A Phase II, Multicenter, Open-label, Randomized Two-year Study to Evaluate the Efficacy and Safety of Deferasirox Film-coated Tablet Versus Phlebotomy in Patients With Hereditary Hemochromatosis.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- Proportion of Patients Achieving Target SF ≤ 100 μg/L for the First Time
研究概览
简要总结
The purpose of this study was to evaluate the efficacy and safety of deferasirox film coated tablet (FCT) versus phlebotomy for the management of iron overload in adults with Hereditary Hemochromatosis (HH) at risk of iron-related morbidity. This evaluation provided information on the two treatment options in terms of the rate of response of proportion of patients reaching the study target SF ≤ 100 μg/L and their associated safety profiles.
In addition to exploring the safety and efficacy of deferasirox FCT in hereditary hemochromatosis (HH), this study is being conducted to fulfill an FDA post-marketing requirement [PMC 750-10 (Exjade) /PMR 2888-8 (Jadenu)] to provide additional randomized data to confirm the ocular safety profile of deferasirox through detailed ocular assessments in patients treated with deferasirox FCT for 2 years.
详细描述
This was a Phase II, multicenter, open-label, randomized two-year study in adults with Hereditary Hemochromatosis (HH) confirmed by HH genotype with iron overload. Eligible subjects were identified during a 4-week screening period, then randomized in a 2:1 ratio to be treated with deferasirox FCT or phlebotomy for up to 24 months (104 weeks).
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Written informed consent must be obtained prior to any screening procedures.
- •Patients eligible for inclusion must meet all following criteria prior to receiving study treatment:
- •Male or female ≥ 18-years-old
- •Documented genotype testing confirming homozygous for the C282Y mutation (C282Y/C282Y)
- •Transferrin saturation ≥ 45% (at either screening visit)
- •Serum ferritin (SF) ≥ 500 μg/L (at either screening visit)
排除标准
- •Medical conditions that preclude inclusion:
- •Iron overload not due to HH
- •Condition which might significantly alter the absorption, distribution, metabolism or excretion of oral deferasirox
- •Systemic disease which prevents taking study treatment or any contraindication to phlebotomy
- •Inflammatory condition or immunological disease which may interfere with the SF interpretation, such as an active infection, collagen vascular disorders, irritable bowel syndrome, lupus, or immune thrombocytopenia
- •Significantly impaired gastrointestinal function or disease that may significantly alter the absorption of oral deferasirox, e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection.
- •Psychiatric or addictive disorder which prevent giving informed consent or undergoing any of the treatment options or unwilling or unable to comply with the protocol
- •Uncontrolled or significant cardiac disease or symptomatic cardiac arrhythmias, e.g., sustained ventricular tachycardia and clinically significant second or third degree AV block without a pacemaker.
- •Illicit drug use and/or alcohol use, defined as an average alcohol consumption greater than one standard drink a day for women or two standard drinks a day for men within the 12 months prior to enrolment. A standard drink is generally considered to be 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits
- •Cirrhosis, including Child-Pugh class A, B, and C, diagnosed by liver biopsy, elastography, radiologic exams, or clinical criteria
- •Active hepatitis B or C (hepatitis B carrier will be allowed)
- •History of HIV seropositivity (ELISA or Western blot)
- •Organ transplant recipient
- •Malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, except localized basal cell carcinoma of the skin, or any history of hepatocellular carcinoma
- •Concomitant therapy that precludes enrollment:
- •Prior iron chelation therapy
- •Prohibited concomitant medications with deferasirox
- •Abnormal Laboratory Values:
- •Significant anemia that contraindicates phlebotomy (males with hemoglobin < 130g/L, females with hemoglobin < 120g/L) in both screening visit samples
- •Platelets ≤ 50 x 109/L in both screening visit samples
- •Urine protein/urine creatinine ratio > 1.0 mg/mg in both non-first void urine screening visit samples
- •Creatinine clearance ≤ 40 ml/min, or use the locally approved contraindication limit in prescribing information if it is stricter, in both screening visit samples
- •Serum creatinine > 1.5 x ULN in both screening visit samples
- •ALT ≥ 5 x ULN in both screening visit samples
- •Total bilirubin > 1.5 x ULN in both screening visit samples
- •Participation in an investigational study:
- •Observational registry study is allowable
- •Within 30 days prior to enrollment or within 5-half-lives of an investigational product, whichever is longer
- •Treatment with a systemic investigational drug within 4 weeks or topical investigational drug within 7 days of starting the study
- •Pregnancy and contraception:
- •Pregnant or nursing (lactating) women
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless using basic methods of contraception, such as:
- •Total abstinence Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are unacceptable methods.
