The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Figures & data

Table 1 Fixed regimen of standard therapy for an acute COPD exacerbation requiring hospitalization

Therapy	Specifications
Systemic steroids	Methylprednisolone 40 mg IV or 32 mg PO OD for 5 days (switch IV to PO as soon as possible)
Antibiotics
First choice	Amoxi–Clavulanate 1 g IV QID or 2 g PO BID for 7 days (or alternative regimen of 1 g IV QID or 875/125 mg PO TID for 7 days)
Alternatives	Moxifloxacin 400 mg IV or 400 mg PO OD for 5 days
In case of:	Intolerance or allergy to Amoxi–Clavulanate
	Clinical failure on GP-initiated Amoxi–Clavulanate treatment
	Anti-pseudomonas antibiotics
In case of:	Bronchiectasis
	History of positive cultures for pseudomonas
	High risk of pseudomonas
	Clinical failure on GP-initiated treatment
Short-acting bronchodilators	Via inhalation
Respiratory support	Oxygen
	Noninvasive ventilationa
	Mechanical ventilationa

Note:

a Considered exclusion criteria if needed at the moment of randomization.

Abbreviations: COPD, chronic obstructive pulmonary disease; IV, intravenous; PO, per os; OD, once a day; QID, four times a day; BID, two times a day; TID, three times a day; GP, general practitioner.

Table 2 Full list of exclusion criteria

Exclusion criteria
1   Mechanical or noninvasive ventilation at the moment of randomization
2   Long QT interval on ECG: QTc >450 ms for male or >470 ms for female
3   History of life-threatening arrhythmias
4   Myocardial infarction (NSTEMI or STEMI) less than 6 weeks before starting the study drug
5   Unstable angina pectoris or acute myocardial infarction (NSTEMI or STEMI) at admission
6   Concomitant use of a drug with high risk for long QT interval and torsade de pointes (amiodarone, flecainide, procainamide, sotalol, droperidol, haldol, citalopram, other macrolides)
7   Documented uncorrected severe hypokalemia (K^+ <3.0 mmol/L) or hypomagnesemia (Mg^2+ <0.5 mmol/L)
8   Chronic systemic steroids (>4 mg methylprednisolone/day for ≥2 months)
9   Actual use of macrolides for at least 2 weeks
10 Allergy to macrolides
11 Active cancer treatment
12 Life expectancy <3 months
13 Pregnant or breast-feeding subjects. Woman of childbearing potential must have a pregnancy test performed and a negative result must be documented before starting the treatment

Abbreviations: ECG, electrocardiogram; NSTEMI, non-ST elevation myocardial infarction; STEMI, ST elevation myocardial infarction.

Figure 1 The BACE trial study design.

Abbreviations: BACE, the Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization; COPD, chronic obstructive pulmonary disease; D1, day 1; D1–3, days 1–3; D4–90, days 4–90; D270, day 270; OD, once a day.

Table 3 Data collected at each study visit

Assessment	Visit
	Screening (48 hours)	Randomization (D1, within 48 hours after hospital admission)	Switch to maintenance dose (D4, + max 72 hours)	Day of discharge (DX, at investigators discretion)	Control visit 1: 1 month after discharge (DX +28, +14-day window)	Control visit 2: End of intervention (D90, allowed from day 86 until day 105)	Telephone call 1 (D150, ±7-day window)	Telephone call 2 (D210, ±7-day window)	Control visit 3: End of follow-up (D270, +14-day window)
Chest X-ray	X
ECG	X		X		Xb	Xb			(Xa,b)
Arterial blood gas	X
Laboratoryc	X		X
Spontaneous sputum sample	X			Xb		Xb			Xb
Pre- and post-bronchodilator spirometry				X		X			X
Eligibility + informed consent	X
Anamnesis + medical history		X
Current respirator medication		X		X		X			X
Vital parameters	X	X	X	X		X			X
mMRC + CAT questionnaire		Xb	Xb	Xb	Xb	Xb	Xb	Xb	Xb
EQ5D questionnaire		Xb		Xb		Xb			Xb
SSQ5 questionnaire		Xb		Xb		Xb			Xb
PROactive substudy				(Xb,d)		(Xb,d)			(Xb,d)
Study drug intake		X	X	X	X	X
Check therapy adherence			X	X	X	X	X	X	X
Check prim/s endpoint			X	X	X	X	X	X	X
Record (serious) adverse events			X	X	X	X	X	X	X
Diary instruction + overview				X	X	X	X	X	X

Notes:

a ECG only to be performed at D270 if long QT, severe arrhythmia’s, or severe conductance disturbances were present on ECG of D90;

b test performed in addition to clinical routine;

c screening laboratory: hemoglobin, hematocrit, total white blood cell count and differentiation, platelets, creatinine, urea, Na⁺, K⁺, Cl⁻, HCO3⁻, Mg²⁺, AST, ALT, LDH, glucose, CRP, high-sensitive troponin T; D4 laboratory: total white blood cell count and differentiation, Na⁺, K⁺, Cl⁻, HCO3⁻, Mg²⁺, CRP, high-sensitive troponin T, 25-hydroxyvitamin D, total IgE, RAST aspergillus, IgG aspergillus;

d DynaPort^® to be worn for 7 days and questionnaire to be completed on day 8 only if patient consented to participation in the PROactive substudy.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; D270, day 270; DX, day X; D1, day 1; D150, day 150; D210, day 210; D90, day 90; ECG, electrocardiogram; EQ5D, European Quality-of-Life – 5 Dimensions; IgE, immunoglobulin E; IgG, immunoglobulin G; LDH, lactate dehydrogenase; mMRC, modified Medical Research Council; RAST, radioallergosorbent test; SSQ5, Speech, Spatial and Qualities of Hearing Scale – 5-items.