A Randomized Controlled Trial Comparing Azithromycin and Clarithromycin in Mycobacterium Avium Complex Pulmonary Disease Treatment
- Trial ID
- 2024-518578-15-00
- Protocol
- PI2017_843_0010
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **non-inferiority** of an azithromycin-containing regimen compared to a clarithromycin-containing regimen in terms of the 6-month sputum conversion rate in the treatment of **Mycobacterium avium complex** (MAC) lung disease. This is clinically relevant as it may provide clinicians with an alternative therapeutic option, potentially improving patient outcomes by allowing flexibility in treatment choices.
Secondary objectives include:
- Comparing azithromycin to clarithromycin regimens in terms of tolerance and safety, focusing on digestive tolerance, hepatitis risk, hearing toxicity, and drug interactions at various endpoints.
- Assessing clinical and radiological improvement at 3, 6, and 12 months of treatment, as well as sputum conversion rates at 3 and 12 months, and the 12-month mortality rate.
- Comparing intracellular concentrations of azithromycin and clarithromycin in plasma and circulating mononuclear cells at 1 and 6 months of treatment.
- Correlating intracellular concentrations of azithromycin and clarithromycin in circulating mononuclear cells and hair with microbiological success at 6 months and treatment tolerability.
- Evaluating the association between different MAC species and the 6-month sputum conversion rate.
Participants
The clinical trial involves participants diagnosed with **Mycobacterium avium complex** lung disease, aiming to evaluate the non-inferiority of azithromycin compared to clarithromycin in terms of a 6-month sputum conversion rate. The study population includes both male and female subjects aged 18 years and older, who meet the ATS/IDSA 2007 criteria for nontuberculous mycobacterial pulmonary infection. These criteria include respiratory symptoms, nodular or cavitary lesions on chest high-resolution computed tomography, and specific microbiological evidence of infection. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Participants were selected based on the presence of clinical and microbiological criteria, with the exclusion of other diagnoses through comprehensive diagnostic evaluations.
Plans and Procedures
The clinical trial is designed to evaluate the **non-inferiority** of azithromycin compared to clarithromycin in the treatment of Mycobacterium avium complex (MAC) pulmonary infections. This is a randomized, prospective, controlled study with a double-blind methodology to ensure unbiased results. The trial is expected to span a duration of approximately ten years, with an estimated recruitment start date of February 5, 2018, and an anticipated end date of February 5, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) 2007 criteria for nontuberculous mycobacterial pulmonary infection. This includes clinical and microbiological criteria such as respiratory symptoms, nodular or cavitary lesions on chest CT, and positive cultures for MAC. Following the screening, participants will be randomized to receive either azithromycin or clarithromycin, both administered orally.
Throughout the study, participants will attend follow-up visits at regular intervals to monitor treatment efficacy and safety. The primary endpoint is the 6-month negative sputum conversion rate, while secondary endpoints include safety assessments, clinical and radiological improvements, and 3 and 12-month sputum conversion rates. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted.
Participant involvement is expected to last up to 12 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide clinicians with evidence to support the choice between azithromycin and clarithromycin for MAC treatment, focusing on efficacy and safety profiles.
Treatment
The clinical trial involves the administration of several **experimental medications** for the treatment of Mycobacterium avium complex pulmonary infections. The first medication is **RIFADINE 300 mg**, which is provided in the form of a hard capsule. The active substance in RIFADINE is **rifampicin**, a chemical compound. The medication is administered orally with a maximum daily dose of 10 mg/kg and a total maximum dose of 3650 mg/kg over a treatment period of up to 365 days. Participant compliance is monitored to ensure adherence to the dosing schedule.
Another medication used in the trial is **CLARITHROMYCINE ARROW 500 mg**, which is a modified-release tablet. The active substance is **clarithromycin**, also a chemical compound. This medication is administered orally with a maximum daily dose of 1000 mg and a total maximum dose of 365000 mg over a 365-day treatment period. The modified-release formulation is designed to maintain therapeutic drug levels over an extended period, and participant compliance is closely monitored.
The trial also includes **DEXAMBUTOL 500 mg**, a film-coated tablet containing **ethambutol hydrochloride** as the active substance. This chemical compound is administered orally with a maximum daily dose of 20 mg/kg and a total maximum dose of 7300 mg/kg over a 365-day treatment period. The film-coated tablet is designed to facilitate oral administration, and participant adherence to the dosing regimen is monitored.
Lastly, **AZITHROMYCINE TEVA 250 mg** is used in the trial, provided as a film-coated tablet. The active substance is **azithromycin**, a chemical compound. This medication is administered orally with a maximum daily dose of 250 mg and a total maximum dose of 87500 mg over a 365-day treatment period. The film-coated formulation aids in the ease of administration, and compliance with the dosing schedule is monitored to ensure effective treatment outcomes.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **6-month negative sputum conversion rate**. This endpoint is designed to evaluate the effectiveness of azithromycin compared to clarithromycin in the treatment of Mycobacterium avium complex (MAC) pulmonary infections. Secondary endpoints include safety assessments such as digestive toxicity measured by WHO criteria and the Rhodes scale, and hepatitis indicated by cytolysis levels exceeding three times the normal rate. Additional efficacy parameters include clinical improvement on analogic scales, radiological improvement based on CT scan criteria, and sputum conversion at 3 and 12 months. The trial will also monitor the 12-month outcome, including mortality, and measure peak serum and mononuclear cell concentrations of azithromycin and clarithromycin, along with their main metabolites, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at 1 and 6 months. The MAC species and 6-month conversion will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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
- AND/OR : Positive culture for MAC on bronchoalveolar lavage or bronchoscopic aspiration
- 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
- 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
- Known hypersensitivity to one of the molecules of the study (rifampin, ethambutol, azithromycin, clarithromycin)
- Relapse of MAC lung infection
- Macrolide resistant strain, based on genotyping susceptibility testing (must be done before inclusion)
- Treatment with molecules able to interfere with cytochrome P450 that cannot be replaced by another therapeutic class
- HIV 1 and 2 human immunodeficiency virus infection
- Renal failure with creatinine clearance less than 30 mL/min
- Pregnancy and breastfeeding
- Contraindications to one of the antibiotic
- Inability to comply with the requirements of the protocol, especially substance abuse, according to the investigator
- Limited life expectancy (e.g 6 months)
- Patients with hematologic malignancies and allogeneic haematopoietic stem cells
- Women of childbearing age and not using an effective method of contraception (Pearl Index <1%)
- The patient is treated with molecules prolonging the QT interval that cannot be replaced by another therapeutic class
- The patient presents a heart failure with left ventricular ejection fraction less than 30%
- Patient already participating in a clinical trial of a treatment or a therapeutic strategy for non-mycobacterial Tubercular
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 05 Feb 2018 | 424 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RIFADINE 300 mg, gélule | Test | GÉLULE | ORAL USE | 10 | 365 | PRD420744 |
CLARITHROMYCINE ARROW 500 mg, comprimé pelliculé à libération modifiée | Comparator | COMPRIMÉ PELLICULÉ À LIBÉRATION MODIFIÉE | ORAL USE | 1000 | 365 | PRD1760368 |
DEXAMBUTOL 500 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL USE | 20 | 365 | PRD2938117 |
AZITHROMYCINE TEVA 250 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL USE | 250 | 365 | PRD986925 |