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CLArithromycin Versus AZIthromycin in the Treatment of Mycobacterium Avium Complex (MAC) Lung Infections (CLAZI)

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ClinicalTrials.gov Identifier: NCT03236987
Recruitment Status : Recruiting
First Posted : August 2, 2017
Last Update Posted : September 19, 2018
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire, Amiens

Brief Summary:

MAC lung infections are a growing public health problem. The ATS / IDSA 2007 guidelines for the treatment of these non-tuberculous mycobacterial infections recommend the use of a macrolide or azalide (clarithromycin or azithromycin), rifampicin or rifabutin and ethambutol.

For MAC disseminated infections, several studies have compared combinations containing clarithromycin or azithromycin and found no significant difference in efficacy. No randomized controlled trials have been performed for pulmonary infections to compare clarithromycin and azithromycin in terms of efficacy. Clarithromycin is often used as a first-line treatment in France, but its tolerance is often poor, particularly in terms of risk of hepatitis, metallic taste in the mouth, nausea or vomiting, and it interacts with many drugs via cytochrome p450 . In particular, it increases the toxicity of rifabutin, in particular in terms of uveitis. Azithromycin has fewer side effects especially less digestive toxicity and drug interactions than clarithromycin.

The hypothesis is therefore that the efficacy of azithromycin would be non-inferior in comparison with that of clarithromycin.


Condition or disease Intervention/treatment Phase
Lung Infection Mycobacterium Avium Complex Drug: Clarithromycin 1000 MG Drug: Azithromycin 250 mg Drug: Rifampicin Drug: Ethambutol Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 424 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CLArithromycin Versus AZIthromycin in the Treatment of Mycobacterium Avium Complex (MAC) Lung Infections
Actual Study Start Date : February 5, 2018
Estimated Primary Completion Date : February 1, 2023
Estimated Study Completion Date : February 1, 2023


Arm Intervention/treatment
Active Comparator: Clarithromycin 1000 MG

The patient will received a combination of 3 antibiotics :

  • Rifampicin (10mg/kg once daily)
  • Ethambutol (15 to 20 mg/kg once daily)
  • Clarithromycin (500 mg twice daily)
Drug: Clarithromycin 1000 MG
The patient will be received for at least 12 months, a daily antibiotic treatment who is a combination of Clarithromycin, Ethambutol and Rifampicin.
Other Name: ZECLAR

Drug: Rifampicin
The patient will be received for at least 12 months, a dailty antibiotic treatment who is a combination of Azithromycin or Clarithromycin (according to the randomisation), Ethambutol and Rifampicin.
Other Name: RIFADINE

Drug: Ethambutol
The patient will be received for at least 12 months, a dailty antibiotic treatment who is a combination of Azithromycin or Clarithromycin (according to the randomisation), Ethambutol and Rifampicin.
Other Name: DEXAMBUTOL

Experimental: Azithromycin 250 MG

The patient will received a combination of 3 antibiotics :

  • Rifampicin (10mg/kg once daily)
  • Ethambutol (15 to 20 mg/kg once daily)
  • Azithromycin (250 mg once daily)
Drug: Azithromycin 250 mg
The patient will be received for at least 12 months, a daily antibiotic treatment who is a combination of Azithromycin, Ethambutol and Rifampicin.
Other Name: ZITHROMAX

Drug: Rifampicin
The patient will be received for at least 12 months, a dailty antibiotic treatment who is a combination of Azithromycin or Clarithromycin (according to the randomisation), Ethambutol and Rifampicin.
Other Name: RIFADINE

Drug: Ethambutol
The patient will be received for at least 12 months, a dailty antibiotic treatment who is a combination of Azithromycin or Clarithromycin (according to the randomisation), Ethambutol and Rifampicin.
Other Name: DEXAMBUTOL




Primary Outcome Measures :
  1. Culture results of respiratory specimens taken 6 months after starting treatment. [ Time Frame: 6 months ]

    Three spontaneous sputum specimens will be obtained at baseline and 6 months. If it's not possible to obtain good quality specimens, the clinician may perform three hypertonic aerosol-induced sputum specimens on 3 consecutive days. In the absence of sputum (spontaneous or induced), bronchoscopic aspiration and two post-bronchoscopy sputum specimens will be performed.

    Microscopic examination will be performed after auramine or Ziehl-Neelsen stain.

    Specimens will be cultured at 37°C after decontamination on Lowenstein-Jensen solid medium and Coletsos medium. Results will be expressed quantitatively as the number of colonies per tube according to a logarithmic scale. Culture on liquid medium will also be performed.

    The analysis will be based on the Mycobacteria National Reference Centre microscopy, culture and antibiotic susceptibility test results.



Secondary Outcome Measures :
  1. Clinical improvement [ Time Frame: 3 months ]

    Several criteria will be determined at baseline and at 3 months and then compared to assess clinical improvement :

    • Presence or absence of cough, sputum, dyspnoea, chest pain and wheezing using a 5-point analogue scale (0=no symptom, 4=permanent symptoms) ;
    • WHO performance status scored from 0 to 4 ;
    • Global score from 0 to 24, taking into account the score of the 5 respiratory symptoms and the WHO performance status ;
    • Presence of blood-stained sputum (haemoptysis greater than 50 mL or requiring specialized medical intervention)
    • Weight in kg (patient weighed in underwear on the same scales, variations taken into account when greater than 5% of the baseline weight).

  2. Clinical improvement [ Time Frame: 6 months ]

    Several criteria will be determined at baseline and at 6 months and then compared to assess clinical improvement :

    • Presence or absence of cough, sputum, dyspnoea, chest pain and wheezing using a 5-point analogue scale (0=no symptom, 4=permanent symptoms) ;
    • WHO performance status scored from 0 to 4 ;
    • Global score from 0 to 24, taking into account the score of the 5 respiratory symptoms and the WHO performance status ;
    • Presence of blood-stained sputum (haemoptysis greater than 50 mL or requiring specialized medical intervention)
    • Weight in kg (patient weighed in underwear on the same scales, variations taken into account when greater than 5% of the baseline weight).

  3. Clinical improvement [ Time Frame: 12 months ]

    Several criteria will be determined at baseline and at 12 months and then compared to assess clinical improvement :

    • Presence or absence of cough, sputum, dyspnoea, chest pain and wheezing using a 5-point analogue scale (0=no symptom, 4=permanent symptoms) ;
    • WHO performance status scored from 0 to 4 ;
    • Global score from 0 to 24, taking into account the score of the 5 respiratory symptoms and the WHO performance status ;
    • Presence of blood-stained sputum (haemoptysis greater than 50 mL or requiring specialized medical intervention)
    • Weight in kg (patient weighed in underwear on the same scales, variations taken into account when greater than 5% of the baseline weight).

  4. Radiological improvement [ Time Frame: 3 months ]

    Chest x-ray will be realised at baseline and at 3 months and described according to :

    • type of lesion: opacity/solitary pulmonary nodule, excavated opacity/ fibrocavitary disease, interstitial syndrome (multiple nodule, dense airspace disease)
    • precise site (upper lobe, right middle or lower lobe, left lower or upper lobe)

  5. Radiological improvement [ Time Frame: 6 months ]

    Chest x-ray and chest high-resolution CT will be realised at baseline and at 6 months.

    Chest x-ray will be described according to:

    • type of lesion: opacity/solitary pulmonary nodule, excavated opacity/ fibrocavitary disease, interstitial syndrome (multiple nodule, dense airspace disease)
    • precise site (upper lobe, right middle or lower lobe, left lower or upper lobe)

    Chest CT will be described according to:

    • type of lesion: nodules, micronodules, bronchiectasis, mass, interstitial syndrome (and its type)
    • precise site of the segment(s) involved
    • number of lesions
    • dimensions of the various lesions (long and short axes) and volume, whenever possible.

  6. Radiological improvement [ Time Frame: 12 months ]

    Chest x-ray and chest high-resolution CT will be realised at baseline and at 12 months.

    Chest x-ray will be described according to:

    • type of lesion: opacity/solitary pulmonary nodule, excavated opacity/ fibrocavitary disease, interstitial syndrome (multiple nodule, dense airspace disease)
    • precise site (upper lobe, right middle or lower lobe, left lower or upper lobe)

    Chest CT will be described according to:

    • type of lesion: nodules, micronodules, bronchiectasis, mass, interstitial syndrome (and its type)
    • precise site of the segment(s) involved
    • number of lesions
    • dimensions of the various lesions (long and short axes) and volume, whenever possible.

  7. Sputum conversion (culture results of respiratory specimens) [ Time Frame: 3 months ]
    Microbiological specimens, preferably 3 sputum specimens, will be obtained and processed at 3 months after treatment according to the same modalities as at baseline.

  8. Sputum conversion (culture results of respiratory specimens) [ Time Frame: 12 months ]
    Microbiological specimens, preferably 3 sputum specimens, will be obtained and processed at 12 months after treatment according to the same modalities as at baseline.

  9. Survival analysis [ Time Frame: 12 months ]
    The 12-month mortality will be determined by the survival at that date. The date of any death occurring during treatment will be recorded and the interval between the start of treatment and death will be calculated. The cause of death will be investigated and reported.

  10. Safety as assessed by adverse events according to the Rhodes scale, and hematological, gastrointestinal and renal toxicities according to the WHO toxicity scale [ Time Frame: 12 months ]

    All adverse events will be notified according to the recommendations. Particular attention will be paid to gastrointestinal adverse effects (the incidence of nausea and vomiting will be recorded). These adverse events will be assessed at each visit according to the Rhodes scale.

    Haematological, gastrointestinal and renal toxicities will be scored according to the WHO toxicity scale.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patients 18 years of age or older
  • having a positive Mycobacterium avium complex sample showing the ATS / IDSA infection criteria and requiring treatment
  • ATS / IDSA infection criteria combine clinico-radiological criteria, associated with microbiological criteria
  • the exclusion of any other diagnosis on the thoracic CT, fibroscopy and bacteriological samples

Exclusion Criteria:

  • Known hypersensitivity to one of the study molecules (rifampicin, ethambutol, azithromycin, clarithromycin)
  • Relapse of an MAC infection,
  • Strain resistant to macrolides, based on genotyping susceptibility testing (genotyping susceptibility testing must be done before inclusion)
  • Treatment that interacts with cytochrome p450 that can not be replaced by another therapeutic,
  • HIV serology 1 and 2,
  • Renal insufficiency with creatinine clearance less than 30 ml / min,
  • Pregnancy and breast feeding,
  • Contra-indication to one of the antibiotics,
  • Impossibility to follow the protocol due in particular to drug addiction according to the investigator,
  • Limited life expectancy, less than 6 months,
  • Patient already participating in a clinical trial on a medical treatment or a therapeutic strategy for non-tuberculous mycobacteria.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03236987


Contacts
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Contact: Claire ANDREJAK, PhD +33322087893 andrejak.claire@chu-amiens.fr

Locations
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France
CHU Amiens Picardie Not yet recruiting
Amiens, Picardie, France, 80054
Contact: Claire ANDREJAK, PhD    +33322455960    andrejak.claire@chu-amiens.fr   
Saint Joseph Hospital Recruiting
Marseille, France, 13000
Contact: Audoly Cristina, PH    +334 91 80 67 05    caudoly@hopital-saint-joseph.fr   
Contact: Bezirganyan Kristina    +334 91 80 65 00    kbezirganyan@hopital-saint-joseph.fr   
Sponsors and Collaborators
Centre Hospitalier Universitaire, Amiens
Investigators
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Study Director: Arnaud COLLIN CHU Amiens-Picardie

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Responsible Party: Centre Hospitalier Universitaire, Amiens
ClinicalTrials.gov Identifier: NCT03236987     History of Changes
Other Study ID Numbers: PI2017_843_0010
First Posted: August 2, 2017    Key Record Dates
Last Update Posted: September 19, 2018
Last Verified: February 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Hospitalier Universitaire, Amiens:
MAC
Clarithromycin
Azithromycin
Efficacy
Safety
Additional relevant MeSH terms:
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Clarithromycin
Infection
Communicable Diseases
Mycobacterium Infections
Mycobacterium avium-intracellulare Infection
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Mycobacterium Infections, Nontuberculous
Anti-Bacterial Agents
Rifampin
Ethambutol
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers