E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cough and lower respiratory tract infections |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 6.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10038738 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
General objective 1. To understand which individuals benefit from antibiotics. To study the clinical effectiveness of antibiotics in community-acquired LRTI by means of a randomised placebo-controlled double-blind trial with patients as unit of randomisation. |
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E.2.2 | Secondary objectives of the trial |
1. To generate the evidence required to contain antibiotic resistance by showing which subgroups of patients benefit and which do not benefit from antibiotics, identified from the observational studies. 2. To assess the role of host and microbial genomics and antibiotic resistance in determining benefit from antibiotics. 3. To estimate the overall benefit from antibiotics and in different age groups (adults and the elderly) and different clinical subgroups (e.g. systemic symptoms, clinical signs). |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
The study will be performed in 13 primary care networks across Europe. Each network is led by a National Network Coordinator (NNC) and a National Network Facilitator (NNF). Eligible patients will be those who are:
Aged 18 years to 59 years and 60 years and over (enrolment will be done in such a way that we will aim to include 1500 patients under 60 and 1500 patients of 60 years and older) Consulting with acute cough as the main symptom (up to and including 28 days duration) or those in whom the general practitioner suspects the presence of acute lower respiratory tract infection Immuno-competent (no serious immunological deficiencies) Consulting for the first time within this illness episode Able to fill out study materials Who have provided written, informed consent to participate Who have not been included earlier in the current GRACE trial, either as a case or a control patient |
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E.4 | Principal exclusion criteria |
Patients who have had antibiotics in the previous month (altered flora) patients who are unable to properly consent or fill out the diary (dementia, psychosis, severe depression) and patients who are pregnant are excluded. Comorbid conditions including asthma and COPD are not exclusion criteria; this is part because there is no evidence that primary care patients with exacerbations benefit from antibiotics. We will exclude patients who are allergic to penicillin, and those with history/physical examination suggestive of community acquired pneumonia (CAP) (16) - i.e. new focal chest signs (focal crepitations or bronchial breathing) plus systemic features (high fever, vomiting, severe diarrhoea) - since there is no clear agreement among the clinical prediction rules that have been used to exclude pneumonia(11;12;14;17), nor about the use of C reactive protein(11;12;18). Our definition of community-acquired LRTI excludes clinically diagnosed CAP on ethical grounds; practitioners would be very unlikely to be willing to randomise patients with CAP.
Patients who require initial antibiotics (e.g. those with a clinical diagnosis of CAP) or those who decline to take the randomised study medication will still be asked to consider having the same measurements performed which will contribute to the observational study (WP9). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome parameters. 1) Deterioration of illness. We will document significant deterioration of illness - which is defined as a return to the doctor with a worsening symptoms, new symptoms, new signs, or requiring admission to hospital within four weeks after the first consultation which has been used as a workable definition in previous studies of respiratory tract infection in the community(21); this includes pneumonia following uncomplicated community-acquired LRTI, sepsis, acute cerebrovascular and cardiovascular disease, exacerbations of concomitant high-risk disease, or death. 2) Symptom severity and duration. Our other main outcome is based on a symptom diary, which uses a format similar to previous diaries, and is based on the premise that the main outcome should reflect when patients report symptoms are a problem. The diary has construct validity - good correlation with the validated Measure Yourself Medical Outcome Profile - is sensitive to change, and internally reliable (Cronbachs alpha 0.75 i.e. in optimal range)(8;22). Our main symptomatic outcomes will be the duration of symptoms rated moderately bad by patients(8), and the mean diary score for days 2 to 4 when symptoms are rated as the worst problem by patients. Before day 2 antibiotics will have little chance to provide benefit, and after day 4 on average symptoms are less than a moderate problem. If the diary is not returned, a short questionnaire will be sent to the patient in an attempt to collect the most relevant information about symptom duration. Patients will also document non-respiratory symptoms, like diarrhoea, skin rash, and vomiting. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |