Antibiotic prophylaxis for recurrent infections (Antibiotische profylaxe voor recidiverende infecties).

Rationale:

Many - mainly young - children suffer from recurrent respiratory infections, which hamper their quality of life and their day-care or school attendance. This is often a cause of great concern for their parents, who also suffer loss of working days. Dutch pediatricians and ENT-surgeons often prescribe co-trimoxazole prophylaxis to children with recurrent respiratory infections, but co-trimoxazole is not registered for this indication in the Netherlands, the use is off-label. Also, the dosages used and duration of prophylaxis differ, and the Dutch registration guidelines concerning the measurement of plasma concentrations
and screening for side effects during long-term use are generally not followed. Data in the literature are limited.


Objective:
The aim of the CO-PRINCE study is to establish the efficacy and safety of long-term antibiotic prophylaxis with co-trimoxazole in children with recurrent upper and/or lower respiratory tract infections (including ear-nose-throat (ENT)), hereafter referred to as ‘recurrent respiratory infections’.


Study design:
The CO-PRINCE study is a double-blind, parallel, placebo-controlled randomized clinical trial in children >6 months and <18 years who visit a pediatrician or ENT-surgeon because of recurrent respiratory infections. After receiving informed consent, and an initial laboratory evaluation has shown no abnormalities, children will be either assigned to oral co-trimoxazole 36mg/kg/day(2) or placebo. The study medication will be started immediately after inclusion, and will be continued until the month of April (inclusive), or for 3 consecutive months, whichever is longer. This schedule is applied to enable variable continuation of the study medication to prevent stopping during the ‘cold season’, as is current common practice. Parents, children, attending physicians, nurses and researchers will be blinded. A balanced allocation procedure within hospitals, age groups, and calendar months will be used to ensure comparability at baseline. The children will be followed up to 12 months after the end of the study medication phase, besides their regular follow-up by their own attending physician(s).


Study Population:
Inclusion criteria: Children >6 months and <18 years with recurrent respiratory infections visiting Dutch pediatricians and ENT-surgeons in participating hospitals will be included if informed consent is obtained from the parents and children (if >11 years). 'Recurrent' respiratory infections will be defined as ≥3 respiratory infections in the 6 months preceding study entry or start of the current therapy, or ≥4 per year (documented by a doctor and treated with antibiotics).
Exclusion criteria: known primary immunodeficiency (e.g. CVID, a/hypogammaglobulinemia); known secondary immunodeficiency (e.g. HIV, chemotherapy, transplantation); eponymous syndromes; chromosomal abnormalities; cleft palate; renal or hepatic insufficiency; known glucose-6-phosphate deficiency, cystic fibrosis, primary ciliary dyskinesia or acute porphyria; children using drugs known to interact with co-trimoxazole; children with previous allergic reaction to co-trimoxazole.


Intervention:
Long-term co-trimoxazole prophylaxis (see study design).


Main study parameters/endpoints:
The primary objective of the study is the effect on infection frequency per person month of long-term use. The secondary objectives of the study are safety and long-term effects (quality of life, antibiotic resistance, side effects, cost-effectiveness.


Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
Co-trimoxazole is a product with marketing authorization. From the experience with the product, no risks can be expected. The safety of the patients will be assessed by monitoring for laboratory safety parameters and any adverse event. The children treated in the co-trimoxazole arm may have direct benefit by this clinical trial (fewer infections), but the children in the placebo arm will not have any direct benefit by participating in this clinical trial.

The aim of the CO-PRINCE study is to establish the efficacy and safety of long-term antibiotic prophylaxis with co-trimoxazole in children with recurrent upper and/or lower respiratory tract infections (including ear-nose-throat).

Inclusion, study visit every 3 months during study medication use and in the 12 months thereafter. Infection frequency per person month as determined by the patient diary and daily chip-thermometer based temperature. Emergence of antibiotic resistance in nosocomial flora (culture, resistance, molecular typing), side effects (chemistry lab, blood levels), quality of life (HUI, RAND) and incremental cost-effectiveness ratios.

After receiving informed consent, and an initial laboratory evaluation has shown no abnormalities, children will be either assigned to oral co-trimoxazole 36mg/kg/day(2) or placebo. The study medication will be started immediately after inclusion, and will be continued until the month of April (inclusive), or for 3 consecutive months, whichever is longer. This schedule is applied to enable variable continuation of the study medication to prevent stopping during the ‘cold season’, as is current common practice.