key: cord-0770904-on1c1ngb
authors: Chaudhuri, K. Ray; Odin, Per; Ferreira, Joaquim J.; Antonini, Angelo; Rascol, Olivier; Kurtis, Mónica M.; Storch, Alexander; Bannister, Kirsty; Soares-da-Silva, Patrício; Costa, Raquel; Magalhães, Diogo; Rocha, José Francisco
title: Opicapone versus placebo in the treatment of Parkinson’s disease patients with end-of-dose motor fluctuation-associated pain: rationale and design of the randomised, double-blind OCEAN (OpiCapone Effect on motor fluctuations and pAiN) trial
date: 2022-03-12
journal: BMC Neurol
DOI: 10.1186/s12883-022-02602-8
sha: 40010b5bcf669f97dfe4c2f8916574f002dd44f5
doc_id: 770904
cord_uid: on1c1ngb

BACKGROUND: Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson’s disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi). METHODS: OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King’s Parkinson’s disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson’s Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient’s Global Impressions of Change, and change in functional status via Hauser’s diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022. DISCUSSION: The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain. TRIAL REGISTRATION: EudraCT number 2020–001175-32; registered on 2020-08-07.

Types of pain and specific features Musculoskeletal pain • Aching, cramping, arthralgic, myalgic sensations in joints and muscles • May include muscle tenderness, arthritic changes, skeletal deformity, limited joint mobility, postural abnormalities, and antalgic gait • May be exacerbated by parkinsonian rigidity, stiffness and immobility, and alleviated by mobility • May fluctuate with medication dose and improves with levodopa Radicular or peripheral neuropathic pain • Pain in root or nerve territory, associated with motor or sensory signs of nerve or root entrapment Dystonia-related pain • Associated with sustained twisting movements and postures; muscular contractions often very forceful and painful • May fluctuate closely with medication dosing: early morning dystonia, OFF dystonia, beginning-of-dose and end-of-dose dystonia, peak dose dystonia Primary/central pain • Burning, tingling, formication, 'neuropathic' sensations; often relentless and bizarre in quality, not confined to root or nerve territory • Pain may have an autonomic character, with visceral sensations or dyspnoea, and vary in parallel with the medication cycle as NMF • Not explained by rigidity, dystonia, musculoskeletal or internal lesion Akathitic discomfort/other pain • Primary headache, visceral, arthritic, non-radicular low back pain, oral and genital pain • Unpleasant agitating sensation associated with restless legs syndrome conditions, exacerbated by a lowered pain threshold that may result from dysfunctional nociceptive processing caused by specific neurodegenerative changes [12, 21, 22] . Abnormal basal ganglia function in PD modulates pain directly and indirectly via mechanisms that impact both affective and cognitive nociceptive processing [23] . Pain has been shown to be associated with sleep disruption and cardiovascular disturbances in PD, and there is an indication that pain, sleep disruption and dysautonomia may share a common pathophysiology involving non-dopaminergic pathways [16] . Several recent publications have reviewed the current treatment options for each type of pain in PD [12, 19, 24, 25] . Pain in PD is also associated with motor fluctuations [11, 26] . The role of dopamine in pain signalling is complex. Pain relief elicits rewards mediated by elevated dopamine in the nucleus accumbens, and reciprocity with higher brain regions such as the anterior cingulate cortex and dopaminergic transmission therein is necessary for the relief of pain aversiveness [27] . Meanwhile, along with serotonin and noradrenaline, dopamine may modulate pre-synaptic inhibition in the mouse spinal cord [28] . The precise mechanism underlying dopamine's role in pain modulation is hitherto equivocal. Clinically, dopaminergic therapies have been shown to alleviate pain in PD [12, 21, 22, 29] and fluctuation-related pain in PD is believed to be partially mediated by dopamine [12, 30] . Studies that manipulate dopamine with the aim of translation to clinical therapy will be hampered by dopamine's role in movement and reward [31] . While optimisation of dopaminergic therapy may alleviate fluctuation-related pain [12, 22, 32, 33] , high-quality evidence of the benefit of dopaminergic therapies in PD-associated pain is lacking [30] , with only one study coming close to providing Level 1 evidence, although failing to meet its primary endpoint at 16 weeks [34] . One reason for this is that, until recently, there were no disease-specific scales to adequately measure the heterogeneous types of pain in PD; this has now been resolved with the development and validation of the King's Parkinson's disease Pain Scale (KPPS) [35] .

Levodopa is still the most effective symptomatic treatment for PD [36] . However, following oral administration, levodopa is extensively metabolised in the periphery by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT), and only 1% of an oral dose of levodopa reaches the brain [37, 38] . Moreover, long-term treatment with levodopa is complicated by the development of wearing off and drug-induced dyskinesia [36, 39] . Pain increases during OFF periods and patients with dyskinesia have increased pain sensitivity [40, 41] . Treatment with levodopa has been shown to improve pain thresholds in patients with PD, unlike the dopamine agonist apomorphine [16, 42] . Inhibitors of DDC (DDCi) and COMT (COMTi) are commonly used as an adjunct to levodopa in patients with PD in order to increase levodopa bioavailability and its delivery to the brain, and thereby ameliorate wearing-off symptoms [38, 43, 44] .

Opicapone (OPC) is a third-generation, once-daily COMTi [37, 38, 45, 46] , which has been shown to be generally well tolerated and efficacious in reducing OFFtime in two pivotal trials in patients with PD and end-ofdose motor fluctuations (BIPARK-I and II) [47, 48] . On the basis of these trials, OPC is approved in the European Union, USA, Japan, Australia and other countries as adjunctive therapy to preparations of levodopa/DDCi in patients with PD and end-of-dose motor fluctuations [49] or OFF episodes [50] . A positive signal for OPC was observed on the Non-Motor Symptoms Scale (NMSS) miscellaneous domain, which includes pain, in both the BIPARK II trial [51] and the OPTIPARK study [52] .

Given the probable dopamine-related pathophysiology of motor fluctuation-associated pain [12] and the encouraging signals detected in previous OPC studies, the Opi-Capone Effect on motor fluctuations and pAiN (OCEAN) study has been designed. This trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/DDCi.

OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo (PLC)-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain (experienced for ≥4 weeks prior to the start of the study, with a score of ≥12 [out of 36] on Domain 3 of the KPPS at screening and baseline). It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period (Fig. 1 ). Following screening, at visit (V) 2 (baseline), eligible patients will be randomised 1:1 to OPC 50 mg or PLC once daily while continuing current treatment with levodopa/DDCi. Since OPC enhances the effects of levodopa, it may be necessary to reduce the patient's levodopa/DDCi dosing within the first days or weeks of OPC treatment; therefore, the investigator may decrease the daily dose of levodopa/ DDCi as needed until V4, while keeping the number of daily intakes unchanged. If necessary, dosing may be increased back to the baseline dose level. After V4, the levodopa/DDCi dose should not be changed until the end of the study. The anti-PD treatment regimen should be stable for at least 4 weeks prior to V1 (Table 2 ) and kept stable throughout the study (except for levodopa/DDCi during the adjustment period). No new anti-PD drugs should be started during the study.

Chronic pain treatment should be stable for at least 4 weeks prior to V1 (Table 2) , and no new pain medication should be started during the study, except the allowed rescue medication (paracetamol or tramadol, based on the experience from the DOLORES trial [53] ). The baseline dose of pain medication may be reduced during the study, if required due to pain medicationrelated adverse events (AEs), and increased again up to baseline dose level if necessary. Further visits will be performed on Day 85 ± 4 days (V5) and Day 169 ± 4 days (V6). The primary analysis will be performed on data collected at V6. A follow-up visit will be performed on Day 183 ± 4 days (V7), approximately 2 weeks after the last intake of study medication (OPC 50 mg or PLC). Patients who discontinue early will be requested to attend an early discontinuation visit. At V6 (or early discontinuation visit, if applicable), the investigator will arrange the patient's subsequent treatment (i.e. either prescribe further OPC or switch to another treatment).

At V1, each patient will be assigned in a chronological order via their electronic case report form to a unique patient number, which will be transferred by the site staff to an interactive web response system (IWRS). At V2b, after eligibility for entry into the treatment phase is confirmed, site staff will contact the IWRS to obtain the appropriate medication number. Randomisation will follow a 1:1 allocation rate (OPC 50 mg or PLC) and the randomisation list will be produced by the contract research organisation (Scope International AG, Mannheim, Germany) using the Statistical Analysis System (SAS) for Windows (SAS Institute Inc., Cary, NC, USA). The original list will be kept at the contract research organisation. Each patient's investigational product will be determined by their randomisation number and corresponding medication number. OPC 50 mg and PLC capsules will be identical in size, colour, taste and appearance, and the packaging and labelling will not allow distinction between treatments. No person involved in conducting the study will have access to the randomisation code before the blind is officially broken. Unblinding will not occur unless there is an actual emergency and knowledge of the patient's allocated treatment arm affects their treatment, in which case the individual treatment assignment for each patient will be available to the principal investigator/authorised delegate and responsible medical monitor via the IWRS. Patients with suspected unexpected serious adverse reactions (SUSARs) will be unblinded for regulatory reporting by the contract research organisation's safety manager. Other study personnel and the investigators will receive blind information on the SUSAR until the study has been unblinded. The medication will be supplied by the sponsor (BIAL -Portela & Ca S.A., Coronado, Portugal) and the investigator/institution and/or a pharmacist or other appropriate individual (designated by the investigator/institution) will maintain records of delivery, inventory usage, and return any unused study medications. The investigator or an authorised delegate will be responsible for dispensing medication to the patients according to the dosage scheme and IWRS. At each study visit, site staff will dispense the appropriate amount of investigational product and rescue medication for each patient and for each treatment interval plus one extra week per 4 treatment weeks. At each visit, patients must bring back the study medication (including empty and partially empty containers) and accountability will be performed and documented. . The protocol will be submitted to national Independent Ethics Committee(s) and Competent Authorities and unconditional approval/favourable opinion must be obtained before the start of the study. All patients must provide written informed consent in order to participate in the study. Data processing will be conducted by the contract research organisation. This will include, but is not limited to, producing the patient diary and electronic case report form, and setting up a relevant database and data transfer mechanisms, along with appropriate validation of data and resolution of queries. Clinical data will be collected in electronic form using an electronic data capture system. All clinical data will be recorded, processed, handled and stored without disclosing personal information of the patients so that the data can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the patients remain protected, in accordance with the applicable rules on personal data protection.

The study will be conducted in approximately 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Other countries and additional sites may be added, if required. Inclusion and exclusion criteria are outlined in Table 2 .

An overview of study assessments is presented in Table 3 and the timing of these assessments is outlined in Fig. 2 . Investigators will be trained on how to perform all assessments during each site initiation visit and at subsequent investigator meetings. Movement Disorder Societysponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) training certificates will be provided to all sites according to MDS procedures.

The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the KPPS. The KPPS evaluates the burden and characterises various Table 3 Overview of study assessments a Paracetamol or tramadol; b haematology, serum biochemistry, pregnancy test (0-4) , resulting in subscores of 0-12. The total KPPS score (0-168) represents the symptomatic burden by pain [35] .

The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). The MDS-NMS comprises 13 domains covering a range of key PD-and treatment-related NMS, and a subscale for NMF that assesses changes in NMS in relation to timing of anti-PD medications across eight domains [54, 55] . Additional secondary efficacy endpoints comprise of other domains and total scores of the KPPS and MDS-NMS, change from baseline in the MDS-UPDRS Parts III and IV, change from baseline in the Parkinson's Disease Questionnaire (PDQ-8), Clinical Global Impression of Change (CGI-C), Patient's Global Impression of Change (PGI-C), change from baseline in functional status via Hauser's PD diary, changes from baseline in morning dystonia, and use of rescue medication ( Table 3) .

The MDS-UPDRS is a revision of the UPDRS originally developed in the 1980s, and evaluates various aspects of PD; it consists of four parts [56] : Parts IA and IB, non-motor aspects of experiences of daily living; Part II, motor aspects of experiences of daily living; Part III, motor examination; and Part IV, motor complications. The PDQ-8 (a short form of the PDQ-39) is a patientreported outcome that assesses eight aspects of functioning and well-being that are usually adversely affected by PD: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. It rates overall health status by providing a single score ranging from 0 (good health) to 100 (poor health) [57] . The CGI-C and PGI-C are, respectively, investigator and patient assessments of how much a patient's overall status has improved or worsened since the start of the study, comprising a 7-point scale: (1, 'very much improved'; 2, 'much improved'; 3, 'minimally improved'; 4, 'no change'; 5, 'minimally worse'; 6, 'much worse'; 7, 'very much worse'). The Hauser's PD diary is a patient record of their mobility during each 30-min period, categorised as: asleep; OFF time; ON time without dyskinesia; ON time with non-troublesome dyskinesia; or ON time with troublesome dyskinesia. When assessing changes from baseline in morning dystonia, the investigator will ask the patient if they experienced any morning dystonia within the last week (based on item 35 of the former UPDRS version). The amount and frequency of intake of rescue medication (paracetamol or tramadol) will be recorded by patients in a diary.

Safety assessments include the incidence of treatmentemergent AEs (TEAEs), and changes from baseline in vital signs, physical and neurological examinations and routine laboratory parameters (Table 3 ; Fig. 2 ). At each study visit, the investigator will ask the patient in a nonleading manner about the state of their health in order to illicit information on TEAEs that may have occurred since the last visit. Any clinically significant observations made during the visit also constitute TEAEs. TEAEs will be documented as soon as possible in the electronic patient report form. The following information will also be specified: date/time of onset of TEAE; action taken with the investigational product; other actions taken; outcome of TEAE; seriousness of TEAE; severity of TEAE (mild, moderate, severe); and causal relationship of TEAE to investigational product (unrelated, unlikely, possible, probably, definite).

For the primary efficacy endpoint (change from baseline in Domain 3 of KPPS), a difference to PLC of 3.0 is regarded as clinically meaningful. From a former study [53] , a standard deviation (SD) of 5.8 can be assumed. With a two-sided significance α of 0.05, a power of 80%, a 1:1 treatment allocation ratio and with the above-mentioned assumptions, 2 × 60 = 120 evaluable patients are required. Assuming a drop-out rate of 15%, a total of 140 patients need to be randomised. Randomisation will follow a 1:1 allocation rate (OPC 50 mg or PLC).

Efficacy assessments will be analysed for the Full Analysis Set, defined as all patients who are randomised and who have at least one measurement of the primary efficacy assessment. For sensitivity purposes, efficacy assessments will additionally be analysed for the Per-Protocol Set, defined as all patients included in the Full Analysis Set who have no major protocol deviations that could influence the primary efficacy assessment. The primary efficacy endpoint will be analysed using analysis of covariance (ANCOVA), with treatment as a fixed factor and baseline KPPS as a covariate, to demonstrate superiority of OPC 50 mg against PLC. Secondary efficacy endpoints will be analysed in an exploratory manner by treatment arm using appropriate parametric and non-parametric statistical methods. Descriptive statistics, including 95% confidence intervals, will be presented per treatment arm. Safety assessments will be analysed for the Safety Set, defined as all patients who take at least one dose of investigational product. TEAEs will be summarised in terms of the number and percentages of patients with TEAEs. Vital signs and laboratory parameters will be summarised using summary statistics of absolute values and changes from baseline. Summary statistics and shift tables will be presented for physical and neurological examinations. Demographic and baseline characteristics will be presented using descriptive statistics. The statistical analysis plan will be carried out by biostatisticians from the contract research organisation.

The first patient was enrolled in February 2021 in the UK. The recruitment window is now open and the last patient is expected to complete the study by late 2022. Timelines might be impacted by recurring COVID-19-related lockdowns impairing the access of patients to healthcare facilities.

Pain has a major impact on the quality of life of patients with PD [23, [58] [59] [60] and nociceptive pain accounts for the majority of reported pain in PD [22] . Since pain modulation involves striatal dopamine D 2 receptors [61] , pain associated with end-of-dose motor fluctuations may be alleviated through optimisation of dopaminergic therapy [12, 21, 22, 29] .

