1. Overview of N-of-1 study suite – lessons learned from three aggregated N-of-1 trials. Geoff Mitchell*, Jane Nikles, Sue-Ann Carmont, Janet Hardy, Phillip Good, Meera Agar, Katherine Clark, Carol Douglas, Rohan Vora, Hugh Senior, David Currow

2. Current N-of-1 Trials in PC Methylphenidate for fatigue in adv Ca Paracetamol for pain in adv Ca Pilocarpine for dry mouth in adv Ca (also known as single patient trials)

3. What are N-of-1 Trials Multiple Cross-over RCTs Provides evidence on treatment effect for an individual patient METHOD: multiple paired treatment periods with random treatment order, e.g.,

4. Benefits of N-of-1 trials Possible to aggregate a series of n-of-1 trials to get a population estimate. N-of-1 like a trial where participant is in both arms of a randomised controlled trial Participant is: Blinded to which arm is going at any one time Contributes data to each side of an RCT “control” and “intervention” participation perfectly matched.

5. When are n-of-1 trials justified? Medicine short acting Immediate treatment effect and short half life Treatment expensive, important side effects or controversial Validated measure of effect available Question is important

6. Usefulness in palliative care RCTs very hard to conduct – very expensive Many fail because sample size is not met Aggregating N-of-1s trials could reduce sample size dramatically, make the gathering of evidence easier

7. What Worked Well MPH exceeded recruitment target Caresearch Database was an efficient method of data management PaCCSC network of sites and skilled research staff facilitated: –Trial establishment –Liaison with pharmacy –Recruitment –Protocol Compliance –Data Integrity

8. What Didn’t Work Well Lower than anticipated recruitment rate and study withdrawals due to: –Very unwell participants –Competing trials in a limited population Medications are not commercial, so had to be compounded Delays due to complex ethics process, multiple ethics applications and SSAs, and legal contract review by lawyers Some patients did not like the taste of pilocarpine or it produced over-salivation

9. What we would do differently We would continue with the Caresearch database and the PaCCSC network Have more realistic timelines on trials that are difficult to recruit in grant applications Ensure eligibility criteria is less restrictive if possible Look at different recruitment strategies including through the community rather than solely hospital based

10. Results Paracetamol for pain pilot trial had major difficulty in recruiting as participants had to not take paracetamol, 7 patients recruited, data still to be analysed Pilocarpine for dry mouth, 22 patients recruited, data still to be analysed MPH for fatigue, see next slide

11. Methyphenidate vs placebo on fatigue (FACIT-F) individual participant scores (Mean difference (95% credible interval)) Did not improve fatigue on a population level, 8 of 33 participants clinically important improvement in fatigue, 1 showed important worsening