| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Mild Cognitive Impairment
Mild Alzheimer's disease |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Psychological processes [F02] |
| MedDRA Classification |
| 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 |
| Do dopaminergic drugs improve memory consolidation when given before sleep to older adults without a diagnosis of memory impairment, to those with a diagnosis of amnesic Mild Cognitive Impairment and to those with a diagnosis of Alzheimer's Disease? |
|
| E.2.2 | Secondary objectives of the trial |
Do two different types of drugs (co-beneldopa & ropinirole) affect memory and sleep in the same way?
Are changes in memory performance related to changes in sleep architecture?
Are changes in memory performance related to the amount of structural integrity in pathways connecting the hippocampus and Ventral Tegmental Areas in the brain, and/or to the strength of functional connectivity when on the drugs? |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All participants must express that they are willing to take part in this study and adhere to the study procedures. They must also be native or fluent English speakers. It is important that participants are highly proficient in the English language as the verbal memory test will be in English. They must also have normal or corrected to normal vision as poor vision may interfere with visual memory testing. We will recruit both men and women.
We aim to recruit healthy participants who are 65 years or older. However, if we recruit a patient who is younger than this, we will attempt to find an age-matched healthy control. All patients participating in this study will either have a diagnosis of MCI or mild AD. Those with a diagnosis of AD or MCI will have been diagnosed by a general practitioner or a neurologist, according to established criteria (Albert et al., 2011; McKhann et al., 2011).
All participants will be capable to consent for themselves. Participants are deemed as capable of giving informed consent if they score above 11/30 in MoCA, and if the person taking consent deems the volunteer capable. MoCA is a conservative test and 11/30 on a MoCA corresponds to 20/30 on the mini mental state examination (MMSE) (Roalf et al., 2013), which is another commonly used diagnostic measure. We have extensive experience assessing capacity in this way and all participants will be reviewed by a consultant neurologist before administering any treatment. |
|
| E.4 | Principal exclusion criteria |
The participants must not have:
clinically significant neurological or psychiatric diagnoses, other than MCI or mild AD in the patient group. This will be assessed by self-report and questionnaires during the screening visit.
known posterior cortical atrophy (mainly relevant for MCI and AD, who will have had a brain scan as a part of the diagnostic procedure)
clinically significant sleep problems in the past year
an undiagnosed skin lesion. Participants will be asked about this.
a known sensitivity to levodopa, ropinirole, benserazide, or domperidone
known lactose intolerance, galactosemia or glucose/galactose malabsorption
known galactose intolerance
known Lapp lactase deficiency
diagnosis of Huntington’s Chorea
clinically significant intention tremor. This will be screened for by a trained investigator
known prolactin-releasing pituitary tumour (prolactinoma)
diagnosis of glaucoma
a history of, or current, malignant melanoma
diagnosed unstable diabetes (people with stable type 2 diabetes diet controlled diabetes may be recruited)
severe endocrine, hepatic, renal, pulmonary, or cardiac disorder
diagnosed electrolyte disturbances
known peptic ulcers
history of a heart-attack or prolongation of cardiac conduction intervals, or any other cardiac problems as taking domperidone increases risk of said problems. An ECG will be taken at the screening visit and heart-rate and blood pressure will be monitored before and after drug administration, as specified elsewhere in this protocol.
current cancer treatment
Body weight higher than 150 kilograms, as this puts participants at a highly elevated risk of having sleep apnea, which will interfere with sleep recordings. High body weight may also cause difficulty in the MR-scanner.
The participant must not be taking:
dopaminergic medications
noradrenergic, serotonergic, or anticholinergic medications started or changed within the past 3 months
monoamine oxidase inhibitors (MAO-I), except if selective MAO-A or MAO-B inhibitors are given alone. MAO-A and MAO-B inhibitors given together are equivalent to non-selective MAO-inhibition and therefore volunteers taking both MAO-A and MAO-B will not be included in this study
cholinesterase inhibitors, except if the participant has been on stable treatment (at least 3 months)
antihypertensive (blood pressure) drugs containing reserpine
ferrous sulphate on the day of testing
opioids or sympathomimetics (e.g. amphetamines, epinephrine/adrenaline)
diazepam or other benzodiasepines, unless none taken for prior 3 days or stable dose has been maintained for more than 3 months
ketoconazole, erythromycin or CYP3A4 inhibitors (e.g. fluoconazole, voriconazole, clarithromycin, amiodarone, telithryomycin)
antibiotics
hormone replacement therapy
anti-fungal agents (pentamidine)
anti-malarial agents
antihistaminics unless stable dose for 3 months or none for 3 days prior to testing sessions
AIDS/HIV medications
if a participant takes antacids or antisecretory agents they should not be taken at the same time as domperidone (but these participants can be included if the medication can be taken at a different time)
The participants will be asked to provide a list of medications they take, including alternative medication, and a clinician will verify that the participant is eligible for the study and that none of these medication interfere with co-beneldopa, ropinirole or domperidone. We will ask participants about the medication they take in the beginning of each visit, and we will re-assess suitability to take part in this study if any changes have taken place.
In this exploratory study, we aim to perform an MRI scan for all our volunteers. However, if a participant is otherwise able to participate in this study, but does not meet the strict inclusion criteria for MRI, they may still take part in all other aspects of this research. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is number of words retrieved after 12h and after 7 days from learning. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 hours and 7 days after drug administration |
|
| E.5.2 | Secondary end point(s) |
Sleep markers recorded from EEG.
Volume of hippocampus and its subfields.
Functional correlativity between hippocampus and VTA.
Reward learning changes.
Reaction time changes. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 hours and 7 days from administering medication. Volumetric changes are not expected to change on medication. |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| investigative/exploratory in single dose |
|
| 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 | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 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
|
LVLS.
The end of the 1-week recall over the phone after the final sleep visit of the final participant recruited to the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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