SECTION 1: INCLUSION/EXCLUSION CRITERIA INCLUSION CRITERIA Please put a cross in the Yes or No box for each question

Transcription

1 Site Number Patient s Initials SECTION 1: INCLUSION/EXCLUSION CRITERIA INCLUSION CRITERIA Please put a cross in the Yes or No box for each question Yes No 1.1 Is the patient receiving invasive mechanical ventilation? Does the patient meet the following ALI criteria? a) Acute onset 1 0 b) Within the same 24 hour time period has the patient had ALL of the following? i. Hypoxic respiratory failure (PaO 2 /FiO 2 40 kpa from 2 blood gases > 1 hour apart) 1 0 ii. Bilateral infiltrates on chest X-ray consistent with pulmonary oedema 1 0 iii. No clinical evidence of left atrial hypertension or if measured, a pulmonary arterial occlusion pressure (PAOP) less than or equal to 18 mm Hg 1 0 If the answer to any of the questions 1.1 to 1.2 is No, the patient is not eligible. EXCLUSION CRITERIA No Yes 1.3 Is the patient less than 16 years old? Is it more than 48 hours from the onset of ALI? Is the patient known to be pregnant? Is Creatinine Kinase (CK) > 10 times the upper limit of normal range? Are Transaminases > 8 times the upper limit of normal range? 1.8 Is the patient currently receiving ongoing and sustained treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone cyclosporine, amiodarone, verampamil or diltiazem? 1.9 Does the patient have severe renal impairment (estimated creatinine clearance less than 30 ml/minute) and is not receiving renal replacement therapy? Does the patient have severe liver disease (Child-Pugh score >12)? Is the patient currently receiving statins (or had treatment with statins within the last two weeks)? 0 1 Page 1 Please return top white copy to the CTU; yellow copy to be retained in site file

2 SECTION 1: INCLUSION/EXCLUSION CRITERIA EXCLUSION CRITERIA 1.13 Patients with high gastric aspirates due to an ileus can be recruited. EXCLUSION CRITERIA DOMICILIARY MECHANICAL VENTILATION CPAP and BIPAP used for sleep-disordered breathing are not included as domiciliary mechanical ventilation. Page 2 Please return top white copy to the CTU; yellow copy to be retained in site file

3 Site Number Patient s Initials SECTION 1: INCLUSION/EXCLUSION CRITERIA (CONTINUED) EXCLUSION CRITERIA Please put a cross in the Yes or No box for each question No Yes 1.12 Has a physician decided that a statin is required for a proven indication? Is there a contraindication to enteral drug administration? Is the patient receiving domiciliary mechanical ventilation with the exception of CPAP and BIPAP used for sleep-disordered breathing? Is the patient known to have enrolled in another clinical trial of an investigational medicinal product (IMP) in the last 30 days? Is treatment withdrawal imminent in the next 24 hours? Is the patient non-english speaking or does not adequately understand verbal or written information unless an interpreter is available? 0 1 If the answer to any of the questions 1.3 to 1.17 is Yes, the patient is not eligible. If the patient is eligible: obtain written consent, answer questions 1.18 & 1.19, then proceed to Section 2 and randomise the patient. Yes No 1.18 Has consent been obtained? Has consent been granted for genetic testing? 1 0 Date of Consent D D M M Y Y Y Y Name of site Investigator completing this form Signature Date form completed D D M M Y Y Y Y PRINT Name Page 3 Please return top white copy to the CTU; yellow copy to be retained in site file

4 SECTION 2: RANDOMISATION The automated telephone randomisation service is open 24 hours per day and 7 days per week. Aberdeen Trials Service: (Contact details are in your trial manual) 1. You will be prompted to enter the information recorded on page 5: Site Number Patient Initials Date of Birth PaO 2 value (e.g. PaO 2 = 14.3 enter 143; PaO 2 = 9.1 enter 091) FiO 2 value (e.g. FiO 2 = 85% enter 085) (the service will automatically calculate the PaO 2 /FiO 2 ratio: if this is > 40 kpa the randomisation will be terminated) 2. You will be asked to confirm whether the patient is receiving vasopressors. 3. You will be asked to confirm that the patient fulfils the eligibility criteria and that written consent has been obtained. 4. You will be given and asked to confirm the allocated Patient Number for this patient. Please record the Patient Number on page 5 before confirming it on your telephone keypad. For detailed instructions please refer to the Telephone Randomisation Service User Guide. Note: Patients may also be randomised via the Web Randomisation Service, please refer to the Web Randomisation Service User Guide provided for further information. Page 4 Please return top white copy to the CTU; yellow copy to be retained in site file

5 Site Number Patient s Initials SECTION 2: RANDOMISATION The following information will be needed by the randomisation service. 2.1 Date of Birth D D M M Y Y Y Y Please record the PaO 2 and FiO 2 values corresponding to the lowest PaO 2 /FiO 2 ratio since onset of ALI 2.2 PaO FiO 2. kpa Yes No 2.4 Is the patient receiving vasopressors? 1 0 Vasopressors are defined as any inotropic/vasopressor agent except dopamine < 6 mcg/kg/min 2.5 Confirm that this patient is eligible Confirm that a consent form has been signed 1 0 Now telephone the randomisation service (Contact details are in your trial manual) The randomisation service will provide you with the patient number for this patient which should be used for the duration of the study. Please record the allocated Patient Number Date and Time of Randomisation D D M M Y Y Y Y H H M M Name of site Investigator completing this form Signature Date form completed D D M M Y Y Y Y PRINT Name Please complete prescription and take to pharmacy Page 5 Please return top white copy to the CTU; yellow copy to be retained in site file

6 SECTION 3: BASELINE ASSESSMENT FORM PLATEAU PRESSURE In volume-controlled ventilation, the plateau pressure is measured following an inspiratory hold (0.5 to 1 second), and the airway pressure, from the initial peak pressure drops down to plateau. In pressure-controlled ventilation, the plateau pressure is estimated by the pressure limit. If the patient is on pressure support, record the plateau pressure field as not available. DEFINITION OF SEPSIS Sepsis is defined as 1. Systemic inflammatory response syndrome (SIRS). Defined by the presence of two or more of the following findings: Body temperature < 36 C or > 38 C Heart rate > 90 beats per minute (tachycardia) or receiving medications that slow heart rate or paced rhythm Respiratory rate > 20 breaths per minute or, on blood gas, a PaCO2 less than 4.3 kpa or need for mechanical ventilation White blood cell count < 4,000 cells/mm3 or > 12,000 cells/mm3, or greater than 10% band forms (immature white blood cells) and 2. Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system INSTRUCTIONS FOR ADMINISTERING HARP-2 DRUG 1. The first dose of study drug should be administered as soon as possible, ideally within 4 hours of randomisation 2. Subsequent doses will be given each morning, starting on the following calendar day. 3. If for any reason a dose is not administered at the intended time, it may be administered subsequently but not more than 12 hours after the intended time of administration. Study drug should be administered even if patient has high gastric aspirate due to an ileus. LABORATORY VALUES CK, AST and ALT must be collected on days 1,3,7,14, 21 and 28 RESEARCH BLOODS & SAMPLES For further guidance on research bloods & samples - please refer to the Sample Handling Guidelines in the HARP-2 Trial Manual Page 6 Please return top white copy to the CTU; yellow copy to be retained in site file

7 Site Number Patient Number Patient s Initials SECTION 3: BASELINE ASSESSMENT FORM Male Female 3.1 Gender Height cm 3.3 Weight kg Sepsis Non Sepsis 3.4 Is the patient Sepsis or Non Sepsis? Please record plateau pressure cmh 2 O 3.6 Date and time of admission to Critical Care Unit D D M M Y Y Y Y H H M M 3.7 What is this patient s ALI aetiology? (please cross all boxes that apply) Direct Indirect Smoke/toxin inhalation Sepsis Gastric content aspiration Cardiopulmonary bypass Near-drowning Pancreatitis Thoracic trauma Non-thoracic trauma Pneumonia Other (please specify) Other (please specify) 3.8 If your unit contributes to the ICNARC Case Mix Programme (CMP) please complete the patient s CMP number: If your unit does not contribute to ICNARC, but you calculate APACHE II scores locally, please enter APACHE II score. If your unit does not contribute to ICNARC and does not calculate APACHE II scores locally, please complete pages 51,53,55 and 57 for the first 24 hours after admission. Mark box when complete: Name of site Investigator completing this section Date form completed Signature D D M M Y Y Y Y PRINT Name Page 7 Please return top white copy to the CTU; yellow copy to be retained in site file

