Efficacy and Safety of Thermotherapy in Combination With Miltefosine Compared Iltefosine Monotherapy for the Treatment of New World Cutaneous Leishmaniasis: A Phase III, Open Label, Multicenter Randomized Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 184
- 试验地点
- 6
- 主要终点
- The proportion of initial clinical cure in each arm.
研究概览
简要总结
This study evaluates if the combination of thermotherapy (one application, 50⁰C for 30") and 3 weeks of miltefosine is safe and have a comparable cure rate with the current recommended first line treatments comprising meglumine antimoniate for 3 weeks for the treatment of uncomplicated cutaneous leishmaniasis cases in the New World.
详细描述
This randomized, open label, multi-centre, non-inferiority study aims to compare that the combination of thermotherapy (one application, 50⁰C for 30") and 3 weeks of miltefosine (2.5 mg/kg/day for 21 days orally) (here after referred to as combination), is non-inferior to the current recommended first line treatment miltefosine monotherapy (2.5 mg/kg/day for 28 days orally), for uncomplicated CL cases in the New World.
Originally, the study was planned to assess the non-inferiority of the combination therapy in comparison to the current recommended first line treatments, meglumine antimoniate or miltefosine monotherapy for 28 days. However, based on the revised treatment guidelines published by WHO-PAHO in 2022 in which the use of systemic antimonial received only a conditional recommendation, principally because of its well-known toxicity, and is recommended to be used only in case where there is no other option, the study protocol amendment 7 was proposed to prematurely discontinue the inclusion of additional patients in the meglumine antimoniate arm.
Primary Objective
• To determine the non-inferior efficacy of the combination in comparison to the standard first line treatment miltefosine monotherapy as measured by the percentage of patients with initial clinical cure at Day 90.
Secondary objectives
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
- Single (Outcomes Assessor)
盲法说明
Initial, late responders and final cure assessments done in a blinded manner by the site clinicians at D90, D105 (if required) and D180, respectively.
入排标准
- 年龄范围
- 12 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females, aged ≥12 and ≤60 years old (upper age limit according to local regulations), and weighing ≥ 30Kg.
- •Patient with a confirmed diagnosis of CL in at least one lesion by at least one of the following methods: 1) microscopic identification of amastigotes in stained lesion tissue, or 2) demonstration of Leishmania by Polymerase Chain Reaction (PCR), or 3) positive culture for promastigotes.
- •Patient has a lesion that satisfies the following criteria:
- •Lesion size ≥ 0.5 cm and ≤ 4 cm (longest diameter).
- •not located on the ear, face, close to mucosal membranes, or on a location that in the opinion of the Principal Investigator (PI) is difficult to apply the TT.
- •Patient with ≤ 4 CL lesions.
- •Duration of lesion less than 4 months by patient history.
- •Patient able to give written informed consent/ assent form.
- •In the opinion of the investigator, the patient is capable of understanding and complying with the protocol.
排除标准
- •Female with a positive urine or blood pregnancy test at screening or who is breast feeding or female at fertile age who does not agree to take appropriate effective contraception during treatment period and up to D180 visit. In Brazil: female at fertile age who does not agree to use two effective methods of contraception: one barrier method and one highly effective method (defined in section 8.2.4) 30 days prior to the treatment onset and up to D180 visit.
- •History of clinically significant medical problems / treatment that might interact, either negatively or positively, with treatment of cutaneous leishmaniasis including any immunocompromising condition.
- •Within 8 weeks (56 days) of Day 1, received treatment for the entry lesion leishmaniasis with any medication including antimonials likely, in the opinion of the PI, to modify the course of the Leishmania infection.
- •Has diagnosis or suspected diagnosis of mucocutaneous leishmaniasis based on physical exam.
- •Has laboratory values at screening as follows:
- •Serum creatinine: above upper normal level*.
- •Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST): 3 times above upper normal level*.
- •Normal ranges obtained from local laboratory.
- •Patient who is not willing to attend the study visits or is not able to comply with follow-up visits up to 6 months.
- •Known history of addiction/ alcohol abuse.
- •Hypersensitivity to miltefosine or any study medication excipients.
- •Patients with Sjogren-Larson Syndrome.
研究组 & 干预措施
Meglumine Antimoniate
Meglumine Antimoniate, 20 mg/kg/day for 20 days parenterally. This trial arm was discontinued after protocol amendment 7. However, patients assigned to this arm before protocol amendment 7 becomes effective will continue in the study and will receive complete treatment as initially planned.
干预措施: Meglumine Antimoniate (Drug)
Miltefosine monotherapy
Miltefosine monotherapy 2.5 mg/kg/day for 28 days orally
干预措施: Miltefosine (Drug)
Thermotherapy + miltefosine
Thermotherapy (one session, 50⁰C for 30" applications*) + miltefosine 2.5 mg/kg/day for 21 days orally.
干预措施: Miltefosine (Drug)
Thermotherapy + miltefosine
Thermotherapy (one session, 50⁰C for 30" applications*) + miltefosine 2.5 mg/kg/day for 21 days orally.
干预措施: Thermotherapy machine (Device)
结局指标
主要结局
The proportion of initial clinical cure in each arm.
时间窗: Day 90
Defined for ulcerated lesions as 100% re-epithelialization of the ulcer(s) on D90 as compared to D1 and for non-ulcerated lesions as flattening and/or no signs of induration of the lesion(s) on D90 as compared to D1.
次要结局
- The number of patients who fulfil the criteria for clinical improvement at D90 and late responders at D105.(Days 90 and 105)
- The number of patients who fulfil the criteria of initial cure at D90 or late responders at D105 and have no relapse by D180 (final cure).(Day 180)
- Percentage of treatment discontinuation, frequency, severity, causality with each study drug and seriousness of AEs by treatment group.(Through study completion, i.e up to 6 months)
- Proportion of lesions with 100% re-epithelialization/flattening at each measurement time point by Leishmania sp.(Days 7, 14 and 21. At end of treatment (days 21 or 28), and at days 45, 63, 90, 105 and 180.)
- The number of patients randomized in the meglumine antimoniate arm until its discontinuation who fulfill the criteria of initial cure at D90 or late responders at D105 and have no relapse by D180 (final cure).(Day 180)