Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia

The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

Note: this intervention is now closed.

The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

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.

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.

Patients are not to receive any systemic corticosteroids, including hydrocortisone, to study day 28 or hospital discharge (whichever occurs first).

50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.

Note: this intervention is now closed.

50mg IV hydrocortisone every 6 hours while the patient is in septic shock

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.

No antiviral agent intended to be active against influenza infection is to be administered

Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first)

Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first)

No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered

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.

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.

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.

Ivermectin administered enterally at a dose of 0.2 mg/kg once daily with a maximum daily dose of 24mg/day.

Note: this intervention is now closed.

No immune modulating agent intended to be active against COVID-19 is to be administered.

Note: this intervention is now closed.

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.

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.

Tocilizumab will be administered as a single dose of 8mg/kg estimated or measured body weight, with a maximum total dose of 800mg.

Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period.

Note: this intervention is now closed.

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.

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.

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.

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.

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.

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.

Note: this intervention is now closed.

No immunoglobulin intended to be active against SARS-CoV-2 infection is to be administered.

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.

No high dose intravenous vitamin C is to be administered

Note: this intervention is now closed.

Intravenous Vitamin C 50mg/kg administered every 6 hours for 16 doses

Note: this intervention is now closed.

No antiplatelet agent or NSAID to be administered.

Note: this intervention is now closed.

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.

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.

No simvastatin intended to be active against COVID-19 is to be administered

Note: this intervention is now closed.

Simvastatin 80mg administered once daily via enteral route, while the patient remains in hospital up to 28 days after randomisation

Note: this intervention is now closed.

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

Note: this intervention is now closed.

Apremilast administered 30mg twice daily for 14 days or until hospital discharge, whichever occurs first.

Note: this intervention is now closed.

Clinician-preferred ventilation strategy, including mode of ventilation and all ventilatory parameters

Invasive mechanical ventilation strategy delivered as outlined in relevant protocol documents for this domain.

No RAS inhibitor (i.e. no ACEi or ARB) is to be administered up to the end of study day 10.

Note: this intervention is now closed.

Site-preferred ACEi agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.

Note: this intervention is now closed.

Site-preferred ARB agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.

Note: this intervention is now closed.

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.

Note: this intervention is now closed.

No cysteamine to be administered until the end of study day 10 or hospital discharge, whichever occurs first.

Note: this intervention is now closed.

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.

Note: this intervention is now closed.

6 mg of IV or enteral dexamethasone will be administered daily for up to 10 days while in hospital.

Baloxavir marboxil administered on days 1 and 4 post-randomisation.

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.

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.

No endothelial modulator (imatinib or another tyrosine kinase inhibitor targeting the same pathway as imatinib) is to be administered.

Enteral imatinib will be administered as a single 800mg loading dose (study day 1) followed by 400mg daily until study day 14 or discharge.

No immune modulating agent intended to be active against influenza is to be administered.

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).

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.

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.