Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson's disease

Abstract

Background: CVT-301 (Inbrija) is a self-administered orally inhaled levodopa approved for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa. Prior studies only evaluated CVT-301 after the first ON of the day. Objective and methods: The objective of this study was to evaluate the safety and tolerability of CVT-301 for early morning OFF. Using a randomized, double-blind, 2-way crossover design, eligible patients in the morning OFF state (having not received PD medication overnight) received a single dose of CVT-301 84 mg or placebo on 2 dosing days, immediately after their first morning oral carbidopa/levodopa dose. Safety assessments included treatment-emergent adverse events, vital signs, and patient-and examiner-reported dyskinesia. An exploratory efficacy assessment was examiner-rated time-to-ON with carbidopa/levodopa + CVT-301 vs carbidopa/levodopa + placebo. Results: Of the 36 patients (mean age 62.9 years) who enrolled and completed the study, 9 (25.0%) reported treatment-emergent adverse events following CVT-301 administration; 4 (11.1%) reported treatment-emergent adverse events following placebo. The most common adverse event was cough (4 [11.1%] for CVT-301 vs 1 [2.8%] for placebo), which was typically mild and transient. Incidence of asymptomatic orthostatic hypotension (CVT-301, 6; placebo, 7) and examiner-rated dyskinesia were similar for both (36-39% mild, 3-6% moderate, and 0% severe). Median time-to-ON was 25.0 min following carbidopa/levodopa + CVT-301 and 35.5 min following carbidopa/levodopa + placebo (P = 0.26). At 30 min, more patients had turned ON following carbidopa/levodopa + CVT-301 administration (66.7%), compared with carbidopa/levodopa + placebo (44.5%) (P = 0.040). Conclusion: Single doses of CVT-301 84 mg administered with oral carbidopa/levodopa for early morning OFF symptoms were well-tolerated, with no notable safety concerns.

A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson's disease

“…On clinic pulmonary evaluations, most patients had <10% change from pre-dose values and tolerated exposure well. TEAEs were generally consistent with those for oral LD except for cough, an expected side-effect with dry powder inhalation, previously reported with CVT-301 [6,10]. Most cough AEs were mild, and all resolved by end of study (although one patient was lost to follow-up).…”

“…Patients were instructed to avoid using CVT-301 for their early morning OFF period prior to their oral CD/LD dose because CD levels in the morning would be low. This was investigated in another study [10] which assessed the safety of CVT-301 when given for morning OFF, after which patients were permitted to take it for early morning OFF. Therefore, for much of the time, the mean number of daily OFF periods that patients were allowed to treat with CVT-301 in the study (which excluded morning OFF) was approximately 2.5 OFF periods daily.…”

“…Initially, the drug could not be used for treatment of early morning OFF periods (ie, for morning akinesia before the first ON period of the day). However, after data from another study [10] became available supporting the safety and tolerability of CVT-301 administration in the early morning, participants were permitted to take CVT-301 with their first morning CD/LD dose for treating initial OFF periods during the remainder of the study. Patients were instructed not to take CVT-301 within 45 min after a previous dose of standard oral PD medication.…”

Medical Management and Prevention of Motor Complications in Parkinson's Disease

“…However, in a study randomizing patients to either a single dose of 84 mg inhaled levodopa or placebo immediately following their first morning dose of oral carbidopa/ levodopa, there were no apparent increases in treatmentrelated adverse events including symptomatic orthostatic hypotension, nausea, or dyskinesia. An exploratory efficacy assessment found that median time-to-ON was 25.0 min following oral CD-LD IR+ inhaled levodopa versus 35.5 min following oral CD-LD IR+ inhaled placebo [66].…”

A Stage-Based Approach to Therapy in Parkinson’s Disease

“…ND062L is a transcutaneous formulation of l -dopa/carbidopa in a patch-pump device [177]. CVT-301 is a l -dopa inhalation, used as a “rescue” therapy for sudden off: a single dose of 84 mg, administered in association with oral l -dopa/carbidopa, for early morning off symptoms seems to be well-tolerated and effective [178,179]. A randomized controlled trial (RCT) has shown that Levodopa-carbidopa intestinal gel (LCIG), administered by continuous intra-intestinal infusion (Duodopa ® ), was more effective than oral l -dopa regarding motor fluctuations.…”