting
Marseille, Cedex 5, France, 13385
St James's Hospital Department of Haematolog Not yet recruiting
Dublin, Ireland
Dipartimento di Scienze Cliniche e Biologiche Not yet recruiting
Orbassano, Torino, Italy, 10043
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Not yet recruiting
Milano, Italy, 20122
AORN Cardarelli Not yet recruiting
Napoli, Italy, 80131
Ospedale Galliera Not yet recruiting
Napoli, Italy, 80131
AOU Policlinico, Università della Campania "Luigi Vanvitelli" Not yet recruiting
Napoli, Italy, 80138
Ospedale Pediatrico Bambino Gesu Not yet recruiting
Roma, Italy, 00165
Universitair Medisch Centrum Utrecht Not yet recruiting
Utrecht, Netherlands, 3584
Hospital Universitari Germans Trias i Pujol Not yet recruiting
Badalona, Barcelona, Spain, 08916
Centre Hospitalier Universitaire Vaudois (CHUV) Not yet recruiting
Lausanne, Switzerland, 1011
Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University Not yet recruiting
Bangkok, Thailand, 10700
United Kingdom
Addenbrooke's Hospital Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Imperial College Healthcare NHS Trust, Hammersmith Hospital Recruiting
London, United Kingdom, W12 0NN
Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.

Responsible Party: Agios Pharmaceuticals, Inc. Identifier: NCT03559699     History of Changes
Other Study ID Numbers: AG348-C-007
First Posted: June 18, 2018    Key Record Dates
Last Update Posted: July 19, 2018
Last Verified: July 2018

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
Pyruvate Metabolism, Inborn Errors
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Hematologic Diseases
Genetic Diseases, Inborn
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases