CTRI/2024/11/076871尚未招募2 期
A Phase 2 Open-label Study to Evaluate the Activity of Etavopivat on Transcranial Doppler Velocities in Pediatric Patients with Sickle Cell Disease who are at Increased Risk for Primary Stroke
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 46
- 试验地点
- 5
- 主要终点
- To evaluate the impact of etavopivat on TCD velocities in patients with aTCD or cTCD velocities
研究概览
简要总结
This is an open-label, Phase 2 study in adolescent patients 12 to 16 years old (inclusive) with increased risk of stroke based on elevated TAMMV in the MCA and/or ICA as measured by TCD, including both cTCD and aTCD. The study will enroll 23 patients (accounting for potential 20% drop-out) into each of 2 treatment cohorts:
Cohort A: Single-agent etavopivat in patients with cTCD, or patients with aTCD who are not candidates for hydroxyurea (HU), as determined by investigator (11 maximum patients with cTCD)
Cohort B: Etavopivat in combination with HU – a) patients with aTCD on stable dose of HU, b) patients with cTCD on stable dose of HU (11 maximum patients)
Patients will be enrolled into a 52-week primary treatment period and a 48-week optional extension treatment period. The optional extension treatment period will allow continued assessment of safety of etavopivat in paediatric patients. A separate study is planned to offer study patients prolonged etavopivat treatment until available for prescription in their country or until development of etavopivat is otherwise discontinued. If/when such a study becomes available, patients may transfer to the new study after completion of the 52-week primary treatment period. Patients need to perform the assessments scheduled for End of Primary Treatment (EOPT) and will not complete the End of Study (EOS) visit before transfer to a separate study. This will potentially lead to closure of study 4202-HEM-204 before all patients have completed the optional extension treatment period. Etavopivat will be administered at 400 mg once daily (QD). The study objectives to assess impact on TCD velocities will be met after all subjects complete 52 weeks of treatment, discontinue, or withdraw
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- None
入排标准
- 年龄范围
- 12.00 Year(s) 至 16.00 Year(s)（—）
- 性别
- All
入选标准
- •Inclusion criteria: Participants are eligible to be included in the study only if all the following criteria apply: Informed Consent
- •Patient’s parent, legal guardian, or legal representative has provided documented informed consent and patients have provided age-appropriate assent Age
- •12 to 16 years of age (inclusive) at time of Screening Type of Participant and Disease Characteristics
- •Confirmed diagnosis of SCD a.
- •Documentation of any SCD genotype (e.g. HbSS, HbSβ0 -thalassemia) 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, or similar testing.
- •Note that Hb electrophoresis, and other forms of Hb subtype quantification, is performed by the local laboratory at Screening.
- •TAMMV Greater than or equal to 170 cm per s in the ICA and or MCA during the Screening Period and confirmed on 2 occasions (TCD No. 1 and No. 2; see Table 1 and Section 8.3.1) and without history of primary ischemic or hemorrhagic stroke, transient ischemic attack, or severe CNS vasculopathy on magnetic resonance angiography (MRA).
- •This includes patients with cTCD (170-199 cm per s) or aTCD (Greater than or equal to 200 cm per s).
- •Note: Patients with aTCD must have refused transfusion therapy.
- •Hb Greater than or equal to 6g per dL and Lesser than or equal to 9 g per dL at Screening.
- •For participants with aTCD and cTCD and already taking HU, the dose of HU (mg per kg) must be stable (no more than a 20-percentage change in dosing except for weight-based changes) for at least 90 days prior to start of study treatment with no anticipated need for dose adjustments except for weight-based changes during the study, in the opinion of the Investigator.
- •Patients, who if female and of childbearing potential, 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 who if male, 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
- •Exclusion criteria: Patients are excluded from the study if they meet any of the following criteria: Medical Conditions
- •Female who is breast feeding or pregnant
- •History of seizure disorder
- •Concern for significant CNS injury, defined as one or more of the following: a.
- •Prior overt stroke (a focal neurological deficit of acute onset) by history or significant concerns for history of overt stroke based on Screening MRI, b.
- •History of transient ischemic attack, c.
- •Focal neurological deficit on standardized neurological examination, d.
- •Concern for moderate or severe neurological deficit (which could be due to stroke) based on a positive “10 questions†screening (see Section 8.1.2).
- •Patients with significant or suggestive severe CNS vasculopathy (ie, moya moya, significant stenosis) of Grade 4 or higher based on MRA read locally.
- •Significant cytopenias (absolute neutrophil count [ANC] Lesser than 1.0 × 103 per µL, platelets Lesser than 100,000 per µL, hemoglobin Lesser than 8g per dL with reticulocytes Lesser than 80,000 per µL)
- •Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory Lesser than 30 mL per min per 1.73 m2) or on chronic dialysis
- •Hepatic dysfunction characterized by alanine aminotransferase (ALT) Greater than 4 × upper limit of normal (ULN) and or direct bilirubin Greater than 3 × ULN
- •Patients with clinically significant bacterial, fungal, parasitic, or viral infection requiring systemic therapy or history of such infections leading to significant neurological impairment: a.
- •Patients with acute bacterial, fungal, parasitic, or viral infection requiring systemic therapy should delay screening or enrollment until active therapy has been completed.
- •Patients enrolled in areas where malaria is prevalent must be on malaria prophylaxis based on regional guidance and resistance results.
- •Note: Infection prophylaxis is allowed (see concomitant medication restrictions).
- •Known human immunodeficiency virus (HIV) positivity
- •Known infection with hepatitis B virus (hepatitis B surface antigen [HepBsAg] and hepatitis B core antibody [HepBcAb] positive)
- •Positive Hepatitis C antibody
- •Untreated iron deficiency or other significant malnutrition detected or diagnosed by the Investigator
- •Significant malnutrition based on height, weight, BMI parameters or as deemed by the Investigator
- •Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
- •Prior or Concomitant Therapy
- •Current use within 28 days of starting study treatment or planned treatment with additional disease modifying therapies (i.e, voxelotor, L-glutamine, and crizanlizumab), including plans for initiating HU after enrollment.
- •For cohort A, patients must be off HU for at least 28 days prior to starting treatment.
- •Transfusion history restrictions defined as one or more of the following: a.
- •Transfusion within 90 days of informed consent/assent, b.
- •History of recently being on a regular transfusion program within the last 1 year or plans to implement a regular transfusion program (also termed chronic, prophylactic, or preventative transfusion), c.
- •History of RBC autoantibody, d.
- •Significant iron overload (ferritin Greater than 1000 ng per mL), or e.
- •History of significant alloimmunization to RBCs
- •Receiving or use of concomitant medications that are moderate/strong inducers of cytochrome p40 (CYP) 3A4 within 14 days of starting study treatment Prior or Concurrent Clinical Study Experience
- •Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of last dose prior to date of informed consent, whichever is longer, participated in other etavopivat trials, or is currently participating in another trial of an investigational agent (or medical device) Other Exclusions
- •Inadequate venous access as determined by the Investigator or site staff
- •Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent/assent
- •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 (e.g., hematopoietic cell transplant, gene modification therapy) 23.
结局指标
主要结局
To evaluate the impact of etavopivat on TCD velocities in patients with aTCD or cTCD velocities
时间窗: Baseline and Week 12
次要结局
- To evaluate the change in TCD velocity over time(Baseline, Weeks 2, 4, 24 and 52)
- To evaluate changes in category of TCD velocity over time(Weeks 2, 4, 12, 24, and 52)
研究者
研究点 (5)
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