the fast study febuxostat vs allopurinol streamlined trial

Ninewells Hospital & Medical School

Research and Trials within BIHS

Tom MacDonald

Salty tablets increase hypertension seven-fold and double mortality

UK Research Paper of the year Nomination

Our Consortium

•University of Dundee (lead)•University of Strathclyde•University of Glasgow•University College London•University of Southern Denmark• ISD Scotland

The need for randomisation in the study of

intended effectsMiettinen OS

Stat Med 1983;2:267-71

Practice does not usually change as a result of observational studies

Lancet 2015

Lancet Editorial 2015

Lancet 2015;386:2059–68

Shortlisted again (one of 5)

Did not win (again)

SCOT Study• >9400 patients screened

• >7300 patients randomised

• Mean FU ~ 3.2 years

• 706 GP practices

• 10 centres

• 3 EU countries

Lee S SimonHarvard then FDA

Prescribing

Hospital Diagnoses

Death Certification

Lab data

Joined-up NHS

NHS: Randomise within a database

Gertrude Elion George HitchingsJames Black

MEMO

Allopurinol and cardiovascular outcomes in patients with ischaemic

heart disease (ALL-HEART)

Funded by the National Institute for Health Research, Health Technology Assessment Programme (www.nihr.ac.uk)

ALL-HEART summary• Does allopurinol improve cardiovascular

outcomes in patients with IHD?• Funded by UK NIHR HTA • Target 5,215 patients with IHD

• Randomised to:Allopurinol 600mg or 300mg added to usual care

vsUsual care

• PROBE Design• Followed up for average of 4 years

– Electronic record-linkage– Annual questionnaire sent by research team– Study ends when 631 events have occurred

22

ALL-HEART GP Sites

Febuxostat versus Allopurinol Streamlined Trial

MEMO

EMA Regulatory Commitment

Post licensing safety study

Why do ‘Industry Research’

• Industry studies: generate infrastructure

=

BMJ 2008;337:1085-7

TIME Subjects

19,191

1,887

6

MEMO

Time Study Song on YouTube

Randomising Patients

• Poor external validity– Only those interested in health participate

– Low event rates

• Expensive

• Bureaucratic

• Time consuming

Evidence Study

BFZ

New Policy

Old Policy

Participating Practices

Indapamide

Advantages of Cluster Randomised Rx policy

• Good external validity

• Efficient

•Quicker

• Cheaper

•Opt-out, not opt-in.

Clinical Trials Unit

Not CTIMP Study

All trials fully recruited>32,000 patients Randomised

ProblemInvite 100 suitable

subjects

Randomise 10-14 (healthy people)

Mr Average

Few Deprived

Few Very Old

Estimated CV event rate> 2.5% / year

Observed adjudicated CV event rate

< 0.9% / year

People interested in their health

Have a low CV event rate

The Drug Song• There's Aspirin, Adrenaline & also Aminophylline,

• Amphetamine, Adenosine, Aldactone & Rifampicin,

• Gentamicin, Bromocriptine, Heparin & Warfarin

• All drugs that are quite hard to use but also relieve suffering

Verse 2• There's Hydrochlorothiazide & also Cyclophosphamide

• & Metoclopramide, Acetazolomide Tropicamide,

• Loperamide, Amiloride & Cyclizine & Frusemide

• and if you think you’re pregnant then you best avoid Thalidomide.

Verse 3• There's Lithium, Fluoxetine & also Amitriptyline,

• Paroxetine, Digoxin, GTN & Azathioprine,

• Miconazole, Atenolol & also Chloramphenicol

• & if you want to overdose there's always Paracetamol.

Verse 4• There's Nabumetone & Phenytoin, Zirtek & Diazepam,

• & Lithium, Temazepam, Midazolam, Clonazepam,

• Testosterone, Aldosterone & Valium & Insulin,

• & those of us with ADH still need to take our Ritalin

Verse 5• There's Cefuroxime, Cefotaxime, Cefalexin, Cephedrine,

• & Chloramphenicol & Ketoconazole, Trimethoprim,

• Erythromycin, Macrolides, and other tablets every day

• that taken lots are bound to cause Clostridium difficile

Verse 6• There's Alcohol & Nicotine, for which you’ll need a PPI

• & Cannabis & Heroin, from which you hope you get a high

• There’s Ecstacy & Methadone & Speed and even raw Cocaine,

• All drugs that make you want to take them all again and then again

Verse 7• Ritixumab, imatinib, mycophenalate mofetil

• Levetiracetam, abciximab are drugs that I can’t spell

• We give them simple names like MabThera, Glivec and ReoPro

• And put these on the pens so the proprietary names we know

Final Bit• Now:• You must remember all these drugs

• The names that you have learned from me

•Or sod it all & get a job in Orthopaedic Surgery