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

• Register: ClinicalTrials.gov
• Last refreshed on: 30 May 2022
• Main ID: NCT03548220
• Date of registration: 24/05/2018
• Prospective Registration: Yes
• Primary sponsor: Agios Pharmaceuticals, Inc.
• Public title: A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
• Scientific 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
• Date of first enrolment: August 9, 2018
• Target sample size: 80
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03548220
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 3

Countries of recruitment

Brazil, Canada, Czechia, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Spain, Switzerland, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Medical Affairs
• Affiliation: Agios Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

Inclusion Criteria:

- Informed consent;

- Male or female, aged 18 years or older;

- Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency,
defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which
at least 1 is a missense mutation;

- Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (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.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Anemia, Hemolytic

Pyruvate Kinase Deficiency

Intervention(s)

Drug: AG-348

Drug: Placebo

Primary Outcome(s)

Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) [Time Frame: Baseline, Weeks 16, 20, 24]

Secondary Outcome(s)

Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 [Time Frame: Baseline, Weeks 16, 20, 24]

Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters [Time Frame: Baseline, Week 24]

Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 [Time Frame: Baseline, Weeks 16, 20, 24]

Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters [Time Frame: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)]

Maximum Plasma Concentration (Cmax) for AG-348 [Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 [Time Frame: Baseline, Weeks 16, 20, 24]

Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 [Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

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

Time to Cmax (Tmax) for AG-348 [Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

Time to Last Measurable Concentration (Tlast) for AG-348 [Time Frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

Maximum Change From Baseline in Hb Concentration [Time Frame: Baseline, up to Week 24]

Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 [Time Frame: Baseline, Weeks 16, 20, 24]

Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 [Time Frame: Baseline, Weeks 16, 20, 24]

Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 [Time Frame: Baseline, Week 24]

Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 [Time Frame: Baseline, Week 24]

Percentage of Participants With Adverse Events [Time Frame: From signing of informed consent form to the end of study, including follow-up (up to Day 197)]

Secondary ID(s)

AG348-C-006

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 24/05/2022
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03548220