Evaluating Customized Antibiotic Duration (CDA) Strategy in Acute Exacerbations of COPD

Background: Antibiotics are routinely given to adults hospitalised with an acute exacerbation of COPD (AECOPD). International guidance (GOLD) advises that treatment should normally last about 5 days, but in many hospitals in Pakistan courses of 14 days remain usual practice. Longer courses increase antibiotic exposure, adverse effects and the risk of antimicrobial resistance, yet there is no randomised evidence from Pakistan on whether a shorter course is as effective for hospitalised patients.

Intervention: The experimental arm receives a 7-day systemic antibiotic course and the active comparator arm the conventional 14-day course. The treating physician chooses the agent, dose and route according to institutional practice and available microbiology, so only the planned duration differs between arms. Duration is counted from the first antibiotic dose for the current exacerbation. All other care, including bronchodilators, corticosteroids, oxygen and ventilatory support, follows usual practice in both arms. The intervention was developed through a three-round Delphi consensus process with prescribers before the trial began.

Procedures: Blood and sputum samples are taken at baseline for culture and susceptibility testing; results may guide a change of agent but do not change the allocated duration. Participants are assessed during treatment (Day 3-5), at Day 7, at Day 14 and at Day 30, in hospital or by telephone. Allocation uses a computer-generated sequence with permuted blocks of variable size, concealed through a web-based randomisation system.

Sample size: Assuming 80% clinical success in both arms, a non-inferiority margin of 10 percentage points, a one-sided alpha of 0.025 and 80% power, 252 evaluable participants per arm are required; allowing for 10% attrition, 560 participants will be enrolled.

Analysis: The primary analysis estimates the risk difference in clinical success at Day 30 (7-day minus 14-day) with a two-sided 95% Miettinen-Nurminen confidence interval. Non-inferiority will be concluded only if the lower confidence limit exceeds -10 percentage points in both the intention-to-treat and per-protocol populations. Full details are given in the study protocol (version 2.0) and statistical analysis plan (version 1.1).

• 7-day antibiotic course (Drug): Systemic antibiotic therapy is given for a total of 7 days, counted from the first dose for the current exacerbation. The agent, dose and route are chosen by the treating physician according to institutional practice, suspected cause and available microbiology; only the planned duration differs from the comparator.
• 14-day antibiotic course (Drug): Systemic antibiotic therapy given for a total of 14 days, counted from the first dose for the current exacerbation, which is usual practice at the study hospital. The agent, dose and route are chosen by the treating physician according to institutional practice, suspected cause and available microbiology; only the planned duration differs from the experimental arm.

Primary outcomes

• Clinical Success at Day 30 [Day 30 (±3 days) after randomisation]: Number and proportion of participants with clinical success at Day 30 (±3 days) after randomisation, compared between arms as a risk difference (7-day minus 14-day) with a non-inferiority margin of -10 percentage points. Clinical success requires all of: (a) resolution or substantial improvement of the exacerbation-related signs and symptoms present at baseline (dyspnoea, sputum volume and sputum purulence), judged by the blinded outcome assessor using predefined criteria, with a reduction of at least 2 points from baseline in the COPD Assessment Test score; (b) no additional or alternative systemic antibiotic for a respiratory indication after the allocated course, and no extension of the course because of lack of improvement; (c) no hospital readmission or emergency department visit for AECOPD; and (d) the participant is alive. Participants who do not meet all four criteria are classified as clinical failures.

Secondary outcomes

• Clinical Success at Day 14 [Day 14 (±2 days) after randomisation]: Number and proportion of participants with clinical success at Day 14 (±2 days) after randomisation, defined as for the primary outcome, compared between arms as a risk difference.
• Time to Resolution of Exacerbation Symptoms [From randomisation up to Day 30]: Number of days from randomisation to resolution of the exacerbation symptoms present at baseline.
• Incidence of Antibiotic-Related Adverse Events and Serious Adverse Events [From randomisation up to Day 30]: Number of participants with at least one adverse event or serious adverse event related to antibiotic treatment.
• Treatment Failure [From randomisation up to Day 30]: Number of participants with treatment failure, defined as the need for additional or alternative systemic antibiotics because of clinical deterioration or lack of improvement, escalation to non-invasive or invasive ventilation or intensive care after Day 3, or death.
• Relapse [From randomisation up to Day 30]: Number of participants with a new or worsening exacerbation requiring systemic antibiotics or corticosteroids after initial clinical improvement.
• Rehospitalisation for Any Cause and for AECOPD [Within 30 days after randomisation]: Number of participants readmitted to hospital, reported separately for any cause and for acute exacerbation of COPD.
• All-Cause Mortality [Within 30 days after randomisation]: Number of participants who die from any cause.
• Total Antibiotic Consumption [From randomisation up to Day 30]: Total systemic antibiotic consumption per participant, expressed in defined daily doses (DDD).

Sex: All, ages: 18 Years to 90 Years

Inclusion Criteria:

* Adults aged 18 years or older.
* Physician-diagnosed COPD, confirmed by post-bronchodilator spirometry (FEV1/FVC < 0.70) where available, or by documented previous spirometry consistent with COPD.
* A current acute exacerbation of COPD for which the treating physician judges antibiotic therapy to be necessary, with at least two of the three cardinal symptoms (increased dyspnoea, increased sputum volume, increased sputum purulence).
* Able and willing to give written informed consent and to follow the study procedures and follow-up schedule.

Exclusion Criteria:

* A documented infection that requires a defined, longer antibiotic course, such as pneumonia with complications, an exacerbation of bronchiectasis, lung abscess or empyema.
* Need for immediate admission to intensive care or for invasive mechanical ventilation at presentation.
* Severe immunosuppression, for example neutropenia, active malignancy under chemotherapy, organ transplantation or advanced HIV infection.
* Suspected or confirmed pulmonary tuberculosis, or another respiratory infection that needs a different antimicrobial approach.
* Pregnancy or breastfeeding.
* Previous enrolment in this trial, or current participation in another interventional trial in AECOPD.
* Systemic antibiotic treatment for the current exacerbation started more than 48 hours before randomisation.

• Chan AW, Boutron I, Hopewell S, Moher D, Schulz KF, Collins GS, Tunn R, Aggarwal R, Berkwits M, Berlin JA, Bhandari N, Butcher NJ, Campbell MK, Chidebe RCW, Elbourne DR, Farmer AJ, Fergusson DA, Golub RM, Goodman SN, Hoffmann TC, Ioannidis JPA, Kahan BC, Knowles RL, Lamb SE, Lewis S, Loder E, Offringa M, Ravaud P, Richards DP, Rockhold FW, Schriger DL, Siegfried NL, Staniszewska S, Taylor RS, Thabane L, Torgerson DJ, Vohra S, White IR, Hrobjartsson A. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. Lancet. 2025 May 17;405(10491):e19-e27. doi: 10.1016/S0140-6736(25)00770-6. Epub 2025 Apr 28. PMID 42290521
• Wang Y, Zijp TR, Bahar MA, Kocks JWH, Wilffert B, Hak E. Effects of prophylactic antibiotics on patients with stable COPD: a systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2018 Dec 1;73(12):3231-3243. doi: 10.1093/jac/dky326. PMID 30189002
• Vanoverschelde A, Van Hoey C, Buyle F, Den Blauwen N, Depuydt P, Van Braeckel E, Lahousse L. In-hospital antibiotic use for severe chronic obstructive pulmonary disease exacerbations: a retrospective observational study. BMC Pulm Med. 2023 Apr 25;23(1):138. doi: 10.1186/s12890-023-02426-3. PMID 37098509

• Study Protocol: Protocol (PDF, 2026-08-01)
• Study Protocol and Statistical Analysis Plan: Study Protocol and Statistical Analysis Plan : Protocol (PDF, 2026-08-01)
• Informed Consent Form (PDF, 2026-07-08)

• Fazal Rabbi, MD, Principal investigator, Capital Development Authority (CDA)