-
Review of the available evidence on
Oral Dopamine Agonists For Parkinson’s Disease
FOR THE WHO MODEL LIST OF ESSENTIAL MEDICINES
ANNEXES
Emilia Romagna Health and Social Care Agency - Drug Evaluation
Unit,
WHO Collaborating Centre in Evidence-Based Research Synthesis
and Guideline Development Emilia Romagna Health and Social Care
Agency
Viale Aldo Moro, 21 - 40127 Bologna, Italy
Email: [email protected]
-
Update of the Cochrane systematic review of dopamine agonist
therapy in early Parkinson’s disease
Clare P. Herd1, Caroline Rick2, Laila Shah2, Rita Champaneria2, Natalie Ives2, Carl E. Clarke1,3
1School of Clinical and Experimental Medicine, College of Medicine and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
2Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2TT, UK 3Department of Neurology, Sandwell and West Birmingham Hospitals NHS Trust, City Hospital, Birmingham, B18 7QH, UK
BackgroundA Cochrane systematic review of the evidence for Dopamine agonist therapy in early Parkinson’s disease was published in 2008 [1]. The authors found 29 eligible trials involving 5247 participants and concluded that although motor complications appeared reduced with dopamine agonists compared with levodopa, other important side effects were increased and symptom control was poorer. They called for further long‐term trials which included assessment of quality of life measures.
For this report, an update of the search used in this Cochrane review has been carried out using the major databases. An overlap of at least 6 months was incorporated to account for delayed addition of citations to the databases. In addition to the therapies reviewed previously, trials of the transdermal dopamine agonist rotigotine are included in this report.
Methods
TypesofstudiesEligible studies were any randomised trials in early Parkinson's disease comparing an orally or transdermally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa, with all other aspects of planned treatment being the same in both arms. Trials involving dopamine agonists administered intravenously were excluded.
TypesofparticipantsPatients with early Parkinson's disease entered into the relevant randomised trials. Early disease was defined as idiopathic Parkinson's disease, diagnosed using specified criteria such as the UK PDS Brain Bank criteria, with no history of motor complications, either untreated or with limited (generally less than 12 months) exposure to anti‐parkinsonian medication. There were no age restrictions.
TypesofinterventionsAny orally or transdermally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa, with all other aspects of planned treatment being the same in both arms.
-
TypesofoutcomemeasuresData extracted included clinician‐rated disability scales, e.g. Unified Parkinson's Disease Rating Scale (UPDRS), motor complications, quality of life scales, other side‐effects, treatment compliance and withdrawals, levodopa dose and mortality.
SearchstrategyWe searched Medline, Embase and CENTRAL using MeSH and free text terms for Parkinson’s disease as well as specific and generic dopamine agonist terms as described fully in the Medline search detailed in Appendix 1, these were combined with appropriate study design filter as described in section 6.4.11 of The Cochrane Handbook of Systematic Reviews of Interventions. No language restrictions were applied but date limits were used to create an overlap of 6 months with the search carried out in the relevant Cochrane review [1]. Protocols were retrieved from controlled‐trials.com for included trials when available.
Results
DescriptionofstudiesThis search was carried out on the 29th October 2014 and 2603 abstracts were retrieved and screened. A total of 32 relevant articles and abstracts as well as 4 available protocols were retrieved contributing to 12 new trials involving 5102 participants. Of these 12 new trials, nine compared dopamine agonist with placebo and three dopamine agonist with levodopa. Trial duration varied from 10 weeks to over 7 years. Trial quality was good overall, with eight of these trials using a computer generated randomisation code and seven using a central randomisation service. Nine trials were double blind, two were open label and one did not provide enough information to determine the level of blinding. Withdrawal rates were generally high ranging from 14% to 60%. Further details of the trials identified by this search can be found in Table 1, which also gives the full reference lists for each trial as well as the primary reference which will be used to identify studies throughout the rest of this report.
Effectsofinterventions
Trials of orally administered dopamine agonists versus placebo Although no data analysis could be carried out to assess the efficacy of dopamine agonists versus placebo in the Cochrane review carried out in 2008, the reviewers tabulated the various clinician rated disability scales used across the trials and the reported results in the form of p‐values. They were then able to qualitatively assess the treatment effect and conclude that dopamine agonists gave a significant improvement in symptom control compared with placebo [1]. Seven new trials reporting a comparison between an orally administered dopamine agonist and placebo were found in the updated search [2‐7]. Many of these trials provided sufficient data for meta‐analysis of UPDRS ADL and/or motor sub‐scores as shown in figures 1 and 2. The results of the forests plots for these newer trials support the conclusions of the 2008 Cochrane review, with both sub‐scores for this clinician rated disability scale showing a significant improvement in favour of dopamine agonist treatment (‐1.24, 95% CI ‐1.58 to ‐0.9, p
-
Figure 1: UPDRS ADL sub‐scores for trials of dopamine agonists (Experimental) versus placebo (Control).
Figure 2: UPDRS Motor sub‐scores for trials of dopamine agonists (Experimental) versus placebo (Control).
Of these seven trials, five reported on the quality of life outcome PDQ‐39 [4‐7]. Only two of these provided data in a usable format for meta‐analysis and the results of this are shown in figure 3 below. Again, a statistically significant result in favour of dopamine agonist treatment was seen.
Figure 3: PDQ‐39 scores for trials of dopamine agonists (Experimental) versus placebo (Control).
Trials of transdermally administered dopamine agonist versus placebo Three trials were found reporting on the transdermally administered dopamine agonist rotigotine [3, 8, 9]. Symptom control measured using UPDRS ADL and motor sub‐scores combined was reported in several trials with enough data to compare the efficacy of the patches with orally administered dopamine agonists as shown in figure 4 below. This indirect comparison shows that there is no statistically significant heterogeneity between the two subgroups (‐6.6, 95% CI ‐8.0 to ‐5.2 versus ‐4.7, 95% CI ‐6.4 to ‐4.9; p=0.10). Both subgroups result in an improvement in excess of minimum clinically important changes (MCIC’S) reported in the recent literature for UPDRS ADL and motor sub‐scores reported to be around ‐0.7 points and ‐2.3 to ‐2.7 points respectively [10, 11].
-
This result should be interpreted with caution due to the small number of studies with data available for inclusion in this analysis as well as the short duration of those studies (10‐39 weeks). Giladi et al provided the only head‐to‐head comparison of rotigotine patch treatment and orally administered dopamine agonists identified by this search. In contrast with our indirect comparison they found a significantly increased symptomatic effect of 3.8 points in combined UPDRS ADL and Motor sub‐scores in favour of ropinirole when compared with rotigotine patch therapy (95% CI’s 1.9 to 5.7; p
-
assessed in their allocated groups for 5 years. If the investigator judged it necessary to start additional therapy for PD because of medical reasons, levodopa and cabergoline were added to the initial cabergoline and levodopa groups but alternative dopamine agonist therapy could not be used. The primary outcome for this trial was incidence of motor complications, they also reported on UPDRS total and sub‐scores (ADL and motor) and gave a complete breakdown of reported adverse events. No quality of life measures were reported for this study. The hazard ratio reported for incidence of motor complications was 0.57 (95% CI, 0.18, ‐1.81; p=0.347) showing no significant difference between the groups, there was also no significant difference in UPDRS ADL, motor or total scores (p=0.280, p=0.398, p=0.140 respectively). The only statistically significant outcome was incidence of adverse events in favour of levodopa treatment (28% versus 53% in cabergoline group; p=0.019). Only the PD MED EARLY 2014 [14] trial compared dopamine agonist versus levodopa using quality of life outcome measures. This trial randomised 1620 participants into its open label parallel group design study. This trial included a third arm of initial monoamine oxidase B inhibitors (MAOBi) therapy, but this arm is not eligible for inclusion in this review. The patients were followed up for over 7 years. Any antiparkinsonian therapy could be added to any arm if symptoms were not adequately controlled by the maximum tolerated dose of the allocated medication. The primary analysis reported in the published report is for levodopa versus levodopa sparing groups, pooling dopamine agonist and MAOBi group data. However, some comments were made about levodopa versus dopamine agonist performance. The trialists stated that levodopa treatment achieved better scores than dopamine agonist treatment on the primary PDQ‐39 mobility outcome, and other patient‐related outcome measures, including ADL and overall quality of life as measured by the PDQ‐39 and EQ‐5D quality of life measures (data not currently available). 179 (28%) of 632 patients allocated dopamine agonists discontinued allocated treatment because of side effects compared with 11 (2%) of 528 patients allocated levodopa (p
-
patch therapy and orally administered dopamine agonists should be analysed to reliably test the non‐inferiority of this type of treatment [3]. The Cochrane review published in 2008 identified 11 trials of dopamine agonists versus levodopa and, using qualitative analysis of reported outcomes, concluded that levodopa initially provides better motor control, but that there is an increased likelihood of motor complications when compared with dopamine agonists therapy. The new trials provide data on quality of life which was not available for analysis in the 2008 review. The results of the PD MED trial found that quality of life was rated more highly by patients given levodopa compared with dopamine agonist therapy. Further analysis of data made available from this trial showed no difference between levodopa and dopamine agonist treated groups for motor fluctuations (p=0.18) and a reduced incidence of dyskinesia with an odds ratio of 0.56 in favour of the dopamine agonist arm. The conclusion drawn by PD MED trialists was that levodopa treatment is more effective and results in no clinically significant increase in involuntary movement over seven years compared with dopamine agonist therapy [14].
TrialDesignSince 2008 there has been an improvement in the standards of reporting in trials of dopamine agonists for early Parkinson’s disease with a larger proportion of trials providing usable data for meta‐analysis and fully disclosing trial methods needed for quality assessment. Inclusion of quality of life outcomes in trial designs, as recommended by the 2008 Cochrane reviewers, has increased with half of the new trials recording and reporting on the Parkinson’s Disease Questionnaire‐39.
-
Table 1: Characteristics of included studies: Further information for 12 studies included in this report, following abbreviations used, Adverse Event (AE), Dopamine Agonist (DA), Levodopa (L‐dopa, Unified Prkinson’s Disease Rating Scale (UPDRS), Activities of Daily Living (ADL), 39‐item Parkinson’s Disease Questionnaire (PDQ‐39), EuroQol (EQ‐5D)
Trial Label/1ry reference
Dopamine Agonist dose Comparator
Treatment schedule
Concomitant PD medications
Summary of results
Bronzova 2010 [2, 15‐17] 1ry ref: Bronzova 2010 [2]
Pardoprunox Placebo
Pardoprudox was titrated from 0.3 mg to 45mg/day over a 2 ‐ 6 week titration phase, treatment discontinued if 9 mg not reached. Individual best maintenance dose (9‐45mg/day) was continued for 3 weeks, followed by 2‐4 days of down titration and discontinuation during a 1 week follow up period.
Not permitted
Both UPDRS‐Motor and ADL scores were improved in pardoprunox group compared to placebo (p=0.0001, 0.0007). There were high levels of nausea in the pardoprunox group compared with placebo group (47% versus 4%).
Brusa 2013 [12, 18] 1ry ref: Brusa 2013 [12]
Cabergoline (mean 6 mg/day) and Rotigotine (patch) (mean 8 mg/day)
Levodopa (mean 357 mg/day)
3 month treatment then cross‐over
15 day wash out period pre‐treatment.
Trial focussed on cognitive function outcomes but reported that UPDRS motor scores showed no significant difference between L‐dopa and DA treated groups.
CASTLE 2012 [13] 1ry ref: Utsumi 2012 [13]
Cabergoline 6 mg/day
Levodopa 600 mg /day
Treatment initiated with doses of Cab 0.25‐2 mg once daily and LD 100‐300 mg/day 2‐3 times daily and titrated up to 6 mg/day and 600 mg/day respectively. 5 year study duration
If necessary for PD symptom control, levodopa and cabergoline were added to the initial cabergoline and levodopa groups. Administration of selegiline and other dopamine agonists was prohibited. Administration of anticholinergics and amantadine was permitted prior to study enrolment only. After onset of the primary endpoint, administration of any anti‐PD drug was permitted.
Trial found no statistically significant difference between incidence of motor complications in cabergoline and L‐dopa groups. The AE rate in the initial L‐dopa group was lower than that in the initial cabergoline group (p=0.019).
Giladi 2007 [3, 19‐22]
Rotigotine (patch) maximum dose 8
Placebo
4 week screening period, ropinirole titrated from 0.25 mg t.i.d to maximal dose of 8 mg t.i.d over 13 weeks, rotigotine titrated from 2 mg/day to max dose 8 mg/day over 4
Patients were permitted to take selegiline, amantadine, or anticholinergic agents or other CNS active drugs if maintained at stable
Responder rate, measured using UPDRS (motor + ADL) scores, was significantly higher in the rotigotine and ropinirole groups than the
-
1ry ref: Giladi 2007 [3]
mg/day and Ropinirole maximum dose 8 mg/day
weeks, followed by a 24‐36‐week maintenance phase, a dose de‐escalation (up to 12 days) and a 4‐week safety follow‐up period.
dosages for 28 days before baseline and throughout the trial.
placebo group. Rotigotine transdermal patch has a similar profile of adverse events to those reported for other dopamine agonists with the exception of application site reactions, the severity of which were mild to moderate.
Jankovic 2007 [8, 23‐26] 1ry ref: Jankovic 2007 [8]
Rotigotine patch Placebo
Titration phase: week 1 2mg, week 2 4mg, week 3 6mg rotigotine patch, 24 week maintenance phase, weaned off the drug stepwise decrements every 2 days ,followed by a final clinical visit 28 days later.
Participants receiving anticholinergic agents, MAOBi, NMDA antagonists, must have had a stable dose for at least 28 days before baseline and were required to maintain that dose for the duration of the trial.
The rotigotine transdermal system consistently demonstrated statistically significant and clinically relevant efficacy over placebo in patients with early Parkinson’s disease (change in UPDRS Motor + ADL score, p=6 months by the time of acquisition of informed consent or other drugs that could possibly affect PD symptoms from at least 4 weeks before the date of first treatment. Patients who had received L‐dopa before study entry had to discontinue L‐dopa at least 2 weeks before the date of the first treatment administration.
The mean change in UPDRS (motor + ADL) scores were more improved in the rotigotine transdermal patch group than in the placebo group (p=0.002), at a level similar to or better than that seen in similar trials for orally administered dopamine agonists. No serious drug related AE’s were reported.
PD MED 2014 [14] 1ry ref: Gray 2014 [14]
Clinician selects preferred DA and dosage
Levodopa Drug titration schedule and dose selected by treating clinician. Patients followed up for at over 7 years.
LD could be added to other treatment arms if symptoms were not adequately controlled by maximum tolerated dose. Patients could only switch drug class if symptoms were still not adequately controlled or because of adverse events.
L‐Dopa treatment achieved better scores than dopamine agonist treatment on the primary PDQ‐39 mobility outcome, and other patient‐related outcome measures, including ADL and overall quality of life as measured by the PDQ‐39 and EQ‐5D quality of life measures. Patient developed more involuntary
-
movements in L‐dopa group.
Poewe 2011 [4, 28‐30] 1ry ref: Poewe 2011 [4]
Pramipexole ER and Pramipexole IR both up to 4.5 mg/day
Placebo
7‐week flexible titration, dose escalation up to 4.5 mg once daily (ER) and 1.5 mg 3 times daily (IR) as tolerated to a response level judged satisfactory by the investigator and at which the patients rated themselves a "little better" on PGI‐I. Maintenance phase of up to 26 weeks at this dose level.
For patients who experienced increased parkinsonism during the maintenance period open label adjunct levodopa was permitted as rescue medication. These subjects were allowed to stay in the trial but their efficacy data was censored after the last assessment before levodopa rescue.
Both pramipexole formulations showed a significant decrease in mean change in UPDRS (motor + ADL) scores (p=
-
mg/day)
permitted this level was kept for entire 24 week maintenance phase. Dose reduction by 1 level for patients on pardoprunox ≥18 mg/day was permitted if required. Total duration 31 weeks followed by 4 day down titration during 1 week follow‐up.
study.
number of drop‐outs due to treatment emergent AE’s (44% versus placebo 8%) and also the overall incidence of these.
Vermeer 2011 [7, 35] 1ry ref: Sampaio 2011 [7]
Pardoprunox flexible dose (12‐42 mg/day) and Pramipexole flexible dose (1.5‐4.5 mg/day)
Placebo
Titration took place over a 4‐7 week period. In flexible dose groups, individual dose adjustments were allowed from week 4 of titration phase, doses above 12 mg/day for pardoprunox and above 1.5 mg/day for pramipexole, in order to find the optimal dose. A decrease by 1 dose level was permitted and this dose level was kept for the entire 24 week maintenance phase with dose reduction by 1 level for patients on pardoprunox ≥18 mg/day or pramipexole ≥2.25 mg/day permitted if required. Total duration 31 weeks followed by 7 day down titration during 1 week follow‐up.
With the exception of levodopa and dopamine agonists (which must have been terminated ≥ 90 days prior to baseline), anti‐PD medication was allowed, with doses stabilised ≥28 days prior to baseline and during the study.
Both pardoprunox and pramipexole showed significantly superior improvements in UPDRS motor score compared to placebo but the difference in PDQ‐39 scores was not significant for either drug. Drop‐out rates due to treatment emergent AE’s were 46%, 15% and 7% for pardoprunox, pramipexole and placebo respectively.
-
December 1, 2014
Appendix 1 1‐10 RCT sensitivity and precision maximising filter as described in section 6.4.11 of The Cochrane Handbook of Systematic Reviews of Interventions. 11 exp Parkinson Disease/ or Parkinson*.mp. 12 exp Dopamine Agonists/ 13 dopamine agonist*.mp. 14 expBromocriptine/ or bromocriptine*.mp. 15 Parlodel*.mp. 16 ropinirole*.mp. 17 Adartrel*.mp. 18 Requip*.mp. 19 Spiroco*.mp. 20 Ralnea*.mp. 21 cabergoline*.mp. 22 cabaser*.mp. 23 expLisuride/ or lisuride*.mp. 24 dopergin*.mp. 25 Proclacam*.mp. 26 Revanil*.mp. 27 expPergolide/ or pergolide*.mp. 28 expPiribedil/ or piribedil*.mp. 29 trivastal*.mp. 30 pronoran*.mp. 31 Trivastan*.mp. 32 trastal*.mp. 33 alpha‐dihydroergotamine*.mp. 34 alpha DHEC*.mp. 35 "CQA 206‐291*".mp. 36 Pramipexole.mp. 37 Mirapexin*.mp. 38 rotigotine.mp. 39 neupro*.mp. 40 Pardoprunox.mp. 41 "SLV‐308*".mp. 42 "SME‐308*".mp. 43 aplindore.mp. 44 "DAB‐452*".mp. 45 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 (32191) 46 10 and 11 and 45 47 limit 46 to yr="2007 ‐Current"
-
December 1, 2014
References 1.
Stowe, R.L., et al., Dopamine agonist therapy in early Parkinson's disease. Cochrane Database of
Systematic Reviews, 2008(2): p. CD006564. 2.
Bronzova, J., et al. (2010) Double‐blind study of pardoprunox, a new partial dopamine agonist, in
early Parkinson's disease. Movement disorders 25, 738‐46 DOI: 10.1002/mds.22948. 3.
Giladi, N., et al. (2007) Rotigotine transdermal patch in early Parkinson's disease: a randomized,
double‐blind, controlled study versus placebo and ropinirole. Movement disorders 22, 2398‐404 DOI: 10.1002/mds.21741.
4.
Poewe, W., et al. (2011) Extended‐release pramipexole in early Parkinson disease: a 33‐week randomized controlled trial. Neurology 77, 759‐66 DOI: 10.1212/WNL.0b013e31822affb0.
5.
Kieburtz, K. (2011) Twice‐daily, low‐dose pramipexole in early Parkinson's disease: a randomized, placebo‐controlled trial. Movement disorders 26, 37‐44 DOI: 10.1002/mds.23396.
6.
Schapira, A.H., et al. (2013) Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed‐start trial. Lancet neurology 12, 747‐55 DOI: 10.1016/S1474‐4422(13)70117‐0.
7.
Sampaio, C., et al. (2011) Pardoprunox in early Parkinson's disease: results from 2 large, randomized double‐blind trials. Movement disorders 26, 1464‐76 DOI: 10.1002/mds.23590.
8.
Jankovic, J., et al. (2007) Transdermal rotigotine: double‐blind, placebo‐controlled trial in Parkinson disease. Archives of neurology 64, 676‐82 DOI: 10.1001/archneur.64.5.676.
9.
Mizuno, Y., et al. (2013) Transdermal rotigotine in early stage Parkinson's disease: A randomized, double‐blind, placebo‐controlled trial. Movement disorders 28, 1447‐50.
10.
Hauser, R.A. and P. Auinger, Determination of Minimal Clinically Important Change in Early and Advanced Parkinson's Disease. Movement Disorders, 2011. 26(5): p. 813‐818.
11.
Shulman, L.M., et al., The Clinically Important Difference on the Unified Parkinson's Disease Rating Scale. Archives of Neurology, 2010. 67(1): p. 64‐70.
12.
Brusa, L., et al. (2013) The effect of dopamine agonists on cognitive functions in non‐demented early‐mild Parkinson's disease patients. Functional neurology 28, 13‐7.
13.
Utsumi, H. (2012) Long‐term effects of cabergoline and levodopa in Japanese patients with early Parkinson's disease: a 5‐year prospective study. Acta medica Okayama 66, 163‐70.
14.
Gray, R., et al., Long‐term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open‐label, pragmatic randomised trial. Lancet, 2014. 384(9949): p. 1196‐205.
15.
Bronzova, J., et al., Pardoprunox (SLV308) improves motor symptoms in patients with early stage Parkinson's disease (PD) ‐ A double‐blind placebo‐controlled multi‐center study. Neurology, 2008. 70(11): p. A59‐A59.
16.
Bronzova, J., C. Sampaio, and R.A. Hauser (2008) Pardoprunox (SLV308) in patients with early stage Parkinson's disease ‐ a phase II, double‐blind, placebo‐controlled, international, multi‐centre study by the Bruegel Study Group. European Jounral of Neurology 15, 103, Abstract no: P1270.
17.
Bronzova, J., et al., Pardoprunox (SLV308) in patients with early stage Parkinson's disease ‐ a double‐blind, placebo‐controlled, multi‐center study by the Bruegel study group. Movement Disorders, 2008. 23(1): p. S194‐S195.
18.
Brusa, L., et al., Rotigotine do not affect cognitive functions in early‐mild de novo Parkinson's disease patients. Parkinsonism and Related Disorders, 2012. 18: p. S130.
19.
Giladi, N., B. Boroojerdi, and E. Surmann (2013) The safety and tolerability of rotigotine transdermal system over a 6‐year period in patients with early‐stage Parkinson's disease. Journal of neural transmission 120, 1321‐9 DOI: 10.1007/s00702‐013‐1001‐5.
20.
Giladi, N., A. Korczyn, and B. Boroojerdi, Rotigotine transdermal patch in early stage Parkinson's disease: Results of a placebo‐ and ropinirole‐controlled trial. Movement Disorders, 2007. 22: p. S202‐S203.
21.
Giladi, N., et al., Effects of long‐term treatment with rotigotine transdermal patch on dyskinesias in early‐stage Parkinson's disease (PD): Results from two open‐label extension trials. European Journal of Neurology, 2010. 17(suppl 3): p. 121.
-
December 1, 2014
22.
Giladi, N., E. Surmann, and B. Boroojerdi, The safety and efficacy of transdermal rotigotine over a 6‐year period in patients with early‐stage idiopathic Parkinson's disease. Movement Disorders, 2011. 26: p. S128‐S129.
23.
Elmer, L.W., et al. (2012) Long‐term safety and tolerability of rotigotine transdermal system in patients with early‐stage idiopathic Parkinson's disease: a prospective, open‐label extension study. Parkinsonism & related disorders 18, 488‐93 DOI: 10.1016/j.parkreldis.2012.01.008.
24.
Watts, R.L., et al. (2007) Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 68, 272‐6 DOI: 10.1212/01.wnl.0000252355.79284.22.
25.
Boroojerdi, B., et al., The long‐term impact of early versus delayed treatment with rotigotine transdermal system in patients with early‐stage, idiopathic Parkinson's disease. Movement Disorders, 2011. 26: p. S121.
26.
Watts, R.L., B. Boroojerdi, and J. Jankovic, Open‐label extension trial assessing the effects of long‐term treatment with rotigotine in subjects with early‐stage, idiopathic Parkinson's disease: Results from up to 7 years. Movement Disorders, 2010. 25: p. S310‐S311.
27.
Mizuno, Y., et al., Investigation of Efficacy and safety of transdermal rotigotine in Japanese de‐novo Parkinson's disease (PD) patients. Movement Disorders, 2010. 25: p. S303.
28.
Hauser, R., L. Salin, and J. Koester (2009) Double‐blind evaluation of pramipexole extended‐release (ER) in early Parkinson's disease. Neurology 72, A412, Abstract no: S43.003.
29.
Salin, L., R. Hauser, and J. Koester, Double‐Blind Evaluation of Maintenance of Efficacy of Pramipexole Extended‐Release in Early Parkinson's Disease. Neurology, 2009. 72(11): p. A319‐A319.
30.
Hauser, R.A., et al. (2010) Randomized, double‐blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease. Movement disorders 25, 2542‐9 DOI: 10.1002/mds.23317.
31.
Kieburtz, K., A Randomized, controlled trial of twice daily pramipexole in early PD. Parkinsonism and Related Disorders, 2009. 15: p. S128.
32.
Schapira, A.H., et al. (2010) Rationale for delayed‐start study of pramipexole in Parkinson's disease: the PROUD study. Movement disorders 25, 1627‐32 DOI: 10.1002/mds.23143.
33.
Schapira, A.H.V., et al. (2008) PROUD: the impact of early vs. delayed treatment with pramipexole on new onset Parkinson's disease. European Jounral of Neurology 15, 132, Abstract no: P1366.
34.
Hauser, R.A., PROUD stands tall: Delayed‐start studies in Parkinson's disease. The Lancet Neurology, 2013. 12(8): p. 728‐729.
35.
Sampaio, C., et al., Pardoprunox in early stage Parkinson's disease: Results from two large studies. Movement Disorders, 2010. 25: p. S308.
-
December 1, 2014
Annex B International availability and proprietary names of DAs
*
** According to the 36th edition of Martindale, the drug is
still marketed in the countries listed in the table. Though,
accessing the individual national drug agencies of most countries,
the drug seems to be unavailable also in some of the countries
included in the table.
International availability of dopamie agonists (Source:
Martindale 36th edition) Medicine Country and trade name
Bromocriptine Argentina: Parlodel; Serocryptin¤; Australia:
Bromohexal; Bromolactin¤; Kripton; Parlodel; Austria: Antipark¤;
Broman¤; Bromed; Cehapark; Maylaktin¤;
Parlodel; Umprel; Belgium: Parlodel; Brazil: Bagren; Parlodel;
Canada: Parlodel; Chile: Criten; Grifocriptina; Kriptonal;
Parlodel; Prigost; Czech Republic: Medocriptine; Parlodel;
Serocryptin¤; Denmark: Bromergon¤; Bromopar¤; Parlodel; Finland:
Parlodel; France: Bromo-Kin; Parlodel; Germany: Bromocrel¤; kirim
gyn; kirim; Pravidel; Greece: Parlodel; Hong Kong: Bromtine;
Medocriptine; Parlodel; Serocryptin¤; Zolac¤; Hungary:
Serocryptin¤; India: Sicriptin; Indonesia: Cripsa; Parlodel;
Ireland: Parlodel; Israel: Parilac; Parlodel; Italy: Parlodel;
Serocryptin¤; Japan: Parlodel¤; Malaysia: Butin¤; Criptamine¤;
Medocriptine; Parlodel; Zolac¤; Mexico: Broptin; Crilem;
Cryocriptina; Inovapar¤; Kriptiser; Lactess¤; Mesiken; Parlodel;
Serocryptin¤; Netherlands: Parlodel; Norway: Parlodel; New Zealand:
Parlodel¤; Philippines: Parlodel; Provasyn; Poland: Bromergon;
Bromocorn; Ergolaktyna; Parlodel; Portugal: Parlodel; Russia:
Bromergon (Бромэргон); Parlodel (Парлодел); South Africa: Parlodel;
Singapore: Butin¤; Parlodel; Serocryptin¤; Suplac¤; Spain:
Lactismine¤; Parlodel; Sweden: Pravidel; Switzerland: Parlodel;
Serocryptin¤; Thailand: Brocaden; Bromergon; Parlodel;
Serocryptin¤; Suplac; Turkey: Gynodel; Parlodel; United Arab
Emirates: Antiprotin; United Kingdom: Parlodel; United States:
Parlodel; Venezuela: Parlodel; Serocryptin
Cabergoline # Argentina: Cabaser; Caberpar; Cieldom; Dostinex;
Lac Stop; Lactamax; Triaspar; Australia: Cabaser; Dostinex;
Austria: Cabaseril; Dostinex; Belgium: Dostinex; Sostilar; Brazil:
Dostinex; Canada: Dostinex; Chile: Dostinex; Czech Republic:
Cabera; Dostinex; Denmark: Cabaser; Dostinex; Finland: Cabaser;
Dostinex; France: Dostinex; Germany: Cabaseril; Dostinex; Greece:
Dostinex; Hong Kong: Dostinex; India: Caberlin; Camforte¤; Ireland:
Cabaser; Dostinex; Israel: Cabaser; Dostinex; Italy: Actualene;
Cabaser; Dostinex; Malaysia: Dostinex; Mexico: Dostinex;
Netherlands: Dostinex; Norway: Cabaser; Dostinex; New Zealand:
Dostinex; Poland: Dostinex; Portugal: Dostinex; Russia: Dostinex
(Достинекс); South Africa: Dostinex; Singapore: Dostinex; Spain:
Dostinex; Sogilen; Sweden: Cabaser; Dostinex; Switzerland: Cabaser;
Dostinex; Turkey: Cabaser; Dostinex; United Kingdom: Cabaser;
Dostinex; United States: Dostinex¤; Venezuela: Dostinex
Dihydro-ergocryptine mesylate **
Germany: Almirid; Cripar; Italy: Daverium; Myrol¤; Mexico:
Diamin; Poland: Almirid; Portugal: Striatal; Russia: Vasobral
(Вазобрал)
Pergolide § Argentina: Aroltex; Breator¤; Celance; Geranil¤;
Parlide¤; Brazil: Celance; Chile: Celance¤; France: Celance;
Germany: Parkotil; Greece: Celance; Hong Kong: Celance¤; Hungary:
Parkotil¤; Ireland: Celance; Poland: Hizest¤; Portugal: Permax;
Singapore: Celance¤; Spain: Pharken; Thailand: Celance¤
Pramipexole Argentina: Maxtenk; Mirapex¤; Nixol; Parfeno;
Parxium; Portiv; Sifrol; Australia: Sifrol; Austria: Sifrol;
Belgium: Mirapexin; Brazil: Mirapex; Sifrol; Canada: Mirapex;
Chile: Sifrol; Czech Republic: Mirapexin; Sifrol; Denmark:
Mirapexin; Sifrol; Finland: Sifrol; France: Sifrol; Germany:
Sifrol; Greece: Mirapexin; Hungary: Mirapexin; Indonesia: Sifrol;
Ireland: Mirapexin; Italy: Mirapexin; Japan: BI-Sifrol; Malaysia:
Sifrol; Mexico: Sifrol; Netherlands: Daquiran¤; Sifrol; Norway:
Sifrol; New Zealand: Sifrol; Philippines: Sifrol; Poland:
Mirapexin; Portugal: Mirapexin; Sifrol; Russia: Mirapex (Мирапекс);
South Africa: Pexola; Singapore: Sifrol; Spain: Mirapexin; Sweden:
Sifrol; Switzerland: Sifrol; Thailand: Sifrol; Turkey: Pexola;
United Kingdom: Mirapexin; United States: Mirapex; Venezuela:
Sifrol/Mirapex;
Ropinirole Argentina: Requip; Australia: Repreve; Austria:
Requip; Belgium: Requip; Canada: Requip; Chile: Requip; Czech
Republic: Adartrel; Requip; Denmark: Requip; Finland: Requip;
France: Adartrel; Requip; Germany: Requip; Greece: Adartrel;
Requip; Hong Kong: Requip; Hungary: Requip; Ireland: Requip;
Israel: Requip; Italy: Requip; Malaysia: Requip; Netherlands:
Requip; Norway: Requip; New Zealand: Requip; Poland: Requip;
Portugal: Requip; Zyatrol; South Africa: Requip; Singapore: Requip;
Spain: Requip; Sweden: Requip; Switzerland: Adartrel; Requip;
Turkey: Requip; United Kingdom: Adartrel; Requip; United States:
Requip;
-
December 1, 2014
§ Pergolide marketed as Permax ® has been withdrawn in these
countries: Australia; Belgium; Canada; Czech Republic; Denmark;
Finland; Mexico; Netherlands; New Zealand; South Africa;
Switzerland; Turkey. (Micromedex- Drug summary Last Modified:
August 08, 2014). In the US pergolide is no more available for the
treatment of PD. Pergolide drug products were voluntarily removed
from the market by the manufacturer on March 29, 2007 due to safety
concerns of an increased risk for serious heart valve damage in
patients taking pergolide for PD. (FDA pergolide) # In the US
cabergoline is no more available for the treatment of PD; the drug
is only available as 0.5 mg tablets that have the following
indication: “treatment of hyperprolactinemic disorders, either
idiopathic or due to pituitary adenomas”. (FDA cabergoline)
International availability of DAs as reported in the Drug Master
File (DMF), Food and Drug administration * (as of 3Q 2014EXCEL) *
DMF# SUBMIT DATE HOLDER SUBJECT
6955 11/05/1987 EUTICALS SPA BROMOCRIPTINE MESYLATE AS MFG IN
MILAN ITALY;
7088 24/07/1987 LABOCHIM BROMOCRIPTINE MESYLATE AS MFG IN MILAN,
ITALY 14768 03/03/2000 TEVA PHARMACEUTICAL INDUSTRIES LTD
BROMOCRIPTINE MESYLATE AS MFG IN OPAVA CZECH REPUBLIC
6984 08/05/1987 CHEMAPOL LTD BROMOCRIPTINE MESYLATE MANUFACTURED
BY GALENA IN CZECHOSLOVAKIA. 11973 06/05/1996 GALENA AS
BROMOCRIPTINE MESYLATE MANUFACTURED IN OPAVA, CZECH REPUBLIC.
10679 15/12/1993 CHEMICAL PHARMACEUTICAL RESEARCH INSTITUTE
NIHFI LTD BROMOCRIPTINE MESYLATE MANUFACTURED IN SOFIA,
BULGARIA.
6737 16/12/1986 GEDEON RICHTER LTD BROMOCRIPTINE MESYLATE USP AS
MFG. IN BUDAPEST, HUNGARY 6827 13/02/1987 LEK PHARMACEUTICALS DD
BROMOCRIPTINE MESYLATE USP AS MFG. IN MENGES, SLOVENIA 7533
23/05/1988 ANTIBIOTICOS SPA CABERGOLINE ACTIVE DRUG SUBSTANCE AS
MFG. IN MILANO, ITALY
18199 21/03/2005 GEDEON RICHTER PLC CABERGOLINE AS MANUFACTURED
IN BUDAPEST AND DOROG, HUNGARY. 18113 21/02/2005 TEVA
PHARMACEUTICAL INDUSTRIES LTD CABERGOLINE AS MANUFACTURED IN OPAVA,
CZECH REPUBLIC. 15933 18/03/2002 IVAX CR CABERGOLINE AS
MANUFACTURED IN OPAVA-KOMAROV, CZECH REPUBLIC 23918 29/12/2010
APICORE US LLC CABERGOLINE AS MANUFACTURED IN SOMERSET NJ 15423
30/04/2001 FINETECH PHARMACEUTICAL LTD CABERGOLINE AS MFG IN
NESHER, ISRAEL 18972 25/11/2005 RESOLUTION CHEMICALS LIMITED
CABERGOLINE DRUG SUBSTANCE AS MANUFACTURED IN HERTFORDSHIRE, UNITED
KINGDOM.
7534 23/05/1988 ANTIBIOTICOS SPA CABERGOLINE FINISHED DOSAGE AS
MFG. IN MILANO ITALY 26235 13/07/2012 APOTEX PHARMACHEM INDIA PVT
LTD CABERGOLINE USP AS MANUFACTURED IN BANGALOR, INDIA 22620
13/03/2009 APOTEX PHARMACHEM INDIA PVT LTD CABERGOLINE USP AS
MANUFACTURED IN BANGALORE INDIA 15180 06/12/2000 GALENA AS
PERGOLIDE MESYLATE AS MANUFACTURED IN CZECH REPUBLIC
24323 28/10/2010 TEVA PHARMACEUTICAL INDUSTRIES LTD PERGOLIDE
MESYLATE AS MANUFACTURED IN OPAVA-KOMAROV CZECH REPUBLIC FOR TEVA
PHARMACEUTICAL INDUSTRIES LTD
17982 12/01/2005 OLON SPA PERGOLIDE MESYLATE AS MANUFACTURED IN
RODANO (MI), ITALY. 15013 24/08/2000 BACHEM SA PERGOLIDE MESYLATE
AS MFG IN VIONNAZ, SWITZERLAND 20330 07/03/2007 PERRIGO API LTD
PRAMIPEXOLE BASE AS MANUFACTURED IN BEER SHEVA ISRAEL 19853
10/10/2006 HETERO DRUGS LTD PRAMIPEXOLE DIHYDROCHLORIDE AS
MANUFACTURED IN ANDHRA PRADESH INDIA
22860 28/08/2009 ORCHID CHEMICALS AND PHARMACEUTICALS LTD
PRAMIPEXOLE DIHYDROCHLORIDE AS MANUFACTURED IN MAHARASHTRA
INDIA
21082 28/11/2007 SANDOZ PRIVATE LTD PRAMIPEXOLE DIHYDROCHLORIDE
AS MANUFACTURED IN MAHASHTRA, INDIA
-
December 1, 2014
22209 17/11/2008 NURAY CHEMICALS PVT LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE (NON-STERILE BULK DRUG SUBSTANCE) AS
MANUFACTURED IN TAMIL NADU, INDIA
23900 22/06/2010 MSN LABORATORIES LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE [ROUTE CODE PP] AS MANUFACTURED IN
ANDHRA PRADESH, INDIA
21095 30/11/2007 APOTEX PHARMACHEM INDIA PVT LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED BY APOTEX PHARMACHEM
INDIA PVT LTD IN KARNATAKA, INDIA FOR APOTEX PHARMACHEM INC
22789 15/05/2009 AUROBINDO PHARMA LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN ANDHRA PRADESH INDIA
20116 03/01/2007 PERRIGO API LTD PRAMIPEXOLE DIHYDROCHLORIDE
MONOHYDRATE AS MANUFACTURED IN BE'ER SHEVA ISRAEL 21791 11/07/2008
CRYSTAL PHARMA SAU PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS
MANUFACTURED IN BEOCILLO (VALLADOLID), SPAIN 20130 08/01/2007
CADILA HEALTHCARE LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS
MANUFACTURED IN GUJARAT INDIA 18836 06/10/2005 ALEMBIC
PHARMACEUTICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS
MANUFACTURED IN GUJARAT, INDIA.
21413 12/03/2008 BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG
PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN
INGELHEIM AM RHEIN, GERMANY
18297 21/04/2005 AMINO CHEMICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE
MONOHYDRATE AS MANUFACTURED IN MARSA, MALTA. 21631 19/05/2008
TORRENT PHARMACEUTICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE
DRUG SUBSTANCE AS MANUFACTURED IN GUJARAT, INDIA
24331 25/10/2010 ERREGIERRE SPA PRAMIPEXOLE DIHYDROCHLORIDE
MONOHYDRATE PH EUR AS MANUFACTURED IN SAN PAOLO D'ARGON (BG)
ITALY
23163 07/10/2009 MACLEODS PHARMACEUTICALS LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE USP (EUSB) AS MANUFACTURED IN GUJARAT
INDIA 25907 30/03/2012 UNICHEM LABORATORIES LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE USP AS MANUFACTURED IN DIST. RAIGAD,
INDIA 21899 25/10/2008 SUN PHARMACEUTICAL INDUSTRIES LTD
PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE USP AS MANUFACTURED IN
GUJARAT, INDIA 18701 25/08/2005 CIPLA LTD PRAMIPEXOLE
DIHYDROCHLORIDE MONOHYDRATE USP AS MANUFACTURED IN MAHARASHTRA,
INDIA. 24781 23/06/2011 WOCKHARDT LTD PRAMIPEXOLE DIHYDROCHLORIDE
USP AS MANUFACTURED IN GUJARAT, INDIA 21712 28/05/2008 MYLAN
LABORATORIES LTD PRAMIPEXOLE DIHYDROCHLORIDE USP AS MANUFACTURED IN
MAHARASHTRA 26414 14/09/2012 NEULAND LABORATORIES LTD ROPINIROLE AS
MANUFACTURED IN ANDHRA PRADESH, INDIA
21938 18/10/2008 ORCHID CHEMICALS AND PHARMACEUTICALS LTD
ROPINIROLE HYDROCHLORIDE (NON-STERILE BULK API) AS MANUFACTURED IN
MAHARASHTRA, INDIA
18412 09/06/2005 DR REDDYS LABORATORIES LTD ROPINIROLE
HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA. 19590
10/07/2006 NEULAND LABORATORIES LTD ROPINIROLE HYDROCHLORIDE AS
MANUFACTURED IN ANDHRA PRADESH, INDIA. 17880 08/12/2004 URQUIMA SA
ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN BARCELONA, SPAIN. 19933
18/08/2006 CADILA PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE AS
MANUFACTURED IN GUJARAT INDIA 20593 12/06/2007 GLENMARK GENERICS
LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA 21331
07/02/2008 WATSON PHARMA PRIVATE LTD ROPINIROLE HYDROCHLORIDE AS
MANUFACTURED IN MAHARASHTRA, INDIA 19045 19/12/2005 USV LIMITED
ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN MAHARASHTRA, INDIA.
18564 30/07/2005 IND SWIFT LABORATORIES LTD ROPINIROLE
HYDROCHLORIDE AS MANUFACTURED IN PUNJAB, INDIA 19198 22/02/2006
PCAS ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN TURKU, FINLAND.
20829 25/04/2007 ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD ROPINIROLE
HYDROCHLORIDE AS MANUFACTURED IN ZHEJIANG, CHINA 18777 14/09/2005
TORRENT PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE DRUG SUBSTANCE
AS MANUFACTURED IN GUJARAT, INDIA. 19780 11/09/2006 ALEMBIC
PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE, USP AS MANUFACTURED
IN GUJARAT INDIA
7513 07/06/1988 NOVARTIS PHARMACEUTICALS CORP STARTING MATERIALS
1 & 3, IN NEW JERSEY AND SWITZERLAND
-
December 1, 2014
In the US cabergoline and pergolide are no more available for
the treatment of PD. Pergolide drug products were voluntarily
removed from the market by the manufacturer on March 29, 2007 due
to safety concerns of an increased risk for serious heart valve
damage in patients taking pergolide for PD. Cabergoline is only
available as 0.5 mg tablets that have the following indication:
“treatment of hyperprolactinemic disorders, either idiopathic or
due to pituitary adenomas”. (FDA pergolide, FDA cabergoline)
-
December 1, 2014
Annex C Indications for use of DAs
Medicine Indications Parkinson ‘s Disease Other conditions
different from Parkinson’s Disease
Bromocriptine ITA, UK, US, China*, Sudan*, Marocco*, India*
Acromegaly (US, ITA, UK) Female infertility - In vitro
fertilization (US: indication not labeled as a therapeutic use)
Female infertility of pituitary - hypothalamic origin –
Hyperprolactinemia (US, ITA, UK) Hyperprolactinemia (US, ITA, UK)
Non-pregnancy related A-G syndrome (US, ITA, UK) Prolactinoma (US,
ITA, UK) Type 2 diabetes mellitus (US) Inhibition of lactation (UK)
Menstrual cycle disorders (ITA, UK)
Cabergoline ITA, UK Hyperprolactinemia (US, ITA, UK) Acromegaly
(US: indication not labeled as a therapeutic use) Erectile
dysfunction (US: indication not labeled as a therapeutic use)
Lactation suppression, Puerperal (ITA, UK) Restless legs syndrome,
Idiopathic (US: indication not labeled as a therapeutic use)
Dihydroergocryptine Mesilate
ITA#, Germany*, Mexico**, Poland*, Portugal*; Russia**, China*
Hyperprolactinemia (ITA)
Pergolide § Acromegaly (no FDA) Cocaine withdrawal (no FDA)
Depression (no FDA) Gilles de la Tourette's syndrome (no FDA)
Hyperprolactinemia (no FDA) Restless legs syndrome (no FDA)
Supranuclear paralysis (no FDA)
Pramipexole ITA, UK, US, China* Restless legs syndrome (Moderate
to Severe) (ITA, UK, US) Ropinirole ITA, UK, US, China* Restless
legs syndrome Moderate to Severe (UK, US) # ITA: Available until
end of supply; * Indications not available from national drug
database; ** National drug database not available on-line §
Pergolide is not available in most developed countries, where drug
databases are available on-line. Countries where drug databases are
not available for on-line access have not been assessed.
-
December 1, 2014
* National Regulatory Agencies’ Databases
The information summarized in the tables of Annexes … and … has
been retrieved from the following on-line drug databases [all
accessed on November 25,
2014]:
UK - https://www.medicines.org.uk/emc/;
http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Aliskiren
ITA - www.codifa.it; Compendio Farmaceutico Ospedaliero
(Farmadati); http://www.agenziafarmaco.gov.it/
USA -
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Czech Republic -
http://www.sukl.eu/modules/medication/search.php
France - http://www.ansm.sante.fr/
Germany - http://www.bfarm.de/DE/Home/home_node.html
Greece -
http://www.eof.gr/web/guest;jsessionid=6de1cb917905ddaf468c14709d7c
Ireland - http://www.hpra.ie/
Poland - http://en.urpl.gov.pl/general-information
Portugal - http://www.infarmed.pt/infomed/pesquisa.php
Spain -
http://www.aemps.gob.es/medicamentosUsoHumano/portada/home.htm
Switzerland -
https://www.swissmedic.ch/arzneimittel/00156/00221/00222/00230/index.html?lang=en
Marocco - http://www.assurancemaladie.ma/anam.php?id_espace
Sudan - http://www.nmpb.gov.sd/drugsearch.php
India - http://www.nppaindia.nic.in/index1.html;
http://www.tnmsc.com/tnmsc/new/index.php
China -
http://app1.sfda.gov.cn/datasearcheng/face3/base.jsp?tableId=85&tableName=TABLE85&title=Database%20of%20approved%20Active%20Pharmaceutical
%20Ingredients%20(APIs)%20and%20API%20manufacturers%20in%20China&bcId=136489131226659132460942000667
-
December 1, 2014
Annex D Results of the search strategy and process of inclusion
Clinical Guidelines Systematic Reviews
Citations excluded: 22 - 4 focused on transdermal DAs - 18 topic
not pertinent
Relevant SRs included in this document: 10
Documents excluded: 12 - 7 not systematic reviews - 1 low
quality (mixing RCTs with observational non-controlled studies) - 2
relevant conflict of interest issues - 1 full text version in
German - 1 search date superseded by one of the selected reference
SRs (Stowe 2010)
Citations excluded: 83
Documents excluded: 6 (not pertinent or duplicated)
Relevant clinical guidelines included in this document: 7
Potentially relevant citations identified and screened for
retrieval: 96 (AAN=1; EFNS=2; HAS=1; ISS=1; MDS=1; NGC=88; NICE=1;
SIGN=1)
Potentially relevant documents retrieved for evaluation: 13
(AAN=1; EFNS=2; HAS=1; ISS=1; MDS=1; NGC=5; NICE=1; SIGN=1)
Potentially relevant documents retrieved for evaluation:
22
Potentially relevant citations identified and screened for
retrieval: 44
-
December 1, 2014
Annex E Summary of the recommendations on the use of DAs from
international guidelines on PD. Use of DAs in the treatment of PD:
synopsis of the recommendations from guidelines.
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
NICE 2006 Early PD
Dopamine agonists may be used as a symptomatic treatment for
people with early PD. [A]
A dopamine agonist should be titrated to a clinically
efficacious dose. If side effects prevent this, another agonist or
a drug from another class should be used in its place. [D
(GPP)]
If an ergot-derived dopamine agonist is used, the patient should
have a minimum of renal function tests, erythrocyte sedimentation
rate (ESR) and chest radiograph performed before starting
treatment, and annually thereafter. [D (GPP)]
In view of the monitoring required with ergot-derived dopamine
agonists, a non-ergotderived agonist should be preferred in most
cases. [D (GPP)]
…
NICE 2006 Advanced PD …
Dopamine agonists may be used to reduce motor fluctuations in
people with later PD. [A]
If an ergot-derived dopamine agonist is used, the patient should
have a minimum of renal function tests, ESR and chest radiograph
performed before starting treatment and annually thereafter. [D
(GPP)]
A dopamine agonist should be titrated to a clinically
efficacious dose. If side effects prevent this, then another
agonist or a drug from another class should be used in its place.
[D (GPP)]
In view of the monitoring required with ergot-derived dopamine
agonists, a nonergot-derived agonist should be preferred in most
cases. [D (GPP)]
SIGN 2010 Early PD
Patients with early Parkinson’s disease and motor symptoms may
be considered for treatment with oral/transdermal dopamine
agonists. [A]
Ergot derived dopamine agonists should not be used as first line
treatment for Parkinson’s disease. [B] When an ergot derived
dopamine agonist is used patients should undergo: 1. baseline
echocardiographic screening and regular follow up scans to identify
cardiac abnormalities; 2.baseline laboratory and radiological
investigations with regular follow up surveillance to identify
serosal fibrosis.
Patients should be warned about the potential for dopamine
agonists to cause impulse control disorders and excessive daytime
somnolence and be informed of the implications for
driving/operating machinery. [A] Healthcare professionals should
discuss impulse control disorders with patients with Parkinson’s
disease who are taking dopamine agonists.
…
-
December 1, 2014
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
SIGN 2010 Advanced PD … Dopamine agonists (oral or transdermal)
may be considered for the management of
motor complications1 in patients with advanced Parkinson’s
disease. The non-ergot agonists (ropinirole, pramipexole, and
rotigotine) are preferable to the ergot agonists. [A]
AMDA 2010 (AHRQ 2010) Early PD
Step 13. Implement appropriate pharmacologic interventions.
Pharmacotherapy should be combined with nonpharmacologic therapy
(e.g., education, exercise, social support, nutrition). Input from
a consultant pharmacist is encouraged. Levodopa combined with
carbidopa has long been considered the gold standard for treating
PD. Dopamine agonists or monoamine oxidase inhibitors (e.g.,
rasagiline, selegiline) are considered an appropriate first-line
therapy for younger patients. In younger patients, because of the
risk of developing levodopa-associated motor complications,
initiation of levodopa may be reserved for later in the course of
PD.2
Side effects from dopamine agonists include confusion,
hallucinations, hypotension, impulse control disorders, memory
impairment, nausea and vomiting, and excessive daytime sedation.
Patients over age 70 or those with dementia are at higher risk for
side effects from dopamine agonists.3
…
AMDA 2010 Errore. Il segnalibro non
è definito. (AHRQ 2010)
Advanced PD … …
HAS 2014 Early PD
Lorsque la gêne est minime, peuvent être utilisés en fonction du
symptôme prédominant et de l’âge: […] Des agonistes
dopaminergiques. […]
Lorsqu’il existe un retentissement fonctionnel, l’âge du patient
conditionne le traitement: chez le sujet jeune (moins de 65 ans),
privilégier les agonistes dopaminergiques, le plus longtemps
possible. […]
…
1
This statement, included in the Quick reference leaflet, is
slightly different from the one in the Full Report/Summary of
Recommendations, stating: “Dopamine agonists (oral or transdermal)
may be considered for the management of complications in patients
with advanced Parkinson’s disease.” The term “Motor complications”
is also featured in the Full Text Key Recommendations. 2 Text from
“Recommendations (Major Recommendations)” section. For grading
schemes see “Summary_Grading.doc”. 3 This statement this is not a
recommendation, being listed in the section “Benefits/Harms of
Implementing the Guideline Recommendations”.
-
December 1, 2014
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
HAS 2014 Advanced PD …
En 1ere intention : Les agonistes dopaminergiques en
administration orale ou transdermique:
- non derives de l’ergot de seigle en premiere intention:
ropinirole, piribedil pramipexole, rotigotine (dispositif
transdermique). - agonistes derives de l’ergot de seigle
(«ergopeptines») qui demandent une surveillance cardiaque annuelle
par echocardiographie (risque de survenue de valvulopathies):
bromocriptine, lisuride;
AAN 2006 Early PD … …
AAN 2006 Advanced PD …
Patients with motor fluctuations: Entacapone and rasagiline
should be offered to reduce off time (Level A). Pergolide,
pramipexole, ropinirole, and tolcapone should be considered to
reduce
off time (Level B). Tolcapone (hepatotoxicity) and pergolide
(valvular fibrosis) should be used with caution and require
monitoring.
Apomorphine, cabergoline, and selegiline may be considered to
reduce off time (Level c).
Sustained release carbidopa/levodopa and bromocriptine may be
disregarded to reduce off time (Level C)
Ropinirole may be chosen over bromocriptine for reducing off
time (Level C). Otherwise, there is insufficient evidence to
recommend one agent over another
(Level U).
-
December 1, 2014
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
EFNS 2011 Early PD
Drug Symptomatic control of parkinsonism Prevention of motor
complications Bromocriptineb Effective (level B) Effective
(level B) Cabergolineb Effective (level B) Effective (level A)
Dihydroergocryptineb Effective (level A) No recommendationc
Lisurideb Effective (level B) Effective (level C) Pergolideb
Effective (level A) Effective (level B) Piribedil Effective (level
C) No recommendationc Pramipexole Effective (level A) Effective
(level A) Pramipexole CRe Effective (level A) Not available
Ropinirole Effective (level A) Effective (level A) Ropinirole CRe
Effective (level A) No recommendation
b Ergot derivates cannot be recommended as a first-line
treatment because of the risk of valvular heart disorder. c No
recommendation can be made because of insufficient data. e
Controlled release. Practical recommendations for the treatment of
early untreated PD
The choice of drug depends on the impact of improving motor
disability (better with levodopa) compared with the risk of motor
complications (more common in younger patients, delayed by
agonists) and neuropsychiatric complications (more common in older
and cognitively impaired patients; greater with agonists) o Oral or
transdermal dopamine agonist.4
Pramipexole, piribedil, ropinirole and rotigotine are effective
(Level A). Initial treatment with an agonist can be recommended in
younger patients (GPP). Ergot derivatives are not recommended as
first-line medication because of the risk of fibrotic reactions
Practical recommendations for the adjustment of initial therapy
in patients without motor complications5 o Patients not on
dopaminergic therapy
If a patient has started on an MAO-B inhibitor, anticholinergic,
amantadine or a combination of these, a stage will come when there
is a requirement for adding levodopa or a dopamine agonist
(GPP)
o Patients on dopaminergic therapy If on dopamine agonist
therapy: Increase the dose (GPP) Switch between agonists (Level C)
Add levodopa (GPP) If on levodopa: Increase the dose (GPP) Add an
agonist (GPP) Add a COMT inhibitor (GPP)
4 In the original GL: orally active dopamine agonist. Pramipexole, piribedil, and ropinirole immediate ‐ or controlled ‐ release are effective as monotherapy in early PD (Level A), with a lower risk of motor complications than levodopa for pramipexole or ropinirole (Level A). Older drugs like bromocriptine are supported by lower class evidence, giving a Level B recommendation. However, there is no convincing evidence that they are less effective in managing patients with early PD. The benefit of agonists in preventing motor complications (Level A, with data up to 5 years only) must be balanced with the smaller effect on symptoms and the greater incidence of hallucinations, impulse ‐ control disorders, somnolence, and leg oedema, as compared with levodopa. Patients must be informed of these risks, e.g. excessive daytime somnolence is especially relevant to drivers. Younger patients are more prone to developing levodopa ‐ induced motor complications, and therefore initial treatment with an agonist can be recommended in this population (GPP). Ergot derivatives such as pergolide, bromocriptine, and cabergoline are not recommended as first – line medication because of the risk of fibrotic reactions. Rotigotine is administered transdermally using a patch and ropinirole CR once daily orally, as opposed to the other agonists that are administered orally three times a day. Subcutaneous apomorphine is not appropriate at this stage of the disease. The early combination of low doses of a dopamine agonist with low doses of levodopa is another option, although the benefits of such a combination have not been properly documented. 5 In the original GL: If on dopamine agonist therapy: • increase the dopamine agonist dose (GPP). However, even when the dopamine agonist dose is increased over time, it cannot control parkinsonian symptoms for more than about 3 – 5 years of follow ‐ up in most patients; • switch between dopamine agonists (Level C); • add levodopa (GPP). If on levodopa: • increase the levodopa dose (GPP); • add a dopamine agonist (GPP), although the efficacy of adding an agonist has been insufficiently evaluated; • add a COMT ‐ inhibitor to levodopa at the transition of a non ‐ fluctuating to a fluctuating status, i.e. if motor fluctuations evolve (GPP) – preferably in older patients and multimorbid patients of any age.
-
December 1, 2014
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
EFNS 2011 Advanced PD …
Motor fluctuations Add dopamine agonists: non-ergot dopamine
agonists are first-line compounds.
Dopamine agonists reduce OFF time. None has proven superior, but
switching from one agonist to another can be helpful (Level
B/C)6
Dyskinesias Reduce levodopa dose, at the risk of increasing OFF.
The latter can be compensated
for by increasing the number of doses or a dopamine agonist
(Level C)7 Off-period and early-morning dystonias Additional doses
of levodopa or dopamine agonist at night may be effective
(GPP)8
6 In the original GL: Add dopamine agonists. Non ‐ ergot dopamine agonists are first ‐ line compounds. Pergolide and other ergot agonists are reserved for second ‐ line treatment, due to their association with lung, retroperitoneal, and heart valve fibrosis. Oral dopamine agonists are efficacious in reducing OFF time in patients experiencing wearing ‐ off. Currently, no dopamine agonist has proven better than another, but switching from one agonist from one agonist to another can be helpful in some patients (Level B/C). 7 In the original GL: Reduce individual levodopa dose size , at the risk of increasing OFF time. The latter can be compensated for by increasing the number of daily doses of levodopa or increasing the doses of a dopamine agonist (Level C). 8 In the original GL: Additional doses of levodopa or dopamine agonist therapy at night may be effective for the control of dystonia appearing during the night or early in the morning (GPP).
-
December 1, 2014
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
MDS, 20119, 10 Early PD
Efficacy
Drug Prevention/delay of clinical progression Symptomatic
monotherapy
Piribedil Insufficient evidence Efficacious Pramipexole
Insufficient evidence Efficacious Pramipexole (ER*) Insufficient
evidence Efficacious Ropinirole Insufficient evidence Efficacious
Ropinirole (PR**) Insufficient evidence Likely efficacious
Bromocriptine Insufficient evidence Likely efficacious Cabergoline
Insufficient evidence Efficacious Dihydroergocryptine Insufficient
evidence Efficacious Lisuride Insufficient evidence Likely
efficacious Pergolide Unlikely efficacious Efficacious
Practice implications
Drug Prevention/delay of clinical progression Symptomatic
monotherapy
Piribedil Investigational Clinically useful Pramipexole
Investigational Clinically useful Pramipexole (ER*) Investigational
Clinically useful Ropinirole Investigational Clinically useful
Ropinirole (PR**) Investigational Possibly useful Bromocriptine
Investigational Possibly useful Cabergoline Investigational
Clinically useful Dihydroergocryptine Investigational Clinically
useful Lisuride Investigational Possibly useful Pergolide Unlikely
useful Clinically useful
* extended release ** prolonged release
Efficacy Drug Symptomatic adjunct to levodopa
Piribedil Efficacious Pramipexole Efficacious Pramipexole (ER*)
Efficacious Ropinirole Efficacious Ropinirole (PR**) Efficacious
Bromocriptine Efficacious Cabergoline Efficacious
Dihydroergocryptine Insufficient evidence Lisuride Likely
efficacious Pergolide Efficacious
Practice implications Drug Symptomatic adjunct to levodopa
Piribedil Clinically useful Pramipexole Clinically useful
Pramipexole (ER*) Clinically useful Ropinirole Clinically useful
Ropinirole (PR**) Clinically useful Bromocriptine Clinically useful
Cabergoline Clinically useful Dihydroergocryptine Investigational
Lisuride Possibly useful Pergolide Clinically useful
* extended release ** prolonged release
9 Transdermal (Rotigotine) and Parenteral (Apomorphine) Nonergot Dopamine Agonist were not included in this summary. 10 Safety details were not reported in this summary. For all Oral Nonergot Dopamine Agonists (Piribedil, Pramipexole, Pramipexole (ER*), Ropinirole, Ropinirole (PR**)) Safety is reported as “Acceptable risk without specialized monitoring”. For all Ergot Dopamine Agonists (Bromocriptine, Cabergoline, Dihydroergocryptine, Lisuride, Pergolide) Safety profile is reported as “Acceptable risk with specialized monitoring”.
-
December 1, 2014
DAs offered as mono therapy DAs offered as add-on therapy with
L-dopa
MDS, 20119, 10, Errore. Il segnalibro non è
definito. Advanced PD
Efficacy
Drug Prevention/delay of motor complications Treatment of
motor
complications Piribedil Insufficient evidence (F, D)
Insufficient evidence (F, D)
Pramipexole Efficacious (F, D) Efficacious (F) Insufficient
evidence (D)
Pramipexole (ER*) Insufficient evidence (F, D) Efficacious (F)
Insufficient evidence (D)
Ropinirole Insufficient evidence (F) Efficacious (D) Efficacious
(F) Insufficient evidence (D)
Ropinirole (PR**) Insufficient evidence (F) Efficacious (D)
Efficacious (F) Insufficient evidence (D)
Bromocriptine Insufficient evidence (F) Likely efficacious (D)
Likely efficacious (F) Insufficient evidence (D)
Cabergoline Efficacious (F, D) Likely efficacious (F)
Insufficient evidence (D) Dihydroergocryptine Insufficient evidence
(F, D) Insufficient evidence (F, D) Lisuride Insufficient evidence
(F, D) Insufficient evidence (F, D)
Pergolide Insufficient evidence (F) Likely efficacious (D)
Efficacious (F) Insufficient evidence (D)
Practice implications
Drug Prevention/delay of motor complications Treatment of
motor
complications Piribedil Investigational (F, D) Investigational
(F, D)
Pramipexole Clinically useful (F, D) Clinically Useful (F)
Investigational (D)
Pramipexole (ER*) Investigational (F, D) Clinically Useful (F)
Investigational (D)
Ropinirole Investigational (F), Clinically useful (D) Clinically
useful (F), Investigational (D)
Ropinirole (PR**) Investigational (F), Clinically useful (D)
Clinically useful (F), Investigational (D)
Bromocriptine Investigational (F), Possibly useful (D) Possibly
useful (F), Investigational (D)
Cabergoline Clinically useful (F, D) Possibly useful (F),
Investigational (D) Dihydroergocryptine Investigational (F, D)
Investigational (F, D) Lisuride Investigational (F, D)
Investigational (F, D)
Pergolide Investigational (F), Possibly useful (D) Clinically
useful (F), Investigational (D)
* extended release ** prolonged release F = motor
fluctuations D = dyskinesia
Early PD= without motor fluctuations; Advanced PD=with motor
fluctuations
-
December 1, 2014
Grading systems adopted in the recommendations summarized
above
SIGN 2010
-
December 1, 2014
NICE 2006
-
December 1, 2014
AMDA 2010 (AHRQ 2010)
Methods Used to Assess the Quality and Strength of the Evidence:
Expert Consensus
Rating Scheme for the Strength of the Evidence: Not
applicable
[…]
Methods Used to Formulate the Recommendations: Expert
Consensus
Rating Scheme for the Strength of the Recommendations: Not
applicable
EFNS 2011
-
December 1, 2014
AAN 2006
Classification of Evidence for Therapeutic Articles: Class I:
Prospective, randomized, controlled clinical trial with masked
outcome assessment, in a representative population. The following
are required: a) primary outcome(s) is/are clearly defined b)
exclusion/inclusion criteria are clearly defined c) adequate
accounting for drop-outs and cross-overs with numbers sufficiently
low to have minimal potential for bias d) relevant baseline
characteristics are presented and substantially equivalent among
treatment groups or there is appropriate statistical adjustment for
differences Class II: Prospective matched group cohort study in a
representative population with masked outcome assessment that meets
a-d above OR a RCT in a representative population that lacks one
criterion a-d. Class III: All other controlled trials including
well-defined natural history controls or patients serving as own
controls in a representative population, where outcome assessment
is independently assessed or independently derived by objective
outcome measurement.* Class IV: Evidence from uncontrolled studies,
case series, case reports, or expert opinion. • Objective outcome
measurement: an outcome measure that is unlikely to be affected by
an observer’s (patient, treating physician, investigator)
expectation or bias (e.g., bloos tests, administrative outcome
data) Classification of Evidence for Prognostic Articles: Class I:
Evidence provided by a prospective study of a broad spectrum of
persons who may be risk of developing the outcome (e.g. target
disease, work status). The study measures the predictive ability
using an independent gold standard for case definition. The
predictor is measured in an evaluation that is masked to clinical
presentation and, the outcome is measured in an evaluation that is
masked to the presence of the predictor. All patients have the
predictor and outcome variables measured. Class II: Evidence
provided by a prospective study of a narrow spectrum of persons at
risk for having the condition, or by a retrospective study of a
broad spectrum of persons with the condition compared to a broad
spectrum of controls. The study measures the prognostic accuracy of
the risk factor using an acceptable independent gold standard for
case definition. The risk factor is measured in an evaluation that
is masked to the outcome. Class III: Evidence provided by a
retrospective study where either the persons with the condition or
the controls are of a narrow spectrum. The study measures the
predictive ability using an acceptable independent gold standard
for case definition. The outcome, if not objective, is determined
by someone other than the person who measured the predictor. Class
IV: Any design where the predictor is not applied in an independent
evaluation OR evidence provided by expert opinion or case series
without controls. Classification of Recommendations: A=Established
as effective, ineffective, or harmful for the given condition in
the specified population. (Level A rating requires at least two
consistent Class I studies.) B=Probably effective, ineffective, or
harmful for the given condition in the specified population. (Level
B rating requires at least one Class I study or at least two
consistent Class II studies.) C=Possibly effective, ineffective, or
harmful for the given condition in the specified population. (Level
C rating requires at least one Class II study or two consistent
Class III studies.) U=Data inadequate or conflicting given current
knowledge, treatment is unproven.
-
December 1, 2014
MDS 2011
All Level-I studies were rated for study quality. The
study quality score was derived from a list of key methodological
topics, according to a published checklist13, relevant for
determining the methodological soundness of the trial (Table 3). A
percentage score (not absolute values) was calculated for each
study and is used as an indicator of the overall quality of the
study.
HAS 2014
Not reported.
-
December 1, 2014
ANNEX F GRADE TABLES
-
Author(s): Francesco NoninoDate: 2014-11-30Question: Should
L-dopa vs L-dopa sparing strategy be used in patients with early
PD?Settings: outpatientsBibliography: PD MED Collaborative Group.
Long-term eff ectiveness of dopamine agonists and monoamine oxidase
B inhibitors compared with levodopa as initial treatment for
Parkinson’s disease (PD MED): a large, open-label, pragmatic
randomised trial Lancet 2014; 384: 1196–205
1 Mean follow up 3 years. Analyses of continuous outocme
measures up to 7 years2 The difference is statistically significant
in favour of L-dopa, but its value is below the minimum threshold
of clinically important difference
Quality assessment No of patients Effect
Quality ImportanceNo of studies Design Risk of bias
Inconsistency Indirectness Imprecision
Otherconsiderations
L-dopa
L-dopa sparing strategy
Relative(95%CI)
Absolute
Mobility (self-rated functional status) (follow-up 0-9 years1;
measured with: PDQ-39 mobility subscale; range of scores: 0-100;
Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 1.8 higher (0.5 to 3 higher)2
����HIGH
Activities of daily living (self-rated functional status)
(follow-up 0-9 years1; measured with: PDQ-39 ADL subscale; range of
scores: 0-100; Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 1.9 higher (0.7 to 3 higher)2
����HIGH
Stigma (self-rated functional status) (follow-up 0-9 years1;
measured with: PDQ-39 stigma subscore; range of scores: 0-100;
Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 1.3 higher (0.2 to 2.3 higher)2
����HIGH
Communication (self-rated functional status) (follow-up 0-9
years1; measured with: PDQ-39 communication subscore; range of
scores: 0-100; Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 0.9 higher (0 to 1.8 higher)2
����HIGH
Cognition (self-rated functional status) (follow-up 0-9 years1;
measured with: PDQ-39 cognition subscore; range of scores: 0-100;
Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 1 higher (0 to 2 higher)2
����HIGH
Bodily discomfort (self-rated functional status) (Copy)
(follow-up 0-9 years1; measured with: PDQ-39 cognition subscore;
range of scores: 0-100; Better indicated by lower values)1
randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 1.4 higher (0.3 to 2.4 higher)2
����HIGH
PDQ-39 Summary Index (self-rated functional status) (follow-up
0-9 years1; measured with: PDQ-39 overall score; range of scores:
0-100; Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 1 higher (0.3 to 1.7 higher)2
����HIGH
quality-adjusted life-years (QALYs) (follow-up 0-9 years1;
measured with: EuroQol EQ-5D14 generic quality-of-life measure;
Better indicated by higher values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 1092 528 - mean 0.03 higher (0.01 to 0.05 higher)
����HIGH
05/12/2014GRADE
Page 1 of 1
-
Author(s): Francesco NoninoDate: 2014-12-01Question: Should
MAOBI vs DA be used in patients with early PD?Settings:
outpatientsBibliography: PD MED Collaborative Group. Long-term eff
ectiveness of dopamine agonists and monoamine oxidase B inhibitors
compared with levodopa as initial treatment for Parkinson’s disease
(PD MED): a large, open-label, pragmatic randomised trial. Lancet
2014; 384: 1196–205
1 Mean follow up 3 years. Analyses of continuous outocme
measures up to 7 years2 The difference is statistically significant
in favour of L-dopa, but its value is below the minimum threshold
of clinically important difference
Quality assessment No of patients Effect
Quality ImportanceNo of
studies Design Risk of bias Inconsistency Indirectness
ImprecisionOther
considerations MAOBI DARelative
(95%CI)
Absolute
Mobility (self-rated functional status) (follow-up 0-9 years1;
measured with: PDQ-39 mobility subscore; range of scores: 0-100;
Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 460 632 - mean 1.4 higher (0 to 2.9 higher)
����HIGH
Cognition (self-rated functional status) (follow-up 0-9 years1;
measured with: PDQ-39 cognition subscore; range of scores: 0-100;
Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 460 632 - mean 1.7 higher (0.5 to 2.9 higher)2
����HIGH
PDQ-39 Summary index (self-rated functional status) (Copy)
(follow-up 0-9 years1; measured with: PDQ-39 overall score; range
of scores: 0-100; Better indicated by lower values)1 randomised
trialsno serious risk of bias
no serious inconsistency
no serious indirectness
no serious imprecision
none 460 632 - mean 0.8 higher (0 to 1.7 higher)2
����HIGH
05/12/2014GRADE
Page 1 of 1
-
Author(s): Francesco NoninoDate: 2014-12-05Question: Should DAs
vs levodopa be used in patients with early PD?Settings:
outpatientsBibliography: Stowe RL, Ives NJ, Clarke C, van Hilten J,
Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R. Dopamine agonist
therapy in early Parkinson's disease. Cochrane Database Syst Rev.
2008 Apr 16;(2):CD006564
1 Most trials did not provide details about allocation
concealment. Unclear how many patients were included in the final
analysis.2 High heterogeneity, explained mainly by different trial
design (open, single-blinded, double-blinded) 3 publication bias
not assessed
Quality assessment No of patients EffectQuality ImportanceNo
of
studies DesignRisk of
bias Inconsistency Indirectness ImprecisionOther
considerations DAs LevodopaRelative(95% CI) Absolute
overall patient withdrawal (assessed with: number of patients
withdrawn)10 randomised
trialsserious1 serious2 no serious
indirectnessno serious imprecision
none3 571/1253
(45.6%)
334/1135(29.4%)
OR 2.02 (1.7 to 2.4)
300 more per 1000 (from 206 more to 412 more)
����LOW
0% -dyskinesia (follow-up 4 to 120 months; assessed with: number
of events)10 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none3 277/1247
(22.2%)
429/1138(37.7%)
OR 0.45 (0.37 to 0.54)
163 fewer per 1000 (from 131 fewer to 194 fewer)
����MODERATE
dystonia (follow-up 4 to 120 months; assessed with: number of
events)7 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none3 193/899(21.5%)
241/794(30.4%)
OR 0.64 (0.50 to 0.81)
85 fewer per 1000 (from 43 fewer to 125 fewer)
����MODERATE
withdrawal due to AEs (assessed with: number of patients
withdrawn)8 randomised
trialsserious1 serious2 no serious
indirectnessno serious imprecision
none3 256/1159
(22.1%)
98/1047(9.4%)
OR 2.47 (1.96 to 3.11)
138 more per 1000 (from 90 more to 197 more)
����LOW
0% -withdrawal due to lack of efficacy (assessed with: number of
patients withdrawn)5 randomised
trialsserious1 serious2 no serious
indirectnessno serious imprecision
none3 79/628(12.6%)
23/523(4.4%)
OR 2.93 (1.94 to 4.42)
85 more per 1000 (from 41 more to 150 more)
����LOW
0% -motor fluctuations (follow-up 4 to 120 months; assessed
with: number of events)7 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none3 310/892(34.8%)
361/875(41.3%)
OR 0.71 (0.58 to 0.87)
80 fewer per 1000 (from 33 fewer to 123 fewer)
����MODERATE
05/12/2014GRADE
Page 1 of 1
-
Author(s): Francesco NoninoDate: 2014-12-05Question: Should DAs
+/- levodopa vs levodopa be used in persons with early PD?Settings:
outpatientBibliography: Stowe RL, Ives NJ, Clarke C, van Hilten J,
Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R. Dopamine agonist
therapy in early Parkinson's disease. Cochrane Database Syst Rev.
2008 Apr 16;(2):CD006564
1 Most trials did not provide details about allocation
concealment. Unclear how many patients were included in the final
analysis.2 publication bias not assessed
Quality assessment No of patients EffectQuality ImportanceNo
of
studies DesignRisk of
bias Inconsistency Indirectness ImprecisionOther
considerationsDAs +/-
levodopa LevodopaRelative(95% CI) Absolute
oedema (follow-up 3 to 5 years; assessed with: number of
events)5 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 133/712(18.7%)
35/605(5.8%)
OR 3.68 (02.62 to 5.18)
126 more per 1000 (from 81 more to 183 more)
����MODERATE
constipation (follow-up 6 to 60 months; assessed with: number of
events)4 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 89/562(15.8%)
53/455(11.6%)
OR 1.59 (1.11 to 2.28)
57 more per 1000 (from 11 more to 115 more)
����MODERATE
dizziness (follow-up 2 to 60 months; assessed with: number of
events)6 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 153/722(21.2%)
98/615(15.9%)
OR 1.45 (1.09 to 1.92)
56 more per 1000 (from 12 more to 107 more)
����MODERATE
hallucinations (follow-up 2 to 60 months; assessed with: number
of events)9 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 76/832(9.1%)
35/691(5.1%)
OR 1.69 (1.13 to 2.52)
32 more per 1000 (from 6 more to 68 more)
����MODERATE
nausea (follow-up 6 to 60 months; assessed with: number of
events)8 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 273/786(34.7%)
191/661(28.9%)
OR 1.32 (1.05 to 1.66)
60 more per 1000 (from 10 more to 114 more)
����MODERATE
insomnia (follow-up 2 to 60 months; assessed with: number of
events)5 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 127/712(17.8%)
95/605(15.7%)
OR 1.32 (1.05 to 1.66)
40 more per 1000 (from 7 more to 79 more)
����MODERATE
somnolence (follow-up 6 to 60 months; assessed with: number of
events)6 randomised
trialsserious1 no serious
inconsistencyno serious indirectness
no serious imprecision
none2 152/760(20%)
92/657(14%)
OR 1.49 (1.12 to 2.00)
55 more per 1000 (from 14 more to 106 more)
����MODERATE
05/12/2014GRADE
Page 1 of 1
-
Author(s): Francesco NoninoDate: 2014-12-05Question: Should DAs
vs placebo be used in patients with advanced PD?Settings:
outpatientsBibliography: Stowe R, Ives N, Clarke CE, Deane K; van
Hilten, Wheatley K, Gray R, Handley K, Furmston A. Evaluation of
the efficacy and safety of adjuvant treatment to levodopa therapy
in Parkinson s disease patients with motor complications. Cochrane
Database Syst Rev. 2010 Jul 7;(7):CD00166
1 Most trials did provided details about allocation concealment.
Unclear how many patients were included in the final analysis.2
Mean age ranged from 57 to 66 years, while the majority of persons
with advanced PD are older. Follow up duration (up to 9 months)
short in relation to the natural history of the disease3
significant statistical heterogeneity4 two placebo arms with zero
events5 low number of events:14/335 and 3/272. Zero events in one
arm of one study
Quality assessment No of patients EffectQuality ImportanceNo
of
studies DesignRisk of
bias Inconsistency Indirectness ImprecisionOther
considerations DAs PlaceboRelative(95% CI) Absolute
overall side effects (follow-up 2 to 36 weeks; assessed with:
number of events)12 randomised
trialsserious1 no serious
inconsistencyserious2 no serious
imprecisionnone 907/1166
(77.8%)
616/970(63.5%)
OR 1.52 (1.22 to 1.90)
330 more per 1000 (from 140 more to 572 more)
����LOW
0% -overall patient withdrawal (follow-up 4 to 36 weeks;
assessed with: number of events)17 randomised
trialsserio