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A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

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ClinicalTrials.gov Identifier: NCT03548220
Recruitment Status : Recruiting
First Posted : June 7, 2018
Last Update Posted : October 14, 2019
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE May 24, 2018
First Posted Date  ICMJE June 7, 2018
Last Update Posted Date October 14, 2019
Actual Study Start Date  ICMJE August 9, 2018
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2018)
Percentage of Participants Achieving a Hemoglobin Response (HR) in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03548220 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
  • Change from Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • Maximum Change from Baseline in Hb Concentration [ Time Frame: Baseline, Part 2, up to Week 24 ]
  • Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More [ Time Frame: Baseline, Part 2, up to Week 24 ]
  • Change from Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • 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 ]
  • Change from Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • Change from Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score [ Time Frame: Baseline, up to Week 24 ]
  • Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score [ Time Frame: Baseline, up to 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) ]
  • Change from Baseline in Bone Mineral Density Z-Score at Week 24 in Part 2 [ Time Frame: Baseline, Part 2: Week 24 ]
  • Change from Baseline in Bone Mineral Density T-Score at Week 24 in Part 2 [ Time Frame: Baseline, Part 2: Week 24 ]
  • 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 ]
  • Maximum Plasma Concentration (Cmax) for AG-348 [ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]
  • Time to Cmax (Tmax) for AG-348 [ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2018)
  • Change from Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • Maximum Change from Baseline in Hb Concentration [ Time Frame: Baseline, Part 2, up to Week 24 ]
  • Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More [ Time Frame: Baseline, Part 2, up to Week 24 ]
  • Change from Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • 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 ]
  • Change from Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • Change from Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2 [ Time Frame: Baseline, Part 2: Weeks 16, 20, 24 ]
  • Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score [ Time Frame: Baseline, up to Week 24 ]
  • Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score [ Time Frame: Baseline, up to Week 24 ]
  • Change from Baseline in Iron Biomarkers at Week 24 in Part 2 [ Time Frame: Baseline, 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) ]
  • Change from Baseline in Bone Mineral Density Z-Score at Week 24 in Part 2 [ Time Frame: Baseline, Part 2: Week 24 ]
  • Change from Baseline in Bone Mineral Density T-Score at Week 24 in Part 2 [ Time Frame: Baseline, Part 2: Week 24 ]
  • 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 ]
  • Maximum Plasma Concentration (Cmax) for AG-348 [ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]
  • Time to Cmax (Tmax) for AG-348 [ Time Frame: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Official Title  ICMJE 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
Brief Summary Study AG348-C-006 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. Participants will be randomized 1:1 to receive either AG-348 or matching placebo. The study is comprised of two parts. During the Part 1 Dose Optimization Period of the study, participants will start on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1, each participant's dose of AG-348 may be sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During the Part 2 Fixed-Dose Period, participants will receive AG-348 at their optimized dose from Part 1.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Pyruvate Kinase Deficiency
  • Anemia, Hemolytic
Intervention  ICMJE
  • 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.

  • 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.

Study Arms  ICMJE
  • 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.

    Intervention: Drug: AG-348
  • 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.

    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 5, 2018)
76
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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;
  • Hb concentration less than or equal to 10.0 g/dL regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
  • 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 with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, 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 study treatment for women and 90 days for men 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 12 months prior to signing informed consent;
  • Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; 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;
  • Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Medical Affairs 833-228-8474 medinfo@agios.com
Listed Location Countries  ICMJE Brazil,   Canada,   Czechia,   Denmark,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Poland,   Portugal,   Spain,   Switzerland,   Thailand,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03548220
Other Study ID Numbers  ICMJE AG348-C-006
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Agios Pharmaceuticals, Inc.
Study Sponsor  ICMJE Agios Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.
PRS Account Agios Pharmaceuticals, Inc.
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP