Peri-operative Azithromycin to Improve Early Allograft Function and Outcome After Lung Transplantation

Study Overview
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Brief Summary
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This study investigates possible beneficial effects of peri-operative treatment (i.e. pre-transplant initiation and prompt post-transplant continuation) with azithromycin in lung transplantation. Our hypothesis is that this therapy will improve early allograft function and outcome following human lung transplantation.

Detailed Description
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After a lung transplant recipient is put on the waiting list for subsequent lung transplantation, informed consent will be sought for the current study. If signed informed is obtained, the patient will be enrolled upon admission for transplantation at which moment he/she will be randomised to placebo or azithromycin according to a blinded randomisation-list. In accordance with his/her attributed study-number, each included patient will be assigned to a pre-numbered bottle containing the study-drug, which was pre-filled and blinded for its content and are delivered in advance to the ward by the University Leuven Hospital Pharmacy. From this bottle, a first loading dose of placebo (25 mL po syrup) or azithromycin (25 mL po syrup = 1000 mg) will be given by the nurse during preparation for subsequent lung transplantation (Day 0). After lung transplantation, 'add on' treatment of placebo (6.25 mL) or azithromycin (6.25 mL = 250 mg) syrup will be given via (naso)gastric tube or per os every other day (days 1,3,5,7,9,11,13,15,17,19,21,23,25,27,29 and 31) by the nurses taking care of the patient in the early post-transplant period. In case of any serious suspected drug-interactions (however very unlikely) or adverse attributable to the study drug, the study will be promptly stopped in this patient. Serious adverse events will be monitored by the treating lung transplant physicians (blinded for the study-drug) and are defined as allergic reactions including skin reactions (rash, urticaria or Stevens-Johnson syndrome), angioneurotic edema and anaphylaxis, cardiac arrhythmias (ventricular tachycardia or torsades de pointes), neurologic disorders (convulsions). Routine immunosuppressive, prophylactic and necessary antimicrobial treatment according to standardized protocol is given to all patients, independent of study drug. After transplantation, routine follow-up (e.g. biochemical and microbiological blood analyses, chest radiography, pulmonary function testing and bronchoscopic evaluation with broncho-alveolar lavage and/or trans- or endobronchial biopsies will be performed as they are currently routinely being performed as part of the standard, prospective follow-up after lung transplantation.

Official Title
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A Prospective, Randomized, Placebo-controlled Trial of Pre-transplant and Prompt Post-transplant Treatment With Azithromycin to Improve Early Allograft Function and Outcome After Lung Transplantation

Conditions
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Disorder Related to Lung Transplantation

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Ora-Plus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Adult (age at least 18 years old at moment of transplantation) Single lung transplantation, sequential single (double) lung transplantation or heart-lung transplantation Exclusion Criteria: Known previous allergy for azithromycin (including skin reactions such as rash, urticaria or Stevens- Johnson syndrome, angioneurotic oedema and anaphylaxis) Retransplantation or multi-organ (other than heart-lung) transplantation Inclusion in Transmedics® Organ Care System (OCS™ LUNG) study (OCS-LUN-03-2010)(S53795).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin<br>A first dose of azithromycin (25 mL po syrup = 1000 mg) will be given during preparation for subsequent lung transplantation (Day 0). After lung transplantation, 'add on' treatment of azithromycin (6.25 mL = 250 mg) syrup will be given via (naso)gastric tube or per os every other day (days 1,3,5,7,9,11,13,15,17,19,21,23,25,27,29 and 31). | Drug: Azithromycin<br>* Zithromax® oral suspension 200 mg/ 5 mL (Pfizer, UK): Zithromax® 1000 mg syrup per os once at recipient intake for lung transplantation (day 0); followed by Zithromax® 250 mg syrup via (naso)gastric tube or per os every other day until one month after lung transplantation (days 1,3,5,7,9,11,13,15, 17,19,21,23,25,27,29 and 31).<br>* Other names: Zithromax®;|
| Placebo Comparator: Ora-Plus<br>A first dose of placebo (25 mL po syrup) will be given during preparation for subsequent lung transplantation (Day 0). After lung transplantation, 'add on' treatment of placebo (6.25 mL) syrup will be given via (naso)gastric tube or per os every other day (days 1,3,5,7,9,11,13,15,17,19,21,23,25,27,29 and 31). | Drug: Ora-Plus<br>* Ora-Plus® oral suspension (Paddock Laboratories, 3940 Quebec Avenue N, Minneapolis, MN 55427, USA; NDC-number: 0574-0303-16): Ora-Plus® 25mL syrup per os once at recipient intake for lung transplantation (day 0); followed by Ora-Plus® 6.25 mL syrup via (naso)gastric tube or per os every other day until one month after lung transplantation (days 1,3,5,7,9,11,13,15, 17,19,21,23,25,27,29 and 31).<br>* Other names: Ora-Plus®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean forced expiratory volume at one second (FEV1, %pred) | Mean FEV1 (%pred) during the first 3 months after lung transplantation (measured at discharge; thereafter twice weekly until 8 weeks post-transplant and weekly from 8 to 12 weeks post-transplant; i.e. total estimated number of 14 spirometries per patient) | at 3 months after lung transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of intubation |  | at 1 month after lung transplantation | 
| Length of Intensive Care Unit (ICU) stay |  | at 3 months after lung transplantation | 
| Length of hospital stay |  | at 3 months after lung transplantation | 
| Partial Pressure of Oxygen in Arterial Blood over fraction of inspired oxygen fraction - ratio (PaO2/FiO2) |  | at 0, 24, 48 and 72 hours after lung transplantation | 
| Primary graft dysfunction (PGD) prevalence and score |  | at 0, 24, 48 and 72 hours after lung transplantation | 
| 6-minute walking distance |  | at 1 month after lung transplantation | 
| Acute rejection (grade A; grade B) prevalence/severity |  | at 1, 3 and 6 months after lung transplantation | 
| Broncho-alveolar lavage neutrophilia and cytokine/protein profile |  | at day 1 and at 1, 3 and 6 months after lung transplantation | 
| Airway colonization | Presence (i.e. growth) of Pseudomonas species or Aspergillus species in routine cultures of broncho-alveolar lavage fluid at day 1 and 1, 3 and 6 months after lung transplantation. | at day 1 and 1, 3 and 6 months after lung transplantation | 
| Plasma C-reactive protein levels |  | at day 1, 3, 5, 7, 14 and 1, 3 and 6 months after lung transplantation | 
| Mortality |  | at 1, 3 and 6 months after lung transplantation | 
| Ventilator-free days | days alive and free from mechanical ventilation | at 6 months after transplantation | 
| Mean forced expiratory volume at one second (FEV1, %pred) | Mean FEV1 (%pred) during the first 6 months after lung transplantation | at 6 months after lung transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Function, Allograft Outcome