Antibiotic Domain

Patients with community-acquired pneumonia admitted to participating intensive care units and requiring empiric antibiotic therapy will be randomised one of five antibiotic interventions. Note: the ceftaroline + macrolide intervention has been closed to recruitment. Drug: Ceftriaxone (The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.) Drug: Moxifloxacin or Levofloxacin (The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.) Drug: Piperacillin-tazobactam (The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.) Drug: Ceftaroline (The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.) Drug: Amoxicillin-clavulanate (The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.)

Macrolide Duration Domain

Patients with community-acquired pneumonia admitted to participating intensive care units who have been allocated to a beta-lactam antibiotic intervention in the Antibiotic Domain will be randomised to either a standard course or extended course of macrolide therapy Drug: Standard course macrolide (Standard course of macrolide therapy, discontinued between study day 3 and the end of study day 5. The dosing of and route of administration is not protocolised, the following guidance is provided: Initial IV administration of a macrolide is strongly preferred The preferred IV macrolide is azithromycin, but IV clarithromycin may be substituted. The preferred enteral macrolide is azithromycin, but enteral clarithromycin or roxithromycin may be substituted.) Drug: Extended course macrolide (Extended course of macrolide therapy discontinued at the end of study day 14 or hospital discharge (whichever occurs first). The dosing of and route of administration is not protocolised, the following guidance is provided: Initial IV administration of a macrolide is strongly preferred The preferred IV macrolide is azithromycin, but IV clarithromycin may be substituted. The preferred enteral macrolide is azithromycin, but enteral clarithromycin or roxithromycin may be substituted.)

Corticosteroid Domain

Patients with community acquired pneumonia (CAP) admitted to participating hospitals will be randomised to a steroid use strategy. Note: this domain is now closed to patients with suspected or proven COVID-19. It remains open to patients with CAP without COVID-19. Other: No systemic corticosteroid (Patients are not to receive any systemic corticosteroids, including hydrocortisone, to study day 28 or hospital discharge (whichever occurs first).) Drug: Fixed-duration Hydrocortisone (50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.) Drug: Shock-dependent hydrocortisone (50mg IV hydrocortisone every 6 hours while the patient is in septic shock) Drug: Fixed-duration higher dose Hydrocortisone (100mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days. Note: this intervention was only available to patients with suspected or proven COVID-19 and is now closed.) Drug: Fixed-duration dexamethasone (6 mg of IV or enteral dexamethasone will be administered daily for up to 10 days while in hospital.)

Influenza Antiviral Domain

Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions. Other: No antiviral agent for influenza (No antiviral agent intended to be active against influenza infection is to be administered) Drug: Five-days oseltamivir (Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first)) Drug: Ten-days oseltamivir (Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first)) Drug: Baloxavir Marboxil (Baloxavir marboxil administered on days 1 and 4 post-randomisation.) Drug: Five-days oseltamivir + baloxavir marboxil (Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first), in addition to baloxavir marboxil administered on days 1 and 4 post-randomisation.) Drug: Ten-days oseltamivir + baloxavir marboxil (Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first), in addition to baloxavir marboxil administered on days 1 and 4 post-randomisation.)

COVID-19 Antiviral Domain

Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to no ivermectin or ivermectin. Note: an earlier version of this domain evaluated lopinavir-ritonavir, hydroxychloroquine, and combination lopinavir-ritonavir and hydroxychloroquine against a 'no antiviral' control. This domain is now closed. Other: No antiviral agent for COVID-19 (No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered) Drug: Lopinavir / Ritonavir (Lopinavir/ritonavir 400/100mg administered enterally, or 5ml 80/20mg per mL solution suspension via gastric tube, every 12 hours. Administered for a minimum of 5 days, including if discharged from ICU prior to end of study day 5. For patients discharged from ICU between study day 6 and study day 14, lopinavir/ritonavir is ceased at ICU discharge. Lopinavir/ritonavir is ceased at the end of study day 14 if the patient remains in ICU. Note: this intervention is now closed.) Drug: Hydroxychloroquine (Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge (whichever occurs first). Note: this intervention is now closed.) Drug: Hydroxychloroquine + lopinavir/ritonavir (Lopinavir/ritonavir 400/100mg administered enterally, or 5ml 80/20mg per mL solution suspension via gastric tube, every 12 hours. Administered for a minimum of 5 days, including if discharged from ICU prior to end of study day 5. For patients discharged from ICU between study day 6 and study day 14, lopinavir/ritonavir is ceased at ICU discharge. Lopinavir/ritonavir is ceased at the end of study day 14 if the patient remains in ICU. Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge (whichever occurs first). Note: this intervention is now closed.) Drug: Ivermectin (Ivermectin administered enterally at a dose of 0.2 mg/kg once daily with a maximum daily dose of 24mg/day.)

COVID-19 Immune Modulation Domain

Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to one of up to five interventions. Note: this domain is now closed. Other: No immune modulation for COVID-19 (No immune modulating agent intended to be active against COVID-19 is to be administered. Note: this intervention is now closed.) Drug: Interferon beta-1a (IFN-β1a 10 μg will be administered as an intravenous bolus injection via a central or peripheral line. IFN-β1a will be administered once daily for 6 days or until ICU discharge, whichever occurs first. Note: this intervention is now closed.) Other Name: IFN-β1a Drug: Anakinra (A loading dose of 300mg anakinra will be administered as a bolus via central or peripheral line. This is followed by maintenance doses of 100mg of anakinra administered every 6 hours. In patients with renal impairment, anakinra will be administered on alternate days. Note: this intervention is now closed.) Drug: Tocilizumab (Tocilizumab will be administered as a single dose of 8mg/kg estimated or measured body weight, with a maximum total dose of 800mg. Note: this intervention is now closed. Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period.) Drug: Sarilumab (Sarilumab will be administered as a single dose of 400mg, via IV infusion through peripheral or central line over a one-hour period. Note: this intervention is now closed.)

Anticoagulation Domain

Patients admitted to participating intensive care units with suspected or microbiological testing confirmed COVID-19 will be randomised to an anticoagulation strategy. Note: A previous version of this domain evaluated local standard venous thromboprophylaxis against therapeutic dose anticoagulation. This domain is now closed. Drug: Local standard venous thromboprophylaxis (Standard venous thromboprophylaxis that complies with local guidelines or usual practice will be administered for 14 days following randomisation or until hospital discharge, whichever occurs first. Note: this intervention is now closed.) Drug: Therapeutic dose anticoagulation (Patients will be administered either low molecular weight heparin (LMWH) or unfractionated heparin (UFH) to achieve systemic anticoagulation. Either agent may be used and the same patient may be switched between UFH and LMWH at the discretion of the treating clinician. Note: this intervention is now closed.) Drug: Conventional low dose thromboprophylaxis (Low dose thromboprophylaxis will be administered for 14 days following randomisation or until hospital discharge, whichever occurs first. Dosing is outlined in the relevant protocol documents for this domain.) Drug: Intermediate dose thromboprophylaxis (Intermediate dose thromboprophylaxis will be administered for 14 days following randomisation or until hospital discharge, whichever occurs first. Dosing is outlined in the relevant protocol documents for this domain.) Drug: Continuation of therapeutic dose anticoagulation (Patients already receiving therapeutic dose anticoagulation at the time of randomisation to this intervention will be administered either unfractionated heparin by IV infusion or low-molecular weight heparin to achieve systemic anticoagulation according to local practice for acute VTE treatment for 14 days following randomisation or until hospital discharge, whichever occurs first.)

Immunoglobulin Domain

Immunosuppressed patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to receive no immunoglobulin for COVID-19, or to receive high-titre convalescent plasma. Note: an earlier version of this domain was not restricted to immunosuppressed patients. Other: No immunoglobulin (No immunoglobulin intended to be active against SARS-CoV-2 infection is to be administered. Note: this intervention is now closed.) Biological: Convalescent plasma (Patients will receive at least one and no more than two units of ABO compatible convalescent plasma within 48 hours of randomisation. Note: this intervention is now closed.) Biological: Delayed administration of convalescent plasma (Note: this intervention is now closed.)

Vitamin C Domain

Patients admitted to participating hospitals with community-acquired pneumonia will be randomised to receive no vitamin C, or vitamin C. Note: this domain is now closed. Other: No vitamin C (No high dose intravenous vitamin C is to be administered) Drug: Vitamin C (Intravenous Vitamin C 50mg/kg administered every 6 hours for 16 doses)

Antiplatelet Domain

Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to receive no antiplatelet, aspirin, or site-preferred P2Y12 inhibitor. Note: this domain is now closed. Other: No antiplatelet (No antiplatelet agent or NSAID to be administered. Note: this intervention is now closed.) Drug: Aspirin (Aspirin administered at either 75mg or 100mg once per day for 14 days or until hospital discharge, whichever occurs first. Note: this intervention is now closed.) Other Name: acetylsalicylic acid Drug: P2Y12 inhibitor (Site-selected P2Y12 inhibitor: Clopidogrel: administered 75 mg once per day for 14 days or until hospital discharge, whichever occurs first. Prasugrel: If patient is aged less than 75 years and measured or estimated weight if 60kg or more, and initial loading dose of prasugrel 60 mg will be administered, followed by maintenance dose of 10 mg per day. Ticagrelor: administered enterally at 60mg twice daily for 14 days or until hospital discharge, whichever occurs first. Note: this intervention is now closed.) Other Name: Clopidogrel, Prasugrel, Ticagrelor