Management of pain, among many other non-motor aspects of PD, remains a key unmet need [62] and there is currently a lack of robust data on the management of pain in PD patients with end-of-dose motor fluctuations. Previous studies in this setting have notable limitations, as well as varying both in the tools used to measure pain and the types of pain assessed. The Phase II PANDA trial was the first randomised controlled trial to specifically assess treatment for PD-associated pain [34] . Eligible patients were randomised to receive either prolonged-release oxycodone-naloxone or placebo. The types of pain patients experienced at baseline included musculoskeletal pain (73% in active arm), nocturnal pain (35%), fluctuation-related pain (32%) and PD-related chronic pain (26%). There was no significant difference between treatment arms in the average 24-h pain score at 16 weeks (primary endpoint). However, the measure used to assess pain was a general pain scale (a Likert scale) and levodopa was used more frequently as a rescue treatment in the placebo arm, both of which factors might have affected the results [34] . The double-blind, exploratory DOLORES trial was the first to investigate the effect of a dopamine agonist (rotigotine; administered as a transdermal patch) on PD-associated pain as primary outcome [53] . The types of pain patients experienced at baseline included musculoskeletal pain (51% in active arm), neuropathic pain (23%) and dystonic pain (14%). Although the findings suggested that rotigotine may improve PDassociated chronic pain in patients with advanced-stage PD, the trial was not powered to detect statistically significant treatment differences, due to the small sample size [53] . Safinamide (an agent with multiple modes of action, including monoamine oxidase-B inhibition) was shown to significantly reduce the need for pain medication, and to significantly improve two out of three PDQ-39 painrelated items, in comparison with placebo, when added to existing levodopa-based therapy [13] . However, these results were based on a post-hoc analysis of two previous trials and must therefore be interpreted with caution.

The design of the OCEAN study will address the current lack of reliable evidence for levodopa-based therapy in the treatment of PD-associated pain. OCEAN features recent validated PD pain-and non-motor-specific scales (such as the KPPS and the MDS-NMS), which might help to record dimensions of PD-associated pain that have not been previously studied. For instance, this study may allow the detection of potential associations between pain and other NMS, such as depression, anxiety and insomnia, and dysautonomic symptoms. The concomitant use of ON/OFF diaries with these scales may also allow a deeper understanding of pain and other NMS, such as the key secondary endpoint anxiety (as assessed by change from baseline in Domain B of the MDS-NMS), during both the OFF and ON states. Anxiety problems, including OFF-period anxiety, are highly prevalent in PD and greatly impact quality of life [63, 64] . Although some data suggest that anxiety symptoms inversely correlate with motor improvement induced by oral levodopa [65] , this has been a neglected area in clinical investigation [30] . Placebo is known to activate dopamine receptors and to induce dopamine-like effects in PD [66] [67] [68] [69] , which are often still apparent in studies at 3 months [34, 47, 48] , tending to wane by the 6-month mark [70, 71] . The 6-month course of OCEAN and its double-blind design might therefore help to disentangle the placebo dopamine-mediated effect from the true pharmacological benefit of OPC, especially when evaluating pain.

In summary, the OCEAN study will provide valuable information on whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The data will address the current lack of Level 1 evidence for the recommendation of strategies to manage aspects of pain in PD. 

He serves as consultant for Boehringer Ingelheim for legal cases on pathological gambling; owns Patent WO2015110261-A1; and owns shares in PD Neurotechnology Limited. OR has participated in advisory boards and/or provided consultancy for AbbVie

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Editorial assistance was provided by John Scopes of mXm Medical Communications and funded by Bial -Portela & Cª, S.A.

All authors participated in the study design. JFR, DM, RC and PSS are participating in the study implementation. All authors were involved in the initial ideas presented in the introduction and discussion of this article. KRC wrote a major part the first draft of the manuscript; PO, JJF, AA, OR, MMK, AS and KB made substantial contributions to the writing and revising of the manuscript; and JFR, DM, RC and PSS provided critical review. All authors approved the final submitted manuscript.

The study design, data collection/analysis/interpretation and editorial assis-