- •Female sterilization (bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. If oophorectomy alone, hormone levels must confirm menopause.
- •Male sterilization (at least 6 months prior to screening). The vasectomized male must be the sole partner.
- •Barrier methods of contraception: condom or occlusive cap For UK: spermicidal foam/gel/film/cream/vaginal suppository
- •Placement of an intrauterine device or intrauterine system
- •Women considered as post-menopausal and not of childbearing potential are allowed to be enrolled in the trial if they have had 12 months of natural (spontaneous) amenorrhea with an expected clinical profile, e.g., age appropriate and history of vasomotor symptoms.
研究组 & 干预措施
Deferasirox FCT Arm
An initial dose of deferasirox FCT 7 mg/kg/day was used for 3 months (12 weeks), then was adjusted according to the serum ferritin (SF) level. Deferasirox was interrupted when the study-defined target SF ≤ 100 μg/L was achieved. Deferasirox was to be reinitiated when SF ≥ 300 μg/L, according to deferasirox label.
干预措施: Deferasirox FCT (Drug)
phlebotomy
Phlebotomy was conducted at a frequency determined by the physician. Phlebotomy was interrupted when the study-defined target SF ≤ 100 μg/L was achieved. Phlebotomy was to be reinitiated when SF > 100 μg/L, based on standard of care practice.
干预措施: Phlebotomy (Procedure)
结局指标
主要结局
Proportion of Patients Achieving Target SF ≤ 100 μg/L for the First Time
时间窗: Up to Month 24
Proportion of participants achieving target serum ferritin (SF) ≤ 100 μg/L on or before Month 24. Participants were considered responders if they met response criteria (target SF ≤100 µg/L) on or before Month 24 (Week 104) during the treatment phase. Any participant who discontinued treatment prematurely before meeting such criterion and participants with unknown or missing SF by Month 24 were counted as non-responder.
次要结局
- Number of Participants With Ocular Treatment Emergent Adverse Events (AEs) by Preferred Term(Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 108 weeks.)
- Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 108 weeks.)
- Categorical Analysis of logMAR Score Changes From Baseline to Best Post-baseline Changes in One Eye With More Extreme Change(Baseline, Weeks 24, 52, 76 and 104.)
- Categorical Analysis of logMAR Score Changes From Baseline to Worst Post-baseline Changes in One Eye With More Extreme Change(Baseline, Weeks 24, 52, 76 and 104.)
- Number of Participants With Ocular Treatment Emergent Adverse Events (AEs)(Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 108 weeks.)
- Number of Participants With Slit Lamp Results for Any Evaluation and Worst Eye(Baseline, up to Week 104)
- Number of Adverse Events in Participants Who Had Study Treatment Interrupted Due to SF ≤ 100 μg/L and Re-initiated Study Treatment When ≥ 300 μg/L(Up to 24 months)
- Categorical Analysis of Worst Post-baseline Values of Intraocular Pressure in One Eye With More Extreme Change(Weeks 24, 52, 76 and 104)
- Categorical Analysis of Changes in Intraocular Pressure From Baseline to Best/Worst Post-baseline Changes in One Eye With More Extreme Change(Baseline, up to Week 104)
- Number of Participants With an Increase From Baseline of ≥1 and ≥2 in LOCS III Grades(Baseline, up to Week 104)
- Number of Participants With Fundus Oculi Results for Any Evaluation and Worst Eye(Baseline, up to Week 104)
- Time to Response (TTR)(Up to Month 24)