Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Henderson EJ, Lord SR, Brodie MA, et al. Rivastigmine for gait stability in patients with Parkinson s disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016; published online Jan 12. http://dx.doi.org/10.1016/s1474-4422(15)00389-0.
Supplementary Appendix 1: Secondary outcome measures Measure Falls and gait measures Description Falls A fall was defined as an unexpected event in which participants come to rest on the ground, floor, or lower level. 1 Data were collected prospectively in diaries and returned monthly, via post. Missing information was rectified via telephone. Physiological falls risk The Physiological Profile Assessment (PPA) consists of five measures of performance including (1) visual contrast sensitivity, (2) proprioception, (3) quadriceps muscle strength, (4) hand reaction time and (5) postural sway. 2 The five PPA components are weighted to compute a composite PPA fall risk score in z score units with higher scores indicating greater falls risk. The PPA was undertaken to understand other factors that may contribute falls risk outside of those typically assessed for PD patients specifically. Visual contrast sensitivity is assessed using the Melbourne Edge Test. The chart has 20 circular patches containing edges with reducing contrast with variable orientation as the identifying feature. Correct identification of the orientation of the edge on the patches provides a measure of contrast sensitivity in decibel units, where 1 db = 10 log10 contrast. Proprioception is measured using a lower-limb matching test, where difference in matching the great toes in degrees is recorded using a vertical clear acrylic sheet inscribed with a protractor and placed between the legs. Quadriceps muscle strength (isometric) in kilograms is examined in the dominant leg using a spring gauge while participants are seated with the hip and the knee joint at 90 of flexion. Simple reaction time in milliseconds is assessed using a light as a stimuli and a finger-depression of a switch as the response. Postural sway (total sway path in millimetres) is assessed using a sway-meter that measures the displacement of the body at waist level while participants stand for 30 seconds on a foam rubber mat with eyes open. Where participants were physically unable to complete the component tests the following scores were used. Proprioception and/ or muscle strength testing: worse score of all participants. Sway: mean +3SD. Participants who scored greater than mean +3SD s for sway were capped so as not to be disadvantaged. Controlled leaning balance Fear of Falling Controlled leaning balance was assessed with the coordinated stability test which requires participants to accurately adjust their position in a steady and coordinated manner when their centre of mass is near the limits of their base of support. 2 In this trial scores ranged from 0 to 79 with higher scores indicating poorer leaning balance. As these data were highly skewed and could not be transformed to meet the assumptions of normality, outcome scores were converted to an ordinally-scaled variable with 4 categories. The Short Form Iconographical Falls Efficacy Scale assesses fear of falling in 10 scenarios presented pictorially. 3 Response is graded on an ordinal 4 point scale from 1: not concerned about falling to 4: very concerned. Total score range 10-40 with higher scores indicating greater fear of falling.
Cognitive measures General cognition Executive function Mood Measured as the total Montreal Cognitive Assessment (MoCA). 4 Scored on a 30 point ordinal scale, range 0-30 with higher scores indicating less impairment. Measured using Frontal Assessment Battery (FAB). 5 Scored on an 18- point ordinal scale with higher scores indicating more severe impairment. Measured using the 15-item Geriatric Depression Score, a 15-point ordinal scale, range 0-15, with higher values indicating more severe depression. 6 Everyday Cognitive failures Measured using the Cognitive Failures Questionnaire, which assesses perceptual, memory and action lapses in day-to day life. Scores range from 0-100 with higher scores indicating greater cognitive failure. 7 Disease measures Parkinson s disease severity Levodopa equivalent dose Freezing of gait Quality of Life Total score from Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). 8 Consists of 65 items divided into four parts: I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Total score range 0-260, with higher values indicating greater disease severity. Comprehensive drug history was obtained including dose, frequency and route of all medications. The total levodopa equivalent dose in milligrams was calculated according to Tomlinson and colleagues for all PD related medications. 9 As these data were highly skewed and could not be transformed to meet the assumptions of normality, total dose was converted to an ordinally-scaled variable with 4 categories: Very Low <550mg/day; Moderate 551 to 889mg/day; High 900 to 1244mg/day; Very high 1255mg/day. Freezing of gait in the past month is derived from Question 1 of the New Freezing of Gait Questionnaire (N-FOGQ): Did you experience freezing of gait episode over the past month 10 with categorical responses coded as either yes =1 or no. The New Freezing of Gait Questionnaire assesses the duration, frequency and impact of freezing. Total score ranges from 0 to 28, with higher scores representing worse freezing. Total scores are presented only for participants who reported having experienced a freeze in the past month. Measured using the EQ-5D-5L which consists 2 parts, a visual analogue scale and 5 dimension of quality of life. The Visual Analogue Score, ranges from 0-100 with higher scores indicating better health. The 5 dimensions of quality of life are assessed on a 5 level ordinal scale from which an index score is derived using Office of Health Economics UK value set. Index scores range from -0 594 to 1 000 with higher index score indicating better quality of life. 11
Supplementary Appendix 2: Baseline categories The table below presents the categorised baseline data for coordinated stability and levodopa equivalent dose. Table 2a. Baseline categorised coordinated stability scores Category Score range Rivastigmine Placebo Low (good performance) 0 9 15/62 6/63 Medium 10 17 18/62 17/63 High 18 27 15/62 15/63 Very high (poor performance) 28 14/62 25/63 Table 2b. Baseline categorised coordinated stability scores Category Score range Rivastigmine Placebo Very low <500mg/day 27/65 9/65 Low 551mg 889mg/day 14/65 19/65 Moderate 900mg 1244mg/day 15/65 18/65 High 1245mg/day 9/65 19/65
Supplementary Appendix 3: Sensitivity Analyses 3a. To assess the sensitivity of the primary analysis the multiple linear model was repeated using a multiple imputed dataset. Table 3a. Primary analysis with intention-to-treat and multiple imputed datasets ITT Analysis Sensitivity analysis with MI Adjusted GMR (95% CI) p value Adjusted GMR (95% CI) p value Condition Normal walk 0 72 (0 58 0 88) 0 002 0 77 (0 61 0 97) 0 03 Simple cognitive task 0 79 (0 62 0 99) 0 05 0 84 (0 65 1 07) 0 15 Complex cognitive task 0 81 (0 60 1 09) 0 17 0 82 (0 61 1 10) 0 19 ITT: Intention to Treat. GMR: Geometric Mean Ratio. MI: Multiple Imputation. CI: Confidence Interval This sensitivity analysis did not qualitatively change the interpretation of results but rendered more conservative point estimates of effect. 3b. The primary analysis was repeated adjusting for levodopa equivalent dose and gender which were, by chance, imbalanced at baseline. Table 3a. Primary analysis with repeated analysis adjusted for levodopa equivalence and gender Condition ITT Analysis Sensitivity analysis adjusting for LED and gender Adjusted GMR (95% CI) p value Adjusted GMR (95% CI) p value Normal walk 0 72 (0 58 0 88) 0 002 0 71 (0.57 0.88 0 002 Simple cognitive task 0 79 (0 62 0 99) 0 05 0 78 (0.61 0.99) 0 04 Complex cognitive task 0 81 (0 60 1 09) 0 17 0 80 (0.59 1.09) 0 15 ITT: Intention to Treat. GMR: Geometric Mean Ratio. CI: Confidence Interval LED: Levodopa equivalent dose. This sensitivity analysis did not qualitatively change the interpretation of results but rendered more precise estimates of effect. 3c. The primary falls analysis using negative binomial regression excluded one participant who was an extreme outlier. A sensitivity analysis was therefore undertaken using multinomial logistic regression, which included the extreme outlier. Fall rate was categorised into quantiles: low, 0-0 262 falls per month; intermediate, 0 263-0 661 falls per month; high, 0 662-2 03 falls per month, or very high, >2 04 falls per month. The extreme outlier was therefore now included in the very high category. Table 3c. Falls sensitivity analysis using multinomial logistic regression Fall category RRR (95% CI) p value Low falls Referent Intermediate falls 0 91 (0 28 2 96) 0 88 High falls 0 18 (0 05 0 63) 0 007 Very high falls 0 17 (0 04 0 72) 0 02 RRR: Relative risk ratio. CI: Confidence Interval
The multinomial logistic regression supports the negative binomial regression model showing that rivastigmine treatment is associated with a reduction in the risk of being in the intermediate /high/ very high falls category compared to the low fall rate category. 3d. The primary falls analysis using negative binomial regression excluded one participant who was an extreme outlier. A further sensitivity analysis was undertaken assigning this participant an arbitrary high but not extreme value (=number of falls +1 of next highest participant in that group) and the analysis repeated using negative binomial regression. Table 3d. Falls sensitivity analysis assigning outlier next highest value +1 using negative binomial regression Unadjusted incident rate ratio between groups (95% CI) Adjusted incident rate ratio between groups (95% CI) p value Primary Falls Analysis 0 60 (0 37 0 96) 0 55 (0 38 0 81) 0 002 Sensitivity Analysis 0.67 (0.41 1.09) 0 58 (0 40 0 0.85) 0 005 Adjusted for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, previous falls categorised as (1, 2-3, 4-6, 7-19, 20+). In this sensitivity analysis, treatment with rivastigmine is associated with a 42% (95%CI 60% 15%) reduction in falls. This is slightly attenuated compared with the primary analysis, which demonstrated a 45% reduction. The overall interpretation of the findings in respect to falls is unchanged.
Supplementary Appendix 4: Serious Adverse Events Table 4a Serious Adverse Events by System Organ Class (including falls) Placebo Rivastigmine Participants (%) Events Participants (%) Events Cardiac disorders Angina pectoris Endocrine disorders Thyroid disorder Gastrointestinal disorders* Abdominal pain Infections and infestations Peritonitis Urinary Tract Infections Injury, poisoning and procedural complications Fall Investigations Biopsy of cervix Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Neoplasm Malignant Pancreatic Cancer Metastatic Nervous system disorders Parkinsonism Transient Ischaemic Attack Surgical and Medical Procedures Foot operation Hernia repair Limb operation TOTAL 0 (0 0) 0 2 (3 5) 2 4 (6 2) 6 5 (7 7) 5 4 (6 2) 6 5 (7 7) 5 1 (1 5) 1 1 (1 5) 1 2 (3 1) 2 3 (4 6) 3 1 (1 5) 1 3 (4 6) 3 1 (1 5) 1 2 (3 1) 2 11 13 14 14 Parkinsonism represents worsening of pre-existing Parkinsonism symptoms
Overall, 27 Serious Adverse Events (SAE s) occurred. 14/27 (52%) occurred in the rivastigmine arm of which only two were assessed as being probably or definitely related to the treatment, both of which were worsening of Parkinsonism. 13/27 (48%) SAE s occurred in the placebo arm, none of which were probably or definitely related to the placebo medication.
Appendix references 1 Lamb SE, Jørstad-Stein EC, Hauer K, Becker C. Development of a common outcome data set for fall injury prevention trials: the Prevention of Falls Network Europe consensus. J Am Geriatr Soc 2005; 53: 1618 22. 2 Lord S, Menz H, Tiedemann A. A physiological profile approach to falls risk assessment and prevention. Phys Ther 2003; 83: 237 52. 3 Delbaere K, Smith ST, Lord SR. Development and initial validation of the Iconographical Falls Efficacy Scale. J Gerontol A Biol Sci Med Sci 2011; 66: 674 80. 4 Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology 2010; 75: 1717 25. 5 Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB A frontal assessment battery at bedside. Neurology 2000; 55: 1621 6. 6 Meara J, Mitchelmore E, Hobson P. GDS-15 geriatric depression scale as a screening instrument for depressive symptomatology in patients with Parkinson s disease and their carers in the community. Age Ageing 1999; 28: 35 8. 7 Broadbent DE, Cooper PF, FitzGerald P, Parkes KR. The Cognitive Failures Questionnaire (CFQ) and its correlates. Br J Clin Psychol 1982; 21: 1 16. 8 Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23: 2129 70. 9 Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson s disease. Mov Disord 2010; 25: 2649 53. 10 Nieuwboer A, Rochester L, Herman T, et al. Reliability of the new freezing of gait questionnaire: agreement between patients with Parkinson s disease and their carers. Gait Posture 2009; 30: 459 63. 11 Office of Health Economics. An EQ-5D-5L Value Set for England. https://www.ohe.org/news/oheseminar-launches-eq-5d-5l-value-set-england (accessed July 16, 2015).