Sleep DeprivationPhase 4NCT00800553
fMRI-behavioral Study of Cholinergic Augmentation With Donepezil in Healthy Sleep Deprived Adults
A Phase 4 study testing donepezil in people with Sleep Deprivation, run by Duke-NUS Graduate Medical School at 1 site in Singapore.
Trial summary
The purpose of this study was to characterize how the anti-cholinesterase inhibitor (AChE-I) donepezil modulates brain regions involved in visual short-term memory, episodic memory and inhibitory efficiency following 24 hours of total sleep deprivation using fMRI as an additional marker for drug effect. Read more about this study
- Who is it for?
- Ages 21 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Sleep Deprivation
- What is being tested?
- donepezil
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 43 participants
- Where
- 1 siteSingapore
- Study dates
- Nov 2006to May 2007
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- The subject is able to read and understand the Subject Information Sheet and comply with protocol requirements, instructions and protocol-stated restrictions.
- Prior to any screening procedures, the subject and the physician must have signed a study-specific Informed Consent Form. No study-related procedures may be performed before the physician has obtained written informed consent from the subject.
- The subject is between 21 years to 35 years of age.
- The subject has a BMI of between 18.5 kg/m2 to 32 kg/m2 and body weight ≥ 50 kg.
- The subject is right-handed.
- The subject has a resting pulse >40 bpm and <90 bpm (normal range). The subject has a resting systolic blood pressure of between 91 mmHg to 140 mmHg (supine normal range) and a resting diastolic blood pressure of between 51 mmHg to 90 mmHg (supine normal range).
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- The subject, in the opinion of the investigator, is in good health on the basis of a pre-study physical examination, medical history, vital signs, electrocardiogram (ECG), and the results of blood chemistry, haematology, and serology tests, and a urinalysis. A subject with a clinical abnormality or laboratory parameters outside the reference range for this age group may be included only if the Investigator considers that the finding will not introduce additional risk factors and will not interfere with the study procedures.
- The subject has habitual good sleeping habits: sleeping on average 6.5 to 9 hours each night in the past month.
- Have regular sleeping hours whereby they sleep no later than 1 am and rise before 9 am each day.
- Have no history of excessive daytime sleepiness or insomnia.
- Score no greater than 22 on the Morningness-Eveningness scale [Horne and Ostberg, 1976].
- If female, the subject must use a double barrier method of contraception (2 separate methods of contraception) from Screening until final discharge from the study. Oral contraceptives are not allowed.
Who cannot join
- The subject has taken prohibited medication within 1 week (or 14 days if the drug is a potential enzyme inducer) or within 5 half-lives prior to first dosing for any medication ingested, whichever is longer) prior to first dosing, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study procedures or compromise safety. Prohibited medication is any prescribed medication or over-the-counter (OTC) medication, including high-dose vitamins or dietary supplements, or any herbal medicine known to interfere with the metabolic CYP pathways, (e.g. St. John's Wort) or cognitive function (e.g. ginko). Paracetamol for mild analgesia will be permitted.
- The subject has a significant history of drug or alcohol abuse, defined as an alcohol intake greater than 21 units per week or a history of drug abuse within the last 6 months, or a history of substance abuse deemed significant by the investigator. A unit of alcohol is defined as 250 mL of lager/beer, 100 mL of Wine, or 25 mL of spirits.
- The subject has an orthostatic blood pressure reduction >20 mmHg (based on the difference of systolic blood pressure between supine and after standing for 1 minute).
- The subject has been exposed to more than 3 new chemical entities (NCEs) within 12 months prior to the first dosing day, or participated in a trial with any drug within 84 days before the start of the study, or participated in a trial with a NCE within 112 days before the start of the study.
- History or presence of hypersensitivity to the study drugs or drugs of this class (hyoscine, atropine, donepezil) or a history of other severe drug allergy or hypersensitivity which, in the opinion of the physician responsible, contraindicates their participation.
- The subject has a serious illness, such as liver or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, infectious, neoplastic, or metabolic disturbance or other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs.
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- The subject has history or presence of peptic ulcer disease, cardiac arrhythmias, cardiac conduction abnormalities, asthma or obstructive pulmonary disease.
- The subject has history or presence of psychiatric or neurological illness, obstructive sleep apnea, narcolepsy or periodic leg movements as ascertained by questionnaire.
- If participation in the study will result in the subject having donated more than 1500 mL blood in the previous 12 months and where participation in study would result in donation of blood in excess of 500 mL within a 56 day period.
- The subject smokes more than 10 cigarettes per day or uses other nicotine containing products equivalent to 10 cigarettes per day (for example, snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) and is not able to refrain from using nicotine containing products during the complete study period.
- The subject tested positive after screening or at baseline for drugs of abuse (opiates, methadone, cocaine, amphetamines, barbiturates, benzodiazepines, and cannabinoids).
- Caffeine intake of greater than 5 drinks per day on average.
- Presence of glaucoma or raised intraocular pressure based on medical history.
- Has an abnormality on acoustic function.
- The presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies.
- The volunteer reports previous marked feelings of claustrophobia in enclosed environments.
- Abnormal anatomical MRI as defined by a radiologist on pre-study screening e.g. tumours, evidence of stroke, localized white matter lesions, excessive atrophy (local or global), aneurysms, vascular malformations.
- Subjects who cannot complete the neuropsychological test battery despite having undergone the training sessions.
- The subject's QTc (using Bazett's correction) is equal or greater than 430 ms (at Screening) as read on the printout of the ECG produced by the ECG equipment and evaluated by the investigator.
- The subject, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any other reason.
Trial locations and contacts
1 site in 1 country.
Singapore1 site
Cognitive Neuroscience Laboratory, Duke-NUS Graduate Medical School
Singapore, 169611
About this study
Official title: The Neural and Behavioral Correlates of How Donepezil Modulates Memory and Inhibitory Efficiency in the Context of 24 Hours of Sleep Deprivation
The purpose of this study was to characterize how the anti-cholinesterase inhibitor (AChE-I) donepezil modulates brain regions involved in visual short-term memory, episodic memory and inhibitory efficiency following 24 hours of total sleep deprivation using fMRI as an additional marker for drug effect.
Read the detailed description
Short-term total sleep deprivation (SD) can result in cognitive impairments (Durmer and Dinges, 2005) that contribute to industrial catastrophes, transportation accidents, and medical errors (Mitler et al., 1988; Dinges, 1995; Barger et al., 2006; Philip and Akerstedt, 2006). This has motivated the use of pharmacological countermeasures, the most widely used being caffeine (Bonnet et al., 2005). Functional imaging studies of sleep-deprived persons could provide information concerning the neural substrates associated with SD-induced cognitive decline and in addition, provide functional assays for assessing drug effects. However, despite the growing number of functional imaging studies involving SD (Chee and Chuah, 2008), neuropharmacological studies in this context are rare (Thomas and Kwong, 2006).
Impairment of attention in sleep-deprived persons (Lim and Dinges, 2008) is an important cognitive deficit that affects other 'higher' cognitive operations, for example, visual short-term memory (VSTM) (Chee and Chuah, 2007). VSTM is used in service of many higher cognitive operations and has a capacity limit (Luck and Vogel, 1997; Cowan, 2000) that has neuroimaging correlates (Linden et al., 2003; Majerus et al., 2007; Mitchell and Cusack, 2007). SD-induced decline in VSTM capacity has been shown to originate from depressed visual attention or visual processing (Chee and Chuah, 2007). This was inferred from observing state-dependent, but load-independent, attenuation of parieto-occipital activation elicited by two visual tasks in which memory and perceptual load were independently and parametrically varied. Critically, the load-independent manner in which SD affected parieto-occipital activation across the tasks signified that something more fundamental than memory was depressed.
We reasoned that the decline in attention/visual processing might arise from reduced noradrenergic and cholinergic drive, given that these neurotransmitters underlie the maintenance of wakefulness (Everitt and Robbins, 1997; Steriade and McCarley, 2005) as well as visuospatial attention (Everitt and Robbins, 1997; Phillips et al., 2000). Increasing cholinergic transmission may improve visual working memory by increasing the selectivity of perceptual processing in the visual cortex (Furey et al., 2000a). Other experiments on visual memory have suggested that behavioral benefit may be associated with increases in extrastriate (Furey et al., 2000a; Lawrence et al., 2002) and superior parietal (Mentis et al., 2001) regions. Conversely, cholinergic blockade using scopolamine may impair orienting responses that involve parietal regions (Davidson and Marrocco, 2000).
Of relevance to the present study, the concentration of cholinergic effects in the parieto-occipital region coincides with the locus of state effects in several functional imaging studies of short term memory (Habeck et al., 2004; Chee and Chuah, 2007; Lim et al., 2007) in sleep-deprived persons.
Collectively, these findings led us to hypothesize that SD-induced deficits in visual processing/attention might benefit from cholinergic augmentation. We anticipated that the neural correlates of such performance modulation could be tracked by observing task-related parieto-occipital activation. To evaluate these hypotheses, we conducted a double-blind, placebo-controlled, cross-over functional imaging study to characterize the effect of donepezil on healthy young adults. In this within-subjects design, volunteers were scanned four times, twice following a normal night's sleep and twice after 24 hours of total SD.
- Conditions
- Sleep Deprivation
- Being tested
- donepezil, Placebo
- Keywords
- sleep deprivation, fMRI, double blind crossover study
- Medical subject headings
- Sleep Deprivation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
donepezilDrug
Also called Aricept
5mg o.m. p.o. for approx. 2 weeks
PlaceboDrug
5mg of placebo for approx. 2 weeks
| Study group | Role | What they receive |
|---|---|---|
| donepezil | Experimental | donepezil, 5 mg p.o. for approx 2 weeks Receives: Drug: donepezil |
| placebo | Placebo comparator | placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
fMRI signal change in response to cholinergic augmentation within the context of sleep deprivation
Measured: approx 1 month
behavioral changes (response accuracy in a visual short term memory task)
Measured: approx 1 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2008 (estimated)
- Study startNov 2006
- Primary completionMay 2007
- Study completionMay 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Sleep DeprivationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- Duke-NUS Graduate Medical School
- Sponsor type
- University, hospital or other
- Collaborators
- GlaxoSmithKline
- Responsible party
- Principal investigator, Michael WL Chee, MBBS, Duke-NUS Graduate Medical School
- Investigators
- Michael WL Chee, MBBS, MRCP, Principal investigator, Duke-NUS Graduate Medical School
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00800553
- Sponsor's protocol ID
- CRT108999
- Status last verified
- Aug 2016
- First submitted
- 1 Dec 2008
- Last updated
- 3 Aug 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Chuah LY, Chee MW. Cholinergic augmentation modulates visual task performance in sleep-deprived young adults. J Neurosci. 2008 Oct 29;28(44):11369-77. doi: 10.1523/JNEUROSCI.4045-08.2008.
PubMed 18971479
Study at a glance
From the registry record, last updated by the sponsor on 3 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Neural and Behavioral Correlates of How Donepezil Modulates Memory and Inhibitory Efficiency in the Context of 24 Hours of Sleep Deprivation
- ClinicalTrials.gov ID
- NCT00800553
- Acronym / sponsor ID
- CRT108999
- Conditions
- Sleep Deprivation
- Keywords
- sleep deprivation, fMRI, double blind crossover study
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- Duke-NUS Graduate Medical SchoolUniversity, hospital or other
- Collaborators
- GlaxoSmithKline
- Study start
- Nov 2006
- Primary completion
- May 2007 (actual)
- Study completion
- May 2007 (actual)
- First posted
- 2 Dec 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study was to characterize how the anti-cholinesterase inhibitor (AChE-I) donepezil modulates brain regions involved in visual short-term memory, episodic memory and inhibitory efficiency following 24 hours of total sleep deprivation using fMRI as an additional marker for drug effect.
Detailed description
Short-term total sleep deprivation (SD) can result in cognitive impairments (Durmer and Dinges, 2005) that contribute to industrial catastrophes, transportation accidents, and medical errors (Mitler et al., 1988; Dinges, 1995; Barger et al., 2006; Philip and Akerstedt, 2006). This has motivated the use of pharmacological countermeasures, the most widely used being caffeine (Bonnet et al., 2005). Functional imaging studies of sleep-deprived persons could provide information concerning the neural substrates associated with SD-induced cognitive decline and in addition, provide functional assays for assessing drug effects. However, despite the growing number of functional imaging studies involving SD (Chee and Chuah, 2008), neuropharmacological studies in this context are rare (Thomas and Kwong, 2006).
Impairment of attention in sleep-deprived persons (Lim and Dinges, 2008) is an important cognitive deficit that affects other 'higher' cognitive operations, for example, visual short-term memory (VSTM) (Chee and Chuah, 2007). VSTM is used in service of many higher cognitive operations and has a capacity limit (Luck and Vogel, 1997; Cowan, 2000) that has neuroimaging correlates (Linden et al., 2003; Majerus et al., 2007; Mitchell and Cusack, 2007). SD-induced decline in VSTM capacity has been shown to originate from depressed visual attention or visual processing (Chee and Chuah, 2007). This was inferred from observing state-dependent, but load-independent, attenuation of parieto-occipital activation elicited by two visual tasks in which memory and perceptual load were independently and parametrically varied. Critically, the load-independent manner in which SD affected parieto-occipital activation across the tasks signified that something more fundamental than memory was depressed.
We reasoned that the decline in attention/visual processing might arise from reduced noradrenergic and cholinergic drive, given that these neurotransmitters underlie the maintenance of wakefulness (Everitt and Robbins, 1997; Steriade and McCarley, 2005) as well as visuospatial attention (Everitt and Robbins, 1997; Phillips et al., 2000). Increasing cholinergic transmission may improve visual working memory by increasing the selectivity of perceptual processing in the visual cortex (Furey et al., 2000a). Other experiments on visual memory have suggested that behavioral benefit may be associated with increases in extrastriate (Furey et al., 2000a; Lawrence et al., 2002) and superior parietal (Mentis et al., 2001) regions. Conversely, cholinergic blockade using scopolamine may impair orienting responses that involve parietal regions (Davidson and Marrocco, 2000).
Of relevance to the present study, the concentration of cholinergic effects in the parieto-occipital region coincides with the locus of state effects in several functional imaging studies of short term memory (Habeck et al., 2004; Chee and Chuah, 2007; Lim et al., 2007) in sleep-deprived persons.
Collectively, these findings led us to hypothesize that SD-induced deficits in visual processing/attention might benefit from cholinergic augmentation. We anticipated that the neural correlates of such performance modulation could be tracked by observing task-related parieto-occipital activation. To evaluate these hypotheses, we conducted a double-blind, placebo-controlled, cross-over functional imaging study to characterize the effect of donepezil on healthy young adults. In this within-subjects design, volunteers were scanned four times, twice following a normal night's sleep and twice after 24 hours of total SD.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| donepezil | Experimental | Drug: donepezildonepezil, 5 mg p.o. for approx 2 weeks |
| placebo | Placebo comparator | Drug: Placeboplacebo |
Who may qualify
- Ages
- 21 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- The subject is able to read and understand the Subject Information Sheet and comply with protocol requirements, instructions and protocol-stated restrictions.
- Prior to any screening procedures, the subject and the physician must have signed a study-specific Informed Consent Form. No study-related procedures may be performed before the physician has obtained written informed consent from the subject.
- The subject is between 21 years to 35 years of age.
- The subject has a BMI of between 18.5 kg/m2 to 32 kg/m2 and body weight ≥ 50 kg.
- The subject is right-handed.
Key exclusion criteria (20 listed)
- The subject has taken prohibited medication within 1 week (or 14 days if the drug is a potential enzyme inducer) or within 5 half-lives prior to first dosing for any medication ingested, whichever is longer) prior to first dosing, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study procedures or compromise safety. Prohibited medication is any prescribed medication or over-the-counter (OTC) medication, including high-dose vitamins or dietary supplements, or any herbal medicine known to interfere with the metabolic CYP pathways, (e.g. St. John's Wort) or cognitive function (e.g. ginko). Paracetamol for mild analgesia will be permitted.
- The subject has a significant history of drug or alcohol abuse, defined as an alcohol intake greater than 21 units per week or a history of drug abuse within the last 6 months, or a history of substance abuse deemed significant by the investigator. A unit of alcohol is defined as 250 mL of lager/beer, 100 mL of Wine, or 25 mL of spirits.
- The subject has an orthostatic blood pressure reduction >20 mmHg (based on the difference of systolic blood pressure between supine and after standing for 1 minute).
- The subject has been exposed to more than 3 new chemical entities (NCEs) within 12 months prior to the first dosing day, or participated in a trial with any drug within 84 days before the start of the study, or participated in a trial with a NCE within 112 days before the start of the study.
- History or presence of hypersensitivity to the study drugs or drugs of this class (hyoscine, atropine, donepezil) or a history of other severe drug allergy or hypersensitivity which, in the opinion of the physician responsible, contraindicates their participation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| donepezilAlso: Aricept5mg o.m. p.o. for approx. 2 weeks | Drug | donepezil |
| Placebo5mg of placebo for approx. 2 weeks | Drug | placebo |
Primary outcome
fMRI signal change in response to cholinergic augmentation within the context of sleep deprivation
Time frame: approx 1 month
behavioral changes (response accuracy in a visual short term memory task)
Time frame: approx 1 month
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Aug 2016.
- Results publication: PubMed 18971479Chuah LY, Chee MW. Cholinergic augmentation modulates visual task performance in sleep-deprived young adults. J Neurosci. 2008 Oct 29;28(44):11369-77. doi: 10.1523/JNEUROSCI.4045-08.2008.
- Cognitive Neuroscience Lab WebpageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael WL Chee, MBBS, MRCP principal investigator
Duke-NUS Graduate Medical School
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing donepezil in people with Sleep Deprivation, run by Duke-NUS Graduate Medical School at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
fMRI signal change in response to cholinergic augmentation within the context of sleep deprivation (time frame: approx 1 month). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00800553, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2016.