Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy
Authors: Richard Gray, Smitaa Patel, Natalie Ives, Caroline Rick, Rebecca Woolley, Sharon Muzerengi, Alastair Gray, Crispin Jenkinson, Emma McIntosh, Keith Wheatley, Adrian Williams, C. E. Clarke, Keith Young, Helen Price, Jon Price, Anne Lambert, Robin Reeve, Martin Sewell, Sally Broome, Adrian Williams, Mary Baker, Carl Clarke, Ray Fitzpatrick, Alastair Gray, Richard Greenhall, Crispin Jenkinson, David Mant, Emma McIntosh, Peter Sandercock, Colin Baugent, Peter Crome, Pui Au, Thomas Boodell, Versha Cheed Cheed, Jane Daniels, Francis Dowling, Lorraine Evans, Robert Hawker, Surinder Kaur, Caroline Rick, Keith Wheatley, Neil Winkles, David Hingley, Lauren Sturdy, Rebecca Wooley, Ryan Ottridge, Lisa Peto, Nicholas Hilken, Carl Counsell, L. Caie, R. Caslake, Richard Coleman, P. Crowley, L. Gerrie, J. Gordon, C. Harris, V. Leslie, M.A. MacLeod, K. Taylor, Paul Worth, R.A. Barker, Duncan Forsyth, M. Halls, J. Young, Wendy Phillips, Mark Manford, N. Thangarajah, Debbie Blake, Richard Prescott, P. Carr, L. Cochrane, A. Rose, Andrew McLaren, M. Drover, P. Karunaratne, Amanda Eady, Magdalena Wislocka-Kryjak, N. Ghaus, A. Grueger, B. Mallinson, G. Wihl, S. Ballantyne, S. Hutchinson, Alistair Lewthwaite, David Nicholl, A. Ritch, S. Coyle, R. Hornabrook, H. Irfan, S. Poxon, Uma Nath, J. Davison, S. Dodds, G. Robinson, C. Gray, Peter Fletcher, P. Morrow, M. Sliva, E. Folkes, A. Gilbert, H. Hayes, E. Burrows, Shona Donaldson, J. Lawrence, G. Rhind, G. Baxter, J. Bell, J. Gorman, Sunku Guptha, C. Noble, John Hindle, S. Jones, P. Ohri, R. Subashchandran, E. Roberts, Jason Raw, U. Wadhwa, L. Aspden, L. Partington, H. Vanek, Alan Whone, Ronald Barber, Beverly Haywood, Peter Heywood, Helen Lewis, Karen O'Sullivan, K. Prout, Liz Whelan, Pippa Medcalf, M Sliva, G. Fuller, P. Morrish, Emma Wales, J. Dalziel, P. Overstall, K. Bouifraden, Caroline Evans, G. Ward, P. Matheson, Timothy Lockington, A. Graham, S.F.M. Grimmer, L.J. Sheehan, H. Williams, Irene Hubbard, R. Walters, R. Glasspool, Peter Critchley, R. Abbott, B. Kendall, M. Lawden, N. Lo, Y. Rajaally, B. Simpson, J. Martey, L. Goodwin Wray, M. Omar, Avinash Sharma, A. Gale, D. Phirii, L. Sekaran, S. Wijayasiri, Monty Silverdale, D. Walker, H. Fleary, A. Monaghan, Viswanathan Senthil, S. Reynolds, M. S. Chong, D. Diem, B. Kundu, D. Arnold, N. Quinn, H. Benamer, J. Billings, R. Corston, D. D'Costa, M. Green, J. Shuri, J.M. Noble, T. Cassidy, A. Gani, R. Lawson, Alagaratnam Nirubin, J. Cochius, D. Dick, M. Lee, B. Payne, M. Roche, K. Sabanathan, S. Shields, M. Hipperson, F. Reading, Julia Saunders, G. Harper, W. Honan, L. Gill, J. Stanley, Nathan Vernon, A. Skinner, P. McCann, Richard Walker, P. Edmonds, S. O'Hanlon, Brian Wood, A. Hand, L. Robinson, Jane Liddle, D. Bolam, Sandip Raha, Louise Ebebezer, S. Thompson, H. Pall, P. Praamstra, Rose Crouch, Karen Healy, M. Johnson, Michael Jenkinson, A. Abdel-Hafiz, F. Al-Modaris, S. Dutta, T. Mallik, B. Mondal, J. Roberts, S. Sinha, Khaled Amar, S. Atkins, G. Devadason, A. Martin, C. Cox, Timothy Malone, G. Fenwick, K. Gormley, N. Gutowski, S. Harris, T. Harrower, A. Hemsley, M. James, M.O. Jeffreys, Vaughn Pearce, Raymond Sheridan, J. Sword, A. Zeman, C. Soper, Joseph Vassallo, J. Bennett, Veronica Lyell, D. Robertson, D. Howcroft, K. Mugweni, A. Stephens, E. Whelan, A. Wright, J. Chamberlain, Diran Padiachy, J. Marigold, J. Lee, Helen Roberts, J. Adams, J. Dulay, S. Evans, J. Frankel, R. Gove, G. Turner, N. Mallik, Tracey McElwaine, S. Morgan, H. Phipps, V. Pressly, V. Queen, R. Tan, Donald Grossett, G. Macphee, Carol Vennard, Irena Rektorova, Zahid Dhakam, G. Carey, B. Castledon, C. Sunderland, E. Kalcantera, C. Long, B. Mandal, V. Martin, R. Nari, V. Nicholas, Virginia Moffitt, S. Hammans, M. Rice-Oxley, Julie Webb, S. Franks, Simon Cooper, M. Hussain, T. Solanki, W. Darch, J. Homan, D. Sharratt, Gareth Griggs, G. Kendall, A. Ford, K. Stocker, Lucy Strens, A. Grubneac, J. Ponsford, L. Teare, Austen Peter Moore, I. O'Brien, D. Watling, L. Wyatt, Syed Rizvi, Elaine Walker, G. Berry, N. Russell, Khalid Rashed, K. Baker, M.R. Qadiri, C. Buckley, S. Bulley, D. Gibbons, R. Goodland, P. Heywood, L. Jones, L. Martin, R. Rowland-Axe, A. Stone, M.R. Whittuck
Journal: JAMA Neurology (2021)

Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy.To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD.This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020.Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor.Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach.Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar.In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy.isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.