Condition category
Respiratory
Date applied
07/07/2006
Date assigned
31/07/2006
Last edited
09/05/2011
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Beat Mueller

ORCID ID

Contact details

Petersgraben 4
Basel
4031
Switzerland
+41 (0)61 265 2525
Happy.Mueller@unibas.ch

Additional identifiers

EudraCT number

ClinicalTrials.gov number

NCT00350987

Protocol/serial number

01

Study information

Scientific title

Acronym

ProHOSP

Study hypothesis

Procalcitonin (PCT) guidance will be non-inferior with at worst 7.5% higher combined failure rate as compared to standard care practice with a reduced total antibiotic (AB) use, hospitalisation rate and duration, respectively.

Ethics approval

Approved by the Local Ethics Committee of Basel, Switzerland (EKBB)

Study design

A non-inferiority multicentre investigator-initiated controlled trial with an open intervention

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Lower respiratory tract infection (LRTI)

Intervention

Patients admitted with lower respiratory tract infection (LRTI) to hospital will be included and randomised either to standard management or to the PCT-guided prescription of AB treatment. Randomisation will be stratified by centre (the hospital) and type of LRTI (Acute bronchitis/AECOPD/CAP).

Participating physicians will receive evidence-based guidelines for the management of patients with LRTIs. Patients with LRTI will be randomised 1:1 to PCT plus guidelines (PCT group) versus PCT-guided prescription of AB treatment (control group). In patients randomised to the PCT group, the use of ABs will be more or less discouraged (less than 0.1 or less than 0.25 ug/l) or encouraged (greater than 0.5 or greater than 0.25 ug/l), respectively. A re-evaluation after 6 to 24 hours in patients in whom antibiotics are withheld with worsening or non-improvement of vital signs, PCT (less than 0.1 or less than 0.25 ug/l) is recommended. During hospitalisation, patients with AB treatment will be reassessed at day 3, 5 and 7 and in patients randomised to the PCT group, it is recommended that AB is stopped based on PCT levels. In AB-treated outpatients or discharged patients with acute exacerbation of COPD (AECOPD) as well as CAP patients randomised to the PCT group with an uncomplicated cause, the recommended duration of AB therapy will be based on the last PCT level and will be as follows: greater than 0.5 ug/l for five days, greater than 0.25 for three days, less than 0.25 stop AB.

Intervention type

Other

Phase

Not Specified

Drug names

Primary outcome measures

To compare the risk of disease-specific failure in patients with LRTIs (pneumonic and non-pneumonic LRTI), managed with or without PCT decision making for AB prescription within 30 days following hospital-admission. The primary endpoint will be assessed by a blinded telephone interview.

Disease-specific failure (combined primary endpoint) will include death, need for intensive care unit (ICU) stay with and without the need for mechanical ventilation, microbiologically confirmed recurrence and relapse in need of AB, clinical and/or radiological recurrence in need of AB, complications from LRTI (persistence or development of pneumonia [including nosocomial], acute respiratory distress syndrome [ARDS], empyema), readmissions to hospital.
The endpoint will be assessed on day 30 (range 26 to 34) by telephone interview with the patient and the general physician, respectively. If discordant, the physician’s information will be considered.
Predefined subgroup analyses will be done for CAP, acute exacerbation of COPD and acute bronchitis, respectively. An additional telephone interview after six months will be performed. The results of the six-month interview will only be included in the subgroup analysis and not for the (primary) overall comparison between the two arms.

Secondary outcome measures

1. To compare AB use for LRTIs in the presence or absence of PCT testing. Specifically, the following parameters will be evaluated in each arm:
1.1. Time to antibiotic treatment (hours) (door-to-needle time)
1.2. Prescription rate of ABs in patients with LRTI
1.3. Event-free survival days without AB until follow-up after 30 days
1.4. Duration of AB treatment (days) and defined daily doses of antimicrobial therapy in each arm
1.5. Duration of AB treatment in hospitalized patients compared to discharged patients
1.6. Rate of adequate antibiotic therapy, time to the first change in antibiotic therapy
1.7. Side-effects from AB treatment (duration and severity), including gastrointestinal signs, allergies

2. To compare hospitalisation in the presence or absence of PCT testing. Specifically, the following parameters will be measured:
2.1. Time to effective hospital discharge (days)
2.2. Time to earliest possible hospital discharge (days) based on objective criteria (possible oral intake of food, liquids and drugs, stable vital signs greater than 24 hours [as defined below], baseline mental status, no evidence of acute serious co-morbidity that necessitates hospitalisation). This endpoint will minimise a bias due to extended hospitalisation for non-disease specific reasons (request from patients or their relatives, lack of adequate home care support, or possibility for transferal to nursery home, lack of assurance about compliance with treatment).

3. Time to clinical stability i.e. time (days) until stable vital signs for greater than 24 hours, temperature less than 38°C, heart rate per minute less than 100, spontaneous respiratory rate less than 24 per minute, systolic blood pressure greater than 90 mmHg (greater than 100 mmHg for patients diagnosed with hypertension) without vasopressor support, baseline mental status, adequate oxygenation on room air or less than 2 l of oxygen therapy (PaO2 greater than 60 mmHg or pulse oxymetry greater than 92%). For patients with chronic hypoxaemia or chronic oxygen therapy, PaO2 or pulse oximetry measurement must be at baseline.

4. Visual analogue scale, LRTI-specific disease activity score, number of days with restriction from LRTI, daily function and health state, worsening of general function and health state, all assessed at baseline and by telephone interview at follow-up after 30 days and six months. Thereby, visual analogue scale will be completed by the blinded interviewer based on the estimation of the patient on the telephone. Components of the combined primary endpoint will also be compared individually.

5. To develop prediction rules for adverse health outcomes in community-acquired LRTIs:
5.1. To assess the diagnostic and prognostic accuracy of clinical signs and symptoms for the severity and the cause of LRTI
5.2. In CAP patients the prognostic accuracy of the PSI, the CURB-65 with and without biomarkers will be compared
5.3. Rate of non-infectious differential diagnosis and time to final diagnosis in patients with suspected bacterial LRTI on admission with or without infiltrate and PCT levels of less than 0.1 and 0.25 ug/l, including congestive heart failure, pulmonary embolism, pulmonary tumor, viral infection, aspiration pneumonia, cryptogenic organising pneumonia (bronchiolitis obliterans organizing pneumonia [BOOP]), exogenous-allergic alveolitis, sarcoidosis, lymphoma
5.4. In COPD patients, the diagnostic accuracy of the Anthonisen criteria will be re-evaluated (namely sputum presence and purulence)

Overall trial start date

01/10/2006

Overall trial end date

01/05/2008

Reason abandoned

Eligibility

Participant inclusion criteria

1. Patients 18 years of age or older, admitted from the community or a nursing home with acute i.e. at least for 1 day but less than 28 days) lower respiratory tract infection (LRTI) as the main diagnosis consisting of having at least two of the following: new or increased respiratory signs or symptoms (i.e. cough, sputum production, dyspnea, auscultatory findings of abnormal breath sounds and rales, pleuritic chest pain) with or without inflammatory signs (core body temperature greater than 38.0°C, leukocyte count greater than 10 or less than 4 x 10^9 cells/l).
Community-acquired pneumonia (CAP) is defined by the presence of LRTI along with a new or increased infiltrate on chest radiograph. Severity scores of CAP (pneumonia severity index [PSI] and CURB-65) will be calculated.
Chronic obstructive pulmonary disease (COPD) is defined by post-bronchodilator spirometric criteria according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as a forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) ratio below 70% and the severity categorized into mild (FEV1 =80% of predicted), moderate (50%= FEV1 <80%), severe (30%= FEV1 <50%) and very severe (FEV1 <30%), respectively. Severity of acute exacerbations of COPD will be graded as proposed.
Acute bronchitis is defined as LRTI in the absence of an underlying lung disease or focal chest signs and infiltrates on chest x-ray, respectively. Patients who are on admission judged as having a LRTI but have another final diagnosis, will be classified as 'others'.
2. Ability to understand verbal and written instructions and informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

1002

Participant exclusion criteria

1. Patients unable to give written informed consent e.g. with severe dementia or patients who cannot understand German (or other local language) and where there are no translators (e.g. family members) available
2. Patients with active intravenous drug use
3. Severe immunosuppression (e.g. patients infected with human immunodeficiency virus [HIV] infection and a CD4 count below 350 x 10^9/l, patients on immunosuppressive therapy after solid organ transplantation and neutropenic patients with present neutrophil count less than 500 x 10^9/l, patients under chemotherapy with neutrophils of 500 - 1000 x 10^9/l with an expected decrease to values of less than 500 x 10^9/l), patients with cystic fibrosis, infected with Mycobacterium tuberculosis, Legionella pneumophila, Listeria spp. and hospital stay within 14 days of inclusion
4. Accompanying chronic (e.g. osteomyelitis), abscess, (e.g. brain, pleural empyema) infection or endocarditis
5. Terminal and very severe medical co-morbidity where death is imminent or is expected in current hospitalisation (e.g. due to malignancy, cardiac, renal or hepatic failure, comfort therapy)

Recruitment start date

01/10/2006

Recruitment end date

01/05/2008

Locations

Countries of recruitment

Switzerland

Trial participating centre

Petersgraben 4
Basel
4031
Switzerland

Sponsor information

Organisation

University Hospital of Basel (Switzerland)

Sponsor details

Petersgraben 4
Basel
4031
Switzerland
+41 (0)61 265 2525
muellerb@uhbs.ch

Sponsor type

University/education

Website

Funders

Funder type

University/education

Funder name

University Hospital of Basel (Switzerland)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Schweizerischer National Fund (SNF) (Switzerland)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2007 protocol in http://www.ncbi.nlm.nih.gov/pubmed/17615073
2. 2008 results in http://www.ncbi.nlm.nih.gov/pubmed/18852401
3. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19738090
4. 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20299634
5. 2011 results in http://www.ncbi.nlm.nih.gov/pubmed/21539743

Publication citations

  1. Results

    Briel M, Schuetz P, Mueller B, Young J, Schild U, Nusbaumer C, Périat P, Bucher HC, Christ-Crain M, Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care., Arch. Intern. Med., 2008, 168, 18, 2000-7; discussion 2007-8, doi: 10.1001/archinte.168.18.2000.

  2. Results

    Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B, , Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial., JAMA, 2009, 302, 10, 1059-1066, doi: 10.1001/jama.2009.1297.

  3. Results

    Müller F, Christ-Crain M, Bregenzer T, Krause M, Zimmerli W, Mueller B, Schuetz P, , Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial., Chest, 2010, 138, 1, 121-129, doi: 10.1378/chest.09-2920.

  4. Results

    Albrich WC, Dusemund F, Rüegger K, Christ-Crain M, Zimmerli W, Bregenzer T, Irani S, Buergi U, Reutlinger B, Mueller B, Schuetz P, Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm., BMC Infect. Dis., 2011, 11, 112, doi: 10.1186/1471-2334-11-112.

  5. Schuetz P, Christ-Crain M, Wolbers M, Schild U, Thomann R, Falconnier C, Widmer I, Neidert S, Blum CA, Schönenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Müller B, , Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial., BMC Health Serv Res, 2007, 7, 102, doi: 10.1186/1472-6963-7-102.

Additional files

Editorial Notes