Dopamine D1agonist effects in late-stage Parkinson’s disease

A bstract Background Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. Objective Explore if a D 1/5 dopamine agonist will have efficacy in LsPD that will be detected most sensitively by caregivers in a phase I study. Methods A double-blind controlled phase Ia/b study compared the D 1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Throughout the study, caregivers were with the patients. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2 and 3). Clinicians and caregivers completed clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Results Neither traditional scales, nor clinician impression of change, detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and engagement. Conclusion D 1/5 agonists may offer potential benefit for LsPD patients. Caregiver perspectives with mixed method analyses may overcome limitations in standard rater/clinician-based evaluations. Further studies are warranted and need to integrate caregiver input as an essential component of outcome evaluations. Trial Registration# ClinicalTrials.gov: NCT03665454