E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute episodes of Pneumonia and sepsis in older adults |
|
E.1.1.1 | Medical condition in easily understood language |
Pneumonia, which is a lung infections with chest symptoms (cough, sputum, breathlessness) and new changes on chest radiograph compatible with this diagnosis |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10035664 |
E.1.2 | Term | Pneumonia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
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 |
Pneumonia (severe lung infection) is one of the commonest causes of death and the death rate has not fallen for many years. Elderly patients are at greater risk of pneumonia and its complications such as sepsis. Usually the immune system works cooperatively to clear infection and prevent organ damage. Neutrophils are cells of the immune system that are critical in clearing bacteria. These cells are the foot soldiers of the immune system and move from the blood into infected tissues/organs to locate and kill the invading bacteria using an arsenal of toxic products. Sepsis occurs when the bodies normally helpful reaction to infection becomes harmful. As part of this process, neutrophils stop working properly, they become less able to clear bacteria and release their toxic products indiscriminately, causing organ damage. Defects in the efficiency of these cells is associated with a poor outcome from pneumonia and sepsis. We have undertaken a pilot study in patients, which |
|
E.2.2 | Secondary objectives of the trial |
1) safety and tolerability of drug in this patient group. 2) relationship of baseline and changes in above to clinical relevant outcomes (survival, development of organ failure, admission to ITU, SOFA score, ventilator free days. 3) do simvastatin influence neutrophil function in cells that have transmigrated across the alveolar epithelium. 4) does simvastatin modulate biomarkers of inflammation and cellular dysfunction in plasma and bronchoalveolar lavage fluid? These assessments will be made at baseline and upon day 4, 7 and convalescent samples. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria 1. Age > 60 years 2. Patients with a diagnosis of community acquired pneumonia. We will use the British Thoracic Society definition of pneumonia; defined as “symptoms and signs consistent with an acute lower respiratory tract infection associated with new radiographic shadowing for which there is no other explanation”. We will include symptoms and signs as having 3 or more of the following: cough, sputum production, breathlessness, pleuritic chest pain, haemoptysis, fever, headache, signs consistent with pneumonia on chest auscultation. 3. Pneumonia patients will also need to meet the criteria for sepsis based on the standard definitions as published in the 2008 Surviving Sepsis Campaign Guidelines. |
|
E.4 | Principal exclusion criteria |
Exclusion criteria • More than 48 hours from admission at time of consent. • Current or recent statin use within 1 month. • known prior myositis. • creatinine kinase >10 times upper limit normal range* • transaminases (ALT/AST) >8 times upper limit of normal range* • severe renal impairment (creatinine clearance <30ml/min) not receiving renal replacement therapy • patients currently receiving ongoing and sustained treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, ciclosporine, amiodarone, verapamil or diltiazem. Fibric acid derivatives (except fenofibrate), danazol. • A family history of muscular disorders. • Known HIV or hepatitis B/C infection. • Contraindication to enteral drug administration (either PO or Per NG) e.g. patients with mechanical bowel obstruction. • Known participation in other investigational medicinal product (IMP_ trials within 30 days. • Consent / relative or advocate assent declined. • Treatment withdrawal imminent within 24 hours. •Immunosuppression due to corticosteroid or other immunosuppressant use • Patient declines consent • Personal Consultee, when available, does not provide assent • Porfessional Consultee, if used, does not provide assent |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is changes to key neutrophil functions in older people with pneumonia and sepsis using Simvastatin. These functions include 1. Assessment of adhesion, chemokinesis and chemotaxis by neutrophils Neutrophil adhesion and migration will be assessed in a microscopy slide based system using established methodology (35). Chemoattractants used will be those that act via CXC receptors (CXCL8 and GROα), those that act through other receptors (e.g., fMLP). 2. Assessment of Neutrophil Extracellular Traps using extracellular DNA staining and visualisation using confocal microscopy. 3. Assessment of bacterial killing The phagocytic function and superoxide production of neutrophils will be examined using standard assays. Respiratory burst in response to fMLP will be determined in isolated neutrophils by measuring the generation of superoxide in a lucigenin-based assay. Phagocytosis of E Coli by neutrophils will be measured using a commercially available kit (Phagotest, Orpegen, Germany). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cell studies will be performed at baseline (day 1), day 4, day 7 and the re-cooperation visit on day 14 |
|
E.5.2 | Secondary end point(s) |
1. Safety and tolerability of drug in this patient group. 2) Relationship of baseline and changes in above to clinical relevant outcomes (survival, development of organ failure,admission to ITU, SOFA score, ventilator free days). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 0, 4, 7 and re-cooperation sample at day 14 |
|
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 | 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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
E.8.7 | Trial has a data monitoring committee | No |
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
|
The end of the trial will be the last visit of the last subject. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 27 |