Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 study

Olanow, C. Warren; Factor, Stewart A.; Espay, Alberto J.; Hauser, Robert A.; Shill, Holly A.; Isaacson, Stuart; Pahwa, Rajesh; Leinonen, Mika; Bhargava, Parul; Sciarappa, Ken; Navia, Bradford; Blum, David; xx, xx

doi:10.1016/s1474-4422(19)30396-5

Cited by 89 publications

(133 citation statements)

References 27 publications

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“…In the double-blind maintenance phase, patients received their optimized dose of apomorphine sublingual film over a 12-week period and were monitored during specified office visits and through patient home dosing and response diaries [10]. Comparably, the open-label titration phase included a short treatment period (≤21 days) in a controlled clinical setting and yielded limited exposure to apomorphine sublingual film, which resulted in differences in the incidence of TEAEs observed between the open-label titration and double-blind maintenance phases.…”

Section: Discussionmentioning

confidence: 99%

“…Comparably, the open-label titration phase included a short treatment period (≤21 days) in a controlled clinical setting and yielded limited exposure to apomorphine sublingual film, which resulted in differences in the incidence of TEAEs observed between the open-label titration and double-blind maintenance phases. For example, nausea and vomiting-events commonly associated with other dopamine agonists [1]-were both reported less frequently during open-label titration (20.6% and 4.3%, respectively) than during double-blind maintenance treatment (27.8% and 7.4%, respectively) [10]. Antiemetic medication was administered concomitantly during the open-label titration phase but could be discontinued at the discretion of the investigator during the double-blind maintenance phase.…”

Section: Discussionmentioning

confidence: 99%

“…The study was a Phase 3, multicenter, randomized, placebocontrolled trial that included screening and open-label titration phases (presented herein) and double-blind treatment (previously published) [10] (Fig. S1).…”

Section: Methodsmentioning

confidence: 99%

“…The most common effective doses of apomorphine sublingual film received during titration (N = 141) were 15 mg and 20 mg (24.8% and 22.0%, respectively; Fig. S2), and 66.1% of patients (n = 109) had their dose successfully titrated with one of the first 3 apomorphine sublingual film doses administered [10]. Thirty-two patients discontinued treatment during titration: 12 (8.5%) due to TEAEs, 10 (7.1%) due to lack of efficacy because they did not achieve a FULL "ON" at any dose of apomorphine sublingual film up to 35 mg (1 additional patient discontinued at the 30-mg dose level), 8 (5.7%) withdrew consent, and 1 (0.7%) was lost to follow-up.…”

Section: Patientsmentioning

confidence: 99%

“…The efficacy and safety of apomorphine sublingual film were evaluated in a double-blind, placebo-controlled, pivotal study [10]. Apomorphine sublingual film resulted in a significant improvement in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score at week 12 (least squares mean difference from placebo, − 7.6 points; P = 0.0002) and was generally safe and well tolerated, with most side effects mild to moderate in severity [10]. The most common (≥10%) treatment-emergent adverse events (TEAEs) associated with apomorphine sublingual film reported during the double-blind maintenance phase were nausea (27.8%) and somnolence (13.0%) [10].…”

Section: Introductionmentioning

confidence: 99%

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Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

Hui

Fox

Neeson³

et al. 2020

Parkinsonism & Related Disorders

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The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of "OFF" episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. Methods: Adult patients with levodopa-responsive PD and "OFF" episodes were enrolled. In practically defined "OFF," patients were observed for a FULL "ON" after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10-35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. Results: Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL "ON" (66.1% at 10-20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). Conclusion: Among eligible patients with PD and "OFF" episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of "OFF" episodes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

Hui

Fox

Neeson³

et al. 2020

Parkinsonism & Related Disorders

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Interventions for preventing falls in Parkinson's disease

Allen

Canning

Almeida

et al. 2022

Cochrane Database of Systematic Reviews

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A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease

Stocchi

Peckham

Pandis

et al. 2022

Clinical Pharm in Drug Dev

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A randomized thorough QT study was conducted to assess the effects of apomorphine sublingual film (SL-APO) on corrected QT interval (QTc) and other cardiac conduction parameters in patients with Parkinson's disease (PD) and "OFF" episodes. Patients were titrated to an SL-APO dose that resulted in FULL "ON," followed by up to two additional doses (maximum 60 mg), then randomized at the highest tolerated dose to a treatment sequence of SL-APO, placebo, and moxifloxacin (400 mg, positive control) in a three-way crossover design. Changes from baseline in time-matched, placeboadjusted Fridericia-corrected QTc interval ( QTcF) and Bazett-corrected QTc interval ( QTcB) were analyzed from postdose electrocardiograms. Forty patients were randomized and received single doses of study treatments. Upper limits of 90% confidence intervals (CIs) for QTcF of SL-APO were below the 10-millisecond regulatory threshold at all prespecified timepoints, demonstrating no clinically significant effect on QTcF. Lower limits of 90% CIs for QTcF of moxifloxacin exceeded the 5-millisecond regulatory threshold at all timepoints up to 3 hours, confirming assay sensitivity.SL-APO had no clinically meaningful effects on QTcB,PR/QRS intervals,heart rate,or electrocardiogramderived morphology (EudraCT identifier: 2016-001762-29; ClinicalTrials.gov identifier: NCT03187301).

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Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 study

Cited by 89 publications

References 27 publications

Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

Interventions for preventing falls in Parkinson's disease

A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease

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