Carbidopa and Levodopa Extended Release Capsules in Patients with and without Troublesome and Non-Troublesome Dyskinesia.
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SUBMITTER: Hauser RA
PROVIDER: S-EPMC7458518 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Carbidopa and Levodopa Extended Release Capsules in Patients with and without Troublesome and Non-Troublesome Dyskinesia.
Hauser Robert A RA Zeitlin Leonid L Fisher Stanley S D'Souza Richard R
Journal of Parkinson's disease 20200101 3
<h4>Background</h4>Carbidopa (CD) and levodopa (LD) extended release (CD-LD ER) capsules are designed to combine both immediate and extended release pharmacokinetics. In the phase 3, randomized, double-blind, ADVANCE-PD trial, patients randomized to CD-LD ER experienced a 1.17-hour greater reduction in OFF time compared to patients randomized to CD-LD IR (p < 0.0001).<h4>Objective</h4>To compare CD-LD IR optimization to CD-LD ER conversion based on patient dyskinesia status at baseline using dat ...[more]
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Project description:OBJECTIVE:IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). METHODS:This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. RESULTS:Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD (P < 0.0001) and Rytary (P ? 0.0290). IPX203 had a 2.7-hour advantage over IR CD-LD (P < 0.0001) and a 0.9-hour advantage over Rytary in "off" time (P = 0.023) and in "good on" time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD-LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. CONCLUSIONS:Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.
| S-EPMC7654938 | biostudies-literature
Project description:Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.
| S-EPMC5066683 | biostudies-literature
Project description:A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson's Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson's disease (PD) treated with immediate-release (IR) carbidopa-levodopa (CD-LD) or an extended-release (ER) formulation of CD-LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single- and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid E(max) transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.
| S-EPMC3798100 | biostudies-literature
Project description:BackgroundThe introduction of carbidopa-levodopa extended-release (CD-LD ER) capsules (Rytary®) did not go as smoothly as expected, largely due to difficulty around dose conversion from available immediate-release (IR) levodopa (LD) formulations. The dose conversion table in the CD-LD ER prescribing information was similar to the table used in the pivotal clinical trial and is considered by many prescribing HCPs to be less than optimal. By the end of the dose conversion period in that trial, dosing in 76% of subjects was adjusted for symptom control; roughly 60% of patients required a higher dose and about half required more frequent administration than the recommended TID dosing.ObjectiveThe primary objective of our nationwide (US) survey was to determine the dose conversion strategy most commonly employed by CD-LD ER frequent prescribers. The survey also aimed to explore additional features regarding CD-LD ER use in clinical practice.MethodsA survey consisting of 21 multiple-choice questions was developed and administered to experts in the use of CD-LD ER, based on prescription volume.ResultsOf the 394 HCPs who were invited to participate, 90 (23%) HCPs completed the survey. All respondents were aware of the dose conversion table; the largest group did not find the table to be helpful and did not use it to convert patients to CD-LD ER. The most common strategy in calculating the CD-LD ER dose was based on the total daily LD IR dose, with the majority of that group initiating dose conversion by doubling the total daily LD dose from CD-LD IR and administering CD-LD ER one less time per day.ConclusionOverall, most survey respondents agreed that a good starting point for CD-LD ER conversion could be doubling the daily LD IR dose and administering it one time less frequently. Moreover, rapid patient follow-up after initial dose conversion to allow for further dose adjustments plays a critical role in achieving success. Gaining experience over time is important for satisfactory conversion.
| S-EPMC7914099 | biostudies-literature
Project description:ImportanceMedical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need.ObjectiveTo evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD.Design, setting, and participantsA randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact.InterventionsPatients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks.Main outcomes and measuresThe primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo).ResultsA total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%).Conclusions and relevanceADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia.Trial registrationclinicaltrials.gov Identifier: NCT02136914.
| S-EPMC5710325 | biostudies-literature
Project description:IntroductionGocovri (amantadine) extended release capsules are approved for treatment of dyskinesia and as a levodopa adjunct for OFF episodes in patients with Parkinson's disease (PD). We report treatment-related effects on non-motor symptoms (NMS) assessed as secondary outcomes in two trials using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I.MethodsEASE LID and EASE LID 3 enrolled levodopa-treated patients with PD and ≥ 1 h/day ON time with troublesome dyskinesia. Patients were randomized to Gocovri (274 mg) or placebo taken daily at bedtime. Treatment differences from baseline to week 12 in MDS-UPDRS Part I were evaluated for the pooled population (N = 196) from both trials. Correlation analyses of NMS (MDS-UPDRS Part I) with dyskinesia using Unified Dyskinesia Rating Scale (UDysRS) scores were performed.ResultsFor changes in the MDS-UPDRS Part I items, the treatment difference favored Gocovri in daytime sleepiness (P = 0.006) and depression (P = 0.049) scores, but favored placebo in cognitive impairment (P = 0.038), and hallucinations and psychosis (P < 0.001) scores. The treatment difference for the changes in total Part I score was -0.8, favoring Gocovri (P = 0.22). At baseline, MDS-UPDRS Part I modestly correlated with UDysRS score (r +0.25, P < 0.001), and improvement in NMS correlated with improvement in dyskinesia at week 12 for Gocovri (r +0.39, P < 0.001) but not placebo (r +0.12, P = 0.29). The most commonly reported adverse events for Gocovri were hallucination (21%); dizziness, dry mouth, and peripheral edema (16% each); and constipation, falls, and orthostatic hypotension (13% each).ConclusionThis post hoc analysis shows potential benefit with Gocovri treatment for the NMS of daytime sleepiness and depression in dyskinetic PD patients. Overall, improvement in NMS scores correlated with improvement in dyskinesia.Trial registrationClinicalTrials.gov identifiers: NCT02136914 and NCT02274766.
