| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10034005 |
| E.1.2 | Term | Parkinson's disease and parkinsonism |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the add-on efficacy of opicapone 50 mg or an extra dose of L-DOPA 100 mg as first strategy for the treatment of wearing-off in patients with PD. |
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| E.2.2 | Secondary objectives of the trial |
| To investigate the safety and tolerability of combined treatment (current L-DOPA/DDCI treatment plus opicapone 50 mg or an extra dose of 100 mg of L-DOPA) for treatment of wearing-off in PD patients. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria at screening (V1)
1. Able to comprehend and willing to sign an informed consent form and to comply with all aspects of the study.
2. Male or female patients aged 30 years or older.
3. Diagnosed with idiopathic PD according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria (2006) or according to the Movement Disorder Society (MDS) Clinical Diagnostic Criteria (2015).
4. Disease severity Stages I-III (Hoehn & Yahr staging) at ON.
5. Treated on a stable regimen for at least four weeks before screening with immediate-release L-DOPA/DDCI, three to four intakes per day, and up to maximum daily dose of 600 mg L-DOPA.
6. In case of any other anti-PD-treatments, they should be on a stable regimen for at least four weeks before screening, and not likely to need any adjustment during the study.
7. Signs of wearing-off phenomenon with average total daily OFF-time while awake of at least 1 hour, including the early morning pre-first dose OFF (i.e. the time between wake-up and response to the first L DOPA/DDCI dosage), despite optimal anti-PD therapy (based on Investigator’s assessment).
8. Experiencing wearing-off phenomenon for at least 4 weeks but less than 2 years prior to screening.
9. For females: Postmenopausal for at least 2 years before screening, surgically sterile for at least 6 months before screening, or practicing effective contraception until the post-study visit. Female patients who request to continue with oral contraceptives must be willing to use non-hormonal methods of contraception in addition during the course of this study.
Inclusion criteria at baseline (V2)
10. Have filled-in self-rating diary charts in accordance with the diary chart instructions and with ≤3 errors per day while awake, in the three consecutive days preceding randomization.
11. With at least 1 hour at OFF state per day, including the early morning pre-first dose OFF period (i.e. the time between wake-up and response to the first L DOPA/DDCI dosage), as recorded in at least two of the three-day self-rating diary charts for the three days preceding randomization.
12. Adequate compliance to relevant concomitant medication during the period between V1 and V2 (based on the Investigator’s judgment).
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| E.4 | Principal exclusion criteria |
Exclusion criteria at screening (V1)
1. Non-idiopathic PD (atypical parkinsonism, secondary [acquired or symptomatic] parkinsonism, Parkinson-plus syndrome).
2. Severe and/or unpredictable OFF periods, according to Investigator’s judgment.
3. Average total daily OFF-time while awake of >5 hours, including the early morning pre-first dose OFF, despite optimal anti-PD therapy (based on Investigator’s assessment).
4. Treatment with prohibited medication: entacapone, tolcapone, monoamine oxidase (MAO) inhibitors (except selegiline up to 10 mg/day in oral formulation or 1.25 mg/day in buccal absorption formulation, rasagiline up to 1 mg/day or safinamide up to 100 mg/day), apomorphine or antiemetics with antidopaminergic action (except domperidone) within the last 4 weeks before screening.
5. Previous or planned (during the entire study duration) deep brain stimulation or stereotactic surgery (e.g. pallidotomy, thalamotomy).
6. Previous or current use of opicapone or L-DOPA/carbidopa intestinal gel infusion.
7. Use of any other investigational product (IP), currently or within the 3 months (or within 5 half-lives of the IP, whichever is longer) before screening.
8. Past (within the past year) or present history of suicidal ideation or suicide attempts.
9. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine.
10. Phaeochromocytoma, paraganglioma, or other catecholamine secreting neoplasms.
11. Known hypersensitivity to the excipients of IP (including lactose intolerance, galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption).
12. History of neuroleptic malignant syndrome or non-traumatic rhabdomyolysis.
13. History of severe hepatic impairment (Child-Pugh Class C).
14. Current or previous (within the past year) diagnosis of psychosis, severe major depression or other psychiatric disorders that, based on the Investigator’s judgment, might place the patient at increased risk or interfere with assessments.
15. Any medical condition that might place the patient at increased risk or interfere with assessments.
16. For females: Pregnant or breastfeeding.
17. Employees of the Investigator, study centre, Sponsor, clinical research organisation and study consultants, when employees are directly involved in this study or other studies under the direction of this Investigator or study centre, and their family members.
18. Persons committed to an institution by virtue of an order issued either by the judicial or other authorities.
Exclusion criteria at baseline (V2)
19. With an average total daily OFF-time while awake of >5 hours, including the early morning pre-first dose OFF period (i.e. the time between wake-up and response to the first L DOPA/DDCI dosage), as recorded in at least two of the three-day self-rating diary charts for the three days preceding randomization.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change in Absolute OFF-time from baseline to end of study |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to end of study |
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| E.5.2 | Secondary end point(s) |
• Proportion of patients with one hour or more reduction in Absolute OFF-time from baseline to end of study (OFF-time responders)
• Change in Absolute ON-time from baseline to end of study
• Proportion of patients with one hour or more increase in Absolute ON-time from baseline to end of study (ON-time responders)
• Change in Percentage OFF-time between baseline and end of study (calculated as the sum in minutes from 30-minute periods classified as OFF divided by the total time awake)
• Change in Percentage ON-time between baseline and end of study (calculated as the sum in minutes from 30-minute periods classified as ON divided by the total time awake)
• Additional efficacy outcomes include the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Movement Disorder Society-Non-Motor Rating Scale (MDS-NMS), the Parkinson’s Disease Questionnaire-8 (PDQ-8), the Clinical Global Impression of Improvement (CGI-I) and the Patient Global Impression of Change (PGI-C)
• Adverse Events (AEs) and • Serious Adverse Events (SAEs) collected from screening to the post-study follow-up visit
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to end of study
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Spain |
| Germany |
| Italy |
| Portugal |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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