Randomized Embedded Multifactorial Adaptive Platform trial for CommunityAcquired

Randomized, Embedded, Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia Delivery of Interventions

Principles across all domains Principles • • • Open label Prescribe using usual processes Dispense from ICU’s own stock No separate supply of ‘study drug’ No placebo (for ‘no intervention’ do not prescribe) Allocated treatment can be modified if it is in the best interests of the patient • If discharged from ICU before the end of the specific treatment course, required duration should be prescribed to continue after ICU discharge (not a protocol violation if ceased by ward team) • All other concomitant care as per treating clinician

Drug accountability • ICH/GCP: • 4. 6. 1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution • 4. 6. 2 Where allowed/required, the investigator/institution may/should assign some or all of the investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution. • 4. 6. 3 The investigator/institution and/or a pharmacist who is designated by the investigator/institution, should maintain records of product delivery, inventory onsite, use by subject and return or disposition of unused products.

Antibiotic Domain • IV Ceftriaxone plus macrolide • IV Piperacillin-tazobactam plus macrolide • IV Amoxicillin-clavulanate plus macrolide • IV Moxifloxacin (or Levofloxacin) • IV Ceftaroline plus macrolide (included in approved protocol but not available at all sites)

Antibiotic Domain Intervention dose and frequency • Is at the discretion of the treating clinician • What you or local guidelines would recommend • Adjust for weight and clearance as you would normally do • Recommended doses in protocol, including adjustment for renal function provided

Antibiotic Domain Macrolide administration within the Antibiotic Domain • If allocated to any of beta-lactam arms must also receive a macrolide • Site's preferred macrolide • IV (at least initially) preferred over enteral • Azithromycin, preferred over others, erythromycin is permitted but excludes from macrolide domain

Antibiotic Domain Macrolide Preference 1. 2. 3. 4. IV azithromycin IV clarithromycin Enteral azithromycin or roxithromycin 5. IV or enteral erythromycin

Antibiotic Domain Duration of therapy & IV-oral switch • As determined by treating clinician • Change to any antibiotic if microbiological diagnosis made • Switch to enteral / oral when clinically appropriate • Cease antibiotics if alternative diagnosis made • Cease antibiotics when sufficient clinical

Antibiotic Domain Changes to empiric antibiotic therapy Treating clinicians need to document (in the patient’s medical record) the reason for ANY change to antibiotic therapy while the patient was in the ICU.

Antibiotic Domain Permitted additional antibiotics • If suspected MRSA, add vancomycin, linezolid or other antibacterial active against MRSA (but not ceftaroline) • Other beta-lactams, carbapenems, monobactams or quinolones not permitted (unless based on results of microbiological tests) • If allocated to moxifloxacin or levofloxacin, addition of macrolide, beta-lactam, carbapenem, or monobactam not permitted • Additional aminoglycoside, clindamycin, cotrimoxazole all permitted • If immune-suppressed should have been excluded from domain • If site has resistance pattern for CAP organisms that is not appropriate for at least two antibiotic interventions, site should not participate in the domain

Macrolide Duration Domain • Short course macrolide discontinued after 3 days unless there is confirmed or strongly suspected microbiological indication for prolonged administration (e. g. confirmed Legionella) • Extended course macrolide prescribed for 14 days or hospital discharge, whichever occurs first

Macrolide Domain Macrolide Preference 1. 2. 3. 4. IV azithromycin IV clarithromycin Enteral azithromycin or roxithromycin • IV to enteral switch can occur when clinically appropriate, at least 2 does of IV macrolide recommended

Macrolide Duration Domain Dose of Macrolide • Dose and frequency at discretion of treating clinician • Protocol provides recommended doses • IV and enteral doses the same • No adjustment for renal function or renal replacement therapy needed

Macrolide Duration Domain Workflow • Patient will have been randomised to Macrolide Duration Domain • Commence macrolide (as per site preference)

Macrolide Duration Domain Workflow Short Duration • Review microbiological results after day 3 • If no results indicate Legionella or other atypical organism (e. g. Chlaymidohila), cease macrolide • If Legionella (or other atypical organism) identified, then effective treatment for ‘atypical’ organisms must be continued, e. g. • Prolonged macrolide (of choice) • Quinolone (of choice)

Macrolide Duration Domain Workflow Extended Duration • Prescribe macrolide for 14 days • IV to enteral switch permitted • Prescribe to continue on ward if discharged from ICU before 14 days (not a protocol violation if ceased by ward staff)

Macrolide Duration Domain Early cessation of macrolide • Cease if patient experiences SAE thought to be related to macrolide (e. g. ventricular tachycardia) • Consider QT interval at time of cessation of continuous ECG monitoring

Macrolide Duration Domain Concomitant care • Low dose erythromycin (for gastric emptying) is permitted (but discouraged) • Duration of macrolide therapy not affected by macrolide susceptibility of infecting organism

Corticosteroid Domain CAP versus shock literature • In shock: ADRENAL and APROCCHSS • No effect on mortality, but maybe… • In pneumonia • Few ICU patients • Outcomes (and doses) differ

Corticosteroid Domain Interventions • IV Hydrocortisone, 50 mg 6 hourly for 7 days • No corticosteroid

Corticosteroid Domain Allocated to hydrocortisone • Prescribe hydrocortisone IV 50 mg 6 hourly • Commence immediately after randomisation • Cease after 7 days or hospital discharge, whichever occurs first • Prescribe to continue on ward if discharged from ICU before 7 days (not a

Corticosteroid Domain • 3 arms: • No hydrocortisone • Hydrocortisone for 7 days or ICU discharge • Hydrocortisone while on “significant” vasopressor support in ICU

Antiviral domain 3 arms • No antiviral agents (no placebo) • 5 days of oseltamivir • 10 days of oseltamivir

Temporary unavailability of intervention • If known that intervention is temporarily not available • Inform Research Staff, who can remove (and restore) interventions from that sites Eligibility e. CRF (Antibiotic Domain) • If not known that intervention is unavailable and allocated to that intervention • Provide appropriate alternative and commence allocated intervention, if still clinically appropriate, as soon as possible • Document what has occurred as a Domain-Specific Protocol Deviation • Patient will be analysed on intention-to-treat basis • If know that intervention is not available but not able to contact Research Staff • Indicate that not all interventions are appropriate for that patient during completion of eligibility CRF (Patient Interest