Below is the protocol for the trial, this outlines the history behind the research and necessary clinical data. It will tell you exactly what we hope to achieve with this study and the potential benefits from the research.
Double-blind placebo-controlled trial assessing the effect of trans-cranial near infrared light on cognitive function in healthy individuals over 45 years of age.
Sponsors: Maculume Ltd
Independent Statistician: Mr P Gedling, Medical Statistician
Primary aim: To determine whether trans-cranial phototherapy with NIR light improves cognitive function in healthy individuals aged between 50 and 90 years of age.
Trial design: Double-blind placebo-controlled randomised trial.
Ethics Committee: North East - York Research Ethics Committee
REC reference: 16/NE/300
Ethical decision: October 21, 2016
The Committee stated that the study did not require ethical review by an NHS REC.
a) The study does not involve the use of a medical device for
treatment or assessment of a medical condition.
b) The study involves only healthy volunteers.
c) The study does not involve NHS patients.
Furthermore, after discussion in the HRA, we do not believe the project requires HRA Approval as healthy volunteers are consented and seen at private non-NHS premises.
“ we are of the view that the project would more appropriately be classified and managed as service evaluation rather than research”
Intervention: Cerebrolite Trans-cranial phototherapy device
With age there is a steady decline in both short-term memory and ability to complete complex intellectual tasks. The exact mechanism of age-related memory and intellectual impairment is not fully understood, however there is a steady loss of neuronal function resulting in age-related cerebral atrophy which is universal 15,17. Studies have demonstrated loss of grey and white matter with advancing years 17
Fjell et al. (2009) 17 conducted a study in healthy individuals and identified volume changes across the entire cortex and in 48 regions of interest. Cortical reductions in the healthy elderly were extensive after only 1 year, especially evident in temporal and prefrontal cortices, where annual decline was 0.5%. All subcortical and ventricular regions except caudate nucleus and the fourth ventricle changed significantly over 1 year, atrophy was found to accelerate with increasing age.17
Allen et al (2005) 15 used high-resolution MRI to investigate grey and white matter aging in the major lobes of the cerebrum (frontal, parietal, temporal, occipital) and the major sectors of the temporal lobe (temporal pole, superior temporal gyrus, infero-temporal region, para-hippocampal gyrus, amygdala, and hippocampus). For the cerebrum in general, grey matter decreased linearly with age, resulting in a decline of about 9.1-9.8% between the ages of 30 and 70 years, and a decline of 11.3-12.3% by the age of 80. In contrast, white matter volume increased until the mid-50s, after which it declined at an accelerated rate. At 70 years, white matter volume was only 5.6-6.4% less than at 30 years, but by age 80, a cubic regression model predicted that the decrease would be 21.6-25.0%. Multivariate analyses indicate that the frontal grey matter was most strongly associated with age, while occipital grey and white matters were least associated. No sex differences in aging were found for any regions of interest.15
Hoffstaedter et al. (2014) demonstrated that the loss of intellectual and motor function is not only related to atrophy but to changes of functional connectivity (FC) as well as regional atrophy. The anterior mid-cingulate cortex showed exclusive age-related decoupling from the anterior cingulate motor area. FC decrease in addition to grey matter atrophy within the striatum may provide a substrate for the declining motor control in the elderly. Age-related FC changes in both the network for movement initiation as well as the network for motor execution are not explained by regional atrophy in the healthy aging brain.19
Pavlopoulos et al (2013) has determined at the molecular level that there is a distinction between Age Related memory Impairment and Alzheimer’s disease.21
Any technology that would improve neuronal cell function may well improve cell connectivity and hence intellectual function.
In 1999 it was conceptualised that Near Infrared light (NIR) may have a beneficial effect on age-related memory impairment. The trans-cranial route was considered as infrared light is used successfully to monitor intracranial oxygenation; approximately 10% of the incident light (on the skin) reaches the surface of the cortex. The brain has very little pigment within its structure to offer much optical impediment to further transmission within the cranium.
NIR light has been shown to have a cyto-protective effect in cell culture, protecting human cells from the deleterious effects of adverse environmental challenges1. One of the protein mediators has been identified as iNOS which has been implicated in cell repair mechanisms1. Animal studies have demonstrated that NIR light can improve rodent memory, improving older rodents’ performance to that of younger rodents2. Further studies at DurhamUniversity have identified that NIR light increases expression of specific protein folding and neuroprotective chaperone proteins including Hsp70 and 27, and reduces the production of Beta Amyloid 5,9 , the latter which is recognised as a key toxic component of the Alzheimer’s disease pathophysiology.
The NIR light has been demonstrated in the laboratory to be neuro-protectie29, and cytoprotective1 in the human lymphocyte model.
There is body of clinical evidence identifying NIR as being therapeutic via the trans-cranial route for the treatment of traumatic brain injury, strokes and neurodegenerative disorders.6,7
There have been no reported adverse effects from using the NIR trans-cranial phototherapy device. A wavelength of light close to that in the application (1064nm) has been used extensively during intrauterine foetal surgery without any adverse effect due to the wavelength of light used 3,4.
