Skip to main content
SpringerLink
Log in

A Review of Randomized Phase III Pharmacological Clinical Trials for Motor Symptoms in Parkinson’s Disease Patients and Quality of Evidence Recommendations

  • Protocol
  • First Online:
Clinical Trials In Parkinson's Disease

Part of the book series: Neuromethods ((NM,volume 160))

  • 581 Accesses

Abstract

The phase III randomized clinical trials designed to improve movement symptomatology in initial and advanced stages of Parkinson disease are critically reviewed. This summary provides the reader with an overall clinical picture of the oral therapies that have been tested to treat motor symptoms in PD in the past decade. The responsiveness and interpretability of reported results are considered and a quality of evidence rating scale is proposed to guide the critical review of randomized clinical trials. These recommendations, along with consideration of the large placebo effect in Parkinson disease patients, will hopefully aid in the design of future clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 59.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 59.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 84.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Postuma RB, Berg D, Stern M et al (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30:1591–1601

    PubMed  Google Scholar 

  2. Fox SH, Katzenschlager R, Lim S-Y et al (2018) International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord 33(8):1248–1266

    CAS  PubMed  Google Scholar 

  3. Task Force of the Movement Disorders Society, Lang AE, Lees A (2002) Management of Parkinson’s disease: an evidence-based review. Mov Disord 17(Suppl 4):S1–S6

    Google Scholar 

  4. Castro Caldas A, Levin J, Djaldetti R et al (2017) Critical appraisal of clinical trials in multiple system atrophy: toward better quality. Mov Disord 32:1–9

    Google Scholar 

  5. Mizuno Y, Hattori N, Kondo T et al (2017) A randomized double-blind placebo-controlled phase III trial of selegiline monotherapy for early Parkinson disease. Clin Neuropharmacol 40:201–207

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Pahwa R, Stacy MA, Factor SA et al (2007) Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 68:1108–1115

    CAS  PubMed  Google Scholar 

  8. Hauser RA, Schapira AHV, Rascol O et al (2010) Randomized, double-blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson’s disease. Mov Disord 25:2542–2549

    PubMed  Google Scholar 

  9. Poewe W, Rascol O, Barone P et al (2011) Extended-release pramipexole in early Parkinson disease: a 33-week randomized controlled trial. Neurology 77:759–766

    CAS  PubMed  Google Scholar 

  10. Schapira AHV, Barone P, Hauser RA et al (2011) Extended-release pramipexole in advanced Parkinson disease: a randomized controlled trial. Neurology 77:759–766

    PubMed  Google Scholar 

  11. Mizuno Y, Yamamoto M, Kuno S et al (2012) Efficacy and safety of extended-versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial. Clin Neuropharmacol 35:174–181

    CAS  PubMed  Google Scholar 

  12. Zhang Z, Wang J, Zhang X et al (2013) The efficacy and safety of ropinirole prolonged release tablets as adjunctive therapy in Chinese subjects with advanced Parkinson’s disease: a multicenter, double-blind, randomized, placebo-controlled study. Park Relat Disord 19:1022–1026

    Google Scholar 

  13. Hauser RA, Hsu A, Kell S et al (2013) Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 12:346–356

    CAS  PubMed  Google Scholar 

  14. Stocchi F, Hsu A, Khanna S et al (2014) Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Park Relat Disord 20:1335–1340

    Google Scholar 

  15. Pahwa R, Tanner CM, Hauser RA et al (2017) ADS-5102 (Amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID study). JAMA Neurol 74:941–949

    PubMed  PubMed Central  Google Scholar 

  16. Oertel W, Eggert K, Pahwa R et al (2017) Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord 32:1701–1709

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Watts RL, Jankovic J, Waters C et al (2007) Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 68:272–276

    CAS  PubMed  Google Scholar 

  18. Schapira AHV, McDermott MP, Barone P et al (2013) Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial. Lancet Neurol 12:747–755

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Olanow CW, Rascol O, Hauser R et al (2009) A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 361:1268–1278

    CAS  PubMed  Google Scholar 

  20. Stocchi F, Borgohain R, Onofrj M et al (2012) A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson’s disease patients. Mov Disord 27:106–112

    CAS  PubMed  Google Scholar 

  21. Schapira AHV, Stocchi F, Borgohain R et al (2013) Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson’s disease. Eur J Neurol 20:271–280

    CAS  PubMed  Google Scholar 

  22. Borgohain R, Szasz J, Stanzione P et al (2014) Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord 29:1273–1280

    CAS  PubMed  Google Scholar 

  23. Schapira AHV, Fox SH, Hauser RA et al (2017) Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations. JAMA Neurol 74:216–224

    PubMed  Google Scholar 

  24. Hauser RA, Shulman LM, Trugman JM et al (2008) Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 23:2177–2185

    PubMed  Google Scholar 

  25. Mizuno Y, Hasegawa K, Kondo T et al (2010) Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord 25:1437–1443

    PubMed  Google Scholar 

  26. Pourcher E, Fernandez HH, Stacy M et al (2012) Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Park Relat Disord 18:178–184

    Google Scholar 

  27. Hauser RA, Stocchi F, Rascol O et al (2015) Preladenant as an adjunctive therapy with levodopa in Parkinson disease: two randomized clinical trials and lessons learned. JAMA Neurol 72:1491–1500

    PubMed  Google Scholar 

  28. Stocchi F, Rascol O, Hauser RA et al (2017) Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology 88:2198–2206

    CAS  PubMed  Google Scholar 

  29. Ferreira JJ, Lees A, Rocha JF et al (2016) Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol 15:154–165

    CAS  PubMed  Google Scholar 

  30. Lees AJ, Ferreira J, Rascol O et al (2017) Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations a randomized clinical trial. JAMA Neurol 74:197–206

    PubMed  Google Scholar 

  31. Lees A, Fahn S, Eggert KM et al (2012) Perampanel, an AMPA antagonist, found to have no benefit in reducing “off” time in Parkinson’s disease. Mov Disord 27:284–288

    CAS  PubMed  Google Scholar 

  32. Investigators PSGQ, Beal MF, Oakes D et al (2014) A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol 71:543–552

    Google Scholar 

  33. Postuma RB, Anang J, Pelletier A et al (2017) Caffeine as symptomatic treatment for Parkinson disease (Café-PD): a randomized trial. Neurology 89:1795–1803. https://doi.org/10.1212/WNL.0000000000004568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sedgwick P (2014) Explanatory trials versus pragmatic trials. BMJ 349:g6694

    PubMed  Google Scholar 

  35. Scientific Advisory Committee of the Medical Outcomes Trust (2002) Assessing health status and quality of life instruments: attributes and review criteria. Qual Life Res 11:193–205

    Google Scholar 

  36. Wyrwich KW, Wolinsky FD (2000) Identifying meaningful intra-individual change standards for health- related quality of life measures. J Eval Clin Pract 6:39–49

    CAS  PubMed  Google Scholar 

  37. Revicki D, Hays RD, Cella D, Sloan J (2008) Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol 61:102–109

    PubMed  Google Scholar 

  38. Beaton DE, Bombardier C, Katz JN, Wright JG (2001) A taxonomy for responsiveness. J Clin Epidemiol 54:1204–1217

    CAS  PubMed  Google Scholar 

  39. Cohen J (1988) Statistical power analysis for the behavioral sciences, 2nd edn. Erlbaum, Hillsdale, NJ

    Google Scholar 

  40. Martinez-Martin P, Reddy P, Katzenschlager R et al (2015) EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease. Mov Disord 30:510–516

    CAS  PubMed  Google Scholar 

  41. Dafsari HS, Reker P, Stalinski L et al (2018) Quality of life outcome after subthalamic stimulation in Parkinson’s disease depends on age. Mov Disord 33:99–107

    PubMed  Google Scholar 

  42. Juhász A, Deli G, Aschermann Z et al (2017) How efficient is subthalamic deep brain stimulation in reducing dyskinesia in Parkinson’s disease? Eur Neurol 77:281–287

    PubMed  Google Scholar 

  43. Mokkink LB, Terwee CB, Patrick DL et al (2010) The COSMIN study reached international consensus on taxonomy, terminology, and definitions of measurement properties for health-related patient-reported outcomes. J Clin Epidemiol 63:737–745

    PubMed  Google Scholar 

  44. Jaeschke R, Singer J, Guyatt G (1989) Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 10:407–415

    CAS  PubMed  Google Scholar 

  45. Wyrwich KW, Norquist JM, Lenderking WR, Acaster S (2013) Methods for interpreting change over time in patient-reported outcome measures. Qual Life Res 22:475–483

    CAS  PubMed  Google Scholar 

  46. Hauser RA, Gordon MF, Mizuno Y et al (2014) Minimal clinically important difference in Parkinson’s disease as assessed in pivotal trials of pramipexole extended release. Park Dis 2014:467131

    Google Scholar 

  47. Stefaniak JD, Lam TCH, Sim NE et al (2017) Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis. Eur J Neurol 24:1071–1076

    CAS  PubMed  Google Scholar 

  48. Hopewell S, Loudon K, Clarke MJ et al (2009) Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Database Syst Rev: MR000006

    Google Scholar 

  49. Richens A (2001) Proof of efficacy trials: cross-over versus parallel-group. Epilepsy Res 45:43–47

    CAS  PubMed  Google Scholar 

  50. De La Fuente-Fernández R, Schulzer M, Stoessl AJ (2004) Placebo mechanisms and reward circuitry: clues from Parkinson’s disease. Biol Psychiatry 56:67–71

    PubMed  Google Scholar 

  51. Shetty N, Friedman JH, Kieburtz K et al (1999) The placebo response in Parkinson’s disease. Parkinson Study Group. Clin Neuropharmacol 22:207–212

    CAS  PubMed  Google Scholar 

  52. Goetz CG, Leurgans S, Raman R, Stebbins GT (2000) Objective changes in motor function during placebo treatment in PD. Neurology 54:710–714

    CAS  PubMed  Google Scholar 

  53. Goetz CG, Wuu J, McDermott MP et al (2008) Placebo response in Parkinson’s disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord 23:690–699

    PubMed  Google Scholar 

  54. Goetz CG (2005) Movement disorders: understanding clinical trials. Lancet Neurol 4:5–6

    PubMed  Google Scholar 

  55. de la Fuente-Fernández R, Schulzer M, Stoessl AJ (2002) The placebo effect in neurological disorders. Lancet Neurol 1:85–91

    PubMed  Google Scholar 

  56. Mischley LK, Lau RC, Shankland EG et al (2017) Phase IIb study of intranasal glutathione in Parkinson’s disease. J Parkinsons Dis 7:289–299

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Frisaldi E, Carlino E, Zibetti M et al (2017) The placebo effect on bradykinesia in Parkinson’s disease with and without prior drug conditioning. Mov Disord 32:1474–1478

    PubMed  Google Scholar 

  58. Benedetti F, Frisaldi E, Carlino E et al (2016) Teaching neurons to respond to placebos. J Physiol 594:5647–5660

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Shin CW, Hahn S, Park BJ et al (2016) Predictors of the placebo response in clinical trials on Parkinson’s disease: a meta-analysis. Park Relat Disord 29:83–89

    Google Scholar 

  60. Hauser RA, Deckers F, Lehert P (2004) Parkinson’s disease home diary: further validation and implications for clinical trials. Mov Disord 19:1409–1413

    PubMed  Google Scholar 

  61. Hauser RA, Cantillon M, Pourcher E et al (2011) Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 10:221–229

    CAS  PubMed  Google Scholar 

  62. LeWitt PA, Guttman M, Tetrud JW et al (2008) Adenosine A 2A receptor antagonist is tradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 63:295–302

    CAS  PubMed  Google Scholar 

  63. Eggert K, Squillacote D, Barone P et al (2010) Safety and efficacy of perampanel in advanced Parkinson’s disease: a randomized, placebo-controlled study. Mov Disord 25:896–905

    PubMed  Google Scholar 

  64. Perry B, Herrington W, Goldsack JC et al (2018) Use of mobile devices to measure outcomes in clinical research, 2010–2016: a systematic literature review. Digit Biomarkers 2:11–30

    Google Scholar 

  65. Shulman LM, Gruber-Baldini AL, Anderson KE et al (2010) The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol 67:64–70

    PubMed  Google Scholar 

  66. Hauser RA, Auinger P, Parkinson Study Group (2011) Determination of minimal clinically important change in early and advanced Parkinson’s disease. Mov Disord 26:813–818

    PubMed  Google Scholar 

  67. Horváth K, Aschermann Z, Ács P et al (2015) Minimal clinically important difference on the motor examination part of MDS-UPDRS. Parkinsonism Relat Disord 21:1421–1426

    PubMed  Google Scholar 

  68. Horváth K, Aschermann Z, Kovács M et al (2017) Minimal clinically important differences for the experiences of daily living parts of movement disorder society-sponsored unified Parkinson’s disease rating scale. Mov Disord 32:789–793

    PubMed  Google Scholar 

  69. Mestre TA, Beaulieu-Boire I, Aquino CC et al (2015) What is a clinically important change in the Unified Dyskinesia Rating Scale in Parkinson’s disease? Parkinsonism Relat Disord 21:1349–1354

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Movement Disorders Unit, Neurology Department, Hospital Ruber Internacional, Madrid, Spain

    Mónica M. Kurtis & Isabel Pareés

  2. National Center of Epidemiology and CIBERNED, Institute of Health Carlos III, Madrid, Spain

    Carmen Rodriguez-Blazquez

  3. Movement Disorders Unit, Neurology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain

    Isabel Pareés

Authors
  1. Mónica M. Kurtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carmen Rodriguez-Blazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Pareés
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mónica M. Kurtis .

Editor information

Editors and Affiliations

  1. National Research Council (CAECHIS-UAI), Buenos Aires, Argentina

    Santiago Perez-Lloret

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Kurtis, M.M., Rodriguez-Blazquez, C., Pareés, I. (2021). A Review of Randomized Phase III Pharmacological Clinical Trials for Motor Symptoms in Parkinson’s Disease Patients and Quality of Evidence Recommendations. In: Perez-Lloret, S. (eds) Clinical Trials In Parkinson's Disease. Neuromethods, vol 160. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0912-5_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-0912-5_4

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0911-8

  • Online ISBN: 978-1-0716-0912-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation