Scientific rationale and general description:
Nontuberculous mycobacteria (NTM) represent all mycobacteria not belonging to the
Mycobacterium tuberculosis complex. This group of mycobacteria was discovered
recently and has demonstrated pulmonary pathogenicity. The presence of a NTM in a
respiratory specimen is therefore not sufficient to confirm the diagnosis of a lung
infection. The ATS/IDSA 2007 guidelines require clinical, radiological and
microbiological criteria to distinguish infection from colonisation.
The main NTM isolated and responsible of NTM pulmonary infections in France is
Mycobacterium avium complex (MAC). MAC organisms are common in many environmental
sites, including water, soil and in animals. Up to now, the main hypothesis for
transmission is inhalation of MAC via aerosol during the shower. Three classical
clinical and radiological patterns are described for MAC: the fibrocavitary lung
disease, the nodular bronchiectatic disease and the hypersensitivity disease. This
last pattern classically doesn't need any antibiotics. So, this study will focus
only on the two first patterns: fibrocavitary form and nodular-bronchiectatic form.
The limitations for effective therapy were the absence of antimicrobial agents with
low toxicity and good in vivo activity against the organism. The major therapeutic
advance is the introduction of the newer macrolides, clarithromycin and
azithromycin, which have substantial efficacy in vitro and clinical activity against
MAC. Structurally, azithromycin is an azalide. However, because of the close
similarity of azalides to macrolides, the term "macrolide" is often used to refer to
azithromycin and clarithromycin. As macrolides are the cornerstone of MAC treatment,
their use in monotherapy is responsible of selection of macrolides MAC resistant
strains that are associated with microbiological and clinical relapse. This is why
all international guidelines and all experts recommended the use of macrolides with
at least two companion drugs, classically rifampicin and ethambutol.
Treatment of MAC lung disease is long and not well tolerated. Despite treatment,
microbiological failure or early relapse occurs in 20-30% of patients. One of the
main failure explanations in NTM disease is the spontaneous treatment stop by the
patient, due to adverse effects. Even if clarithromycin is often used in first line
in France and is the only one macrolide with indication in its Summary of Product
Characteristics, its tolerance is often poor. Adult patients generally cannot
tolerate clarithromycin at more than 1,000 mg/day. The most common toxicities seen
with clarithomycin are gastro-intestinal (metallic taste, nausea, and vomiting) and
it interacts with numerous drugs via P450 cytochrome. Moreover, clarithromycin
enhances rifabutin toxicity, especially uveitis. Azithromycin toxicity is dose and
serum-level related. Most adult patients with MAC lung disease do not tolerate
azithromycin doses of greater than 300 mg/day because of frequent adverse events,
including gastrointestinal symptoms (primarily diarrhea).
The main hypothesis is the non-inferiority of azithromycin containing regimen
efficacy in comparison to clarithromycin. Moreover differences in intracellular
concentration of azithromycin and clarithromycin may result in differences in
efficacy and safety. The investigators also suggest that intracellular concentration
of azithromycin or clarithromycin may be correlated with microbiological success at
6 months of treatment. If this study could demonstrate that azithromycin is not
inferior to clarithromycin in term of efficacy, azithromycin could be used in first
line to improve patient tolerance and adherence to the treatment.
Study design and randomization method:
The CLAZI study is a multicentre, controlled open-label clinical trial studying two
treatment regimens containing two molecules, rifampin and ethambutol, in combination with
a third randomized molecule, either clarithromycin or azithromycin.
41 centres located in France will participate.
After having confirmed the presence of all inclusion criteria and the absence of all
exclusion criteria, and after having obtained the patient's free and informed consent,
the patient will be included and randomized to one of the treatment regimens. An
interactive web response system will be used to randomize patients using a minimization
algorithm stratified on centre, radiological form (nodular bronchiectatic form and
fibrocavitary form).
- Study treatment procedure:
After inclusion, the patients will receive the treatment as follow:
Rifampin 10 mg/kg once daily on an empty stomach (600 mg for patients weighing more
than 50 kg, 450 mg for patients weighing less than 50 kg) at least 30 minutes before
a meal, in combination with ethambutol 15 to 20 mg/kg once daily and clarithromycin
1,000 mg/day in two divided doses
Rifampin 10 mg/kg once daily on an empty stomach (600 mg for patients weighing more
than 50 kg, 450 mg for patients weighing less than 50 kg) at least 30 minutes before
a meal, in combination with ethambutol 15 to 20 mg/kg once daily and azithromycin
250 mg once daily
Treatments will not be provided because they are prescribed in their indication. They
will be issued in the dispensary. The compliance of treatment will be evaluated for each
period by the investigator, from the book of compliance, given to the patient at the
beginning of treatment and bring each consultation.
- Study procedures: The planned inclusion period is 48 months. However, the number of
inclusions will be evaluated at 18 months in order to request extension of the
inclusion period, if necessary. Each patient will be followed for the first 12
months of treatment.
Monitoring will be performed throughout treatment, comprising:
Monitoring of liver function tests (transaminases, gamma GT, alkaline phosphatase,
bilirubin) weekly for the first two weeks, then monthly throughout treatment. Liver
function tests will be repeated more frequently whenever an abnormality is detected.
CBC, clotting parameters at M1 then only in the presence of abnormal liver function
tests.
Monthly ophthalmological examination (colour vision and, if abnormal, visual field
examination) and an additional consultation if the patient reports any symptoms.
Depending on the patient's concomitant treatment and any possible drug interactions,
pharmacological assays of the patient's usual medications (e.g. digoxin) left to the
discretion of the patient's clinician.
Electrocardiogram two weeks after starting treatment
Clinical surveillance
A nested pharmacokinetic study will be done on 100 patients with peak serum and
mononuclear cells concentration of azithromycin and clarithromycin and their main
metabolites (D azithromycin and 14OH clarithromycin respectively). Indeed, a correlation
could exist between intracellular concentration and microbiological success. These
dosages will be done at 1 and 6 months.
Dosages in hair samples will be done at M6, as it is the best reflect of macrolides use.
Indeed, most drugs present in the bloodstream also reach and stay in the forming hair
where their concentrations can be measured and interpreted as an overall chronic
exposure.
For all patients, a baseline assessment will be performed on inclusion and the same
criteria will then be assessed at 3, 6 and 12 months in order to determine the clinical
and radiological outcome.
Long-term follow-up of the included patients will be proposed, with recording of any new
adverse effects emerging at the end of treatment (between 12 and 18 months), any
relapses, and survival at 18, 24, 36 months and, whenever possible, 5 years.
If a patient who initially clears sputum, but then turns positive again while still on
therapy could be a failure of treatment or a re-infection. To distinguish between failure
and re-infection, genotyping will be performed.
Relapse is defined by the presence of two positive cultures on respiratory specimens
obtained at least 6 months after stopping treatment.
Cure is defined by classical bacteriological criteria, i.e. 2 negative cultures during
the last 3 months of treatment and 3 years after stopping treatment. When specimens are
not obtained 3 years after stopping treatment, the definition of clinical cure will be
based on the absence of relapse at 3 years in survivors.
- Statistical methods: Quantitative variables will be presented as the mean ± standard
deviation or the median [range] and qualitative variables as percentage.
Analysis of the primary point:
Non-inferiority will be established if the upper limit of the two-sided 95% confidence
interval of the difference in the proportion of 6-month negative sputum rate between the
two groups (Control arm - Experimental arm) is lower than the non-inferiority margin
(10%). Intention-to-treat analysis will be performed followed by a per protocol analysis.
A multiple imputations analysis will be performed if more than 5% of the data are missing
for the primary endpoint. Farrington-Manning p-value for non-inferiority will be
calculated and a two-sided p-value < 0.05 will be required for statistical significance.
Analyses of secondary endpoints:
The tolerance and safety will be compared between the two arms with a χ2 or Fisher
exact test as appropriate.
Clinical improvement will be compared with Student or Wilcoxon test and radiological
improvement with χ2 or Fisher exact test.
The 3, and 12-month sputum conversion rate will be compared with a χ2 or Fisher
exact test as appropriate and asymptotic or exact 95% confidence intervals will be
given.
12-month death will be compared with χ2 or Fisher exact test and Kaplan-Meier curves
will be displayed graphically.
Serum and mononuclear cells concentration of azithromycin and clarithromycin and
their metabolites will be compared with Student or Wilcoxon test.
For each arm, association between azithromycin/clarithromycin intracellular
concentration in circulating mononuclear cells and microbiological success at 6
month will be assessed with a logistic regression model.
For each arm, association between azithromycin/clarithromycin intracellular
concentration in circulating mononuclear cells and tolerability of treatment will be
assessed with a logistic regression model.
Association between MAC species (avium, intracellulare and chimaera) and 6-month
conversion will be assessed with a logistic regression model with adjustment by the
treatment arm.
Given the substantial number of analyses for secondary endpoints, the step-down
Bonferonni procedure will be used to control the type I error rate.
Statistical analysis will be performed using SAS® version 9.4 (SAS Institute, Cary, NC).