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History of Changes for Study: NCT03548220
A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Latest version (submitted May 20, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 June 5, 2018 None (earliest Version on record)
2 July 18, 2018 Contacts/Locations, Study Status, Eligibility and Study Description
3 September 14, 2018 Recruitment Status, Study Status, Contacts/Locations, Eligibility and Outcome Measures
4 November 13, 2018 Study Status and Contacts/Locations
5 December 26, 2018 Contacts/Locations and Study Status
6 February 21, 2019 Contacts/Locations and Study Status
7 February 21, 2019 Study Status
8 March 5, 2019 Study Status
9 March 28, 2019 Contacts/Locations and Study Status
10 May 7, 2019 Contacts/Locations and Study Status
11 June 7, 2019 Contacts/Locations and Study Status
12 July 8, 2019 Contacts/Locations and Study Status
13 August 14, 2019 Study Status and Contacts/Locations
14 October 10, 2019 Contacts/Locations, Study Status, Eligibility and Study Description
15 November 20, 2019 Contacts/Locations and Study Status
16 December 10, 2019 Study Status
17 January 14, 2020 Study Status and Contacts/Locations
18 February 12, 2020 Study Status and Contacts/Locations
19 March 17, 2020 Recruitment Status, Study Status, Contacts/Locations and Study Design
20 April 9, 2020 Study Status
21 May 8, 2020 Study Status
22 June 4, 2020 Study Status
23 July 8, 2020 Study Status
24 August 6, 2020 Study Status
25 September 8, 2020 Study Status and Study Design
26 October 5, 2020 Study Status
27 November 9, 2020 Recruitment Status and Study Status
28 October 8, 2021
Quality Control Review has not concluded Returned: November 5, 2021
Outcome Measures, Study Status, Arms and Interventions, Document Section, IPDSharing, Contacts/Locations, Eligibility and Study Description
29 December 23, 2021
Quality Control Review has not concluded Returned: January 21, 2022
Outcome Measures, Adverse Events, Baseline Characteristics, Participant Flow, Arms and Interventions, Document Section, Study Status and Study Description
30 February 15, 2022
Quality Control Review has not concluded Returned: February 22, 2022
Outcome Measures, Study Status
31 May 20, 2022 Outcome Measures, Study Status
Comparison Format:

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Study NCT03548220
Submitted Date:  June 5, 2018 (v1)

Open or close this module Study Identification
Unique Protocol ID: AG348-C-006
Brief Title: A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Official Title: 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
Secondary IDs:
Open or close this module Study Status
Record Verification: June 2018
Overall Status: Not yet recruiting
Study Start: June 2018
Primary Completion: December 2020 [Anticipated]
Study Completion: January 2021 [Anticipated]
First Submitted: May 24, 2018
First Submitted that
Met QC Criteria:
June 5, 2018
First Posted: June 7, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
June 5, 2018
Last Update Posted: June 7, 2018 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Agios Pharmaceuticals, Inc.
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: This study will evaluate the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase deficiency (PKD), who are not 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.
Detailed Description:
Open or close this module Conditions
Conditions: Pyruvate Kinase Deficiency
Anemia, Hemolytic
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Triple (Participant, Care Provider, Investigator)
Allocation: Randomized
Enrollment: 76 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: AG-348

Part 1 (Dose Optimization Period): Participants will receive AG-348 for 12 weeks. Investigators will assess the need for dose increases every 4 weeks.

Part 2 (Fixed Dose Period): Participants will receive their optimized dose of AG-348 as determined by the individual's response in Part 1.

Drug: AG-348

Part 1 (Dose Optimization Period): 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 daily.

Placebo Comparator: Placebo

Part 1 (Dose Optimization Period): Participants will receive placebo matching AG-348 for 12 weeks. Investigators will assess the need for dose increases every 4 weeks.

Part 2 (Fixed Dose Period): Participants will receive their optimized dose of placebo matching AG-348 as determined by the individual's response in Part 1.

Drug: Placebo

Part 1 (Dose Optimization Period): Participants will begin by receiving placebo matching AG-348 orally, twice a day. Each participant's dose of placebo matching AG-348 may be increased to 20 mg twice a day or 50 mg twice a day depending on their response to the placebo matching AG-348 and their tolerance.

Part 2 (Fixed Dose Period): Last dose received in Part 1, twice daily.

Open or close this module Outcome Measures
Primary Outcome Measures:
1. Percentage of Participants Achieving a Hemoglobin Response (HR) in Part 2
[ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]

Secondary Outcome Measures:
1. Change from Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2
[ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]

2. Maximum Change from Baseline in Hb Concentration
[ Time Frame: Baseline, Part 2, up to Week 24 ]

3. Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
[ Time Frame: Baseline, Part 2, up to Week 24 ]

4. Change from Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2
[ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]

5. Change from Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 in Part 2
[ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]

6. Change from Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2
[ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]

7. Change from Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2
[ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]

8. Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score
[ Time Frame: Baseline, up to Week 24 ]

9. Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score
[ Time Frame: Baseline, up to Week 24 ]

10. Change from Baseline in Iron Biomarkers at Week 24 in Part 2
[ Time Frame: Baseline, Part 2: Week 24 ]

11. Percentage of Participants Experiencing an Adverse Event
[ Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31) ]

12. Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)
[ Time Frame: Through 4 weeks after last dose (approximately Part 2, Week 31) ]

13. Change from Baseline in Bone Mineral Density Z-Score at Week 24 in Part 2
[ Time Frame: Baseline, Part 2: Week 24 ]

14. Change from Baseline in Bone Mineral Density T-Score at Week 24 in Part 2
[ Time Frame: Baseline, Part 2: Week 24 ]

15. Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
[ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]

16. Maximum Plasma Concentration (Cmax) for AG-348
[ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]

17. Time to Cmax (Tmax) for AG-348
[ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]

18. Time to Last Measurable Concentration (Tlast) for AG-348
[ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]

Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • Informed consent;
  • Male or female, aged 18 years or older;
  • Documented clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
  • 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 and their partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 28 days (both men and women) 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 60 days prior to signing informed consent;
  • Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted; 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.
Open or close this module Contacts/Locations
Central Contact Person: Medical Affairs
Telephone: 833-228-8474
Email: medinfo@agios.com
Study Officials: Medical Affairs
Study Chair
Agios Pharmaceuticals, Inc.
Locations: United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
United States, California
UCSF Benioff Children's Hospital
Oakland, California, United States, 94609
Stanford University
Palo Alto, California, United States, 94304
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Indiana
Indiana Hemophilia and Thrombosis Center
Indianapolis, Indiana, United States, 46260
United States, Massachusetts
The Children's Hospital Corporation d/b/a Boston's Children Hospital
Boston, Massachusetts, United States, 02115
Massachusetts General Hospital
Boston, Massachusetts, United States, 46260
United States, Michigan
Wayne State University School of Medicine, Children's Hospital of Michigan
Detroit, Michigan, United States, 48304
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27705
United States, Texas
Houston Methodist Research Institute
Houston, Texas, United States, 77030
United States, Utah
Primary Children's Hospital Univ. of Utah
Salt Lake City, Utah, United States, 84112
Canada
Toronto General Hospital, University Health Network
Toronto, Canada, M5G 2C4
Denmark
University of Copenhagen, Herlev Hospital
Herlev, Denmark, 2730
France
CHU Amiens Picardie
Amiens, France, 80054
Hospital La Timone
Cedex 5, France, 13385
Henri-Mondor hospital
Créteil, France, 94010
CHU Grenoble, Hopital Nord Michallon
La Tronche, France, 38700
Hôpital Saint Vincent de Paul / Universite Catholique de lille / service d'hematologie
Lille, France, 59 000
Germany
Universitätsklinikum Würzburg
Würzburg, Germany, 97080
Italy
Ospedale Pediatrico Microcitemico
Cagliari, Italy, 09121
Ospedale Galliera
Genova, Italy, 16128
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Milano, Italy, 20122
AOU Policlinico, Università della Campania "Luigi Vanvitelli"
Napoli, Italy, 80138
Japan
Kansai Medical University, Department of Pediatrics, Hirakata Hospital
Osaka, Japan
Korea, Republic of
Yeungnam University Hospital
Daegu 705-703, Korea, Republic of, 42415
Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, Netherlands, 3584
Poland
Klinika Hematologii - Instytut Hematologii i Transfuzjologii
Warsaw, Poland, 02-776
Portugal
Hospital Universitário de Coimbra
Coimbra, Portugal, 3000-075
Spain
Hospital U. Vall d'Hebron Servicio de Hematología Clínica
Barcelona, Spain, 08035
Hospital de Sant Pau
Barcelona, Spain, 8041
Hospital universitario La Paz
Madrid, Spain, 28046
Spain, Barcelona
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain, 08916
Switzerland
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Switzerland, 1011
Thailand
Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
Bangkok, Thailand, 10700
United Kingdom
Addenbrooke's Hospital
Cambridge, United Kingdom, 94609
Imperial College Healthcare NHS Trust, Hammersmith Hospital
London, United Kingdom, W12 0NN
University College London
London, United Kingdom, W12 0NN
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links:
Available IPD/Information:

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