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Trial record 3 of 8 for:    Pyruvate Kinase Deficiency

A Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02476916
Recruitment Status : Active, not recruiting
First Posted : June 22, 2015
Last Update Posted : February 5, 2020
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE June 10, 2015
First Posted Date  ICMJE June 22, 2015
Last Update Posted Date February 5, 2020
Actual Study Start Date  ICMJE June 26, 2015
Actual Primary Completion Date May 8, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2018)
Percentage of Participants Experiencing Adverse Events in the Core Period [ Time Frame: Day 1 to Week 24 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 17, 2015)
Safety: incidence of adverse events [ Time Frame: 24 weeks, on average ]
Change History Complete list of historical versions of study NCT02476916 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 17, 2015)
  • Pharmacokinetic parameters of AG-348 and its metabolite area-under-the-curve (AUC) 0-12hr [ Time Frame: 24 weeks ]
  • Pharmacokinetic parameters of AG-348 and its metabolite (Tmax) [ Time Frame: 24 weeks ]
  • Pharmacokinetic parameters of AG-348 and its metabolite (Cmax) [ Time Frame: 24 weeks ]
  • Pharmacokinetic parameters of AG-348 and its metabolite (Cl/F) [ Time Frame: 24 weeks ]
  • Change from baseline in whole blood concentration of adenosine triphosphate (ATP) [ Time Frame: 24 weeks ]
  • Change from baseline in whole blood concentration of 2,3 - diphosphoglycerate (2,3-DPG) [ Time Frame: 24 weeks ]
  • Change from baseline in hemoglobin. [ Time Frame: 24 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency
Official Title  ICMJE A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency
Brief Summary Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 in patients with PK deficiency.
Detailed Description This is a Phase 2, open label, two arm, multicenter, randomized, dose-ranging study during which adult patients with PK deficiency will receive multiple doses of AG-348 for up to 24 weeks (Core Period); eligible patients may enter an Extension Period to receive AG-348 for up to 8 additional years. Data will be reviewed on a regular basis and study design, dose and schedule will be adapted based on these reviews. The study will evaluate the safety and tolerability of multiple doses of AG-348, pharmacokinetic (PK) and pharmacodynamic (PD) profile of AG-348 and early indicators of clinical efficacy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pyruvate Kinase Deficiency
Intervention  ICMJE Drug: AG-348
See arm for intervention description.
Study Arms  ICMJE
  • Experimental: AG-348 50 mg
    Participants with PK deficiency received AG-348, 50 milligrams (mg), twice daily for the Core Period (Week 24). At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. Participants were assigned to initial doses (50 or 300mg) and were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges.
    Intervention: Drug: AG-348
  • Experimental: AG-348 300 mg
    Participants with PK deficiency received AG-348, 300 mg, twice daily for the Core Period (Week 24). At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. Participants were assigned to initial doses (50 or 300mg) and were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges.
    Intervention: Drug: AG-348
Publications *

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 21, 2016)
52
Original Estimated Enrollment  ICMJE
 (submitted: June 17, 2015)
75
Estimated Study Completion Date  ICMJE April 2025
Actual Primary Completion Date May 8, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Informed consent
  2. Male or female, aged 18 years and older
  3. Known medical history of PK deficiency
  4. PK deficiency confirmed by enzymatic assay at Screening
  5. Genotypic characterization of PKR gene at Screening
  6. Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1) gene to document underlying Gilbert's disease (Gilbert's disease pts are eligible)
  7. Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL
  8. Transfusion independent, defined as no more than 3 units of red blood cells (RBC) transfused in 12 months prior to the first day of study dosing and no transfusions within 4 months of first day of study dosing
  9. Splenectomized patients must have had the procedure at least 6 months prior to Screening and must be up-to-date in recommended vaccinations
  10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  11. Must be taking at least 1 mg folic acid daily in the 21 days prior to screening
  12. Adequate organ function defined by liver function, kidney function, platelet count and coagulation assessments
  13. Agreement to use approved contraceptive measures
  14. Women must not be breastfeeding

    For entry into the Extension Period, patients must meet criteria # 15-16:

  15. Must have completed 24 weeks of treatment during the Core Period and tolerated AG-348
  16. The treating Investigator agrees that there is a potential for clinical benefit to continued treatment and recommends participation in the Extension Period and the Medical Monitor approves

Exclusion criteria

  1. Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female
  2. Additional diagnosis of other congenital or acquired blood disorder
  3. Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic insufficiency
  4. Bone marrow or stem cell transplant
  5. Clinically symptomatic cholelithiasis or cholecystitis
  6. Currently enrolled in any other investigational trial. Participation in the PK Deficiency Natural History Study (NCT02053480) is permitted
  7. Exposure to any investigational drug, device or procedure within 28 days prior to screening or during trial participation
  8. Concurrent medical condition such as poorly controlled hypertension, heart failure, active infection, frequent post-splenectomy sepsis, Hepatitis B or C, Human Immunodeficiency Virus type 1 (HIV1) or Human Immunodeficiency Virus type 2 (HIV2) infection, poorly controlled diabetes mellitus, history of primary malignancy with the exception of curatively treated nonmelanomatous skin cancer, cervical cancer of breast cancer in situ
  9. Major surgery in the last 6 months
  10. Psychiatric disorder that could compromise the ability of the patient to cooperate with the study
  11. Serum bilirubin higher to the upper limit of normal attributable to factors other than hemolysis or Gilbert's Syndrome
  12. Use of restricted products known to strongly inhibit cytochrome P450 (CYP) 3A4 metabolism within 5 days prior to Prior Day 1 dosing, or to strongly induce cytochrome P450 3A4 (CYP3A4) metabolism within 28 days prior to Day 1 dosing, or to strongly inhibit P-glycoprotein transporter within 5 days prior to Day 1 dosing, or digoxin within 5 days prior to Day 1 dosing.
  13. Heart-rate corrected QT interval - Fridericia's method (QTcF) interval ˃ 450 ms in male, QTcF > 470 ms in female, with the exception of patients with a left Bundle Branch Block
  14. Cardiac arrhythmias that are clinically significant or treated with drugs that are substrates of CYP3A4
  15. Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson Syndrome
  16. Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to participate in the study
  17. Patients will not be permitted to enter the Extension Period if: The patient experienced AEs during the Core Period that are considered by the treating Investigator or the Sponsor's designated Medical Monitor to pose a significant safety risk to the patient if treatment were to be extended
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Italy,   Netherlands,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02476916
Other Study ID Numbers  ICMJE AG348-C-003
2015-000484-13 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Agios Pharmaceuticals, Inc.
Study Sponsor  ICMJE Agios Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Agios Pharmaceuticals, Inc.
Verification Date January 2020

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