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

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. Note: this intervention is now closed.

DRUG

Amoxicillin-clavulanate

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

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.

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. Note: this intervention is now closed.

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.

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)

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. Note: this intervention 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.

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. Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period. Note: this intervention is now closed.

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.

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. Note: this intervention is now closed.

OTHER

No immunoglobulin

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

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.

BIOLOGICAL

Delayed administration of convalescent plasma

Note: this intervention is now closed.

OTHER

No vitamin C

No high dose intravenous vitamin C is to be administered Note: this intervention is now closed.

DRUG

Vitamin C

Intravenous Vitamin C 50mg/kg administered every 6 hours for 16 doses Note: this intervention 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.

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

No simvastatin

No simvastatin intended to be active against COVID-19 is to be administered Note: this intervention is now closed.

DRUG

Simvastatin

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.

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 Note: this intervention is now closed.

DRUG

Apremilast

Apremilast administered 30mg twice daily for 14 days or until hospital discharge, whichever occurs first. Note: this intervention is now closed.

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.

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. Note: this intervention is now closed.

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. Note: this intervention is now closed.

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. Note: this intervention is now closed.

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. Note: this intervention is now closed.

OTHER

No cysteamine

No cysteamine to be administered until the end of study day 10 or hospital discharge, whichever occurs first. Note: this intervention is now closed.

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. Note: this intervention 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.

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.

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.

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).

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.

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.

All-cause mortality

Time frame: Day 90

Days alive and not receiving organ support in ICU

Time frame: Day 21

Primary end-point for patients with suspected or proven COVID-19 pandemic infection

What is a clinical trial?

A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.

Is it safe to participate?

Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.

Will I be compensated?

Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.

Will I receive a placebo instead of treatment?

When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.

Can I leave a trial if I change my mind?

Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.

How long does a clinical trial last?

Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.