A Single Arm, Open Label, Phase 1/2 Study to Evaluate the Pharmacokinetics and Safety of Etavopivat in Pediatric Patients With Sickle Cell Disease
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 95
- 试验地点
- 32
- 主要终点
- Single-dose: area under the plasma concentration time curve from dosing (time 0) to time t ((AUC)0-t)
研究概览
简要总结
The purpose of this study is to evaluate the pharmacokinetics and safety of etavopivat in paediatric participants with sickle cell disease (SCD). Participants will receive etavopivat and will be enrolled in a staggered manner, starting with the oldest age group and followed sequentially by younger cohorts after review of pharmacokinetic and safety data from the preceding cohort. All participants will undergo a 24-week primary treatment period followed by a 72-week extension treatment period to further evaluate long-term safety and pharmacokinetics of etavopivat. The total duration of the study will be approximately 96 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type of Participant and Disease Characteristics
- •Patient's parent, legal guardian, or legal representative has provided documented informed consent and patients have provided age-appropriate assent
- •Age greater than or equal to (≥) 6 months and lesser than (<) 18 years of age at time of enrollment, according to the enrolling cohort:
- •Cohort 1: age 12 to < 18 years (adolescents)
- •Cohort 2: age 6 to < 12 years
- •Cohort 3: age 2 to < 6 years
- •Cohort 4: age 6 months to < 2 years
- •Patient has confirmed diagnosis of SCD
- •Documentation of SCD genotype (HbSS, HbSβ0-thalassemia or other sickle cell syndrome variants) based on prior history of laboratory testing. Molecular genotyping is not required. SCD genotype may be determined from the results of Hb electrophoresis, high-performance liquid chromatography (HPLC), or similar testing. Note that Hb electrophoresis is performed by the local laboratory at Screening.
- •Hemoglobin ≥ 5.5 and lesser than or equal to (≤) 10.5 grams per deciliter (g/dL)
- •Pediatric patients with severe SCD, as defined by at least 1 of the following:
- •2-15 episodes of documented VOC within the 12 months prior to screening. Documentation must exist in the patient's medical record prior to screening. Events based solely on patient recall without supporting documentation should not be counted towards eligibility.
- •Hospitalization for any SCD-related complication in the last 12 months prior to starting study treatment
- •Proteinuria, defined as an albumin:creatinine ratio (ACR) > 100 mg/g on 2 measures (separated by ≥ 1 month) as an indicator of early renal disease
- •History of a conditional TCD in the last 12 months prior to starting study treatment, but not currently being treated with chronic transfusion therapy (applicable to participants > 2 years of age). Conditional TCD is defined as a TAMMV of 170-199 cm/s by TCD or 155-184 cm/s by imaging TCD (TCDi).
- •For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable (no more than a 20% change in dosing) for at least 90 days prior to start of study treatment with no anticipated need for dose adjustments during the study, in the opinion of the Investigator
- •Patients on crizanlizumab or L-glutamine treatment at the time of consent may be eligible if they:
- •Have been on a stable dose for ≥ 12 months at the time of consent (ie, no changes to the dose except for changes to weight or for safety reasons)
- •For patients on crizanlizumab, have been ≥ 80% compliant with the planned regimen during the 12 months prior to the time of consent
- •Female patients of childbearing potential who are using acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and male patients who are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug.
排除标准
- •Medical Conditions
- •Female who is breastfeeding or pregnant
- •More than 15 VOCs within the 12 months prior to starting study treatment that required a hospital, emergency room (ER), or clinic visit
- •Hospitalized for sickle cell crisis or other vaso-occlusive event occurring in the 14 days prior to starting study treatment
- •Abnormal TCD in the 12 months prior to starting study treatment
- •Prior/Concomitant Therapy
- •Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion)
- •Received any blood products within 30 days of starting study treatment
- •Receiving or use of concomitant medications that are strong inducers of cytochrome P450 (CYP) 3A4/5 within 2 weeks of starting study treatment
- •Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study
- •Receipt of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study
- •Receipt of prior cellular based therapy (eg, hematopoietic cell transplant, gene modification therapy)
研究组 & 干预措施
Cohort 1: Etavopivat (12 to less than [<] 18 years)
Participants aged 12 to less than 18 years with sickle cell disease will receive etavopivat to evaluate pharmacokinetics and safety in this age group.
干预措施: Etavopivat (Drug)
Cohort 2: Etavopivat (6 to <12 years)
Participants aged 6 to less than 12 years with sickle cell disease will receive etavopivat to evaluate pharmacokinetics and safety in this age group.
干预措施: Etavopivat (Drug)
Cohort 3: Etavopivat (2 to <6 years)
Participants aged 2 to less than 6 years with sickle cell disease will receive etavopivat to evaluate pharmacokinetics and safety in younger children.
干预措施: Etavopivat (Drug)
Cohort 4: Etavopivat (6 months to <2 years)
Participants aged 6 months to less than 2 years with sickle cell disease will receive etavopivat to evaluate pharmacokinetics and safety in infants.
干预措施: Etavopivat (Drug)
结局指标
主要结局
Single-dose: area under the plasma concentration time curve from dosing (time 0) to time t ((AUC)0-t)
时间窗: During the 24-week primary treatment period
Single-dose: area under the plasma concentration time curve from zero to time infinity (AUC0-inf)
时间窗: During the 24-week primary treatment period
Number of dose interruptions
时间窗: During the 24-week primary treatment period
Single-dose: maximum plasma concentration (Cmax)
时间窗: During the 24-week primary treatment period
Steady-state maximum plasma concentration (Cmax,ss)
时间窗: During the 24-week primary treatment period
Steady-state area under the concentration time curve over the dosing interval (AUCtau,ss)
时间窗: During the 24-week primary treatment period
Steady-state average plasma concentration (Cavg,ss)
时间窗: During the 24-week primary treatment period
Steady-state minimum plasma concentration (Cmin,ss)
时间窗: During the 24-week primary treatment period
Incidence of adverse events (AEs), serious adverse events (SAEs), and AEs related to etavopivat
时间窗: During the 24-week primary treatment period
Number of premature discontinuations
时间窗: During the 24-week primary treatment period
Number of dose reductions
时间窗: During the 24-week primary treatment period
次要结局
- Incidence of AEs, SAEs, and AEs related to etavopivat(During the 72-week treatment extension period)
- Number of premature discontinuations(During the 72-week treatment extension period)
- Number of dose interruptions(During the 72-week treatment extension period)
- Number of dose reductions(During the 72-week treatment extension period)
- Hemoglobin (Hb) response rate(Baseline, week 12 and 24)
- Change in Hb from baseline(Baseline, week 12 and 24)
- Change from baseline in Annualized Rate of VOC(Baseline and week 24)
- Change from baseline in number of vaso-occlusive crises (VOCs)(Baseline and week 24)
- Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale(Baseline, week 12 and 24)
- Change from baseline in time-averaged mean of the maximum velocity (TAMMV) by transcranial Doppler ultrasonography (TCD)(Baseline, week 24, 48, and 96)