8 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Data for day 1 (the day of randomisation) should be recorded from the time of randomisation to 23:59 apart from ALT, AST and CK which are the values taken to determine eligibility. These safety bloods can be taken up to 72 hours before randomisation. If these bloods are taken prior to day 1 (i.e. the day of randomisation), please record the date in the date fields beside ALT, AST and CK. If these bloods are taken on the day of randomisation, please leave these date fields blank. Daily data collection should continue until day 28 after randomisation or until discharge from critical care area (level 2 or 3) or death, even if the trial drug is terminated early. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure Page 8 Please return top white copy to the CTU; yellow copy to be retained in site file

9 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day 1 Randomisation Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Research blood sample collected Research urine sample collected Yes No Yes No Yes No Yes No Value Value Value Value Lowest Glasgow Coma Scale (If sedated, give pre-sedation GCS) Lowest PaO 2 (kpa)/fio 2 Mean airway pressure (cmh 2 0) (at time of lowest PF ratio) Lowest Platelets (x10 9 /L) Highest Bilirubin (umol/l) Highest Creatinine (umol/l) Lowest Mean arterial pressure (mmhg) Highest Dopamine (mcg/kg/min) Highest Dobutamine (mcg/kg/min) Highest Adrenaline (mcg/kg/min) Highest Noradrenaline (mcg/kg/min) Highest ALT (U/L) D D M M Y Y Highest AST (U/L) D D M M Y Y Highest CK (U/L) D D M M Y Y Number of tablets administered Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data Page 9 Please return top white copy to the CTU; yellow copy to be retained in site file

10 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Daily data collection should continue until day 28 after randomisation or until discharge from critical care area (level 2 or 3) or death, even if the trial drug is terminated early. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure Page 10 Please return top white copy to the CTU; yellow copy to be retained in site file

11 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Research blood sample collected Research urine sample collected Yes No Yes No Yes No Yes No Value Value Value Value Lowest Glasgow Coma Scale (If sedated, give pre-sedation GCS) Lowest PaO 2 (kpa)/fio 2 Mean airway pressure (cmh 2 0) (at time of lowest PF ratio) Lowest Platelets (x10 9 /L) Highest Bilirubin (umol/l) Highest Creatinine (umol/l) Lowest Mean arterial pressure (mmhg) Highest Dopamine (mcg/kg/min) Highest Dobutamine (mcg/kg/min) Highest Adrenaline (mcg/kg/min) Highest Noradrenaline (mcg/kg/min) Highest ALT (U/L) Highest AST (U/L) Highest Creatinine Kinase (U/L) Number of tablets administered Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data + - Page 11 Please return top white copy to the CTU; yellow copy to be retained in site file

12 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Daily data collection should continue until day 28 after randomisation or until discharge from critical care area (level 2 or 3) or death, even if the trial drug is terminated early. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure Page 12 Please return top white copy to the CTU; yellow copy to be retained in site file

13 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Yes No Yes No Yes No Yes No Value Value Value Value Number of tablets administered Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data Page 13 Please return top white copy to the CTU; yellow copy to be retained in site file

14 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Daily data collection should continue until day 28 after randomisation or until discharge from critical care area (level 2 or 3) or death, even if the trial drug is terminated early. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure Page 14 Please return top white copy to the CTU; yellow copy to be retained in site file

15 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Research blood sample collected Research urine sample collected Yes No Yes No Yes No Yes No Value Value Value Value Lowest Glasgow Coma Scale (If sedated, give pre-sedation GCS) Lowest PaO 2 (kpa)/fio 2 Mean airway pressure (cmh 2 0) (at time of lowest PF ratio) Lowest Platelets (x10 9 /L) Highest Bilirubin (umol/l) Highest Creatinine (umol/l) Lowest Mean arterial pressure (mmhg) Highest Dopamine (mcg/kg/min) Highest Dobutamine (mcg/kg/min) Highest Adrenaline (mcg/kg/min) Highest Noradrenaline (mcg/kg/min) Highest ALT (U/L) Highest AST (U/L) Highest Creatinine Kinase (U/L) Number of tablets administered Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data + - Page 15 Please return top white copy to the CTU; yellow copy to be retained in site file

16 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Daily data collection should continue until day 28 after randomisation or until discharge from critical care area (level 2 or 3) or death, even if the trial drug is terminated early. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure Page 16 Please return top white copy to the CTU; yellow copy to be retained in site file

17 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Number of tablets administered Yes No Yes No Yes No Yes No Value Value Value Value Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data Page 17 Please return top white copy to the CTU; yellow copy to be retained in site file

18 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Daily data collection should continue until day 28 after randomisation or until discharge from critical care area (level 2 or 3) or death, even if the trial drug is terminated early. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure.1 Page 18 Please return top white copy to the CTU; yellow copy to be retained in site file

