N-ALIVE trial NALoxone InVEstigation

Prison-based Naloxone-on-release pilot randomised controlled prevention trial

Angela Meade

MRC CTU at UCL

On behalf of the N-ALIVE trial team

Background

• Heroin-related deaths account for 8% of all UK deaths in individuals aged 15 – 44 years and an increasing number of deaths in those aged 45+

• 1 in 200 prisoners with a history of heroin use by injection dies from drugs-related death in the first 4 weeks following release from prison (Bird and Hutchinson: Addiction 2003)

• Prisoners who have ever injected heroin are 7.5 times more likely to die in the first 2 weeks after prison release than per 2-weeks (fortnight) during weeks 3-12 at liberty (Seaman, Brettle & Gore: BMJ 1998)

• One third to half of all injectors reports having been incarcerated in the past year

Naloxone

• Rapid-acting antidote to the effects of heroin and other opiates • Has been used within the NHS for years; and routinely carried in

ambulances • Can be administered by anyone in the event of an overdose to save life

(added to Exempt List of POMs in 2005) • Given by injection into muscle, fat or vein • Buys time: allows treatment of the overdose in the interval between

calling the emergency services and their arriving

• Concern expressed: providing Naloxone could have the adverse effect of increasing risk behaviour precisely because Naloxone provides a ‘safety net’ The Patient Information Sheet clearly states: ‘We do not want you to take

more heroin just because you carry Naloxone.’ • Scotland (and Wales) have rolled out use of Take-home Naloxone -

including on release from prison. Scotland resourced its prisons to do so.

NALoxone InVEstigation

• N-ALIVE is the brainchild of John Strang, Sheila Bird and Max Parmar - the ‘three musketeers’

• The N-ALIVE Main Trial: large prison-based randomised controlled trial, designed to test the effectiveness of giving Naloxone-on-release to prisoners with a history of injecting heroin use to prevent deaths from overdose

N-ALIVE Pilot

• We know that Naloxone works ….

• But, we don’t know whether:

• Prisons will agree to participate in the numbers we hope for..

• Participants … • Will prisoners accept randomisation and agree to take part?

• If allocated a Naloxone pack, will 75% carry it with them in the first 4 weeks after release?

• Will participants tell their family and friends that they are carrying Naloxone?

• Will participants randomised to Naloxone report more risky use of heroin?

• Will the Naloxone be used in case of an emergency?

• Hence the N-ALIVE Pilot Trial . . .

NALoxone InVEstigation

• The N-ALIVE Pilot Trial: MRC-funded prison-based randomised feasibility trial recruiting up to the first 10% of participants for the N-ALIVE main trial

N-ALIVE Outcome Measures

N-ALIVE Main Trial

• Primary:

• DRDs within 12 weeks of the prisoner’s N-ALIVE release date

• Secondary:

• DRDs within 4 weeks of the prisoner’s N-ALIVE release date

• NFOAs to A&E within 12 weeks of the N-ALIVE release date

Why have an RCT?

Main Reasons: • Naloxone-on-release is not currently prescribed in English Prisons

• RCT is preferable to an uncontrolled observational study

• Prisoners realise that in order for prisons to improve their health services,

effectiveness has to be beyond question

• Prison-based research deals with a ‘captive population’ – the highest ethical and scientific standards must apply

• Observational study would not assess whether prisons and prisoners would enter the N-ALIVE main trial in sufficient numbers

N-ALIVE Pilot Trial Approvals/Collaborations

• Medical Research Council: peer-review to fund

• National Ethics Approval: Updated REC approval was obtained in September 2011 (protocol changed due to the introduction of the Scottish programme)

• Ministry of Justice Research Quality Assurance (Nov 2010)

• National Research Committee (approval to approach governors) (Aug 2011)*

• Formal adoption of the N-ALIVE trial into the Mental Health Research Network (MHRN)trial portfolio

• Global Research & Development (R&D) approval

• Office for National Statistics - for linkage with Register of Deaths

• NHS HSCIC: Hospital Episode Statistics – for A&E data on NFOAs

• Local Prison Governor Approval/including engaging a local Principal Investigator

• Local R&D approval * Home Office/Ministry of Justice split required the N-ALIVE team to re-obtain relevant permissions

Eligibility Criteria

Inclusion criteria

• History of heroin use by injection

• Aged 18 years or older

• Have been in prison for at least seven

days

• Likely release date within three

months

• Not previously randomised and then

withdrawn their consent prior to

release

• Written informed consent

Exclusion criteria

• History of anaphylactic reaction to

Naloxone

• Pregnant or planning to become

pregnant within 6 months

• Resident outside of Scotland,

England and Wales

• Most recent N-ALIVE release date

is within 6 months

• Most recent N-ALIVE release date

is missing but participant was

randomised in N-ALIVE in the

past year

Participants receiving opiate substitution

treatment are not excluded from

participating in N-ALIVE

Consent & Randomisation (prisoners incarcerated >7 days, &

randomised <3 months prior to release date)

