Background

• Commissioned call NIHR HTA

• Objective: To determine if invasive ventilation using protocolised weaning that includes non-invasive ventilation (NIV) as an intermediate step is clinically and cost effective compared to protocolised weaning without NIV

Study summary

• Design: Pragmatic, open label, RCT• Population: Adults, ventilated > 48 hr, fail SBT• Intervention: Weaning using NIV• Comparator: Protocolised invasive weaning• Outcome: Time to liberation from ventilation• Sample size: 920 over 30 months

Study Timeline

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 23 24 25 26 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr Nov Dec Jan Feb Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov DecNOTES:48 Months (4 years)

TASK:Trial Set UpSite Set UpPatient Recruitment3 Month Follow-up6 Month Follow-UpData AnalysisReporting

2013 2014 2015 2016

Timeline

Recruitment PlanTarget for sites 1.5 patients per month

Outcomes

Primary clinical outcome:

Time from randomisation to liberation from ventilation

Secondary clinical outcomes• 30, 90 and 180 day all cause mortality• Duration of invasive mechanical ventilation and total

ventilator days • Time to meeting ICU discharge criteria• Hospital length of stay• Antibiotic use• Re-intubation, tracheostomy; adverse events• Health related quality of life

Inclusion criteria

• Is the patient age 16 years or older?• Has the patient received invasive mechanical

ventilation for respiratory failure for greater than 48 hours?

• Is the patient ready for weaning?

Exclusion criteria

• Patient known to be pregnant• Presence of tracheostomy• Profound neurological deficit • Any absolute contraindication to NIV • Home ventilation prior to ICU admission • Decision not to re-intubate / withdrawal • Further surgery / procedure requiring sedation planned in

next 48 hours • Previous participation in the Breathe study

Daily ScreeningAll ventilated patients will be assessed each morning for eligibility by ICU nursing / medical staff. Patients will be identified as potentially eligible if they fulfil the following criteria:

• anticipated or actual requirement for invasive ventilation for > 24 hours• at least partial reversal of the condition precipitating invasive

ventilation• stabilisation of "other" organ system failures (i.e. no worsening) • arterial oxygen saturation measured using pulse oximetry (SpO2) ≥ 90%

with fractional concentration inspired oxygen (FiO2) ≤ 0.70 • PEEP ≤ 10 cmH2O• the absence of trial exclusion criteria (above)

A screening log will be maintained at each site which will include the reasons for non-enrolment.

Obtain consent

Spontaneous Breathing Trial

Record baseline characteristics

ExcludedPASS

Daily screening for eligibility and assess for readiness to wean

RANDOMISE

Protocolised NIV

weaning arm

Protocolised Invasive

weaning arm

FAIL

* England, Wales, NI

CONSENT PROCESS

Cooperative and pain freeGood cough

PaO2 : FiO2 ratio >24 kPaPEEP <10 cmH2O

Hb >7 g dL-1 Temperature 36 - 38.5°CVasoactive drugs stable

Spont respiratory rate >6 min-1

Readiness to wean

Walsh BJA 2004

Record baseline characteristics

• Exhaled minute volume• Total respiratory rate• PEEP• Plateau pressure• Heart rate• Systolic blood pressure• Arterial blood gases

SBTTo be performed in accordance with local unit practices

30 mins duration

• T-piece• Psupp 5cm H2O• CPAP

Pass – ExtubateFail - Randomise

Ely N Engl J Med 1996

Standardised protocols

• Ventilator care bundle– head up position; oral decontamination;

sedation hold; peptic ulcer prophylaxis • Tracheostomy–More than 7 days IMV; inability to protect

airway; persistent inability to remove respiratory secretions

• Re-intubation– Protocolised and clinical endpoints

Data collection

Baseline variables• Patient identifiers • Inclusion and exclusion criteria • APACHE II (at admission) • Admission diagnosis • Presence of COPD • Height and weight• Duration of ventilation prior to randomisation • CAM-ICU

Daily data• Ventilation status

(IMV, NIV, self-ventilating)

• Organ support requirements

• Level of critical care• Antibiotic use for

respiratory and non-respiratory infection

• Adverse events • Sedation usage • Weaning and

ventilator bundle compliance

Study endpoints

• Liberation from ventilation– Add definition from CRF

• Death• Tracheostomy• Re-intubation

– Actual– Protocolised

• ICU discharge data

Discontinuation of intervention

• NIV arm – re-intubation• IPPV arm – tracheostomy• Withdrawal of consent

• Need to continue data collection after discontinuation of intervention until ICU / hospital discharge

Endpoints

After dischargeBefore hospital discharge

(on site)

• Consent• Antibiotic use if

started within ICU • Acute hospital

discharge date and status

• HRQoL

After hospital discharge(WCTU)

• Survival to 180 days• EQ-5D and SF-12• Healthcare resource

use questionnaire

Serious Adverse EventsA serious adverse event is an AE that fulfils one or more of the following criteria:• Results in death• Is immediately 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 an important medical condition.

The causality of SAEs (i.e. relationship to trial treatment) will be assessed by the investigator(s) and recorded on the SAE form.**Do not report death, pneumonia, organ failure as SAE**

Safety Reporting

All suspected SAE’s report to Warwick Clinical Trials Unit within 24 hours

(Tel: 02476 575849 Fax: 02476 150549)

Patient Follow-up

Health-related quality of life: EQ-5D, SF12 at baseline (estimated)

Patient follow-up: 3 and 6 months EQ-5D and SF12

Study team

Chief Investigator: Prof Gavin PerkinsProject Manager: Sarah DugganTrial Coordinator: Bev HoddellTrainee Trial Coordinator: Jess SmithResearch Facilitator: Laura BlairResearch Nurse: Vikki Gordon

Pilot Study Sites

Hospital PIResearch Nurse

HEFT – Heartlands Prof Fang Gao-SmithPeter Sutton

UHCW Chris BassfordMarie McCauley

Guys & St Thomas’ Nick Hart & Luigi Camporota Katie Lei/John SmithQEHB Catherine Snelson

Arlo WhitehouseBristol RI Tim Gould & Sanjoy Shah

Katie SweetRVH Belfast Danny McAuleyJR Oxford Duncan Young

Questions?Contact: Bev Hoddell, Trial Coordinator. Tel No: 02476-575849 Email: b.hoddell@warwick.ac.uk Address: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL