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Istradefylline Versus Opicapone for “Off” Episodes in Parkinson’s Disease: A Systematic Review and Meta-Analysis

Istradefylline Versus Opicapone for “Off” Episodes in Parkinson’s Disease: A Systematic Review... Background: In recent times, the US-FDA approved istradefylline and opicapone as an adjunct to levodopa/carbidopa for managing the "off" episodes in Parkinson’s disease. Purpose: Current meta-analysis was performed to determine the safety and efficacy of these drugs in the management of “off” episodes and to recognize which among them would provide therapeutic benefits clinically. Methods: A thorough literature search was performed through the Cochrane Library, PubMed, and clinicaltrials.gov for a period from January 2003 to October 2020, with the following keywords: Istradefylline, KW-6002, opicapone, BIA 9-1067, and Parkinson’s disease. Those randomized, double-blind placebo/active comparator-controlled trials that analyzed the efficacy and safety of istradefylline and opicapone and that were published in the English language were included. In this analysis, the outcomes focused on the least square mean change in “off” time and Unified Parkinson’s Disability Rating Scale (UPDRS) III score from baseline to the end of the study, and the incidence of treatment-emergent adverse events (TEAEs) and dyskinesia. Results: Both drugs have shown significant reduction in “off” time duration (mean difference [MD] = –0.70; 95% CI [–1.11, –0.30]; P < 0.001 for istradefylline and MD = –0.85; 95% CI [–1.09, –0.61]; P < .001 for opicapone). Istradefylline showed significant improvement in UPDRS III (MD = –1.56; 95% CI [–2.71, –0.40]; P < .008), but the same was not observed with opicapone (MD = –0.63; 95% CI [–1.42, –0.15]; P < .12). The incidence of TEAEs and dyskinesia reportedly were higher in the intervention group rather than with the placebo, (risk ratio RR =1.11, 95% CI [1.02,1.20] for istradefylline and RR =1.12, 95% CI [1.00,1.25] for opicapone, and for dyskinesia particularly, the incidence was higher with opicapone as compared to istradefylline (RR = 3.47, 95% CI [2.17, 5.57], and RR = 1.77, 95% CI [1.29, 2.44], respectively). Conclusions: Both drugs were comparable in efficacy; however, istradefylline seemed to be better in reducing the UPDRS III score. Although the incidence of TEAEs and dyskinesia were higher with both the drugs, the incidence of dyskinesia was more in the opicapone group. Keywords Opicapone, Istradefylline, “Off” episodes, Parkinson’s disease Received 19 January 2021; revised 15 July 2021; accepted 3 August 2021 rigidity) and nonmotor (flat affect, excessive salivation, Introduction staring appearance, autonomic dysfunction, and psychiatric 4,5 Parkinson’s disease (PD), the second most common disorder) clinical features during the disease. progressive neurodegenerative disorder, with an annual Among the wide variety of pharmacotherapeutic options incidence of 11-19/100000, has affected more than six million available to manage a case of PD, like dopamine precursors 1,2 people globally. The pathological changes like loss of with peripheral dopa decarboxylase inhibitors, dopamine dopaminergic neurons from substantia nigra and accumulation agonists, anticholinergics, monoamine oxidase B (MAO-B) of Lewy bodies in the remaining neurons, along with mitochondrial dysfunction, endoplasmic reticulum stress Department of Pharmacology, All India Institute of Medical Sciences, (ER), altered ER-Golgi transport, and proteotoxicity Raipur, Chhattisgarh, India secondary to accumulation of over-produced α-synuclein, are Corresponding author: responsible for bringing about an array of clinical features. Alok Singh, Department of Pharmacology, All India Institute of Medical The patients of PD experience both motor (bradykinesia, Sciences, Raipur, Chhattisgarh 492099, India. tremors, shuffling gait, postural instability, and muscular E-mail: draloksingh@aiimsraipur.edu.in Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 66 Annals of Neurosciences 28(1-2) inhibitors, and catechol-o-methyl transferase (COMT) inhibitors, the levodopa/carbidopa combination therapy stands out to be a gold standard treatment as it has been seen that levodopa can provide persistent mobility benefits. In contrast, carbidopa helps to maintain an appropriate level of 6–8 levodopa in the substantia nigra. But with the chronic use of this combination, the therapeutic effects start to wane off (wearing off phenomenon) and gradually get outweighed by the adverse effects like “on-off” fluctuations with or without dyskinesia. This “on-off” phenomenon is clinically symbolized by the absence and reappearance of motor symptoms while the patient is on therapy. Moreover, once these fluctuations deteriorate the quality of life, they become troublesome. To alleviate these symptoms, the drugs which can be utilized as an adjunct can either be a potent dopaminergic agonist (apomorphine) or inhibitor of enzymes that are responsible for degrading dopamine (COMT inhibitors and selective MAO-B inhibitors) or noncompetitive inhibitor of NMDA receptors (amantadine). Among these groups, istradefylline and opicapone have Figure 1. PICOS Criteria. been recently approved by the US-FDA to manage “off” 11–12 Source: The authors. episodes in PD. With the intermittent levodopa therapy, there occurs an up-regulation of adenosine A receptors, 2A contributing to the precipitation-of “off” episodes. Based on Parkinson’s disease.” Other studies were also searched for this mechanism, the action of istradefylline, a selective A 2A any missing data, if any. receptor antagonist, has been defined in managing the “off” 1. Patients: Adults with Parkinson’s disease. episodes by enhancing the effects of levodopa. While for 2. Intervention/Comparator: Istradefylline (40 mg/d), opicapone, a COMT inhibitor produces its effects by opicapone (50 mg/d), placebo/ active comparator. inhibiting the enzyme catechol-o-methyltransferase, which is Both drugs were used as an add-on to levodopa/ responsible for degrading levodopa in the periphery, thus carbidopa, and their maximal recommended doses increasing its level in Central Nervous System (CNS). Since were compared for their efficacy and safety. both these drugs have been introduced recently for managing 3. Primary Outcome: Least square mean change in daily the same condition, this meta-analysis was conducted to “off” time duration from baseline to end-point. compare and appraise their efficacy and safety in patients of 4. Secondary Outcomes: PD who are already on levodopa/carbidopa therapy and are a. The least-square mean change in Unified experiencing “off” episodes. Parkinson’s Disability Rating Scale (UPDRS) part III in the “on” state from baseline to end-point. Methods b. Incidence of Treatment-Emergent Adverse Events (TEAE). This meta-analysis was performed as per the guidelines of c. Incidence of dyskinesia. preferred reporting items for systematic reviews and meta- 5. Study Design: Data extraction was performed by two analyses statement (PRISMA). Furthermore, no ethical authors. The primary demographic details from all the approval was required for this review. clinical trials assessing the safety and efficacy of istradefylline or opicapone against placebo/active comparator among PD patients were also noted. Literature Search and Data Extraction Two authors performed the systematic search (Alok Singh Risk of Bias Assessment and Dhyuti Gupta) among the databases PubMed, Cochrane library, and Clinical Trial Registry https://clinicaltrials.gov/ Quality assessment of the individual study and the risk of bias for a timeline from January 2003 to October 2020 using the was performed as per the preferred reporting items for following keywords: “istradefylline, KW-6002, and systematic reviews and meta-analyses statement (PRISMA) Parkinson’s disease,” and “opicapone, BIA 9-1067, and guidelines and duly demonstrated in the forest plot. Singh et al. 67 male. In a few studies, the standard deviation (SD) for Statistical Analysis continuous data was missing; hence these values were The authors’ assessed the MD and RR with a confidence imputed from other studies with maximum values being interval (CIs) of 95% for continuous and dichotomous considered. variables, respectively. In missing data (standard deviation), Primary Outcome the highest values were imputed from other studies for the 15 2 2 same parameter. I statistics (I > 50% indicated Based on the funnel plot obtained for the primary outcome, heterogeneity) were used to check for heterogeneity among the authors did not observe any publication bias (Figure 2), the included studies. This meta-analysis was performed but heterogeneity was observed (I = 95%, heterogeneity P < using a random-effect model with Review Manager v5.4 for .00001) among these trials (Figure 3). For the least square windows. Moreover, we obtained a funnel plot to assess for mean change in time spent in “off” episodes, both drugs any publication bias (of the primary outcome). showed a significant reduction from baseline to the end of the study period (MD = –0.70; 95% CI [–1.11, –0.30]; P < 0.001 for istradefylline and MD = –0.85; 95% CI [–1.09, –0.61]; Results P < .001 for opicapone), with opicapone performing marginally better than istradefylline (P = .56; Figure 3). Literature Search and Study Characteristics The initial search yielded 236 studies, that is, 57 of Secondary outcomes istradefylline and 179 of opicapone. On further exploring the For the secondary outcomes, the performance of istradefylline clinical trial registry https://clinicaltrials.gov/, we found a was significantly better than the placebo (MD = –1.56; 95% total of 11 clinical trials for istradefylline and five for CI [–2.71, –0.40]; P < .008), but the same cannot be inferred opicapone belonging to different phases. On the other hand, for opicapone (MD = –0.63; 95% CI [–1.42, –0.15]; P < .12). in PubMed, we found a total of ten published clinical trials for The patients who were randomized to receive istradefylline istradefylline and nine for opicapone. The inclusion criteria reported an improvement in the UPDRS III score, but it was set by the authors were met by four clinical trials of 17–23 insignificant compared to opicapone users (MD: –1.56 vs istradefylline and three clinical trials of opicapone. The –0.63; P = .20; Figure 4). reasons for excluding other studies were the pooled analysis Broadly referring to the treatment-emergent adverse of trials, pharmacokinetic studies, different end points, and events (TEAEs), the users of drugs, that is, istradefylline and different doses of the drugs. The relevant characteristics of opicapone, reported more TEAEs than those who were on the included studies have been mentioned in Table 1. The diagnosis of PD among all the included trials was established placebo adjunct (RR = 1.11, 95% CI [1.02, 1.2] for based on the United Kingdom Parkinson’s Disease Society istradefylline and RR = 1.12, 95% CI [1.00, 1.25] for Criteria, and the majority of the recruited participants were opicapone). However, the risk was still comparable among Table 1. Important Characteristics of Included Clinical Trials No. of Patients in Age (y) mean Study N Study Design Each Arm Dose (mg/day) ± SD % Male Lewitt et al. 2008 196 RDBPCT IST: 130 IST: 40 IST: 63 ± 9 59.7 PLB: 66 PLB:64 ± 10 (117/196) Mizuno et al. 357 RDBPCT IST: 124 IST: 40 IST: 63.7 ± 8.6 42.1 2010 PLB: 118 PLB: 65 ± 7.6 (150/357) Pourcheret al. 605 RDBPCT IST: 152 IST: 40 IST: 63 ± 9.3 66.6 2012 PLB: 151 PLB: 63 ± 8.3 (403/605) Mizuno et al. 366 RDBPCT IST: 123 IST: 40 IST: 65.7 ± 9 44.3 (162/366) 2013 PLB: 123 PLB: 65.8 ± 8.6 Ferreira et al. 599 RDBPCT OPC: 115 OPC: 50 OPC: 63.5 ± 9.2 59.1 (354/599) 2016 PLB: 121 PLB: 64.3 ± 9.3 Lees et al. 2017 407 RDBPCT OPC: 135 OPC: 50 OPC: 65.5 ± 8.4 59.5 PLB: 147 PLB: 61.5 ± 8.9 (242/407) Takeda et al. 437 RDBPCT OPC: 145 OPC: 50 OPC: 67.4 ± 7.8 39.8 (174/437) 2020 PLB: 147 PLB: 68.5 ± 8.6 Source: The authors. Abbreviations: RDBPCT: Randomized double-blind placebo-controlled clinical trial; IST: Istradefylline; OPC: Opicapone; PLB: Placebo 68 Annals of Neurosciences 28(1-2) these drugs (P = 0.88; Figure 5). Furthermore, the incidence opicapone), with the patient randomized to receive opicapone of dyskinesia among the active drug users in trials was more reporting more significantly of it than those who received as compared to the placebo (RR = 1.77, 95% CI [1.29, 2.44] istradefylline (P = .02; Figure 6). A comparison of different for istradefylline and RR = 3.47, 95% CI [2.17, 5.57] for outcomes is presented in Table 2. Table 2. Comparison Between Istradefylline and Opicapone for Different Outcomes S. No. Outcomes IST40 OPC50 P-Value 1. The least-square mean change in daily "off" time duration from baseline to –0.70 –0.85 .56 end-point (MD compared to placebo) 2. Least square mean change in Unified Parkinson’s Disability Rating Scale (UPDRS) –1.56 –0.63 .2 part III in the “on” state from baseline to end-point. (MD compared to placebo) 3. Incidence of treatment-emergent adverse events (RR) 1.11 1.12 .88 4. Incidence of dyskinesia (RR) 1.77 3.47 .02* Source: The authors. Note: * statistically significant. Abbreviations: IST: Istradefylline; OPC: Opicapone; MD: Mean difference; RR: Risk ratio Figure 2. Funnel Plot for Studies. Source: The authors. Singh et al. 69 Figure 3. Forest Plot for Least Square Mean Reduction in “off’ Time From Baseline to End Point. Source: The authors. Figure 4. Forest Plot for Least Square Mean Reduction in UPDRS III From Baseline to End Point. Source: The authors. 70 Annals of Neurosciences 28(1-2) Figure 5. Forest Plot for Incidence of Treatment-emergent Adverse Events. Source: The authors. Figure 6. Forest Plot for Incidence of Dyskinesia. Source: The authors. Singh et al. 71 any modulatory effect of opicapone on DRs. More clinical Discussion studies are needed to substantiate this finding. Both drugs had a similar incidence of TEAEs, but the The present meta-analysis includes two recently approved incidence of dyskinesia was more with opicapone, and it was drugs for “off” episodes in PD. Our study incorporates statistically significant. Increased incidence of dyskinesia randomized clinical trials, which were mostly of high quality. with opicapone may be attributable to the increased We found that certain biases might have existed, that is, availability of levodopa in CNS, and this effect lacks in selection and detection bias in few studies (mentioned in 17,19,20 istradefylline. This also agrees that istradefylline is less forest plot). The possible explanations for biases were effective in reducing “off” time duration