An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 90
- 试验地点
- 42
- 主要终点
- All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
研究概览
简要总结
This is an open-label, multicenter, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with mitapivat in participants who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be willing and able to comply with study visits and procedures.
- •Have signed written informed consent prior to participating in this extension study.
- •Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit.
- •Cohorts 2 and 3: Have demonstrated clinical benefit from mitapivat treatment in the antecedent study, in the opinion of the Investigator.
- •For women of reproductive potential, have a negative pregnancy test during screening of this extension study.
- •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 drug for women and 90 days following the last dose of study drug for men.
排除标准
- •Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG- 348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the participant to complete study visits and procedures.
- •Are currently pregnant or breastfeeding.
- •Have a splenectomy scheduled during the study treatment period.
- •Meet the withdrawal criteria of his/her antecedent mitapivat study during screening of this extension study.
- •Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4 that have not been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug on this extension study.
- •Have received anabolic steroids, including testosterone preparations, within 28 days prior to start of study drug on this extension study.
- •Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this extension study.
- •Have exposure to any investigational drug other than mitapivat, device, or procedure within 3 months prior to start of study drug on this extension study.
研究组 & 干预措施
Cohort 1
Participants who received placebo in Study AG348-C-006 and met the eligibility criteria of this extension study were enrolled to receive mitapivat tablets, 5 milligrams (mg), twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined at Week 12, and participants then received that optimized dose for a period of 12 weeks (Weeks 13-24) as a fixed dose and from Week 25 to Week 193, until study withdrawal, or the study was closed.
干预措施: Mitapivat (Drug)
Cohort 2
Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-006 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.
干预措施: Mitapivat (Drug)
Cohort 3
Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-007 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.
干预措施: Mitapivat (Drug)
结局指标
主要结局
All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
时间窗: Up to 197 weeks
A clinical adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation
时间窗: Up to 197 weeks
A clinical AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Number of participants with TEAEs leading to dose reduction, treatment interruption and treatment discontinuation are reported.
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs
时间窗: Up to 197 weeks
Clinical laboratory assessments including hematology, clinical chemistry, triglycerides, urate, coagulation, urinalysis, and liver function tests were performed in the study. Clinically significant treatment-emergent laboratory abnormalities were graded according to the NCI CTCAE; Version 4.03: grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. Clinical significance was determined based on the judgment of the Investigator.
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs
时间窗: Up to 197 weeks
Vital signs and physical examinations including height, weight, body mass index (BMI), systolic blood pressure, diastolic blood pressure, pulse rate, temperature were assessed. Number of participants who experienced clinically significant abnormalities in vital signs and physical examinations as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD)
时间窗: Up to 192 weeks
BMD was measured by dual-energy X-ray absorptiometry (DXA) scans during the study. Number of participants with clinically significant abnormalities were reported. Clinical significance was determined based on the judgment of the Investigator.
All Cohorts: Change From Baseline in Adjusted Spine T-score
时间窗: Baseline, Week 192
T-score of adjusted spine were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between \< -1 and \> -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.
All Cohorts: Change From Baseline in Adjusted Spine Z-score
时间窗: Baseline, Week 192
The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
All Cohorts: Change From Baseline in Femoral Total T-score
时间窗: Baseline, Week 192
T-score of femoral total were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between \< -1 and \> -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.
All Cohorts: Change From Baseline in Femoral Total Z-score
时间窗: Baseline, Week 192
The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs
时间窗: Up to 197 weeks
The following ECG parameters including RR, PR, heart rate-corrected QT interval using the Fridericia's formula (QRS), QT, and QTc were assessed during the study. Number of Participants with clinically significant abnormalities in ECG parameters as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.
次要结局
- Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat(Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12)
- Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat(Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12)
- Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response(Baseline up to Week 24)
- Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24(Baseline, Weeks 16, 20, and 24)
- Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat(Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12)
- Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat(Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12)
- Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat(Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12)
- Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat(Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12)
- Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters(First dose to up to 24 weeks)
- Cohorts 1 and 2: Change From Baseline in Hb Concentration(Baseline, Week 192)
- Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin(Baseline, Week 192)
- Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)(Baseline, Week 192)
- Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels(Baseline, Week 192)
- Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio(Baseline, Week 192)
- Cohort 3: Change From Baseline in Number of Transfusion Episodes(Baseline, Week 192)
- Cohort 3: Change From Baseline in Number of Red Blood Cell (RBC) Units Transfused(Baseline, Week 192)
- All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)(Baseline, Week 24)
- All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)(Baseline, Week 24)