Version 1.1 added assessment of Freezing of Gait (FOG) using the FOG-Q for subjects with PD, PDD, and DLB.

UK Version 2.0 added exclusion criterion #11 for known hypersentitivity to Spiropent (clenbuterol), Corgard (nadolol) or intolerance to lactose, and added the exclusion criterion for females who were breastfeeding. This amendment added the Columbia Suicide Severity Rating Scale (C-SSRS), including revising exclusion criterion #15 to specify suicidal ideation with actual intent or plan (“Yes” answer on the C-SSRS ideation items 4 or 5).

UK Version 3.0 deleted use of the BioStamp digital device for activity tracking. A separate AUS/NZ version of the protocol was generated when Australian and New Zealand sites were initiated. The major difference was that AUS/NZ versions included the Sustained Attention Response Task (SART) and the BioStamp activity assessment whereas the UK/EU versions did not.

UK Version 4.0 (Amendment 4) and AUS/NZ Version 3.0 (Amendment 3) added neuromelanin-sensitive MRI as an optional procedure based on imaging capabilities) for an added exploratory objective to characterize locus coeruleus volume and contrast ratio.

UK Version 5.0 (Amendment 5) and AUS/NZ Version 4.0 (Amendment 4) added the verbal fluency test (alphabet and category) and added the Stop Signal Task to the CANTAB assessments. The UK version, but not the AUS/NZ version, deleted the SART.

UK/EU Version 6.0 (Amendment 6) and AUS/NZ Version 5.0 (Amendment 5) included 3 main changes to the protocol. • HADS was deleted as an inclusion criterion but kept as an outcome measure. HADS led to a high screen failure rate. The criterion was intended to select subjects with a score cutoff of very mild depression but it was found that the FERT was sensitive even in subjects who did not have depressed mood so the criterion was not necessary. • APOE4 genotyping was added as an exploratory endpoint. The epsilon4 allele of the apolipoprotein E gene (APOE4) has been consistently associated with cognitive function in Alzheimer’s disease and recently has also been found to be an important predictor of cognitive function in Parkinson’s disease across multiple domains. Therefore, it would be important to ascertain whether the subjects in the study carry this allele as it is an important covariate to consider in the cognition data analysis. • The amendment allowed for the washout period between Treatment Periods 1 and 2 to be extended with Medical Monitor approval to accommodate holiday closure schedules at the clinical study centers as well as to accommodate subject availability.

UK/EU Version 7.0 (Amendment 7) and AUS/NZ Version 6.0 (Amendment 6) were the final protocol versions and included 2 main changes: • Exclusion criterion #9 for subjects with a calculated creatinine clearance of ≤70 mL/min according to the Cockcroft-Gault equation was updated to ≤60 mL/min. A substantial number of potential patients in the study were older than 60 years of age and therefore were expected to have a GFR in the range of 60 to 70 mL/min so the criterion was modified to take that into account. This exclusion criterion was intended to ensure that patients who were medically ill with poor renal function were excluded from the trial. Subjects who were deemed to have normal to mildly impaired renal function based on either physical examination and/or laboratory values were eligible if their eGFR values were age-appropriate and not below 60 mL/min. • Wording was revised to clarify that the inclusion/exclusion criteria were to be evaluated only at Screening, Lead-In, and pre-dose on Day 1 of Treatment Period 1 (and not re-evaluated pre-dose on Day 1 of Treatment Period 2).