19 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Research blood sample collected Research urine sample collected Lowest Glasgow Coma Scale (If sedated, give pre-sedation GCS) Yes No Yes No Yes No Yes No Value Value Value Value Lowest PaO 2 (kpa)/fio 2 Mean airway pressure (cmh 2 0) (at time of lowest PF ratio) Lowest Platelets (x10 9 /L) Highest Bilirubin (umol/l) Highest Creatinine (umol/l) Lowest Mean arterial pressure (mmhg) Highest Dopamine (mcg/kg/min) Highest Dobutamine (mcg/kg/min) Highest Adrenaline (mcg/kg/min) Highest Noradrenaline (mcg/kg/min) Highest ALT (U/L) Highest AST (U/L) Highest Creatinine Kinase (U/L) Number of tablets administered Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data Page 18 Please return top white copy to the CTU; yellow copy to be retained in site file

20 SECTION 4: DAILY DATA COLLECTION Data are collected by calendar days including for day of randomisation. A patient should be recorded as having received an intervention if they had it for any part of a day between 00:00 and 23:59, or for a complete calendar day. For example, an intervention started at the time of randomisation at 22:00 on day 1 and continued until 01:00 on day 3 should be recorded as occurring on days 1, 2 and 3. Please record the Mean Airway Pressure closest in time to the lowest PF ratio For drug doses (dopamine, dobutamine etc) please record the highest drug dose in a 24 hour period Ventilatory Support Unassisted breathing i.e. no ventilatory support is defined as extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 O without pressure support. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Definitions of organ support (from Version 3 ICMPDS 2007/2008) Advanced cardiovascular support: One or more of the following: multiple intravenous vasoactive and/or rhythm controlling drugs (e.g. inotropes, nitrates etc.) to support arterial pressure, cardiac output or organ perfusion receiving critical care after resuscitation following cardiac arrest (not usually valid for longer than one calendar day after day of resuscitation) invasive measurement of cardiac output and other indices (e.g. with a pulmonary artery catheter, lithium dilution, pulse contour analyses, oesophageal doppler etc.) intra aortic balloon pump in place temporary cardiac pacemaker (valid each day while connected for therapeutic reasons to a functioning external pacemaker unit) gastrointestinal tonometer in place Neurological support: One or more of the following: central nervous system depression sufficient to prejudice their airway and protective reflexes, except depression caused by sedation prescribed to facilitate mechanical ventilation receiving invasive measurement of ICP (intracranial pressure), jugular bulb sampling, cerebral function monitoring, or cooling etc. external ventricular drain (EVD) for drainage purposes requiring constant nursing attention (close attendance for 95% of the time) and/or heavy sedation due to being severely agitated or epileptic Renal support receiving acute renal replacement therapy e.g. haemodialysis, haemofiltration etc. Liver support receiving extracorporeal liver replacement via a device e.g. MARS - molecular absorbent recirculating system etc. and includes charcoal haemoperfusion via a haemofiltration machine where it is being used to replace liver function. Glasgow Coma Scale Only GCS assessed when the patient is free from the effects of sedative and/or paralysing or neuromuscular blocking agents are valid. For patients sedated or paralysed for part of the first 24 hrs, give the lowest GCS prior to sedation or during the periods they were free of drug effects. For patients sedated for whole 24 hr ICU period, give lowest in-hospital GCS in the 24hr period prior to sedation. Level of Care: Level 1 Level 2 Level 3 Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice and support from the critical care team Patients requiring more detailed observation or intervention including support for a single failing organ system or post operative care and those stepping down from higher levels of care Patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure.3 Page 18 Please return top white copy to the CTU; yellow copy to be retained in site file

21 Site Number Patient Number Patient s Initials SECTION 4: DAILY DATA COLLECTION Please complete a column for every day this patient is in critical care up to day 28 after randomisation. Please put a cross in the Yes OR No box for each intervention on that day. For clinical parameters collect the worst value of the calendar day. Days 1 28 (Treatment period) Day Date DD MM YY DD MM YY DD MM YY DD MM YY Ventilatory support Advanced cardiovascular support Neurological support Renal support Liver support Non-trial statin administered Research blood sample collected Research urine sample collected Yes No Yes No Yes No Yes No Value Value Value Value Lowest Glasgow Coma Scale (If sedated, give pre-sedation GCS) Lowest PaO 2 (kpa)/fio 2 Mean airway pressure (cmh 2 0) (at time of lowest PF ratio) Lowest Platelets (x10 9 /L) Highest Bilirubin (umol/l) Highest Creatinine (umol/l) Lowest Mean arterial pressure (mmhg) Highest Dopamine (mcg/kg/min) Highest Dobutamine (mcg/kg/min) Highest Adrenaline (mcg/kg/min) Highest Noradrenaline (mcg/kg/min) Highest ALT (U/L) Highest AST (U/L) Highest Creatinine Kinase (U/L) Number of tablets administered Highest tidal volume (ml) Daily Fluid balance (ml) (circle negative or positive balance) Level of care (1 / 2 / 3) Initials of person collecting data + - Page 19 Please return top white copy to the CTU; yellow copy to be retained in site file

