1. Polypharmacy or monotherapy in the first 5 years of PD- which is the best approach? Dr Nin Bajaj Clinical Director NPF Centre of Excellence in PD, University of Nottingham

2. The Issues 60-80% of dopaminergic neurones are lost at initial diagnosis Internal audit data at RDH (2002-2011) Of the 238 PD patients having FP-CIT at presentation, 27.7% were grade 1, 43.3% grade 2 and 29% grade 3 This equates to a moderate-severe dopa deficit in almost 3/4 of patients- in part motor, in part non-motor

3. Audit of Grade of FP-CIT abnormality at presentation in 238 PD patients

4. The Issues The first year is all about reversing this huge dopa deficit This means using larg(ish) doses of dopamine agonists and clinically realistic doses of Ldopa in year 1 After you’ve made up the deficit, it’s all coasting there-on- until they dement…

5. The Issues ADAGIO suggests early treatment might be neuroprotective DATATOP may also show this Similar trials with pramipexole (PROUD) have failed to demonstrate a class effect STRIDE has also failed to show a beneficial effect of dopa plus entacapone early on (polypharmacy failure?)

6. The Issues- early v late Rx; the case of neuroprotection Immediate Rx would add an estimate extra £3.2 million to an annual PD meds bill of £100 million (2008 data; Clarke et al Mov Dis 2011) Earlier Rx might expose patients to a greater life-time risk of ICD with dopamine agonists or dyskinesia/wearing off with Ldopa Selegiline was implicated in some trials with increased mortality rate (?cardiac)

7. DATATOP second randomization showed that patients treated with selegiline for up to 7 years experienced slower decline in UPDRS (2.3 total UPDRS units) compared with patients who were changed to a placebo after about 5 years of treatment Perhaps prolonged Rx course better than short for selegiline Is this neuroprotection or just symptomatic improvement?

8. TEMPO Trial- Rasagaline- 404 patients 2mg/day all along>>delayed 2mg (UPDRS 2.3)(p=0.01); immediate 1mg/day just>delayed 2mg (UPDRS 1.8)(p=0.05) 2mg/day delayed 6/12 2mg/day1mg/day Problems- only mildest patients enter a delayed start trial; there is a high drop-out rate in the delayed start arm; some studies suggest 8 UPDRS points is clinically meaningful, especially in early PD but perhaps a cumulative effect on UPDRS is meaningful

9. ADAGIO- 1176 patients 1mg immediate>1mg delayed (UPDRS 1.7)(p=0.02) BUT no sig diff 2mg arms 1mg/daily 18 months 2mg/daily for 18/12 2mg/daily delayed until 9/12 1mg/daily delayed until 9/12 Perhaps 2mg treatment effect masks neuroprotective effect at higher UPDRS; sub-group analysis showed this to be true but only at borderline significance 1mg looks good in ADAGIO; 2mg better in TEMPO

10. CALM-PDREAL-PETPROUD Issues- which agent should go first- dopa or DA’s?

11. CALM-PD N=151 Pramipexole 0.5mg tdsWeeks 11-23 open label N=150 Ldopa equivalent to 125mg tds Weeks 11-23 open label

12. CALM-PD Motor complication in favour of pramipexole (p<0.001) UPDRS favoured Ldopa group (p<0.001) Somnolence greater in pramipexole group Ldopa group showed greater decline in B-CIT (25% v 20%)(p=0.15) Month 23.5

13. CALM-PD- 6 year follow-up N=151 pramipexoleLdopa or other N=150 ldopaOther PD Med

14. CALM-PD- 6 year follow-up ADL no different (p=0.19) Motor complications (dyskinesia, wearing off, on- off) in favour DA (p=0.002) ESS favours Ldopa (p=0.002) UPDRS no difference (p=0.11)

15. REAL-PET N=68 Requip group Putaminal Ki -14% N=59 Ldopa group Putaminal Ki -23% 18F PET putaminal Ki primary outcome measure Less decline with requip (p<0.001)

16. PROUD-pramipexole Immediate 1.5mg/daily pramixole Delayed 1.5mg/daily pramipexole 6-9/12 UPDRS No sig diff p=0.65

17. Issues- is LCE polypharmacy better than LC? Stride PD, N=747 Ldopa/carbidopa qds Ldopa/carbidopa/entacapone qds LCE group develop dyskinesia sooner and more frequently; no difference in motor scores

18. Issues- is early Rx better than late- PD-LIFE PDQ39 of earlier Rx patients stable; those untreated declined 61 patients left untreated at 9/12 FU 198 early PD patients 53 patients Rx at 9/12 FU But no randomisation to early or no Rx and some of the untreated group showed faster deterioration at 9/12 than Rx group

19. The Issues- putting all of this together… But what we are suggesting is not so much early treatment, but clinically effective treatment, not under-dosing and not ignoring functional disability- these are different (albeit related) themes And the later we leave Ldopa Rx, the more denervated the striatum, and the greater the Ldopa related side-effects

20. The issues- polypharmacy is better than monotherapy Several trials suggest early Rx is better than late- PD-LIFE, ELLDOPA, ADAGIO, TEMPO, DATATOP DA trials show DA have fewer motor complications than dopa as first line Rx ELLDOPA shows high incidence of motor complications related to dopa dose BUT DA trials show higher efficacy for dopa

21. Putting it all together- Chronologically Young DA best first line; MAOI do not have the efficacy given the moderate-severe deficit of most patients Ldopa second add-in if motor deficit not reversed- otherwise MAOI COMPT third line add in Polypharmacy in 5 years avoids functional disability and ICD

22. Putting it all together- Chronologically Old Ldopa best first line; MAOI do not have the efficacy given the moderate-severe deficit of most patients; DA too many side-effects Low dose DA second add-in if motor deficit not reversed, e.g. low dose adjuvant rotigotine- otherwise COMPT MAOI third line add in Polypharmacy in 5 years avoids high dose dopa

23. The Issues- if polypharmacy is good, how do we deliver it? Should we be using a polypill? Probably not given the STRIDE Data- but rasagaline plus dopa? Dopa plus nocturnal rotigotine for the non-motor stuff?

24. Polypill-V1 All PD patient>70 as first treatment Rasagiline Ldopa No titration issue- standard dose of rasagline in all tablets

25. Polypill-V2 All PD <70 Sinemet CR + Entacapone nocte Long acting Dopamine Agonist nocte No titration issue wrt sinemet/enta capone dosage

26. Polypill-V3 All PD >70 Coenzyme Q10 Ldopa CoQ10 may have a beneficial effect on mitochondrial function

27. Polypharmacy-V1 PD patients>70; rotigotine for the nocturnal off Rotigotine 2-4mg Ldopa

28. Polypharmacy PDD or DLBD Ldopa Rivastigmine