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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061536 |
E.1.2 | Term | Parkinson's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
investigate whether early treatment with cholinesterase inhibitors delays the progression of minor VH to major visual hallucinations without insight or Parkinson's disease associated psychosis. |
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E.2.2 | Secondary objectives of the trial |
In addition, we will measure motor control, psychotic symptoms, cognitive impairment, mood disorders, adverse events and compliance, quality of life, caregiver burden and care use. We assess the cost-effectiveness of early chronic treatment of VH with ChEI. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. idiopathic PD with bradykinesia and at least two of the following signs; resting tremor, rigidity, and asymmetry (in accordance with clinical diagnostic criteria of the UK PD Society Brain Bank);
2. the presence of minor visual hallucinations for at least 4 weeks, defined by a score of 1 or 2 on the hallucinations item of the Unified Parkinson’s Disease rating Scale (UPDRS)1-MDS;
3. age 40 years and over.
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E.4 | Principal exclusion criteria |
1. Parkinson's disease associated psychosis, defined as the need for antipsychotic drug treatment in the opinion of the treating neurologist;
2. Parkinson's disease dementia, defined by a score of 26 or lower on the Mini Mental State Examination (MSSE);
3. current delirium (caused by infection or metabolic disturbance);
4. current treatment with drugs that have important central anticholinergic effects
5. current or recent (<6 months) treatment with Cholinesterase inhibitors, such as rivastigmine (Exelon) or galantamine (Reminyl);
6. VH in response (≤ 1 month) to increase of dopamingergic treatment
7. history of psychosis, (known) sick sinus syndrome or other arrhythmia
8. current severe ophtalmologic disease (defined as a visual acuity score of < 0.5 based on Snellen eye test);
9. permanent stay in a nursing home;
10. no informed consent.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is the time until Parkinson's disease patients with minor visual hallucinations progress to major visual hallucinations without insight. The clinical endpoint is defined as the start with antipsychotic treatment. This decision is left to the discretion of the treating neurologist. In this manner the design represents clinical practice. (The severity of visual hallucinations is measured as a secondary outcome with the UPDRS 1 – MDS, to confirm insight is lost.) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
I. Motor control measured with the UPDRS – MDS part 3;
II. Psychotic symptoms using the UPDRS – MDS part 1 (hallucinations item) and the Schedule for Assessment of Positive Symptoms (SAPS); Besides changes in the severity of psychotic symptoms, the proportion of patients that progresses to a score ≥ 3 (i.e. loss of insight) in the two treatment groups (rivastigmine and placebo) is measured after the total 24 months follow-up period.
III. Cognitive function based on the Mini mental state examination (MMSE), Montreal Cognitive Assessment and Parkinson’s Disease-Cognitive Rating Scale (PD-CRS);
IV. Mood disturbance according to the Hospital Anxiety and Depression Scale (HADS);
V. Daytime sleepiness on the Epworth Sleepiness Scale (ESS);
VI. Cholinergic deficiency, as a possible predictor for response to treatment, measured with the Cholinersterase Inhibitor Prognosticator (ChIP)
VII. Number and type of adverse events;
VIII. Compliance to treatment measured by the number of remaining capsules after every 6 months of follow-up;
IX. Disability based on the AMC Linear Disability Score (ALDS);
X. Caregiver burden according to the Zarit Caregiver Burden Inventory (ZCBI);
XI. Care use measured with the EuroQol-5D (EQ-5D).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |