Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT00273676 |
Other study ID # |
OG 99-64 |
Secondary ID |
|
Status |
Completed |
Phase |
Phase 4
|
First received |
January 5, 2006 |
Last updated |
January 5, 2006 |
Start date |
July 2000 |
Est. completion date |
March 2004 |
Study information
Verified date |
January 2006 |
Source |
UMC Utrecht |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
Netherlands: The Health Care Insurance Board |
Study type |
Interventional
|
Clinical Trial Summary
Patients with severe community-acquired pneumonia are included Half of the patients are
treated with a 3 day course of intravenous antibiotics, followed, when clinical stable, by a
course of oral antibiotics. Efficacy of this treatment is compared to a standard course of 7
days of intravenous antibiotics, which treatment is assigned to the other half of patients.
Outcomes measured are clinical cure and costs.
Description:
Study design A multi-center, randomized open label clinical trial was performed in 2
university medical centers and 5 teaching hospitals in the Netherlands. The study was
approved by the medical ethics committees of all participating hospitals and all patients
provided written informed consent prior to enrollment.
After inclusion in the trial, treatment allocation was established through an independent
central randomization center. Stratified randomization per center was based on computer
generated tables. Patients were either randomized to the intervention group, where
clinically stable patients were switched from IV to oral antibiotics on the 3rd day of
hospitalization to complete a total of 10 days antibiotic treatment, or to the control
group, who received a standard regimen of 7 days of intravenous therapy. Clinical stability
was defined as respiratory rate < 25/min, O2 saturation > 90% or arterial pO2>55mmHg,
hemodynamically stable, > 1oC decrease in temperature in case of fever, absent mental
confusion and the ability to take oral medication 10. Antibiotic choices were left to the
discretion of the attending consultant and were based on Dutch treatment guidelines 20.
Patients Adult patients (age 18 or above) with severe CAP admitted to general hospital wards
were eligible for inclusion in the study. Pneumonia was defined as a new or progressive
infiltrate on a chest X-ray plus at least two of the following criteria: cough, sputum
production, rectal temperature > 38oC or < 36.1oC, auscultatory findings consistent with
pneumonia, leucocytosis (>10.000/mm3, or >15% bands), C-reactive protein > 3 times the upper
limit of normal, positive blood culture or positive culture of pleural fluid. 21 Severe
pneumonia was defined as Fine class IV or V or fulfilling the ATS-criteria for severe
community-acquired pneumonia. 16;22 Patients with cystic fibrosis, a history of colonization
with Gram negative bacteria due to structural damage to the respiratory tract, malfunction
of the digestive tract, life expectancy of less than 1 month due to underlying diseases,
infections other than pneumonia needing antibiotic treatment, severe immunosuppression
(neutropenia (<0,5 x 109 / l) or a CD4 count < 200 / mm3) and needing mechanical ventilation
in an intensive care unit were excluded.
Baseline, follow up and outcome measurements Patients were followed for a maximum of 28
days. On admission, a complete physical examination, chest radiography and blood sampling
for arterial blood gas analysis and for hematological and biochemical analysis were
performed. Demographic data, initial intravenous therapy and clinical data were recorded.
During the follow-up period, in-hospital clinical data were recorded. Clinical stability was
evaluated after 3 days of intravenous therapy in both study groups and discharge criteria
(temperature < 37.8 oC, saturation >92%, normal blood pressure, heart rate < 100/min,
respiratory rate < 25/min, absence of mental confusion and ability to take oral medication )
were evaluated daily thereafter. If patients were discharged within 28 days after admission
they were asked to return to the out-patient clinic 28 days after inclusion, where history,
physical examination, blood chemistry analysis and a chest X-ray were taken and health-care
consumption after discharge was recorded.
Questionnaires were used to evaluate the effects on health care resource use outside the
hospital (recorded daily after discharge). Quality of life was determined with the short
form health survey questionnaire (www.sf-36.org) recorded at days 3, 10 and 28 of the study.
Additional questionnaires were used to measure the effects of an early discharge on the
workload for family members (questionnaire at day 28 of study) and effects of administration
route on freedom of movement, adverse events and compliance (questionnaire at day 7 of
study). Treatment failures were defined as death, clinical deterioration (clinical worsening
such that the patient needed mechanical ventilation, re-administration of intravenous
antibiotics after a switch to oral therapy, readmission for pulmonary reinfection after
discharge, increase in temperature after initial improvement) or hospitalization at day 28
of the study. Clinical cure was defined as discharged in good health without signs and
symptoms of pneumonia and no treatment failures during the follow-up period. 21
Microbiological analyses Sputum samples and blood samples were collected, cultured and
evaluated following standard procedures. Micro-organisms cultured in blood or sputum were
recorded. In addition, Binax NOW-tests were used to detect urinary antigen for Legionella
pneumophila and S. pneumoniae. Acute and convalescent serology samples were collected and
evaluated for Mycoplasma pneumoniae, L. pneumophila and Chlamydia pneumonia. Any
non-contaminating micro-organism cultured from a blood or sputum sample or detected by
urinary antigen testing was considered a cause for the episode of pneumonia. For Mycoplasma
pneumoniae, a fourfold or greater increase in titer in paired sera or a single titer of
greater than or equal to 1:40 was considered indicative of infection. 23 (Immune
fluorescence agglutination, Serodia-MycoII ®, Fujirebio, inc.) For Legionella pneumophila, a
fourfold increase in the antibody titer to 1:128 or greater, or single titers of 1:256 or
more were considered suggestive of Legionella pneumonia.24 For Chlamydia pneumoniae,
detection of IgM above established values, seroconversion of IgG between acute and
convalescence samples, high amounts of IgG in single titers or a combination of these
factors were considered serological evidence of infection, according to the manufacturers
instructions. (ELISA, Savyon Diagnostics Ltd)
Economic evaluation The societal perspective was used to calculate direct medical costs
associated with the treatment in both study groups. Costs were assessed in 2002 euros. Costs
per patient were calculated by multiplying resource use by the unit costs. Resource use
during hospital stay for diagnostic and therapeutic interventions, consultations of medical
or paramedic specialists and antibiotic use was measured. Resource use outside the hospital
was evaluated using questionnaires which recorded contacts with general practitioners,
specialists, extra diagnostic procedures, use of medication, readmissions, home care and
other disease-related costs. Additional costs associated with specific diagnostic tests were
based on tariffs. Costs of hospital stay, diagnostic procedures and specialist
consultations, were calculated using unit costs as determined within the realm of the Dutch
guidelines for pharmaco-economic analyses 25. Costs for readmissions and reinfections were
assessed specifically for the study cohort and included costs for extra diagnostic
procedures, treatment and hospitalizations. Costs of antibiotics prescribed were estimated
using Dutch 2002 formulary cost-prices 26
Sample size and statistical analysis To demonstrate equivalence in efficacy of the two
treatment groups, initially, the sample size was set at 250 patients in each study group
based on an expected cure rate of 85% in the IV group and acceptance of a 75% cure rate in
the switch group. (=0.05, 2 sided; 1-=0.80). The absolute difference in cure rate
including 95% CI was calculated. Equivalence was rejected if the lower limit of the CI
exceeded -10%. Eventually, with less than anticipated enrolment, a 15% lower effectiveness
in the intervention group could be excluded with =0.05 and 1-=0.80.
Analyses were performed on an intention-to-treat basis. Differences in continuous variables
were presented as absolute differences with their corresponding 95% CI´s. Dichotomous data
were compared with chi-square statistics. Alike cure rate differences in proportions were
presented including 95% CI´s. For cost-calculations, arithmetic means of both study groups
were compared. The uncertainty surrounding the cost-calculations was evaluated by means of
standard bootstrap techniques. 27 Ultimately, the balance between costs and effects was
compared for both strategies and incremental costs per therapy failure averted at 28 days
were calculated. The uncertainty surrounding the incremental cost-effectiveness ratio was
again evaluated by means of bootstrapping.