Apomorphine Sublingual Film Compared with Subcutaneous Apomorphine for OFF Episodes in Parkinson's Disease: An Open-Label, Randomized, Crossover Study

Abstract

Background: Apomorphine sublingual film (SL-APO) and subcutaneous apomorphine (SC-APO) have been used for the treatment of OFF episodes in Parkinson's disease (PD). No study has prospectively compared efficacy and safety of these formulations.

Objective: To compare SL-APO with SC-APO for treatment of OFF episodes in PD.

Methods: An open-label, randomized, crossover study assessed SL-APO versus SC-APO in patients with PD and OFF episodes (N = 113). Doses were optimized in randomly assigned order. SL-APO dose initiation (10 mg) occurred in clinic; further dose optimization (15-30 mg; 5-mg increments) occurred primarily at home. SC-APO dosing (2-6 mg; 1-mg increments) occurred entirely in clinic. After a 3-7-day washout, patients were randomized 1 : 1 to 4 weeks of treatment with their optimized dose of SL-APO or SC-APO, followed by washout and 4 weeks of crossover treatment.

Results: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n = 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD.

Conclusions: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes.

Results: No difference was observed between SL-APO and SC-APO for change from predose to 90 minutes postdose in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score at week 4 (primary endpoint), assessed by a blinded rater (-13.6 vs. -13.8, respectively; p = NS). Overall, 72.2% of patients preferred SL-APO compared with SC-APO/no preference (p = 0.0002) per the Treatment Preference Questionnaire (secondary endpoint). Patients reported greater satisfaction with SL-APO compared with SC-APO, per mean scores of convenience (73.7 vs. 53.5) and global satisfaction (63.9 vs. 57.6) on the Treatment Satisfaction Questionnaire for Medication (other endpoint). The safety profiles of both treatments were generally comparable and were well-tolerated.

Conclusions: Patients reported overall preference for and greater satisfaction with SL-APO over SC-APO.

Keywords: Apomorphine sublingual film; OFF episode; Parkinson’s disease; carbidopa/levodopa; subcutaneous apomorphine.

Fig. 1

Study design. ^aPatients in a practically defined OFF received 10 mg of SL-APO in the clinic and if a FULL ON (defined as the period when medication provided benefit with regard to mobility, stiffness, and slowness and the patient having adequate motor function to perform normal daily activities) was not achieved within 30 min, up-titration (5-mg dose increases; 30-mg dose maximum) during subsequent practically defined OFF episodes could continue at home without in-person observation. If a FULL ON was achieved at home, patients returned to the clinic for a dose-confirmation visit, during which the investigator could adjust the dose, if necessary. ^bPatients in a practically defined OFF received 2 mg of SC-APO in the clinic and if a FULL ON was not achieved within 30 min, up-titration (1-mg dose increases; 6-mg dose maximum) during subsequent OFF episodes continued in the clinic. ^cPatients could administer study drug for up to 5 OFF episodes per day, with doses separated by ≥2 h. ^dTreatment Preference Questionnaire was performed at week 4 after both regimens had been completed. SC-APO, subcutaneous apomorphine; SL-APO, apomorphine sublingual film.

Fig. 2

Consort flow diagram. ^aPatients can be included in more than 1 category of ineligibility. ^bThe dose-optimization safety population was defined as all patients who received ≥1 dose of study medication in the open-label dose-optimization phase (N = 112). ^cEarly termination at sponsor request. mITT, modified intention-to-treat; SC-APO, subcutaneous apomorphine; SL-APO, apomorphine sublingual film.

Fig. 3

Change from predose in MDS-UPDRS Part III score at week 4 over time (treatment phase mITT population). Data represent MDS-UPDRS Part III scores achieved with the optimized dose of each apomorphine formulation at week 4 of the treatment phase. LS, least squares; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; mITT, modified intention-to-treat; SC-APO, subcutaneous apomorphine; SE, standard error; SL-APO, apomorphine sublingual film.

Fig. 4

Investigator- and patient-rated durability of response^a at week 4 (treatment phase mITT population). ^aDefined as patient achievement of a FULL ON within 30 min postdose and maintenance of that response at 90 min postdose. mITT, modified intention-to-treat; SC-APO, subcutaneous apomorphine; SL-APO, apomorphine sublingual film.