and has less inappropriate information provided in the text regarding the dyskinesia. As “off” episodes are usually encountered after method of randomization, allocation concealment, and five to seven years of therapy with ongoing neurodegeneration, outcome assessment. In few studies, SD was not mentioned, the drugs offer nonphysiologic replacement of dopamine imputed from other studies, and the maximum value was possibly due to the increase in levodopa, which is responsible taken, which is the simplest method of imputation. In for its beneficial effects, is also responsible for the dyskinesia general, all the included trials had a low number of participants as the replacement is nonphysiologic. The development of (196–605). Although PD is the most common movement dyskinesia may be a limiting factor in the wide acceptance of disorder of neurodegenerative nature, the absolute incidence opicapone. is low, that is, 11–19/100000 per year, which may be one of Both drugs had common adverse effects of dopamine the reasons for the low number of participants. Clinically, excess in CNS, that is, hallucination(s) and impulse control the “on-off” phenomenon starts manifesting after a few years disorder; however, hallucinations are more common with of treatment; this may also be a contributing factor in istradefylline. Hallucinations with istradefylline have been relatively fewer participants. Most of the participants of the reported in every clinical trial, but only one clinical trial included trials were male and were in the sixth decade of their 17–20,23 reported hallucination with opicapone. Further on life that follows the usual epidemiological trend. carefully observing clinical trials of istradefylline, the For the efficacy outcomes, both drugs showed a significant hallucination appears to be dose-dependent. This fact has also reduction in “off” time and an improvement in UPDRS III been substantiated in the real-world study of istradefylline. score from baseline to end-point as compared to placebo. The In addition to these adverse effects, opicapone had peripheral reduction in “off” time by opicapone was slightly higher than adverse effects of dopamine excess, that is, hypotension and by istradefylline. Reduction in "off" time indicates that both arrhythmias, which can be dangerous in the geriatric drugs restored the effectiveness of levodopa/carbidopa, which population. Both drugs must be avoided in case of severe was compromised due to ongoing neurodegeneration, though hepatic impairment, and dose reduction is required in by different mechanisms. UPDRS is used to assess the moderate hepatic dysfunction. The opicapone is to be taken symptoms of Parkinson’s and is divided into four segments, without food, whereas istradefylline can be taken with or in which part III deals with the motor symptoms of PD. The 34,35 without food. adenosine antagonist, that is, istradefylline, had better improvement than opicapone in UPDRS III “on” state. The adenosine receptor heterodimerizes with the dopamine Limitations receptor (D2), thereby modulates dopamine response and motor behavior. Chronic levodopa therapy possibly This study has got certain limitations, that is, a relatively up-regulates the adenosine receptor and may be responsible fewer number of studies were included, and the included for the precipitation of “off” episodes. Istradefylline may studies were of relatively less duration (12–14 weeks). The prevent heterodimerization, leading to increased dopaminergic missing SD in some of the studies was imputed from other activity and possibly explaining the better UPDRS III score. studies. The effects of istradefylline (40 mg) were similar to the 26–29 previous meta-analysis. On the other hand, an increase in levodopa level in CNS by opicapone may be responsible for Conclusion the significant reduction in “off” time; however, the same was not observed with UPDRS III. The positive correlation of Practically, the “off” phenomena can be considered a change levodopa and improvement in UPDRS III has been shown in in a PD patient's clinical state where motor and/or nonmotor 30–32 previous studies. As opicapone’s primary mechanism symptoms appear or worsen, resulting in functional disability. involves increased availability of levodopa into the CNS, it Amongst the various classes of drugs available to manage was expected to improve UPDRS III significantly. This PD, nondopaminergic drugs can be utilized to manage “off” unanticipated finding may be attributable to a severe loss of episodes with the long-term levodopa/carbidopa therapy, and dopaminergic neurons to the extent that even levodopa and a detrimental effect eventually develops, that being “on-off” opicapone could not improve UPDRS III along with lack of fluctuations. 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Istradefylline Versus Opicapone for “Off” Episodes in Parkinson’s Disease: A Systematic Review and Meta-Analysis

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© 2021 Indian Academy of Neurosciences (IAN)
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0976-3260
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10.1177/09727531211046362
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Abstract

Background: In recent times, the US-FDA approved istradefylline and opicapone as an adjunct to levodopa/carbidopa for managing the "off" episodes in Parkinson’s disease. Purpose: Current meta-analysis was performed to determine the safety and efficacy of these drugs in the management of “off” episodes and to recognize which among them would provide therapeutic benefits clinically. Methods: A thorough literature search was performed through the Cochrane Library, PubMed, and clinicaltrials.gov for a period from January 2003 to October 2020, with the following keywords: Istradefylline, KW-6002, opicapone, BIA 9-1067, and Parkinson’s disease. Those randomized, double-blind placebo/active comparator-controlled trials that analyzed the efficacy and safety of istradefylline and opicapone and that were published in the English language were included. In this analysis, the outcomes focused on the least square mean change in “off” time and Unified Parkinson’s Disability Rating Scale (UPDRS) III score from baseline to the end of the study, and the incidence of treatment-emergent adverse events (TEAEs) and dyskinesia. Results: Both drugs have shown significant reduction in “off” time duration (mean difference [MD] = –0.70; 95% CI [–1.11, –0.30]; P < 0.001 for istradefylline and MD = –0.85; 95% CI [–1.09, –0.61]; P < .001 for opicapone). Istradefylline showed significant improvement in UPDRS III (MD = –1.56; 95% CI [–2.71, –0.40]; P < .008), but the same was not observed with opicapone (MD = –0.63; 95% CI [–1.42, –0.15]; P < .12). The incidence of TEAEs and dyskinesia reportedly were higher in the intervention group rather than with the placebo, (risk ratio RR =1.11, 95% CI [1.02,1.20] for istradefylline and RR =1.12, 95% CI [1.00,1.25] for opicapone, and for dyskinesia particularly, the incidence was higher with opicapone as compared to istradefylline (RR = 3.47, 95% CI [2.17, 5.57], and RR = 1.77, 95% CI [1.29, 2.44], respectively). Conclusions: Both drugs were comparable in efficacy; however, istradefylline seemed to be better in reducing the UPDRS III score. Although the incidence of TEAEs and dyskinesia were higher with both the drugs, the incidence of dyskinesia was more in the opicapone group. Keywords Opicapone, Istradefylline, “Off” episodes, Parkinson’s disease Received 19 January 2021; revised 15 July 2021; accepted 3 August 2021 rigidity) and nonmotor (flat affect, excessive salivation, Introduction staring appearance, autonomic dysfunction, and psychiatric 4,5 Parkinson’s disease (PD), the second most common disorder) clinical features during the disease. progressive neurodegenerative disorder, with an annual Among the wide variety of pharmacotherapeutic options incidence of 11-19/100000, has affected more than six million available to manage a case of PD, like dopamine precursors 1,2 people globally. The pathological changes like loss of with peripheral dopa decarboxylase inhibitors, dopamine dopaminergic neurons from substantia nigra and accumulation agonists, anticholinergics, monoamine oxidase B (MAO-B) of Lewy bodies in the remaining neurons, along with mitochondrial dysfunction, endoplasmic reticulum stress Department of Pharmacology, All India Institute of Medical Sciences, (ER), altered ER-Golgi transport, and proteotoxicity Raipur, Chhattisgarh, India secondary to accumulation of over-produced α-synuclein, are Corresponding author: responsible for bringing about an array of clinical features. Alok Singh, Department of Pharmacology, All India Institute of Medical The patients of PD experience both motor (bradykinesia, Sciences, Raipur, Chhattisgarh 492099, India. tremors, shuffling gait, postural instability, and muscular E-mail: draloksingh@aiimsraipur.edu.in Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 66 Annals of Neurosciences 28(1-2) inhibitors, and catechol-o-methyl transferase (COMT) inhibitors, the levodopa/carbidopa combination therapy stands out to be a gold standard treatment as it has been seen that levodopa can provide persistent mobility benefits. In contrast, carbidopa helps to maintain an appropriate level of 6–8 levodopa in the substantia nigra. But with the chronic use of this combination, the therapeutic effects start to wane off (wearing off phenomenon) and gradually get outweighed by the adverse effects like “on-off” fluctuations with or without dyskinesia. This “on-off” phenomenon is clinically symbolized by the absence and reappearance of motor symptoms while the patient is on therapy. Moreover, once these fluctuations deteriorate the quality of life, they