Oral Azitromycin Prophylaxis, 250 Mg Once Daily Three-Times a Week, in Primary Antibody Deficiencies: A Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial

Background. Lacking protective antibodies, patients with Primary Antibody Deficiencies (PAD) suffer from frequent respiratory infections leading chronic pulmonary damage. Macrolides prophylaxis has been proven effective in chronic respiratory diseases, including chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in PAD patients with chronic infection-related pulmonary diseases. Methods. A 3-year, randomized, double-blind, placebo-controlled trial was conducted in seven Italian immunology units. Eligible patients were aged 18-74 years, had a diagnosis of PAD with chronic infection-related pulmonary disease. Patients were randomly assigned (1:1) to receive azithromycin 250 mg once daily three-times a week for 2 years, or placebo. The primary outcome was the number of annual episodes of respiratory exacerbations. Secondary endpoints included time to the first exacerbation, additional doses of antibiotics to treat exacerbations, number of hospitalizations. Analysis was performed by modified intention to treat. This trial is registered with the Agenzia Italiana del Farmaco, Clinical Trials number: EUDRACT 2011-004351-39. Findings. Between November 2012 and December 2016, 90 patients were enrolled. We randomly assigned 89 patients to receive azithromycin (n=44) or placebo (n=45); 89 participants were comprised the modified intention-to-treat population. The number of exacerbations was 3·6 per patient-year (95%CI 2·5-4·7) in the azithromycin arm, and 5·2 (95%CI 4·1-6·4) in the placebo arm (p=0·02). In the azithromycin group the HR for having an acute exacerbation was 0·5 (95%CI 0·3-0·9, p=0·03) and the HR for hospitalization was 0.5 (95%CI 0·2-1·1) (p=0·04). The rate of additional antibiotic treatment per patient-year was 2·3 (95%CI 2·1-3·4) in the intervention and 3·6 (95%CI 2·9-4·3) in placebo groups (p=0·004). Four patients receiving placebo and none receiving azithromycin reported drug-related adverse events leading to treatment discontinuation. H.influenzae and S.pneumoniae were the prevalent isolates and they were non-susceptible to macrolides in 25% of patients of both arms. Interpretation. The study reached the main outcome centered in the reduction of exacerbation episodes per patient-year, leading to reduction of additional courses of antibiotics, and of risk of hospitalization. Adding azithromycin to the treatment regimen of PAD with respiratory exacerbation should be considered as a valuable option. Trial Registration Number: This trial is registered with the Agenzia Italiana del Farmaco, Clinical Trials number: EUDRACT 2011-004351-39. Funding. AIFA, Agenzia Italiana del Farmaco. Declaration of Interest: IQ and AP receipt of consultation fees and grants by Shire, CSL Behring, Octapharma and Kedrion; CA and AM receipt of consultation fees by Shire, Roche, CSL Behring, Octapharma, Novartis. CM, FP, FC, AP, MC, GL, VL, GF, BM, ST, DA, AS, GS, RMD and AV had none conflict of interest. Ethical Approval: The study protocol (EUDRACT: 2011-004351-39) was reviewed and approved by the Ethical Review Committee of Sapienza, University of Rome, Italy.