Therapeutic Efficacy Comparison of a Six-month Treatment by Itraconazole and Nebulised Ambisome® Versus Treatment by Itraconazole Alone in Non- or Mildly- Immunocompromised Patients with Chronic Pulmonary Aspergillosis: a Prospective, Randomized, Single Blind Study, (single Aspergilloma Excluded)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 224
- 试验地点
- 1
- 主要终点
- Composite efficacy criterion defined by the association of clinical improvement/stability and radiological improvement evaluated at 6 months
研究概览
简要总结
This study compares the therapeutic (clinical and radiological) efficacy of a six-month treatment by itraconazole and nebulised Ambisome® (liposomal amphotericin B = LAmB) versus treatment by itraconazole alone, in non - or mildly - immunocompromised patients affected by Chronic Pulmonary Aspergillosis (single aspergilloma excluded).
• Control arm: Itraconazole 200 mg x 2/day associated with inactive nebulised treatment twice a week during 24 weeks.
• Experimental arm: Itraconazole 200 mg x 2/day associated with nebulised LAmB, at 25 mg twice a week during 24 weeks.
Follow up duration for the patients will be 24 months (12 months minimum) after discontinuation of the treatment being studied.
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 (Participant)
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
- •All adult patients affected with Chronic Pulmonary Aspergillosis (CPA) "de novo" or in relapse (without any history of resistance to itraconazole) combining the following criteria are eligible:
- •Patient with an Aspergillus bronchopulmonary infection, be it cavitary, fibrotic, necrotizing (SIA/Semi Invasive Aspergillosis) or nodular and documented by compatible thoracic CT-scan images ;
- •Associated with one of the following criteria:
- •positive detection of anti-Aspergillus IgG and/or precipitating anti-aspergillus antibodies, according to the positivity threshold of the laboratory performing the technique,
- •positive direct examination of Aspergillus or positive culture, from bronchopulmonary samples (expectoration or endoscopic aspiration),
- •revealing aspergillar hyphae/filaments on histological samples
- •Men or women age ≥ 18 years;
- •For the women of childbearing age: women having a negative serum pregnancy test, having a contraception highly effective and accepting to pursue it during at least the first 12 months of the study;
- •Patient legally free and not subject to any custody, guardianship, tutelage or subordination measures;
- •Participants must be affiliated to France's Health Care Regime (" Sécurité Sociale ");
- •Free and informed consent signed by each participating patient.
排除标准
- •Patient affected with single aspergilloma
- •Patient presenting a contraindication to itraconazole (including all contraindicated co-administrated medications as listed in the itraconazole SmPc, including notably medications with potential to prolong theQT interval)
- •Patient presenting a contraindication to voriconazole and posaconazole (including all contraindicated coadministrated medications as listed in the SmPc)
- •Intolerance to beta2-agonists
- •Notion of relapse with isolation of an Aspergillus resistant to itraconazole
- •History of hypersensitivity reaction to liposomal amphotericin B or to itraconazole or to any other constituent
- •Patient having presented complications related to a previous treatment by nebulised LAmB
- •Patient received an oral (excepted oral Amphotericin B), parenteral or intra-cavity antifungal treatment within the last 2 months
- •Severe renal failure (clearance <30 ml / min).
- •Hepatic failure with transaminase and alkaline phosphatase values > 5 times normal
- •Significant abnormality of the blood cell and platelet counts (at the discretion of the investigator)
- •Concomitant use of one or several of treatments contra-indicated with the experimental or non-experimental treatment
- •Ventricular dysfunction such as congestive cardiac failure or history of congestive cardiac failure or patients with risk(s) factors of cardiac arrhythmia or symptomatic arrhythmia with a prolongation of the corrected QT interval > 450 msec in men and 470 msec in women or treated by medication known to prolong QT interval, or prolongation of the corrected QT interval > 450 msec in men and 470 msec in women.
- •Invasive pulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis
- •Chronic Pulmonary Aspergillosis with indication for surgical intervention within 6 months from the start
- •Patients with Cystic Fibrosis
- •Immunocompromised patients
- •Threatening hemoptysis, with impossibility to defer surgical procedures (but patients contraindicated to surgery may be included after resolution of the hemoptysis)
- •Tuberculosis or progressive non-tuberculous mycobacteria
- •Respiratory infection aggravating the underlying CPA (patient may be included after eradication of infection)
- •Patient refusing to participate
- •Protected majors in the meaning of the law, non affiliated persons or with no social security scheme, persons deprived of liberty by a judicial or administrative decision, persons staying in a health or social institution, adults under legal protection, and finally patients in emergencies.
- •Patient in exclusion period following participation in another interventional study evaluating antifungals or medicines
- •Women at age to procreate and not using highly effective contraception, pregnant or breastfeeding women
研究组 & 干预措施
Itraconazole & inhaled placebo
Itraconazole 200 mg x 2/day associated with inactive nebulised treatment (isotonic saline) twice a week during 24 weeks.
干预措施: inhaled placebo (Drug)
Itraconazole & inhaled placebo
Itraconazole 200 mg x 2/day associated with inactive nebulised treatment (isotonic saline) twice a week during 24 weeks.
干预措施: Itraconazole (Drug)
Itraconazole & inhaled Ambisome®
Itraconazole 200 mg x 2/day associated with inhaled liposomal amphotericin B (Ambisome®) at 25 mg twice a week during 24 weeks
干预措施: inhaled Ambisome® (Drug)
Itraconazole & inhaled Ambisome®
Itraconazole 200 mg x 2/day associated with inhaled liposomal amphotericin B (Ambisome®) at 25 mg twice a week during 24 weeks
干预措施: Itraconazole (Drug)
结局指标
主要结局
Composite efficacy criterion defined by the association of clinical improvement/stability and radiological improvement evaluated at 6 months
时间窗: 6 months
• Clinical improvement or stability is evaluated using the Respiratory Symptom Score based on 6 items (cough, expectoration, dyspnea, hemoptysis, chest pain, and nocturnal awakening ) quoted with a 10 cm visual analogical scale). Stability is defined by a score variation between -25 and +25%, while improvement is defined by a decrease in score greater than 25%. • Radiological improvement is based on the analysis of CT-scan parameters (a committee consisting on two chest radiologists wil perform centrally and parallel analyses of each CT-scan blinded to the study treatment allocation to reach a final decision by consensus) The radiological improvement (binary variable) is defined by a consensual score based on the evolution of the various radiological parameters (cavity, fungus ball, alveolar condensation, nodules) according to validated thresholds.
次要结局
- relapse(month 6 to month 30)
- major events during follow-up period(month 6 to month 30)
- mycological response(after 3 months and 6 months)