| S-EPMC8140024 | biostudies-literature
Project description:BackgroundThe treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy.ObjectiveThe purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial.MethodsPD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure.ResultsAt week 12, least-squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P < .0001), indicating improvement in levodopa-induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS-5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference -1.1 hours, 95% confidence interval -2.0 to -0.2, P = .0199). The most common adverse events (ADS-5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively.ConclusionADS-5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa-induced dyskinesia and improving OFF time. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC5763269 | biostudies-literature
Project description:Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by resting tremor, rigidity, bradykinesia, gait disturbance, and postural instability. Levodopa, the precursor to dopamine, coadministered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors, is the most effective and widely used therapeutic agent in the treatment of PD. With continued levodopa treatment, a majority of patients develop motor complications such as dyskinesia and motor 'on-off' fluctuations, which are, in part, related to the fluctuations in plasma concentrations of levodopa. A new extended-release (ER) carbidopa-levodopa capsule product (also referred to as IPX066) was developed and approved in the US as Rytary® and in the EU as Numient®. The capsule formulation is designed to provide an initial rapid absorption of levodopa comparable to immediate-release (IR) carbidopa-levodopa, and to subsequently provide stable levodopa concentrations with reduced peak-to-trough excursions in plasma concentrations in order to reduce motor fluctuations associated with pulsatile stimulation of dopamine receptors and to minimize dyskinesia. Phase III studies of this ER carbidopa-levodopa capsule formulation in patients with PD have shown a significant reduction in 'off' time compared with IR carbidopa-levodopa and carbidopa-levodopa-entacapone. We present a review of the clinical pharmacokinetics and pharmacodynamics of this ER product of carbidopa-levodopa in healthy subjects and in patients with PD.
| S-EPMC5563351 | biostudies-literature
Project description:ObjectiveThe purpose of this study was to assess the effect of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) in advanced Parkinson's disease patients with troublesome dyskinesia.MethodsPost hoc analyses of patient data from a 12-week, randomized, double-blind study and a 54-week open-label study were performed. Efficacy was assessed in the subgroup of patients defined by ?1 hour of "on" time with troublesome dyskinesia at baseline as recorded in Parkinson's disease symptom diaries (double blind: n?=?11 levodopa-carbidopa intestinal gel, n?=?12 oral levodopa-carbidopa; open label: n?=?144 levodopa-carbidopa intestinal gel). The changes in "off" time, "on" time with and without troublesome dyskinesia, and the overall safety and tolerability of levodopa-carbidopa intestinal gel were analyzed.ResultsAlthough not significantly different from oral levodopa treatment (P?>?.05) in the double-blind study, levodopa-carbidopa intestinal gel treatment resulted in a reduction from baseline in "on" time with troublesome dyskinesia (mean [standard deviation] hours: baseline?=?3.1 [1.7], change from baseline to final?=?-1.8 [1.8], P?=?.014), increase in "on" time without troublesome dyskinesia (baseline?=?7.4 [2.2], change?=?4.4 [3.6], P?=?.004), and decrease in "off" time (baseline?=?5.5 [1.3], change?=?-2.7 [2.8], P?=?.015). Similar trends were found in the open-label study. An increase in levodopa-carbidopa intestinal gel dose was not significantly correlated with increased "on" time with troublesome dyskinesia in either study (double blind: r?=?-.073, P?=?.842; open label: r?=?-0.001, P?=?.992). Adverse events were usually mild to moderate in severity and related to the gastrointestinal procedure.ConclusionOur exploratory analyses suggest that optimizing levodopa delivery with levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.
| S-EPMC5066747 | biostudies-literature
Project description:Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) is an unmet need. ADS-5102 (amantadine) extended-release capsules is being developed for the treatment of LID in patients with PD.Evaluate the long-term safety and tolerability of 274?mg ADS-5102 for LID in PD.In an ongoing, open-label safety study (NCT02202551), PD patients with LID received 274?mg of ADS-5102 once daily at bedtime. Patients were recruited from previous ADS-5102 trials. In addition, patients were enrolled who were ineligible for previous ADS-5102 trials due to previous implantation of deep-brain stimulation (DBS) devices. The primary outcome measure was safety assessed through adverse events (AEs). Efficacy was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part IV and its subparts.For this interim analysis, 223 patients received ADS-5102 for a mean duration of 348 (SD 182) days. The most common AEs included falls (25.1%), visual hallucinations (19.3%), peripheral edema (13.0%), and constipation (12.6%). Overall, 32 patients (14.3%) discontinued due to an AE. In patients receiving placebo in previous studies, the mean MDS-UPDRS, Part IV scores decreased by 3.4 points from baseline (n?=?78) to week 8 and remained stable through week 64 (n?=?21). In patients receiving ADS-5102 in previous studies, the mean baseline (n?=?61) MDS-UPDRS, Part IV score was low due to the response to ADS-5102 in previous studies and remained stable through week 64 (total of 88 weeks; n?=?21). The effect was primarily due to reduction in item 4.2 (functional impact of dyskinesia) and item 4.4 (functional impact of motor fluctuations).ADS-5102 was generally well tolerated in all groups, including DBS patients, and the safety profile was consistent with previous controlled studies. Long-term durability and tolerability were shown from the double-blind studies through participation in the open-label study up to 88 weeks.
| S-EPMC5611804 | biostudies-other