E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lower respiratory tract infection |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008477 |
E.1.2 | Term | Chest infection |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024968 |
E.1.2 | Term | Lower respiratory tract infection |
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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 |
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 | No |
E.3 | Principal inclusion criteria |
• Age 18 years to 59 years and 60 years and over (enrolment will be done in such a way with the aim to include 1500 patients under 60 and 1500 patients of 60 years and older) • Consultation 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 subject (no serious immunological deficiencies) • Consultation for the first time within this illness episode • Ability to fill out study materials • Subject provided written, informed consent to participate • Subject has not been included earlier in the current GRACE trial, either as a case or a patient
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E.4 | Principal exclusion criteria |
• Patients who have had antibiotics in the previous month • Patients who are unable to properly consent or fill out the diary (dementia, psychosis, severe depression) • Patients who are pregnant • Allergy to penicillin or contra-indication for amoxicillin because of a major interaction with other medication • community acquired pneumonia in history or found during physical examination i.e. new focal chest signs (focal crepitations or bronchial breathing) plus systemic features (high fever, vomiting, severe diarrhoea) - clinically diagnosed CAP on ethical grounds (practitioners would be very unlikely to be willing to randomise patients with CAP).
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E.5 End points |
E.5.1 | Primary end point(s) |
1) Deterioration of illness. Documentation of 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; 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. 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 (Cronbach’s alpha 0.75 i.e. in optimal range). Main symptomatic outcomes will be the duration of symptoms rated moderately bad by patients, 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.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 28 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 230 |
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 | Yes |
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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Last visit of the last subject (i.e. one month after enrolment of the last subject). Data monitoring committee is very unlikely to stop the trial prematurely (life threatening complications are rare, as described in the literature). |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |