| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Pulmonary Aspergillosis |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022881 |
| E.1.2 | Term | Invasive bronchopulmonary aspergillosis |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main objective is to compare the therapeutic (clinical and radiological) efficacy of a six-month treatment by itraconazole and nebulised Ambisome® versus treatment by itraconazole alone, in non - or mildly - immunocompromised patients affected by Chronic Pulmonary Aspergillosis (single aspergilloma excluded). |
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| E.2.2 | Secondary objectives of the trial |
To compare both strategies regarding:
1. clinical and/or radiological evolution after 3 and 6 months,
2. major events during follow-up period (M6-M30),
3. relapse between M6 and M30,
4. mycological response after 3 (M3) and 6 months (M6),
5. number of medical consultations or hospitalizations for respiratory symptoms,
6. clinical and biological tolerance,
7. improvement in quality of life evaluated by the VQ-11 Questionnaire
- To estimate concordance for CPA diagnosis and CPA evolution under treatment between clinical, radiological, mycological and serological parameters.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Performances and relevance of Aspergillus biomarkers during Chronic Pulmonary Aspergillosis : an ancillary study of the CPAAARI study-Version n°1 du 26.02.2018 |
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| E.3 | Principal inclusion criteria |
All adult patients affected with CPA “de novo” or in relapse (without any history of resistance to itraconazole) combining the following criteria are eligible:
1. Patient with an Aspergillus bronchopulmonary infection over at least 3 months of observation, be it cavitary, fibrotic or nodular and documented by compatible thoracic CT-scan images [8, 16];
2. Associated with one of the following criteria:
- documented anti-Aspergillus IgG and/or precipitin antibodies,
- positive direct examination of Aspergillus or positive culture, from bronchopulmonary samples (expectoration or endoscopic aspiration),
- revealing aspergillar hyphae on histological analysis
3. Men or women age ≥ 18 years;
4. 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;
5. Patient legally free and not subject to any custody, guardianship, tutelage or subordination measures;
6. Participants must be affiliated to France's Health Care Regime (« Sécurité Sociale »);
7. Free and informed consent signed by each participating patient.
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|
| E.4 | Principal exclusion criteria |
1 - Patient affected with single aspergilloma
2 - Patient presenting a contraindication to itraconazole (including contraindicated medications with potential to prolong the QT interval as listed in the itraconazole SmPC)
3- Patient presenting a contraindication to voriconazole or posaconazole
4 – Intolerance to beta2-agonists
5 – Notion of resistance to itraconazole
6 - History of hypersensitivity reaction to liposomal amphotericin B or to itraconazole or to any other constituent
7 - Patient treated by nebulised LAmB during the previous month, or having presented complications related to a previous treatment by nebulised LAmB
8 – Patient received an oral (excepted oral Amphotéricine B), parenteral or intra-cavity antifungal treatment within the last 2 months
9 - Severe renal failure (clearance <30 ml / min).
10 - Hepatic failure with transaminase and alkaline phosphatase values > 5 times normal
11 - Significant abnormality of the blood cell and platelet counts (at the discretion of the investigator)
12 - Concomitant use of one or several of treatments contra-indicated with the experimental or non-experimental treatment
13 - 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 QTc interval > 450 msec in men and 470 msec in women or treated by medication known to prolong QT interval, or prolongation of the QTc interval > 450 msec in men and 470 msec in women.
14 - Invasive pulmonary Aspergillosis, Allergic Bronchopulmonary Aspergillosis
15 - Chronic Pulmonary Aspergillosis with indication for surgical intervention from the start
16 - Patients with Cystic Fibrosis
17 - Immunocompromised patients (HIV Seropositivity, AIDS, progressive neoplastic disease, systemic disease in active phase, immunosuppressor treatment, allograft or autograft of bone marrow, haematologic disease (acute or chronic leukaemia, multiple myeloma, Hodgkin's disease …), organ transplants, neutropenia (ANC < 500 / mm3) during the 3 months preceding the inclusion, systemic corticotherapy > 7,5 mg / day prednisolone (or equivalent) > 3 weeks
18 - Threatening hemoptysis, with impossibility to defer surgical procedures (but patients contraindicated to surgery may be included after resolution of the hemoptysis)
19 - Tuberculosis or progressive non-tuberculous mycobacteria
20 - Respiratory infection aggravating the underlying CPA (patient may be included after eradication of infection)
21 – Patient refusing to participate
22 – Persons benefiting from enhanced protection, namely minors, persons deprived of their liberty by a judicial or administrative decision, persons staying in a health or social institution, adults under legal protection, and finally patients in emergencies
23 - Patient in exclusion period following participation in another interventional study evaluating antifungals or medicines
24 - Women at age to procreate and not using highly effective contraception (either hormonal / mechanical [oral, injection, subcutaneous, implantable, intrauterine device] or surgical [tubal ligation, hysterectomy, total ovariectomy]: at least as concerns the initial 12 months of the study, pregnant or breastfeeding women
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Therapeutic efficacy at 6 months (visit M6) is a composite criterion defined by the association of clinical improvement/stability and radiological improvement.
• Clinical improvement or stability between M0 and M6 is evaluated using the Respiratory Symptom Score, validated for CPA, based on 6 items (cough, expectoration, dyspnea, hemoptytic expectoration, chest pain, and nocturnal awakening), using 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 defined as follows:
• in case of cavity:
- decrease ≥20% (with a minimum of 2 mm) in pleural thickness
- or decrease ≥20% (with a minimum of 2 mm) in cavitary wall thickness
- or disappearance of a fungal ball and/or ribbons
• in case of no cavity:
- decrease >1 point in the semi-quantitative score of alveolar condensations (0: 0; 1: 0-25%; 2: 25%-50; 3: 50-75%; 4: 75-100%)
- or decrease >1 point in the semi-quantitative score of nodules >5mm (0:0; 1: slight; 2: moderate; 3: severe)
- or decrease ≥50% in the volume of a macronodule
The rates of patients showing therapeutic efficacy will be compared between the two arms.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
-Clinical evolution patient will be classified in one of 3 classes: improvement or stability or clinical deterioration.
-Radiological evolution a patient will be classified in one of 3 classes: improvement or stability or deterioration.
-Major events follow-up period after stopping study treatment
-Relapse
-Mycological response
-Number of medical consultations or hospitalizations for respiratory symptoms
-Improvement in quality of life evaluated by the VQ-11 Questionnaire
-Concordance evaluation assessment between parameters for CPA diagnosis and evolution (see ancillary project annex 3 of this protocol)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Clinical evolution after 3 or 6 months
-Radiological evolution after 3 or 6 months
-Major events during the 24-months (i.e.; between visit M6 (at 6 months) and visit M30 (at 30 months).
-Relapse during the 24-months (between visits M6 and M30).
-Mycological response after 3 and 6 months of study treatment.
-Number of medical consultations or hospitalizations for respiratory symptoms 6-month study and the 24-month
-Clinical and biological tolerance
- VQ-11 Questionnaire: during 24 months
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 29 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 54 |
| E.8.9.1 | In the Member State concerned days | |
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