Clinical trial NCT03692052: A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
Official title: A Phase 2, Open-label, Multicenter Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Subjects With Non-transfusion-dependent Thalassemia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Thalassemia
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-10-02
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study AG348-C-010 is a multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of treatment with AG-348 in adult participants with non-transfusion-dependent thalassemia (NTDT). This study includes a core period (up to 24 weeks) followed by an extension period (up to 10 years) for eligible participants. 20 participants with NTDT were enrolled. The initial dose of AG-348 was 50 milligrams (mg) twice daily (BID) with one potential dose-level increase to 100 mg BID at the Week 6 visit based on the participant's safety and hemoglobin (Hb) concentrations.


Eligibility criteria: Inclusion Criteria:

* Informed consent;
* Known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes;
* Documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or deoxyribonucleic acid (DNA) analysis, either from medical records or during the screening period;
* Hb concentration ≤10.0 grams per deciliter (g/dL), regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the screening period;
* Considered non-transfusion-dependent, defined as having no more than 5 units of red blood cells (RBCs) transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug;
* Adequate organ function;
* For women of reproductive potential: negative serum pregnancy test during the screening period and a negative serum or urine pregnancy test on Day 1;
* 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 agreement 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 drug for women and 90 days following the last dose of study drug for men;
* Willingness to comply with all study procedures for the duration of the study;

Exclusion Criteria:

* Known history of diagnosis of Hb S or Hb C forms of thalassemia;
* Significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data;
* Splenectomy scheduled during the study treatment period or having 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;
* Exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug;
* Prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy;
* 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 day of study drug;
* Currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug;
* Currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug;
* Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins), if initiated ≤8 weeks prior to the first day of study drug;
* 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 (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).

Primary outcomes:
measure: Percentage of Participants Achieving a Hemoglobin Response (HR)
timeFrame: Up to 12 weeks
Secondary outcomes:
measure: Average Change From Baseline in Hb Concentrations From Week 12 to Week 24
timeFrame: Baseline, Week 12 to Week 24
measure: Percentage of Participants Achieving a Sustained Hb Response (sHR)
timeFrame: Week 12 to Week 24
measure: Percentage of Participants Achieving a Delayed Hb Response
timeFrame: Week 12 to Week 24
measure: Change From Baseline in Hb Concentration Over the Duration of the Extension Period
timeFrame: Baseline up to approximately 10.5 years
measure: Time to First ≥1.0 g/dL Increase in Hb Concentration
timeFrame: Up to Week 24
measure: Change From Baseline in Reticulocyte Count
timeFrame: Up to approximately 10.5 years
measure: Change From Baseline in Bilirubin
timeFrame: Up to approximately 10.5 years
measure: Change From Baseline in Lactate Dehydrogenase (LDH)
timeFrame: Up to approximately 10.5 years
measure: Change From Baseline in Haptoglobin
timeFrame: Up to approximately 10.5 years
measure: Change From Baseline in Nucleated Red Blood Cells (NRBCs)
timeFrame: Up to approximately 10.5 years
measure: Change From Baseline in Erythropoietin (EPO)
timeFrame: Up to approximately 10.5 years
measure: Change From Baseline in Soluble Transferrin Receptor
timeFrame: Up to approximately 10.5 years
measure: Drug Concentrations Over Time for AG-348
timeFrame: Predose (60 minutes) and 0.00 hour, 0.50 hour, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348
timeFrame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348
timeFrame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: Cmax: Maximum Observed Plasma Concentration of AG-348
timeFrame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax)
timeFrame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: Tlast: Time of the Last Quantifiable Concentration of AG-348
timeFrame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: Ctrough: Observed Plasma Concentration at the End of a Dosing Interval of AG-348
timeFrame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
measure: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), and TEAEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation
timeFrame: From signing the inform consent form up to data cut-off date: 20 August 2020 (Up to approximately 19 months)
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Toronto
country: Canada
facility: University Health Network (Toronto General Hospital)
state: Ontario
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust (Hammersmith Hospital)
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References:
citation: Kuo KHM, Layton DM, Lal A, Al-Samkari H, Bhatia J, Kosinski PA, Tong B, Lynch M, Uhlig K, Vichinsky EP. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study. Lancet. 2022 Aug 13;400(10351):493-501. doi: 10.1016/S0140-6736(22)01337-X.