CLAZI : CLArithromycin versus AZIthromycin in the treatment of Mycobacterium avium complex pulmonary infections: A randomized prospective controlled study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Amiens Picardie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

5 Feb 2018 → ongoing

Decision date (initial)

2024-10-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518578-15-00

EudraCT number

2017-001087-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

To demonstrate the non-inferiority in term of 6-month sputum conversion rate of azithromycin- to clarithromycin-containing regimen in the Mycobacterium avium complex (MAC) lung disease treatment.

Secondary objectives 5

1. To compare azithromycin to clarithromycin containing regimen in the MAC lung disease in terms of: - Tolerance/safety (especially digestive tolerance, hepatitis, hearing toxicity, drugs interaction) at different endpoints
2. 2) To compare azithromycin to clarithromycin containing regimen in the MAC lung disease in terms of: - Clinical, radiological improvement at 3, 6, 12 months of treatment - 3 months- and 12 months- sputum conversion rate - 12 months mortality rate
3. 3) To compare azithromycin and clarithromycin intracellular concentration in plasma and circulating mononuclear cells at 1 month and 6 months of treatment (nested study)
4. 4) To correlate azithromycin and clarithromycin intracellular concentration in circulating mononuclear cells and in hair to : - microbiological success at 6 months - tolerability of treatment.
5. 5) To evaluate the association between MAC species with 6-month conversion

Conditions and MedDRA coding

Is to demonstrate a non inferior efficacy of azithromycin and so the possibility for clinician to choose between two drugs for Mycobacterium avium complex treatment.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. In order to be included, each eligible patient, 18 years old or orlder, must present ATS/IDSA 2007 criteria for nontuberculous mycobacterial pulmonary infection (3). These criteria are as follows: - Clinical criteria o Respiratory symptoms and the presence of nodular or cavitary lesion on chest highresolution computed tomography. Lesions may also present in the form of diffuse micronodular syndrome.
2. AND Microbiological criteria : At least two positive cultures for MAC on two sputum specimens obtained on two different days collected at lesast 7 days apart
3. AND/OR : Positive culture for MAC on bronchoalveolar lavage or bronchoscopic aspiration
4. AND/OR : Transbronchial biopsy or surgical lung biopsy presenting histology in favour of mycobacterial infection (granuloma or positive Ziehl-Neelsen stain) and positive culture for MAC OR biopsy showing histology compatible with mycobacterial infection and one or more sputum cultures positive for MAC
5. AND : Exclusion of other diagnoses more likely than Mycobacterium avium infection on CT scan, bronchoscopy or bacteriological specimens (Bronchoscopy is not required if two good-quality sputum samples, collected 7 days apart, are available)In the presence of common bacteria, persistence of clinical symptoms and radiological signs after well-conducted antibiotic therapy suggests the diagnosis of MAC infection. The presence of criteria of Aspergillus fumigatus infection associated with the presence of microbiological criteria of MAC infection will lead to the diagnosis of MAC and Aspergillus fumigatus co-infection.

Exclusion criteria 15

1. Known hypersensitivity to one of the molecules of the study (rifampin, ethambutol, azithromycin, clarithromycin)
2. Relapse of MAC lung infection
3. Macrolide resistant strain, based on genotyping susceptibility testing (must be done before inclusion)
4. Treatment with molecules able to interfere with cytochrome P450 that cannot be replaced by another therapeutic class
5. HIV 1 and 2 human immunodeficiency virus infection
6. Renal failure with creatinine clearance less than 30 mL/min
7. Pregnancy and breastfeeding
8. Contraindications to one of the antibiotic
9. Inability to comply with the requirements of the protocol, especially substance abuse, according to the investigator
10. Limited life expectancy (e.g 6 months)
11. Patients with hematologic malignancies and allogeneic haematopoietic stem cells
12. Women of childbearing age and not using an effective method of contraception (Pearl Index <1%)
13. The patient is treated with molecules prolonging the QT interval that cannot be replaced by another therapeutic class
14. The patient presents a heart failure with left ventricular ejection fraction less than 30%
15. Patient already participating in a clinical trial of a treatment or a therapeutic strategy for non-mycobacterial Tubercular

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the 6-month negative sputum conversion rate.

Secondary endpoints 7

1. For safety: digestive toxicity (WHO criteria and Rhodes scale (28, 29)), for hepatitis (cytolysis higher than 3 times normal rate)
2. Clinical improvement on analogic scales
3. Radiological improvement on CT scan criteria (dimensions of the lesions compared to the baseline CT, classified as complete resolution of the lesions, partial resolution of the lesions: reduction of at least 50% of the lesions, stabilization: size of the lesion between 50% and 130% compared to baseline, deterioration of lesions: appearance of new lesions or greater than 30%
4. 3 and 12 months sputum conversion (Culture results of respiratory specimens taken 3 and 12 months after starting treatment)
5. 12 months outcome (death)
6. 1 month and 6 months peak serum and mononuclear cells concentration of azithromycin and clarithromycin and their main metabolites (D-azithromycin and 14-OH clarithromycin respectively) determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS)
7. MAC species and 6-month conversion

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Amiens Picardie

Sponsor organisation

Centre Hospitalier Universitaire Amiens Picardie

Address

1 Rond Point Du Pr Christian Cabrol

City

Amiens Cedex 1

Postcode

80054

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Amiens Picardie

Contact name

Claire ANDRJEAK

Public contact point

Organisation

Centre Hospitalier Universitaire Amiens Picardie

Contact name

Claire ANDRJEAK

Locations

1 EU/EEA country · 60 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications