Azithromycin did not reduce the prevalence of bronchiectasis or airways disease severity at age 3 years in infants with cystic fibrosis. However, children receiving azithromycin had fewer hospitalizations, intravenous antibiotic days, and courses of inhaled/oral antibiotics per year compared to placebo. Limitations included not reaching the target sample size and potential impacts of concurrent medications introduced during the study period. The cohort will be followed to determine if early azithromycin intervention has long-term effects.

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The effect of azithromycin on structural lung disease in infants with cystic fibrosis
(COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trial
Prof Stephen M Stick, PhD, Alexia Foti, BSc, Prof Robert S Ware, PhD, Prof Harm A W
M Tiddens, PhD, Barry S Clements, FRACP, David S Armstrong, MD, Prof Hiran
Selvadurai, PhD, Andrew Tai, PhD, Peter J Cooper, FRACP, Prof Catherine A Byrnes,
MD, Yvonne Belessis, PhD, Prof Claire Wainwright, MD, Prof Adam Jaffe, MD, Prof
Philip Robinson, PhD, Lisa Saiman, MD, Prof Peter D Sly, DSc
The Lancet Respiratory Medicine
DOI: 10.1016/S2213-2600(22)00165-5
Copyright © 2022 Elsevier Ltd Terms and Conditions

2. Cystic Fibrosis Transmembrane Regulator (CFTR)
Protein
Zhang et al. J Struct Biol 2009;167:242
CFF Patient Registry 2008 (US)
O’Sullivan & Freedman. Lancet 2009;373:1891-1904
NBD1
ATP binding /
hydrolysis
NBD2
ATP binding /
hydrolysis
Intracellular
Extracellular
R domain
cAMP/PKA
regulation
Cl-
• ~90% of CF individuals have at
least one F508del allele
• ~50% have 2 copies
(homozygous); ~40% have one
copy (heterozygous)
• F508del-CFTR has a protein-
folding defect that
• Inhibits trafficking
• Enhances degradation
• Reduces CFTR membrane channel function F508del

3. CF
• Progressive
• Mucous obstruction,
• Neutrophilic inflammation
• Recurrent lower airway infection
• Structural lung disease
• End stage lung disease- respiratory failure

4. J Cyst Fibros. 2010 Jul; 9(4): 250–256.

5. Progression
Cogen, J.D., Ramsey, B.W. (2020). The Changing Face of Cystic Fibrosis. In: Davis, S.,
Rosenfeld, M., Chmiel, J. (eds) Cystic Fibrosis. Respiratory Medicine. Humana, Cham.

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Figure 2. Mean rates of FEV1 decline during the 2-year known treatment period. FEV1 = forced expiratory volume in 1
second; HDI = high-dose ibuprofen.
Annals ATS, 2018
https://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201706-486OC
Michael W. Konstan; Donald R. VanDevanter; Gregory S. Sawicki; David J. Pasta; Aimee J. Foreman; Evgueni A. Neiman;

7. Hypothesis
• Continuous treatment with azithromycin after
diagnosis with CF:
Reduce structural lung damage detected on chest
CT scans at age 36 months
Reduce lower airway inflammation (free
neutrophil elastase activity & IL-8 BAL)

8. Primary outcomes
• The proportion of children with radiologically-
defined bronchiectasis at age 3 years
• The percentage of lung tissue affected by airways
disease at age 3 years

9. Secondary outcomes
i. The extent and severity of bronchiectasis at age 3 years
ii. The volume of trapped gas at age 3 years
iii. CF-related quality of life
iv. Time to first pulmonary exacerbation
v. Proportion of participants experiencing exacerbation
vi. Number of courses of inhaled or oral antibiotics

10. Secondary outcomes
vii. Number of days of inhaled antibiotics
viii. Hospitalizations/A&Evisits for an exacerbation
ix. Number of days hospitalized for acute exacerbation
x. Number of days of intravenous antibiotics
xi. Body mass index at 3-years of age

11. Study Design
• Phase three,
• Multicentre,
• Randomised, double-blind,
• Placebo-controlled,
• investigator-initiated trial
• Eight paediatric CF clinics Australia and New Zealand.

12. Inclusion criteria
Infants aged 3–6 months with a confirmed
diagnosis of cystic fibrosis after newborn
screening
Participants who, in the opinion of the
investigator, are able to comply with the protocol
for its duration.

13. Exclusion
Gestation <30 weeks
prolonged mechanical ventilation in the 3 mth,
 significant medical disease or comorbidity other
than cystic fibrosis, and
macrolide hypersensitivity
Participation in another RCT
Previous major surgery except for meconium ileus

14. Randomisation and masking
• Randomly assigned (1:1) azithromycin/ placebo
• Stratified by site.
• A permuted block strategy
• Block size assigned on a site-by-site basis
• Blinding maintained until the last participant
completed the trial

15. Intervention
• Study medication orally three times per week
(Monday, Wednesday, and Friday) 10 mg/kg
• Enrolment until age 36 months
• Azithromycin and matched placebo
• Supplied as powder for suspension and administered
orally
• Identical bottles

16. • Diary cards - each visit
 drug adherence,
record concurrent medications,
and adverse events

17. • 13 study visits over 36 months.
• Every 3 months,
• Coincide with routine clinical assessments.
• Study visit calculated on the basis of month of age

18. • Chest CT - 12 months and 36 months under general
anaesthesia PRAGMA-CF scoring algorithm
• Bronchoalveolar lavage at enrolment, 12 months and
36 months

19. Exacerbations
• Treatment with oral, inhaled, or IV antibiotics
Sats <90% or ≥5% decline from previous baseline
New lobar infiltrate on CXR
Haemoptysis (more than streaks >1 occasion)
Increased work of breathing or RR
Increased cough
Increased chest congestion or change in sputum
 New or increased adventitial sounds on lung exam
Weight loss ≥5% BW or decrease 1 weight percentile

20. Outcomes
• Single primary outcome was the prevalence of
bronchiectasis.
• Airways disease severity was added during the trial
after the PRAGMA-CF algorithm was validated
specifically for use in infants and preschool children
aged 3–6 years with cystic fibrosis

21. Sample size
• Prevalence of bronchiectasis in placebo group was
assumed to be 50%.
• 50% reduction in bronchiectasis prevalence at 36
months with 80% power (α=0·05),
• 116 children (58 per group) were required
• Anticipating 10% attrition 130 children

23. • Two interim analyses 50% 12-month CT scan,
• All participants completed the 12-month CT scan
• The interim results did not meet stopping criteria
• Analysis was completed with the intention-to-treat
principle

24. • For the primary outcomes, airways disease severity
was analysed with median regression,
• Prevalence of bronchiectasis was analysed with
logistic regression.
• Regression models included treatment group
(azithromycin or placebo) as the main effect.

25. • June 15, 2012, to July 10, 2017
• 133 participants enrolled study and randomly assigned.
• 3 withdrew before first dose of study medication.
• 130 children began the intervention (68 in the
azithromycin group vs 62 in the placebo group

26. Figure 1
The Lancet Respiratory Medicine DOI: (10.1016/S2213-2600(22)00165-5)
Copyright © 2022 Elsevier Ltd Terms and Conditions

27. • Median enrolment age 3·3 months (IQR 2·8–4·4).
• 107 participants completed all 13 trial visits (82%; 59
in the azithromycin group vs 48 in the placebo group)
• 104 had CT scans acceptable for PRAGMA-CF analysis
(80%; 57 azithromycin vs 47 placebo)
• Adherence (95% in each group)

28. Primary outcome

29. Figure 2
The Lancet Respiratory Medicine DOI: (10.1016/S2213-2600(22)00165-5)
Copyright © 2022 Elsevier Ltd Terms and Conditions

30. Secondary outcomes,
• Children on Azithromycin spent
Less days inhospital for exacerbations/ year (mean
difference −6·3 days, 95% CI −10·5 to −2·1; p=0·0037),
Fewer days of IV abs each year (0·2 vs 6·7/ year);
median difference −6·7, 95% CI −12·2 to −1·2; p=0·018),
Fewer courses of inh/ oral antibiotics/year
(incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088)

31. Exacerbations

33. Discussion
• Azithromycin might not alter the trajectory of
progressive lung damage
• ? adherence was lower than parents reported
• The cohort will be followed - whether early
intervention with azithromycin has an

34. Limitations
• Did not reach the primary sample size
• ?ITT
• Assumed only 50% will have bronchiectasis at 3 years

36. ? Antibiotic resistance
• Low micro-organism identification
• MRSA in 4vs 1
• ? Long term

37. ? Concurrent medications
• Orkambi became
available 2-5 years in
October 2019

38. Do we change our practice?