22 SECTION 5: VENTILATION HISTORY The primary outcome measure of the study is ventilator free days (VFD) defined as the number of days from the time of initiating unassisted breathing, to day 28 after randomisation. VFDs to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomisation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. Any other assisted breathing in a calendar day does not count as VFD. Unassisted breathing i.e. no ventilatory support is defined as, extubated with supplemental oxygen or room air; or open T-tube breathing; or tracheostomy mask breathing; or CPAP 5 cm H 2 0 without pressure support for a calendar day. Patients receiving pressure support via non-invasive ventilation will be defined as receiving ventilatory support. Page 20 Please return top white copy to the CTU; yellow copy to be retained in site file

23 Site Number Patient Number Patient s Initials SECTION 5: VENTILATION HISTORY Please provide details of whether the patient achieved unassisted breathing during the study period. Days 1 28 (Treatment period) 5.1 Did the patient achieve unassisted breathing by day 28? Yes 1 No 0 Only record Yes if the patient achieved unassisted breathing prior to day 28 and did not return to assisted breathing by day Please confirm the date that the patient achieved their first full calendar day of unassisted breathing? D D M M Y Y Y Y Please note this date should be the patient s final period of unassisted breathing Name of site Investigator completing this form Signature Date form completed D D M M Y Y Y Y PRINT Name Page 21 Please return top white copy to the CTU; yellow copy to be retained in site file

24 Page 22 Please return top white copy to the CTU; yellow copy to be retained in site file

25 Site Number Patient Number Patient s Initials SECTION 6: REASON FOR TERMINATION OF STUDY DRUG Please complete this section for all patients 6.1 Reason for termination of study drug (please put a cross in one box only) a) 28 days after randomisation 1 b) Discharge from critical care 2 c) Liver Transaminases > 8 times upper limit normal 3 d) Creatinine Kinase > 10 times upper limit normal 4 e) Request for discontinuation of trial drug by patient or legal representative 5 f) Discontinuation of active treatment 6 g) Development of a condition requiring immediate treatment with statin 7 h) Decision by a Physician on safety grounds 8 i) Death 9 j) Other (please specify) 10 Page 23 Please return top white copy to the CTU; yellow copy to be retained in site file

26 SECTION 7: CRITICAL CARE UNIT DISCHARGE Please complete Section 7 when the patient is discharged from critical care or dies prior to discharge from critical care. If the patient is discharged alive If you discharge a patient from an ICU alive please enter the date of discharge from ICU and complete 7.2 indicating where the patient was discharged to (note: this may be a HDU, or a ward in this hospital or an ICU/HDU or ward in another hospital. If the patient is transferred to a combined ICU/HDU in another hospital please select ICU in another hospital from the options available. If the patient is transferred to another hospital please complete full contact details for the hospital (and Ward). Please also record any further movement of the patient between ICU/HDU/Ward prior to hospital discharge in 7.3. If the patient has been transferred to a combined ICU/HDU please select ICU from the options available. Description of SAE A serious adverse event is defined as an adverse event that fulfills one or more of the following criteria: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Is a congenital abnormality or birth defect Is any other important medical event (s) that carries a real, not hypothetical, risk of one of the outcomes above (i.e. medically important) Because HARP-2 is recruiting a population that is already in a life-threatening situation, it is expected that many of the participants will experience SAEs. Events that are expected in this population and those that are collected as outcomes of the trial should not be reported as SAEs unless they are related to the study drug. This includes: Death Organ failure Other SAEs that occur between trial entry and 30 days after the end of the trial drug should be reported using the SAE form on page 37, 39 and 41. The following events should be reported: SAEs not associated with underlying condition and deemed to be unexpected Adverse reaction to simvastatin regarded as severe Page 24 Please return top white copy to the CTU; yellow copy to be retained in site file