Prisoner’s N-ALIVE Release Date Prisoner given pack on release from custody

Naloxone Group

Control Group

Optional: Once-only Phone Contact in either weeks 1-2 or 3-4

post-release. Ratio: 2:1:1

Pre-paid Anonymised N-ALIVE Reply Card: re critical events

12 Weeks Post-Release

● National Death Record Review

● Retrospective prisoner consented A&E database linkage

Returned Prisoner Self-Questionnaire -

completed next time in prison

Up to 3 months

pre-release

Prison release date

12 weeks post-

release

Up to 6 months after

prisoner’s N-ALIVE

release date

Trial Design

1:1

Summary

• Treatment allocation • 1:1 ratio • N-ALIVE pack contains: Naloxone-filled syringe plus information; or

(for controls) contains the information but no Naloxone-filled syringe • There is no placebo

• Participants and N-ALIVE worker do not know to which group the participant has been assigned

• All trial documentation, and the N-ALIVE pack itself, encourages the participant to open the pack immediately upon release

• Follow-up

• Tracking of participants on ONS central register of deaths • Checking for A&E admissions by linking to Hospital Episode Statistics

• Follow-up of returning prisoners via brief self-Q • MRC addition in Pilot only: optional single phone contact in 1st or

2nd fortnight after release for HALF only of participants who agree to participate & in PILOT RCT only . . .

(This contact contaminates N-ALIVE intervention)

Trial Oversight

• Day-to-day management by the N-ALIVE trial team at MRC CTU at UCL

• In constant communication with each other and our prisons

• Weekly team meetings

• Trial Management Group comprising the three co-CIs (JS, SB and MP) and the N-ALIVE trial team

• Monthly (occasionally bimonthly) meetings, usually face-to-face

• Joint Trial Steering and Data Monitoring Committee

• Chaired by Professor Deborah Ashby

• Act as the oversight body on behalf of the Sponsor/Funder

• safeguard the interests of trial participants

• monitor the main outcome measures of the trial

N-ALIVE Conduct

• N-ALIVE has been designed to cleave to prison routines

• N-ALIVE worker: resource is allocated to each prison

• N-ALIVE worker will carry out almost all trial-related activities at the prison (introducing the trial, informed consent, randomisation,

liaison with pharmacy & MRC CTU)

• N-ALIVE worker will take advice from prison healthcare team on how to fit trial activities into the routine prison schedule

• N-ALIVE DVD: can be included in prison induction (& pre-release) sessions or shown on prison TV channels

• N-ALIVE pack: N-ALIVE pack be handled by pharmacy & escort staff as a medicine that accompanies prisoner to court, on transfers (but is issued only on release)

• This is key to the trial success and has been one of the bigger issues we have faced

N-ALIVE Conduct

• N-ALIVE introduced during induction sessions

• DVD or section of the DVD shown?

• Flyers included in prisoner introduction information (if relevant)

• Posters hung around the wings, in waiting areas, in family rooms

• Prisoners who are interested in finding out more ask to see/are referred to the N-ALIVE worker

• Can be provided with summary Patient Information Sheet

• In practice, the high recruiting prisons tend to screen healthcare lists of prisoners for potentially eligible participants and approach them about the trial

N-ALIVE Conduct

• N-ALIVE worker organises one-to-one information and consent session for individual prisoners

• Full patient information sheet discussed

• Explain the trial, the returned prisoner questionnaire and the phone contact sub-study

Prisoner must be given opportunity to ask questions to ensure they fully understand the Pilot N-ALIVE trial

• Ensure prisoner has sufficient time to make up his/her mind

N-ALIVE Conduct

• N-ALIVE worker randomises eligible participants (involves a telephone call to the MRC CTU)

• If relevant, tells participant their allocation in the phone contact study

• N-ALIVE worker liaises with pharmacy/security staff to confirm where participant’s allocated N-ALIVE pack will be stored until their release

• N-ALIVE worker flags participation in N-ALIVE on the prisoners health record on System One

• N-ALIVE worker liaises with healthcare/prison staff to ensure that N-ALIVE pack is provided on release

• N-ALIVE worker informs MRC CTU of prisoner’s date of release and whether pack was provided

Getting Packs to Participants on Release

• The plan was for assigned N-ALIVE packs to be stored with participants valuable property

• For various reasons this has not been easy to arrange at most prisons …. and this has caused problems!

• Over-reliance on reception staff

• N-ALIVE workers needing to be present at release …difficult!

• Solution in some prisons (increasing number)

• Re-engaging with prison governors

• Agreeing written procedures … prisons like procedure and order!

• Give examples of prisons where the procedure works

• Provision of a pack from valuables, or by reception staff, does not constitute secondary prescribing

N-ALIVE Pack

N-ALIVE Milestones

• First site opened

• HMP Nottingham opened on 28th May 2012

• First participant randomised

• HMP Nottingham randomised first 3 participants on 29th May 2012

N-ALIVE Milestones

• 100 participants randomised

• HMP Nottingham randomised N-ALIVE’s 100th participant on 22nd Jan 2013

N-ALIVE Milestones

• 10 sites open to recruitment

• HMP Liverpool opened on 20th May 2013

N-ALIVE Milestones

• 500 participants randomised

• HMP Lincoln randomised N-ALIVE’s 500th participant on 01st Oct 2013

N-ALIVE Milestones

• 15 sites open to recruitment

• HMP Oakwood opened on 11th Feb 2014

• Five sites opened in Jan/Feb 2014

• First female prison

• HMP Holloway opened on 17th Jan 2014

• First female randomised on 27th Feb 2014

N-ALIVE Site Progress

Sites Open MHRN Hub N-ALIVE Workers Open Date Total No. Randomised

HMP Nottingham East Midlands Elizabeth Andrew, Amy Shuttlewood, Natalie

Marking, Julie Mernick 28th May 2012 217

HMP Lincoln East Midlands Anne Chafer, Diane Brennan 08th October

2012 92

HMP Winchester South London and

South East Winner Chimbwanda

12th October 2012

113

HMP Exeter/Channings Wood/Dartmoor

West Sian Lison, Sue Bartram 29th October

2012 129

HMP Gloucester (now closed)

West Genevieve Riley, Emma

Page, Simon Ball 2nd November

2012 11

HMP Dovegate (Managed Privately by

Serco) East Midlands

Kim Thompson, Tim Lewington

26th November 2012

119

HMP Bristol West Sheila Shatford, Karen

Alloway 27th November

2012 315

HMP Liverpool North West Kelly Palethorpe, Heather

Morrison Opened 20th

May 2013 191

HMP Doncaster (Managed Privately by

Serco) East Midlands

Opened 12th July 2013

84

HMP Leeds North West Pippa Hearty Opened 15th January 2014

99

HMP Holloway North London Saloni Dosani Opened 17th January 2014

17

HMP Elmley South London and

South East Laiza Rangarira

Opened 10th February 2014

1

HMP Rochester South London and

South East Laiza Rangarira

Opened 10th February 2014

0

HMP Oakwood (Managed Privately by

G4S) East Midlands Angela Hoadley

Opened 11th February 2014

4

Total Recruitment (1392 up to 31st August 2014) 1392

MHRN Networks & N-ALIVE Sites

Actual vs Target Accrual

Recruitment per 6 months by prison

Accrual as at 10.15am this morning!

N-ALIVE Trial Team

• N-ALIVE Co-Chief Investigators

• John Strang

• Max Parmar

• Sheila Bird

• N-ALIVE Trial Team at MRC CTU at UCL

• Angela Meade – Scientific Project Lead

• Lizzie Armstrong – Clinical Project Manager

• Monica Mascarenhas – Trial Manager (new in post)

• Tracey Pepple – Data Manager (acting TM)

• Gemma Cook – Data Manager

• Louise Choo - Statistician

Acknowledgements

• All of our participants and those who expressed interest in the trial

• N-ALIVE workers, Principal Investigators and all staff involved at each of our prisons

• N-ALIVE trial team: mrcctu.nalivepilot@ucl.ac.uk

• TMG

• TS-DMC

• MHRN network co-ordinators

•

N-ALIVE : Updated Design Assumptions (n=30,000)

Eligibility: 18+ years, history of heroin injection, 7+ days’ incarceration

1. At 70% of overdoses, some-one else is present 2. 75% chance ex-prisoner carries Naloxone in 1st 4 weeks post-release; 60% chance in next 8 weeks 3. 75% chance that Naloxone is administered by present other Effectiveness in 1st 4 weeks = 39% Effectiveness in weeks 5 to 12 = 31% 4. 21st C: One overdose death in 1st 4 weeks per 200 ever-IDUs randomised to control group

If N-ALIVE is as successful as envisaged:

• 37% reduction in DRDs within 12 weeks of release

N-ALIVE : Original Design Assumptions (n=56,000)

Eligibility: 18-44 years, history of heroin injection, 7+ days’ incarceration

1. At 80% of overdoses, some-one else is present 2. 75% chance ex-prisoner carries Naloxone in 1st 4 weeks post-release; 50% chance in next 8 weeks 3. 50% chance that Naloxone is administered by present other Effectiveness in 1st 4 weeks = 30% Effectiveness in weeks 5 to 12 = 20% 4. 21st C: One overdose death in 1st 4 weeks per 200 ever-IDUs randomised to control group

If N-ALIVE is as successful as envisaged:

• 28% reduction in DRDs within 12 weeks of release