Inhaled Levodopa (CVT-301) for the Treatment of Parkinson Disease

Abstract

Purpose of Review

To investigate the efficacy and safety of CVT-301 in treating motor fluctuation in patients with Parkinson disease (PD).

Recent Findings

This study demonstrated that the CVT-301 group had a higher proportion of patients achieving an ON state than the placebo group (odds ratio [OR] = 2.68; 95% confidence interval [CI]: 1.86–3.86; p < 0.00001). Moreover, CVT-301 had also shown to improve motor function by Unified Parkinson Disease Rating Scale part III score (standardized mean difference = 3.83; 95% CI: 2.44–5.23; p < 0.00001) and promote an overall improvement of PD by Patient Global Impression of Change self-rating (OR = 2.95; 95% CI: 1.78–4.9; p < 0.00001). The most common adverse events encountered were respiratory symptoms (OR = 12.18; 95% CI: 5.01–29.62; p < 0.00001) and nausea (OR = 3.95; 95% CI: 1.01–15.41; p = 0.05).

Summary

CVT-301 had the potential to be an alternative or even a preferred treatment for motor fluctuation in patients with PD.

After 50 years of clinical use, levodopa remains the most effective agent in the treatment of Parkinson disease (PD).^1,2 As the disease progresses, the efficacy of oral levodopa becomes less consistent and its therapeutic window begins to narrow, causing unpredictable motor fluctuations known as ON-OFF phenomenon.³ Motor fluctuation between doses of oral levodopa affected 39%–48% of patients with PD within 2 years of levodopa use, increased to 82% after 6 years, and can severely interfere with the patient's quality of life.^4,5 Treating OFF periods by adjusting levodopa dose intervals, adding adjunctive drugs (e.g., intrajejunal percutaneous infusion of levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine, catechol-O-methyltransferase, and monoamine oxidase B inhibitors), and using sustained-release formulation of oral levodopa have not been effective to resolve these problems.^6,7 The only drug approved and recommended by an expert consensus group for this indication is subcutaneous apomorphine injection.⁸ However, patients may find difficulty in self-administering the drug because it is not easy to assemble and inject apomorphine during their OFF states. Another limitation is the complex initial titration schedule and requirement of antiemetic drug premedication because apomorphine is a strong emetic and frequently causes nausea and vomiting.^9,10 A noninvasive and well-tolerated treatment to address motor fluctuations is still an unmet need for many patients with PD. CVT-301 is a novel inhalation powder consisting of levodopa and administered by oral inhalation using a passive breath-actuated delivery system.¹¹ This drug has undergone extensive clinical trials and was approved by the Food and Drug Administration in 2018 for the intermittent treatment of OFF periods in patients with PD.¹² In several randomized controlled trials (RCTs), CVT-301 has consistently demonstrated its effectiveness in treating OFF periods and improving motor symptoms in patients with PD.^13-17 It also did not noticeably affect the pulmonary function and was generally well tolerated in patients with PD.^18,19 In contrast to oral levodopa, CVT-301 provides a faster therapeutic onset in patients with PD because it is rapidly absorbed into the lung epithelium and directly transported to the CNS.¹⁷ Based on these findings, it can be postulated that CVT-301 has the potential not only to become an alternative therapy but also as a preferred drug for OFF period treatment in patients with PD. However, there is still limited evidence, and no clear consensus has been reached on the efficacy and safety of CVT-301. Hence, we performed a meta-analysis and trial sequential analysis of RCTs to evaluate the efficacy and safety of CVT-301 in treating motor fluctuation in patients with PD.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

This study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria.²⁰ Because this study did not directly involve human participants, while using only data from published articles, institutional review board approval was not required. The protocol used in this study had been registered and approved by the International Prospective Register of Systematic Reviews (CRD42021237829).

Eligibility Criteria

Type of Study

Only RCTs were included in the study. Reviews, book sections, conference papers, letters to editor, correspondences, case reports/series, and observational studies were excluded. Papers with unavailable full text were also omitted.

Population

Patients diagnosed with PD were included in this study. There were no restrictions on age, races, occupation, economy or social status, religion, country, underlying conditions, etc.

Intervention

Studies evaluating CVT-301 for the treatment of PD were included.

Comparison

Patients treated with placebo and/or standard-of-care treatment were used as comparators.

Outcome

Outcomes of interest were efficacy and safety of CVT-301 for the treatment of PD. The efficacy assessment included the changes of the mean Unified Parkinson Disease Rating Scale part III (UPDRS-III) score²¹ from predose to postdose of interventions, the overall improvement of disease in patients with PD assessed using the Patient Global Impression of Change (PGIC) self-rating scale,²² and the occurrence of an ON state during the 60-minute postdose. An “ON state” was defined as the time when medication is providing alleviation of all PD symptoms. The ON state was measured by Hauser home PD diary.²³ PGIC was used to measure the patient's belief about the efficacy of treatment. It consisted of a 7-point Likert scale ranging from 1 (very much worse) to 7 (very much improved). Safety assessment included the incidence of any adverse events reported during treatment with CVT-301.

Search Strategy and Study Selection

Literature search was conducted using multiple electronic databases, such as PubMed, ScienceDirect, EBSCO, and ProQuest until March 1, 2021. No time and language restrictions were applied. The search was performed by 4 independent reviewers (G.G., T.H., J.B., and G.M.) using keywords (((“CVT-301” OR “inhaled levodopa”) AND (“parkinson's disease” OR “PD”) AND (“motor fluctuation” OR “wearing off” OR “ON-OFF phenomenon” OR “OFF periods”))).

Articles were identified using the keywords described earlier. After removing duplicates, retrieved articles were screened based on their titles and abstracts. Thereafter, potentially eligible full-text articles were thoroughly assessed using the eligibility criteria described earlier. Any emerging discrepancies would be resolved by consensus among the review team. The planned procedure is further described in the eAppendix (links.lww.com/CPJ/A325).

Data Extraction

The following data were extracted from the studies selected for inclusion: (1) first author, (2) publication year, (3) region, (4) study design, (5) sample characteristics and size, (6) staging, (7) intervention (dose, route of administration, duration, and other treatments besides CVT-301) and control, (8) duration of study, and (9) efficacy and safety of CVT-301.

Data Synthesis and Statistical Analysis

Odds ratio (OR) and standardized mean differences (SMDs) with a confidence interval (CI) of 95% were used to determine the efficacy and safety of CVT-301 for the treatment of PD. The effect was considered significant if the value was not equal to 1 with p < 0.05. The combined effect size was plotted using a forest plot. Either fixed-effects or random-effects model was used depending on the study heterogeneity. The heterogeneity of included studies was assessed using Cochrane Q test of homogeneity and Higgins I² statistics. Subgroup analysis was conducted to find the possible cause of heterogeneity. A funnel plot was used to assess publication bias visually. An asymmetric funnel plot indicated the possibility of publication bias.²⁴ This was confirmed through the Begg and Mazumdar rank correlation test and Egger test of the intercept to determine the presence of publication bias statistically.^25,26 Furthermore, sensitivity analysis was performed to confirm the robustness of this meta-analysis. All statistical tests were performed using Review Manager (RevMan), version 5.3.²⁷

Quality Assessment and Reliability of Data

The Cochrane risk of bias (RoB)2 tool was used to assess the quality of the included RCTs.²⁸ Four researchers (G.G., T.H., J.B., and G.M.) independently evaluated the quality of each study with any discrepancies resolved through discussion.

Trial sequential analysis (TSA) was performed to determine the required sample size and confirm whether the result of meta-analysis was conclusive. TSA generates thresholds for declaring significance of the result to avoid the overestimation of intervention effects and prevent the spurious results. When the Z curves surpass the futility boundary, the level of evidence is adequate and further trials will be judged as futile. The level of evidence will also be judged as adequate and conclusive, if the Z curves surpass the conventional and trial sequential significance boundaries. On the contrary, when the Z curves do not cross any boundaries or only surpass the conventional boundary, the level of evidence is inadequate and more trials are needed to clarify the conclusion.²⁹ A 2-sided trial sequential monitoring boundary type was used in our TSA. The required information size was calculated with α = 0.05. TSA was performed using TSA, version 0.9.5.10 beta.³⁰

Confidence in Cumulative Evidence

The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method was used to determine the confidence in cumulative evidence. Judgment was made considering the presence of study limitations, consistency, directness, imprecision, and/or reporting bias. Overall certainty of evidence was shown as high, moderate, low, or very low quality.³¹

Data Availability

Data not provided in the article because of space limitations may be shared (anonymized) at the request of any qualified investigator for purposes of replicating procedures and results.

Results

Search Result

Initial search using the electronic database yielded 2,504 studies, of which 398 were duplicates and therefore excluded. After screening the remaining 2,106 studies by title and abstract, 8 studies were further assessed for eligibility. Finally, 5 studies were included in our systematic review and meta-analysis. The searching strategy and selection methods are illustrated in Figure 1.

Figure 1. PRISMA Flow Diagram of Study Selection.

The diagram summarized the search strategy and selection process applied to include articles eligible for this meta-analysis. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Study Characteristics

Five RCTs were conducted in various countries, such as the United States,^14-16 Canada,¹⁴ Israel,^15,17 United Kingdom,^13,17 Serbia,^13,17 Italy,¹⁴ Poland,¹⁴ Spain,¹⁴ and other European countries.¹⁵ All the studies were double-blind, except for 1, which was an open-label study.¹⁵ Most of the participants were diagnosed with early stages of PD. The amount of CVT-301 given to the participants ranged from 25 to 84 mg mostly in respirable fine-particle dose. Nonrespirable lactose monohydrate was commonly used as a placebo drug. The duration of study varied from 39 days to 12 months. All the studies had registered their trial protocols at the National Library of Medicine, except in 1 study.¹⁷ The study characteristics are summarized in Table 1.

Table 1.

Characteristics of Studies

All the studies had low bias arising from a randomization process, deviations from intended intervention, and missing data. One study had some concerns that knowledge of the intervention status could have influenced outcome assessment (even there is no reason to believe that it did).¹⁵ In addition, 1 study showed some concerns in the selection of the reported result because the authors did not present analysis plans; hence, the present reports could not be compared with the planned measurements and analysis.¹⁷ Methodological quality is summarized in Table 2.

Table 2.

Methodological Quality

Efficacy of CVT-301

In the CVT-301 group, the proportion of patients achieving an ON state was higher than the placebo group (OR = 2.68; 95% CI: 1.86–3.86; p < 0.00001; I² = 5%; Figure 2A). The improvement of motor function was also significantly higher in the CVT-301 group. The changes of mean UPDRS-III score from predose to postdose were higher in the CVT-301 group compared with those in the placebo group (SMD = 3.83; 95% CI: 2.44–5.23; p < 0.00001; I² = 96%; Figure 2B). In addition, the PGIC self-rating scale was also used to assess the patient's rating to the overall improvement of the disease. PD improvement was reported to be higher in the CVT-301 group than in the placebo group (OR = 2.95; 95% CI: 1.78–4.9; p < 0.00001; I² = 0%; Figure 2C).

Figure 2. Efficacy of CVT-301 on the Treatment of Parkinson Disease.

(A) Proportion of patients achieving an ON state, (B) changes of UPDRS-III score, and (C) PGIC self-rating scale. The horizontal line indicates 95% CI of a study. The square represents the result of each individual study. The size of the square varies according to the weight of a particular study. The black diamond at the bottom of the plot represents the pooled analysis of all included studies. The outer edges of the diamond indicate the CIs. CI = confidence interval; df = degree of freedom; I² = test of heteogeneity; M-H = Mantel-Haenszel; PGIC = Patient Global Impression of Change; UPDRS-III = Unified Parkinson Disease Rating Scale part III.

Safety of CVT-301

In this study, we found that the incidence of adverse events in the CVT-301 group was higher than in the placebo group (OR = 2.47; 95% CI: 1.52–4.03; p < 0.00003; I² = 55%; Figure 3). Among all the adverse events documented, respiratory symptoms and nausea showed the highest risk of occurrence. The incidence of respiratory symptoms, such as cough, discolored sputum, and throat irritation, was found to be higher in the CVT-301 group than in the placebo group (OR = 12.18; 95% CI: 5.01–29.62; p < 0.00001; I² = 0%). The incidence of nausea also seemed to be higher in the CVT-301 group than in the placebo group (OR = 3.95; 95% CI: 1.01–15.41; p = 0.05; I² = 0%). By contrast, our study demonstrated no statistical difference between the CVT-301 and placebo groups in the incidence of dyskinesia (p = 0.09), fall (p = 0.21), respiratory tract infections (p = 0.44), and other adverse events (p = 0.77).

Figure 3. Safety of CVT-301 on the Treatment of Parkinson Disease.

Incidence of adverse events: dyskinesia, fall, respiratory tract infections, respiratory symptoms, nausea, and others. The horizontal line indicates 95% CI of a study. The square represents the result of each individual study. The size of the square varies according to the weight of a particular study. The black diamond at the bottom of the plot represents the pooled analysis of all included studies. The outer edges of the diamond indicate the CIs. CI = confidence interval; df = degree of freedom; I² = test of heteogeneity; M-H = Mantel-Haenszel.

Trial Sequential Analysis

TSA showed that the results for the proportion of patients achieving an ON state, the improvement of motor function by UPDRS-III score, and the incidence of adverse events were significant and succeeded to avoid type I and type II errors because the cumulative Z curve crossed exceeded both the conventional significance boundary and the trial sequential significant boundary. Although the result for the overall improvement of disease was also found to be significant, it only succeeded to avoid type I errors because the cumulative Z curve exceeded only the conventional boundary. Moreover, only the effect for the proportion of patients achieving an ON state and the overall improvement of disease had already exceeded the required meta-analysis sample size boundaries, but not the other effects (eFigure 1, links.lww.com/CPJ/A325).

Confidence in Cumulative Evidence

Overall studies were judged to have low-to-moderate risk of bias according to Cochrane RoB2. Sensitivity analysis also showed robustness of this meta-analysis even when studies with some concerns of bias were included; hence, plausible bias was unlikely to seriously alter the results. No serious indirectness was found in this study that could affect the whole results. However, we observed inconsistency in the ability of CVT-301 to improve motor function. This might be due to the differences in the amounts of CVT-301 given to participants across studies. Although the reliability of the data was confirmed through TSA, except in overall improvement of disease, imprecision was quite serious because almost all the included studies had wide confidence intervals. The publication bias could not be assessed in all the outcomes because the number of included studies did not reach 10. Overall, we had moderate quality of evidence for patients receiving CVT-301 to achieve an ON state, to show disease improvement, and if they had some concerns on adverse events. Meanwhile, evidence on the improvement of motor function after CVT-301 therapy was deemed as low quality. The GRADE evidence profile was generated, as summarized in eTable 1 (links.lww.com/CPJ/A325).

Discussion

With 5 RCTs and 4,962 patients with PD included, this study demonstrated that CVT-301 seemed to be beneficial in improving motor fluctuation in patients with PD. It was effective in reducing the number of OFF periods and increasing the number of ON periods in patients with PD compared with that in the placebo group. Moreover, our data also showed that CVT-301 was also able to improve motor function and promote an overall improvement of the disease. The underlying reason of these findings was the remarkable ability of CVT-301 in bypassing the slow gastrointestinal absorption and avoiding the first-pass drug metabolism.^32,33 By having immediate access to the alveolar capillary network in the lung, CVT-301 is able to be absorbed rapidly into the CNS through the aorta and carotid arteries and provide consistent stimulation to the striatal dopamine receptors.^17,34 It is widely believed that the development of motor fluctuation in PD is caused by the intermittent delivery of levodopa provided by oral administration. There are slow absorption of levodopa into the gastrointestinal tract and competition with other large neutral amino acids to get absorbed into the brain leading to pulsatile stimulation of striatal dopamine receptors and dysregulation of the basal ganglia motor circuit.^35-37 Therefore, consistent delivery of levodopa to the brain suggested that it could delay or even prevent the motor fluctuation in patients with PD.^36,37 Furthermore, the favorable clinical improvement observed among patients was also attributed to the rapid acting of CVT-301 in providing quick relief from the OFF state. CVT-301 reached peak plasma concentrations at 5 minutes (the earliest time point measured) compared with the more gradual onset and peak at 57–240 minutes after oral administration.^38,39

Moreover, our study also suggested that CVT-301 was well tolerated by the patient because it did not cause any serious adverse events. Nausea and respiratory symptoms, such as cough, discolored sputum, and throat irritation, showed to be the most common adverse event encountered among treated patients. In several studies, the pulmonary function of treated patients was also found to be relatively unchanged compared with pretreatment, indicating that CVT-301 was well tolerated.^18,19 CVT-301 is even proven to be well tolerated and still provides a robust effect in a patient with persistent asthma.⁴⁰

In addition, our pooled analysis results were also confirmed by TSA to be statistically significant. TSA showed that most of the effect was robust, and additional data are not likely to change the summary effect, except for the effect of the overall improvement of disease by PGIC score. Moreover, the overall quality of evidence assessed using the GRADE method was identified as low to moderate. Because we used only randomized clinical trials, we started the assessment as a high quality of evidence. Owing to the imprecision found in all the included studies, the quality of evidence was downgraded to the moderate quality. A possible explanation for the imprecision observed in this study was because of the small number of participants used in individual studies or low variability of the population. However, the quality of evidence for the improvement of motor function was further downgraded to low quality because it had high heterogeneity among the included studies. Despite some imprecision and heterogeneity in the outcomes, we still suggest a strong recommendation for using CVT-301 as one of the treatments for motor fluctuation because it has already proven to have a promising result for patients with PD.

We report a comprehensive meta-analysis to review the efficacy and safety of CVT-301 for the treatment of motor fluctuation in patients with PD. This study also provides strong evidence because it included only RCTs to generate the outcomes. However, this study has several limitations as well. First, this study was unable to assess the publication bias because it only included less than 10 studies. Second, this study was unable to determine the superiority of CVT-301 over the current rescue therapies because it compared only the CVT-301 with the placebo. Third, this study was unable to determine the efficacy of CVT-301 in the more severe stage of PD (Hoehn and Yahr stages 4–5) because it included only PD patients with Hoehn and Yahr stages 1–3. Moreover, the outcome measurements eligible for analysis were limited; hence, complete evaluation of benefits and risks of CVT-301 was not possible. These limitations support the need for further larger studies to provide credible results.

Motor fluctuation in patients with PD has always been an unresolved clinical problem that is challenging to treat. A reliable, rapid onset, and easily administered drug is still a major unmet need in the treatment of PD. CVT-301 has demonstrated a remarkable ability in reducing the OFF state, improving motor function, and promoting an overall improvement of the disease in patients with PD. Moreover, it also showed to be well-tolerated and did not cause any serious adverse events, with respiratory symptoms and nausea being the most common adverse events encountered. Our data suggested that CVT-301 could be an alternative and even preferred treatment for motor fluctuation in patients with PD. However, further clinical and pharmacology studies are still needed to more clearly elucidate the benefit of CVT-301 in patients with PD.

TAKE-HOME POINTS

• → Motor fluctuation in patients with PD has always been an unresolved clinical problem that is challenging to treat.

• → In this study, CVT-301 has been shown to be well tolerated and effective in reducing the OFF state, improving motor function, and promoting an overall improvement of the disease in patients with PD.

• → Our data suggested that CVT-301 could be an alternative and even preferred treatment for motor fluctuation in patients with PD.

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.