SUPPLEMENTARY MATERIALS: The efficacy and safety of piribedil relative to
pramipexole for the treatment of early Parkinson’s disease: a systematic literature review
and network meta-analysis
Xianwen Chen a*, Cuiping Ren a, Juan Li a, Shangpei Wang a, Louis Dron b, Ofir Harari b, Craig
Whittington c
a Department of Neurology, the First Affiliated Hospital of Anhui Medical University, No. 218
Jixi Road, Hefei City, Anhui Province, China
b MTEK Sciences, 777 Broadway, Vancouver, British Columbia, Canada
c Doctor Evidence, 301 Arizona Ave. #301, Santa Monica, U.S.A.
Corresponding Author:
Xianwen Chen
Email: [email protected]
Department of Neurology, the First Affiliated Hospital of Anhui Medical University
No. 218 Jixi Road, Hefei City, Anhui Province, China
Tel：86 13956939016
Appendix A
Table S1. Search terms for Pubmed (date searched: November 28, 2017; date updated: January
7, 2020)
Search term Number of hits
Nov 2017 Jan 2020
(parkinson disease[mh] OR parkinson*[tiab])
AND
((piribedil or eu-4200[tiab] or eu4200[tiab] or et495[tiab] or et-
495[tiab] or trivastal[tiab] or trastal[tiab])
OR
(pramipexole or dexpramipexol[tiab] or snd919*[tiab] or snd-
919*[tiab] or kns-760704[tiab] or kns760704[tiab] or 597 94 mirapex[tiab] or sifrol[tiab]))
AND
eng[la]
NOT
(“animals”[mesh] NOT “humans”[mesh])
NOT
(case report[ti] OR case reports[pt])
2 Table S2. Search terms for Embase (date searched: November 28, 2017; date updated: January
7, 2020)
Number of hits
Line Search term Nov 2017
1 *parkinson disease/ or parkinson$.ti,ab. 148037
*piribedil/ or (piribedil or et495 or et 495 or eu4200 or eu 4200 or trastal
2 or trivastal).ti,ab. 1179
*pramipexole/ or (pramipexole or snd 919$ or snd919$ or kns 760704
3 or kns760704 or mirapex or sifrol).ti,ab. 2155
4 2 or 3 3294
5 1 and 4 1588
6 5 not ((exp animal/ or nonhuman/) not exp human/) 1403
7 limit 6 to (yr="2016 -Current" and conference abstract) 49
8 limit 6 to (article or article in press or conference paper) 619
9 7 or 8 668
10 9 not (case report/ or case report.ti.) 564
11 limit 10 to english 486
12 remove duplicates from 11 474
Number of hits
Line Search term Jan 2020
1 parkinson disease’ or parkinson$.ti,ab. 153360
3 2 ‘piribedil’ or (piribedil or et495 or et 495 or eu4200 or eu 4200 or trastal 1841
or trivastal).ti,ab.
3 ‘pramipexole’ or (pramipexole or snd 919$ or snd919$ or kns 760704 or 7028
kns760704 or mirapex or sifrol).ti,ab.
4 2 or 3 8513
5 1 and 4 4758
6 ('animal'/exp OR 'nonhuman'/exp) NOT 'human'/exp 7100771
7 5 not 6 4583
8 7 and [28-11-2017]/sd not [8-1-2020]/sd 355
9 8 and ('article'/it OR 'article in press'/it or 'conference abstract'/it or 262
'conference paper'/it)
10 9 and not 'case report’ not 'case report':ti 194
11 10 and [english]/lim 191
Table S3. Search terms for Cochrane Central Register of Controlled Trials (CENTRAL) (date searched: Issue 10, October 2017; date updated: January 2020)
Line Search term Number of hits
Oct 2017 Jan 2020
1 [mh "parkinson disease'] or parkinson*:ti,ab 6095 9674
(piribedil or eu-4200 or eu4200 or et-495 or et495 or 85 90 2 trivastal or trastal):ti,ab
(pramipexole or dexpramipexol or snd919* or snd-919* 255 408 3 or kns-760704 or kns760704 or mirapex or sifrol):ti,ab
4 Line Search term Number of hits
Oct 2017 Jan 2020
4 #2 or #3 339 496
5 #1 and #4 154 235
6 #5 NOT (pubmed or embase):an 27 66
7 limit to central 15
5 Appendix B
The following study level variables were extracted:
Study design
Randomized controlled trial (RCT) (crossover, follow-up/extension, subgroup, post hoc)
Stratification type (age, gender, baseline measurements)
Allocation method
Randomization method
Blinding (single, double, open-label)
Primary and secondary endpoints
Methods to account for missing data
Study dates (database cut-off, primary analysis, secondary analysis)
Study phases
Treatment duration
Follow-up duration
Inclusion and exclusion criteria
Trial setting
Trial location
Intervention level variables:
Dosage
Route of administration
Frequency of administration
Treatment period, inclusive of titration, dose reduction, and maintenance periods
6 Concomitant therapies
Background therapies
Prior therapies
Patient level variables:
Age
Gender
Ethnicity/race
Hoehn and Yahr score
UPDRS score (either II, III or both where available)
Patient reported questionnaire scores (e.g. Beck depression inventory, Epworth
Sleepiness Scale)
Outcomes
Efficacy data, including:
o Prevention/Delay of Dyskinesia
o Motor symptoms: measured with the Unified Parkinson's Disease Rating Scale
(UPDRS)
. Total
. UPDRS II – Activities of Daily Living
. UPDRS III – Motor performance
o Prevention/Delay of Non-Motor Symptoms (including anxiety/depression,
cognitive function, restless legs syndrome)
o Exercise complications: the delayed effect of exercise complications (incidence)
Adverse events, including:
7 o Nausea
o Constipation
o Vomiting
o Sleep attack
o Insomnia
o Headache
o Impulse Control Disorder
o Hypotension
o Peripheral Edema
o Fatigue
o Dyskinesia
o Anxiety
o Depression
8 Appendix C
Table S4. Judgements on each risk of bias item
Trial Selection bias Performance Detection Attrition bias Reporting Other bias
bias bias bias
Random Allocation Blinding of Blinding of Incomplete Selective Other sources
sequence concealment participants outcome outcome data reporting of bias
generation and personnel assessment
Barone et al 201014 Low risk Low risk Low risk Low risk Low risk Low risk Unclear risk
Castro-Caldas et al 200615 Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Eggert et al. 201416 Unclear risk Unclear risk High risk Low risk Low risk Low risk Unclear risk
Holloway et al. 200419; Hauser Low risk Low risk Low risk Low risk Low risk Low risk Unclear risk
et al 200617; Hauser et al 201018
Hubble et al. 199520 Unclear risk Unclear risk Low risk Low risk Low risk Low risk Low risk
Kieburtz et al. 201121 Low risk Low risk Low risk Low risk Low risk Low risk Low risk
Navan et al. 200322 Low risk Low risk High risk Low risk Unclear risk Low risk Low risk
Olanow et al. 201723 Low risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Parkinson Study Group 199724 Low risk Low risk Low risk Low risk Low risk Low risk Unclear risk
9 Parkinson Study Group 200025 Low risk Low risk Low risk Low risk Low risk Low risk Low risk
Poewe et al. 201126 Low risk Low risk Low risk Unclear risk Low risk Low risk Low risk
Pogarell et al. 200227 Low risk Low risk Low risk Low risk Low risk Low risk Low risk
Rascol et al. 200628 Low risk Low risk Unclear risk Unclear risk Unclear risk Low risk Low risk
Rascol et al. 201029 Unclear risk Unclear risk Low risk Unclear risk Low risk Low risk Low risk
Sampaio et al. 201130 Low risk Low risk Low risk Low risk Low risk Low risk Low risk
Schapira et al. 201331 Low risk Low risk Low risk Low risk Low risk Low risk Low risk
Seiple et al 201632 Unclear risk High risk High risk Low risk Low risk Low risk Low risk
Shannon et al. 199733 Unclear risk Unclear risk Low risk Unclear risk Low risk Low risk Low risk
Thomas et al. 200634 Low risk High risk High risk Low risk Unclear risk Low risk Low risk
Viallet et al. 201335 Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Unclear risk
Wong et al. 200336 Unclear risk Unclear risk Unclear risk Unclear risk Low risk Low risk Low risk
Ziegler et al. 200337 Unclear risk Unclear risk Low risk Unclear risk Low risk Low risk Low risk
10 Appendix D
Table S5. Change in UPDRS II and III from baseline for pramipexole and placebo compared to piribedil, adjusted for dose-titration phase
Treatment (time point) Difference in UPDRS II, change Difference in UPDRS III, change
from baseline (95% CrI) from baseline (95% CrI)
Placebo (10-18 weeks) 0.60 2.21
(-0.7, 1.84) (-0.05, 4.61)
Pramipexole (10-18 weeks) -1.20 -2.46
(-2.59, 0.17) (-4.97, 0.18)
Results are presented as mean change in UPDRS score relative to piribedil, with positive
values indicating the comparator treatment increasing UPDRS score relative to piribedil.
Values in bold and with an asterisk represent statistically significant results. All analyses use a
fixed effects model.
95% CrI: 95% credible interval.
11 Appendix E
Table S6. Patient baseline characteristics for trials incorporated in analyses of UPDRS score
change
Proportion Average Average
Hoehn & baseline baseline
Mean Proportion Yahr score of UPDRS II UPDRS III
Trial age males 1 score score
Barone et al 201014 67.0 47.1 10.5 11.7 25.6
Hauser et al 201018 62.1 55.6 NR 6.8 21.7
Kieburtz et al. 201121 62.7 66.6 26.4 7.1 19.7
Poewe et al. 201126 61.6 55.5 NR 7.8 21.5
Pogarell et al. 200227 63.6 72.0 12.1 12.3 33.2
Rascol et al. 200628 62.3 60.8 27.6 6.8 15.3
Sampaio et al. 201130 62.5 64.4 39.8 NR NR
Shannon et al. 199733 62.7 60.6 NR 8.3 18.8
Wong et al. 200336 59.9 69.3 NR 10.8 26.6
Ziegler et al. 200337 64.1 59.4 NR NR 28.5
12