become troublesome. To alleviate these symptoms, the drugs which can be utilized as an adjunct can either be a potent dopaminergic agonist (apomorphine) or inhibitor of enzymes that are responsible for degrading dopamine (COMT inhibitors and selective MAO-B inhibitors) or noncompetitive inhibitor of NMDA receptors (amantadine). Among these groups, istradefylline and opicapone have Figure 1. PICOS Criteria. been recently approved by the US-FDA to manage “off” 11–12 Source: The authors. episodes in PD. With the intermittent levodopa therapy, there occurs an up-regulation of adenosine A receptors, 2A contributing to the precipitation-of “off” episodes. Based on Parkinson’s disease.” Other studies were also searched for this mechanism, the action of istradefylline, a selective A 2A any missing data, if any. receptor antagonist, has been defined in managing the “off” 1. Patients: Adults with Parkinson’s disease. episodes by enhancing the effects of levodopa. While for 2. Intervention/Comparator: Istradefylline (40 mg/d), opicapone, a COMT inhibitor produces its effects by opicapone (50 mg/d), placebo/ active comparator. inhibiting the enzyme catechol-o-methyltransferase, which is Both drugs were used as an add-on to levodopa/ responsible for degrading levodopa in the periphery, thus carbidopa, and their maximal recommended doses increasing its level in Central Nervous System (CNS). Since were compared for their efficacy and safety. both these drugs have been introduced recently for managing 3. Primary Outcome: Least square mean change in daily the same condition, this meta-analysis was conducted to “off” time duration from baseline to end-point. compare and appraise their efficacy and safety in patients of 4. Secondary Outcomes: PD who are already on levodopa/carbidopa therapy and are a. The least-square mean change in Unified experiencing “off” episodes. Parkinson’s Disability Rating Scale (UPDRS) part III in the “on” state from baseline to end-point. Methods b. Incidence of Treatment-Emergent Adverse Events (TEAE). This meta-analysis was performed as per the guidelines of c. Incidence of dyskinesia. preferred reporting items for systematic reviews and meta- 5. Study Design: Data extraction was performed by two analyses statement (PRISMA). Furthermore, no ethical authors. The primary demographic details from all the approval was required for this review. clinical trials assessing the safety and efficacy of istradefylline or opicapone against placebo/active comparator among PD patients were also noted. Literature Search and Data Extraction Two authors performed the systematic search (Alok Singh Risk of Bias Assessment and Dhyuti Gupta) among the databases PubMed, Cochrane library, and Clinical Trial Registry https://clinicaltrials.gov/ Quality assessment of the individual study and the risk of bias for a timeline from January 2003 to October 2020 using the was performed as per the preferred reporting items for following keywords: “istradefylline, KW-6002, and systematic reviews and meta-analyses statement (PRISMA) Parkinson’s disease,” and “opicapone, BIA 9-1067, and guidelines and duly demonstrated in the forest plot. Singh et al. 67 male. In a few studies, the standard deviation (SD) for Statistical Analysis continuous data was missing; hence these values were The authors’ assessed the MD and RR with a confidence imputed from other studies with maximum values being interval (CIs) of 95% for continuous and dichotomous considered. variables, respectively. In missing data (standard deviation), Primary Outcome the highest values were imputed from other studies for the 15 2 2 same parameter. I statistics (I > 50% indicated Based on the funnel plot obtained for the primary outcome, heterogeneity) were used to check for heterogeneity among the authors did not observe any publication bias (Figure 2), the included studies. This meta-analysis was performed but heterogeneity was observed (I = 95%, heterogeneity P < using a random-effect model with Review Manager v5.4 for .00001) among these trials (Figure 3). For the least square windows. Moreover, we obtained a funnel plot to assess for mean change in time spent in “off” episodes, both drugs any publication bias (of the primary outcome). showed a significant reduction from baseline to the end of the study period (MD = –0.70; 95% CI [–1.11, –0.30]; P < 0.001 for istradefylline and MD = –0.85; 95% CI [–1.09, –0.61]; Results P < .001 for opicapone), with opicapone performing marginally better than istradefylline (P = .56; Figure 3). Literature Search and Study Characteristics The initial search yielded 236 studies, that is, 57 of Secondary outcomes istradefylline and 179 of opicapone. On further exploring the For the secondary outcomes, the performance of istradefylline clinical trial registry https://clinicaltrials.gov/, we found a was significantly better than the placebo (MD = –1.56; 95% total of 11 clinical trials for istradefylline and five for CI [–2.71, –0.40]; P < .008), but the same cannot be inferred opicapone belonging to different phases. On the other hand, for opicapone (MD = –0.63; 95% CI [–1.42, –0.15]; P < .12). in PubMed, we found a total of ten published clinical trials for The patients who were randomized to receive istradefylline istradefylline and nine for opicapone. The inclusion criteria reported an improvement in the UPDRS III score, but it was set by the authors were met by four clinical trials of 17–23 insignificant compared to opicapone users (MD: –1.56 vs istradefylline and three clinical trials of opicapone. The –0.63; P = .20; Figure 4). reasons for excluding other studies were the pooled analysis Broadly referring to the treatment-emergent adverse of trials, pharmacokinetic studies, different end points, and events (TEAEs), the users of drugs, that is, istradefylline and different doses of the drugs. The relevant characteristics of opicapone, reported more TEAEs than those who were on the included studies have been mentioned in Table 1. The diagnosis of PD among all the included trials was established placebo adjunct (RR = 1.11, 95% CI [1.02, 1.2] for based on the United Kingdom Parkinson’s Disease Society istradefylline and RR = 1.12, 95% CI [1.00, 1.25] for Criteria, and the majority of the recruited participants were opicapone). However, the risk was still comparable among Table 1. Important Characteristics of Included Clinical Trials No. of Patients in Age (y) mean Study N Study Design Each Arm Dose (mg/day) ± SD % Male Lewitt et al. 2008 196 RDBPCT IST: 130 IST: 40 IST: 63 ± 9 59.7 PLB: 66 PLB:64 ± 10 (117/196) Mizuno et al. 357 RDBPCT IST: 124 IST: 40 IST: 63.7 ± 8.6 42.1 2010 PLB: 118 PLB: 65 ± 7.6 (150/357) Pourcheret al. 605 RDBPCT IST: 152 IST: 40 IST: 63 ± 9.3 66.6 2012 PLB: 151 PLB: 63 ± 8.3 (403/605) Mizuno et al. 366 RDBPCT IST: 123 IST: 40 IST: 65.7 ± 9 44.3 (162/366) 2013 PLB: 123 PLB: 65.8 ± 8.6 Ferreira et al. 599 RDBPCT OPC: 115 OPC: 50 OPC: 63.5 ± 9.2 59.1 (354/599) 2016 PLB: 121 PLB: 64.3 ± 9.3 Lees et al. 2017 407 RDBPCT OPC: 135 OPC: 50 OPC: 65.5 ± 8.4 59.5 PLB: 147 PLB: 61.5 ± 8.9 (242/407) Takeda et al. 437 RDBPCT OPC: 145 OPC: 50 OPC: 67.4 ± 7.8 39.8 (174/437) 2020 PLB: 147 PLB: 68.5 ± 8.6 Source: The authors. Abbreviations: RDBPCT: Randomized double-blind placebo-controlled clinical trial; IST: Istradefylline; OPC: Opicapone; PLB: Placebo 68 Annals of Neurosciences 28(1-2) these drugs (P = 0.88; Figure 5). Furthermore, the incidence opicapone), with the patient randomized to receive opicapone of dyskinesia among the active drug users in trials was more reporting more significantly of it than those who received as compared to the placebo (RR = 1.77, 95% CI [1.29, 2.44] istradefylline (P = .02; Figure 6). A comparison of different for istradefylline and RR = 3.47, 95% CI [2.17, 5.57] for outcomes is presented in Table 2. Table 2. Comparison Between Istradefylline and Opicapone for Different Outcomes S. No. Outcomes IST40 OPC50 P-Value 1. The least-square mean change in daily "off" time duration from baseline to –0.70 –0.85 .56 end-point (MD compared to placebo) 2. Least square mean change in Unified Parkinson’s Disability Rating Scale (UPDRS) –1.56 –0.63 .2 part III in the “on” state from baseline to end-point. (MD compared to placebo) 3. Incidence of treatment-emergent adverse events (RR) 1.11 1.12 .88 4. Incidence of dyskinesia (RR) 1.77 3.47 .02* Source: The authors. Note: * statistically significant. Abbreviations: IST: Istradefylline; OPC: Opicapone; MD: Mean difference; RR: Risk ratio Figure 2. Funnel Plot for Studies. Source: The authors. Singh et al. 69 Figure 3. Forest Plot for Least Square Mean Reduction in “off’ Time From Baseline to End Point. Source: The authors. Figure 4. Forest Plot for Least Square Mean Reduction in UPDRS III From Baseline to End Point. Source: The authors. 70 Annals of Neurosciences 28(1-2) Figure 5. Forest Plot for Incidence of Treatment-emergent Adverse Events. Source: The authors. Figure 6. Forest Plot for Incidence of Dyskinesia. Source: The authors. Singh et al. 71 any modulatory effect of opicapone on DRs. More clinical Discussion studies are needed to substantiate this finding. Both drugs had a similar incidence of TEAEs, but the The present meta-analysis includes two recently approved incidence of dyskinesia was more with opicapone, and it was drugs for “off” episodes in PD. Our study incorporates statistically significant. Increased incidence of dyskinesia randomized clinical trials, which were mostly of high quality. with opicapone may be attributable to the increased We found that certain biases might have existed, that is, availability of levodopa in CNS, and this effect lacks in selection and detection bias in few studies (mentioned in 17,19,20 istradefylline. This also agrees that istradefylline is less forest plot). The possible explanations for biases were effective in reducing “off” time duration and has less inappropriate information provided in the text regarding the dyskinesia. As “off” episodes are usually encountered after method of randomization, allocation concealment, and five to seven years of therapy with ongoing neurodegeneration, outcome assessment. In few studies, SD was not mentioned, the drugs offer nonphysiologic replacement of dopamine imputed from other studies, and the maximum value was possibly due to the increase in levodopa, which is responsible taken, which is the simplest method of imputation. In for its beneficial effects, is also responsible for the dyskinesia general, all the included trials had a low number of participants as the replacement is nonphysiologic. The development of (196–605). Although PD is the most common movement dyskinesia may be a limiting factor in the wide acceptance of disorder of neurodegenerative nature, the absolute incidence opicapone. is low, that is, 11–19/100000 per year, which may be one of Both drugs had common adverse effects of dopamine the reasons for the low number of participants. Clinically, excess in CNS, that is, hallucination(s) and impulse control the “on-off” phenomenon starts manifesting after a few years disorder; however, hallucinations are more common with of treatment; this may also be a contributing factor in istradefylline. Hallucinations with istradefylline have been relatively fewer participants. Most of the participants of the reported in every clinical trial, but only one clinical trial included trials were male and were in the sixth decade of their 17–20,23 reported hallucination with opicapone. Further on life that follows the usual epidemiological trend. carefully observing clinical trials of istradefylline, the For the efficacy outcomes, both drugs showed a significant hallucination appears to be dose-dependent. This fact has also reduction in “off” time and an improvement in UPDRS III been substantiated in the real-world study of istradefylline. score from baseline to end-point as compared to placebo. The In addition to these adverse effects, opicapone had peripheral reduction in “off” time by opicapone was slightly higher than adverse effects of dopamine excess, that is, hypotension and by istradefylline. Reduction in "off" time indicates that both arrhythmias, which can be dangerous in the geriatric drugs restored the effectiveness of levodopa/carbidopa, which population. Both drugs must be avoided in case of severe was compromised due to ongoing neurodegeneration, though hepatic impairment, and dose reduction is required in by different mechanisms. UPDRS is used to assess the moderate hepatic dysfunction. The opicapone is to be taken symptoms of Parkinson’s and is divided into four segments, without food, whereas istradefylline can be taken with or in which part III deals with the motor symptoms of PD. The 34,35 without food. adenosine antagonist, that is, istradefylline, had better improvement than opicapone in UPDRS III “on” state. The adenosine receptor heterodimerizes with the dopamine Limitations receptor (D2), thereby modulates dopamine response and motor behavior. Chronic levodopa therapy possibly This study has got certain limitations, that is, a relatively up-regulates the adenosine receptor and may be responsible fewer number of studies were included, and the included for the precipitation of “off” episodes. Istradefylline may studies were of relatively less duration (12–14 weeks). The prevent heterodimerization, leading to increased dopaminergic missing SD in some of the studies was imputed from other activity and possibly explaining the better UPDRS III score. studies. The effects of istradefylline (40 mg) were similar to the 26–29 previous meta-analysis. On the other hand, an increase in levodopa level in CNS by opicapone may be responsible for Conclusion the significant reduction in “off” time; however, the same was not observed with UPDRS III. The positive correlation of Practically, the “off” phenomena can be considered a change levodopa and improvement in UPDRS III has been shown in in a PD patient's clinical state where motor and/or nonmotor 30–32 previous studies. As opicapone’s primary mechanism symptoms appear or worsen, resulting in functional disability. involves increased availability of levodopa into the CNS, it Amongst the various classes of drugs available to manage was expected to improve UPDRS III significantly. This PD, nondopaminergic drugs can be utilized to manage “off” unanticipated finding may be attributable to a severe loss of episodes with the long-term levodopa/carbidopa therapy, and dopaminergic neurons to the extent that even levodopa and a detrimental effect eventually develops, that being “on-off” opicapone could not improve UPDRS III along with lack of fluctuations. 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