Simvastatin Domain

Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to receive no simvastatin, or simvastatin. Note: this domain is now closed. Other: No simvastatin (No simvastatin intended to be active against COVID-19 is to be administered) Drug: Simvastatin (Simvastatin 80mg administered once daily via enteral route, while the patient remains in hospital up to 28 days after randomisation)

COVID-19 Immune Modulation (2) Domain

Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to receive one of three interventions. Note: this domain is now closed. Other: Placebo Drug: Eritoran (Eritoran initiated with a 26.24 mg loading dose (6.56 mg/h IV for 4 hours), followed by a second 13.12 mg loading dose (6.56 mg/h IV for 2 hours) at 12 hours after initiation. Patients will then receive twenty-six 6.56 mg maintenance doses (3.28 mg/h IV for 2 hours) every 12 hours thereafter (total of 14 days). Dosing will be stopped if the patient is discharged from hospital) Drug: Apremilast (Apremilast administered 30mg twice daily for 14 days or until hospital discharge, whichever occurs first. Note: this intervention is now closed.)

Mechanical Ventilation Domain

Patients with community-acquired pneumonia admitted to participating intensive care units who are intubated and receiving invasive mechanical ventilation will be randomised to protocolised mechanical ventilation strategy, or clinician-preferred mechanical ventilation strategy Procedure: Clinician-preferred mechanical ventilation strategy (Clinician-preferred ventilation strategy, including mode of ventilation and all ventilatory parameters) Procedure: Protocolised mechanical ventilation strategy (Invasive mechanical ventilation strategy delivered as outlined in relevant protocol documents for this domain.)

ACE2 RAS Domain

Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to one of up to five renin-angiotensin system blockade strategies. Note: this domain is now closed. Other: No renin-angiotensin system inhibitor (No RAS inhibitor (i.e. no ACEi or ARB) is to be administered up to the end of study day 10.) Drug: Angiotensin converting enzyme inhibitor (Site-preferred ACEi agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.) Other Name: Ramipril, Lisinopril, Perindopril, Enalapril, Trandolapril, Captopril Drug: Angiotensin Receptor Blockers (Site-preferred ARB agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.) Other Name: Losartan, Valsartan, Candesartan, Irbesartan, Telmisartan, Olmesartan Drug: ARB + DMX-200 (Site-preferred ARB agent administered in combination with DMX-200 for 10 days or until hospital discharge, whichever occurs first. ARB administered as directed by the treating clinician. DMX-200 administered enterally at a dose of 120mg twice daily.)

Cysteamine Domain

Patients admitted to participating hospitals with severe community-acquired pneumonia, including patients with suspected or proven influenza or COVID-19, will be randomised to receive no cysteamine, or cysteamine. Note: this domain is now closed. Other: No cysteamine (No cysteamine to be administered until the end of study day 10 or hospital discharge, whichever occurs first.) Drug: Cysteamine (Cysteamine administered every 8 hours at a dose of 5 mg/kg estimated or measured body weight (maximum dose of 500mg), for ten days or until ICU discharge, whichever occurs first.)

Endothelial Domain

Patients admitted to participating hospitals with severe community-acquired pneumonia, including patients with suspected or proven influenza or COVID-19, will be randomised to receive no endothelial modulator or enteral imatinib. Other: No endothelial modulator (No endothelial modulator (imatinib or another tyrosine kinase inhibitor targeting the same pathway as imatinib) is to be administered.) Drug: Imatinib (Enteral imatinib will be administered as a single 800mg loading dose (study day 1) followed by 400mg daily until study day 14 or discharge.)

Influenza Immune Modulation

Patients with community-acquired pneumonia admitted to participating intensive care units with microbiological testing confirmed influenza infection will be randomised to one of three interventions. Other: No Immune Modulator for Influenza (No immune modulating agent intended to be active against influenza is to be administered.) Drug: Tocilizumab (Tocilizumab will be administered as a single dose of 8mg/kg estimated or measured body weight, with a maximum total dose of 800mg. In children weighing less than 30kg, tocilizumab dose will be 12mg/kg. Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period.) Drug: Baricitinib (Baricitinib will be administered at a dose that is determined by age and renal function, for up to 10 days or hospital discharge (whichever occurs first).)

COVID-19 Antiviral (II) Domain

Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to one of up to four interventions. Other: No antiviral agent for COVID-19 (No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered) Drug: Nirmatrelvir/ritonavir (Nirmatrelvir-ritonavir will be administered at a dose that is dependent on renal function, for five days.) Other Name: Paxlovid Drug: Remdesivir (Remdesivir is administered at 200 mg on day one followed by 100 mg daily for a further four doses (i.e., for five doses in total) or until hospital discharge, whichever occurs first.) Drug: Nirmatrelvir/ritonavir + remdesivir (Nirmatrelvir-ritonavir will be administered at a dose that is dependent on renal function, for five days. Remdesivir is administered at 200 mg on day one followed by 100 mg daily for a further four doses (i.e., for five doses in total) or until hospital discharge, whichever occurs first.)