Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial

LeWitt, Peter A.; Hauser, Robert A.; Pahwa, Rajesh; Isaacson, Stuart; Fernández, Hubert H.; Lew, Mark F.; Saint‐Hilaire, Marie; Pourcher, Emmanuelle; López-Manzanares, Lydia; Waters, Cheryl; Rudzińska, Monika; Sedkov, Alexander; Batycky, Richard; Oh, Charles

doi:10.1016/s1474-4422(18)30405-8

Cited by 89 publications

(82 citation statements)

References 16 publications

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“…Nonetheless, an improvement in motor function was documented in patients with Parkinson's disease using CVT-301 at 84 mg/dose in a pivotal Phase III study. 11…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease

Safirstein¹,

Ellenbogen

Zhao

et al. 2020

Clinical Therapeutics

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Purpose: Levodopa (LD) is the most effective oral pharmacotherapy for the management of motor symptoms in Parkinson's disease. However, LD use is complicated by a progressive shortening of the duration of efficacy of a dose, resulting in episodes of inadequate responsiveness, or OFF periods. OFF periods may also occur unpredictably, partly due to the pharmacokinetic (PK) variability of oral LD, resulting from gastrointestinal dysfunction and from the effects of food on absorption. CVT-301 is a levodopa inhalation powder for the treatment of OFF period symptoms in patients on oral dopadecarboxylase inhibitor/LD. PK and safety profiles of single dose CVT-301, administered with oral carbidopa (CD) and oral CD/LD, were examined in patients with Parkinson's disease in the fed state. Methods: Eligible patients were aged 30e85 years, with a clinical diagnosis of Parkinson's disease and a body mass index of 18e32 kg/m 2 , and were receiving treatment with a stable regimen that included oral CD/ LD (25/100 mg) (total LD, 800 mg/d). A high-fat/ protein meal was eaten 4e5 h after the administration of the morning oral CD/LD dose. Blood samples for predose PK analysis were obtained after the meal, followed by a single inhaled dose of CVT-301 84 mg (+25 mg of oral CD) or oral CD/LD (25/100 mg) or vice versa in 2 dosing periods in a crossover design. Blood was sampled at 0, 5, 10, 15, 30, and 45 min and at 1, 1.5, 2, 3, and 4 h postdose. Tolerability assessments included treatment-emergent adverse events. Findings: Twenty-three patients were enrolled (65.2% male; 87.0% white; mean age, 69.3 years; mean body mass index, 26.9 kg/m 2 ; mean Parkinson's disease duration, 8.2 years; mean baseline LD dosage, 460.9 mg/ d; 73.9% at Hoehn and Yahr stage <2.5). PK analyses were based on LD concentrations without baseline adjustment. Median T max values with CVT-301 and oral CD/LD were 15 and 120 min (P < 0.001). C max with CVT-301 was lower than with oral CD/LD (590.3 vs 844.3 ng/mL). C 10min and C 30min values with CVT-301 were approximately twice those with CD/LD (522.9 and 531.5 ng/mL vs 247.3 and 300.9 ng/mL, respectively). %CV for C 5min to C max with CVT-301 was lower than that with oral CD/LD. The most common treatmentemergent adverse event was cough (CVT-301, 7 patients [30.4%]; oral CD/LD, 1 patient [4.5%]). Implications: PK properties showed that CVT-301 was more rapidly absorbed, with higher plasma LD concentrations in the first 45 min, and demonstrated lower interpatient variability, than was oral CD/LD in the fed condition. The study findings suggest that CVT-301 can be used without regard to food intake. ClinicalTrials.gov identifier: NCT03887884.

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“…Nonetheless, an improvement in motor function was documented in patients with Parkinson's disease using CVT-301 at 84 mg/dose in a pivotal Phase III study. 11…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease

Safirstein¹,

Ellenbogen

Zhao

et al. 2020

Clinical Therapeutics

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“…Home diaries did not show significant differences in OFF time between inhaled levodopa and placebo at 12 weeks, although patients did not administer medication as often as allowed. Patients reported 3.5 OFF periods per day at baseline but only administered inhaled levodopa 84 mg approximately twice daily despite being allowed up to 5 administrations per day [65].…”

Section: Orally Inhaled Levodopamentioning

confidence: 99%

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

Aradi

Hauser

2020

Neurotherapeutics

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Levodopa is the most effective medication for the treatment of the motor symptoms of Parkinson's disease. However, over time, the clinical response to levodopa becomes complicated by a reduction in the duration and reliability of motor improvement (motor fluctuations) and the emergence of involuntary movements (levodopa-induced dyskinesia). Strategies that have been attempted in an effort to delay the development of these motor complications include levodopa sparing and continuous dopaminergic therapy. Once motor complications occur, a wide array of medical treatments is available to maximize motor function through the day while limiting dyskinesia. Here, we review the clinical features, epidemiology, and risk factors for the development of motor complications, as well as strategies for their prevention and medical management.

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“…CVT-301 bypasses the gastrointestinal tract and enters the circulatory system rapidly and predictably [13,14]. In a crossover study in patients with PD, plasma LD concentrations increased more rapidly after CVT-301 inhalation and with less variability in concentration than after oral CD/LD dosing, and in a pivotal phase 3 study it met the primary endpoint, improving the change in UPDRS-III score at 30 min post-dose compared with placebo at week 12, when administered during an OFF period [15]. The adverse events (AEs) and safety profile of CVT-301 were consistent with earlier studies [13,14].…”

Section: Introductionmentioning

confidence: 99%

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

Hauser

Isaacson

Ellenbogen

et al. 2019

Parkinsonism & Related Disorders

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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.

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Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial

Cited by 89 publications

References 16 publications

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease

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

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

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