Previous Studies in trans-cranial phototherapy
A review of published27 and unpublished literature revealed two papers with a double blind placebo controlled design, one conducted in USA28 and one in South Africa. In addition to the double blind studies several cohort studies using transcranial NIR. These double blind placebo controlled studies despite recruiting relatively small numbers, 40 and 18 respectively demonstrated statistically significant efficacy as compared to placebo.
Several studies assessment trans-cranial NIR phototherapy as a treatment for traumatic brain injury have shown efficacy, without any documented adverse events.
Objective of the study
To determine whether NIR trans-cranial phototherapy improves early stages of information processing (sensory coding and selective attention) in individuals with age related intellectual impairment over an assessment and intervention period of 56 days.
Early stages of information processing involve the detection of and response to simple stimuli and can be assessed with a simple reaction time (spot the dot) and a choice reaction time (symbol recognition). These tests have been demonstrated to be sensitive to pharmacological agents.10-14
The auditory response to stimuli is evaluated using sounds of differing tone or a single tone.
ANAM (Automated Neuropsychological Assessment Metrics) – this a computer based test which is FDA ( USA Food and Drug Agency) approved for psychometric testing.
Stroop test: The Stroop Test contains three subtests: Colour Naming, Word Reading, and Interference. During the Colour Naming subtest, individuals are instructed to name the colour of rectangles out loud (vocalized response). The Word Reading sub-test requires participants to read words printed in black ink, while the Interference trials consists of words printed in an incongruous ink colour (i.e. the word “green” printed in red ink). Participants are required to inhibit the automatic tendency to read the words, and instead must name the colour of the ink for each word. There are 3 pages, 100 of words (page1), 100 of colour rectangles (page 2) and 100 words printed in incongruous ink colour (page 3).
Interference = time to read page 3 – ((time to read page 1) + (time to read page 2))/2
Primary outcome measures
- Automated Neuropsychological Assessment Metrics, comparison, pre and post treatment.
- Comparison between pre and post intervention Stroop interference
Secondary outcome measures (Appendix IV)
1. Self-assessment cognitive Score.
Population to be studied
Members of the general population between the age of 50 and 90 years.
· Aged between 45 years and 90 years
· MMSE score >28 (out of 30)
· No chronic illnesses other than hypertension, asthma or mild COPD
· Stable, controlled chronic illness e.g. hypertension, asthma, COPD
· Diagnosed actively-growing intracranial pathology (tumours etc.)
· Mental health illness
· Misuse of illegal substances or alcohol
· Use of regular systemic steroids or cancer drugs
· Cancers that affect your body
· Not fluent in English
· Depressed, or feeling depressed.
· Lacking capacity to give informed consent
· Previous history of stroke
· History of aggression or violence
· Inability to attend the research venue for assessment
· Assessed as probably being non-complaint with the intervention regime
· Diagnosed with a neurological condition eg. Parkinson’s disease, multiple sclerosis
· Diagnosed with dementia of any cause
· Chronic pain disorders
· Volunteers taking medication which would impair cognitive function such as gabapentin, pregabalin, strong opiates (e.g. morphine)
· Any chronic illness other than hypertension, asthma or mild COPD.
· Not being available for all the assessment sessions.
· Participants currently involved in any other research program
A sample of 100 volunteers will be recruited (50 in the active group and 50 in the placebo group) to achieve 90% power to detect a difference on the simple reaction time assessment between active and placebo groups, with a two-sided test at the 5% significance level, assuming an attrition rate of 20%.
Other sites in USA are recruiting 130 participants.
Sample size calculation
Please see review by Peter Gedling.
Method of Recruitment:
From the general population.
Adverts will be placed in the local press, professional press (medical, legal, accounting and engineering) The wording will be identical to the poster.
Email: If supported by the R&D offices of the local CCGs an email shot will be sent to NHS employees in the northeast of England alerting them to the presence of the trial. The same wording will be used as in the poster.
If supported by the University, an email shot of the same content to the University staff in the Northeast of England.
The volunteers will be randomly assigned to active trans-cranial phototherapy or placebo trans-cranial phototherapy, starting from the lowest allocation number according to a computer-generated randomisation scheme.
The randomisation code will be locked and retained by the independent medical statistician.
Each group will be allocated one of two intervention arms:
Method of Masking
NIR light is invisible to the human eye, therefore the placebo units will operate in an identical manner to that of the active units.
The active and placebo helmets will look identical and their external operation will appear identical, each device will be marked with a code by the manufacturer, there will be no way to identify a device from active or placebo. The user records will identify which device they have received, the manufacturer will have the code locked in locked cupboard in a locked room.
The manufacturer will assign each device with a number, the active and placebo units will be numbered according to a computerised randomisation code. Once delivered to the Lead Investigator, the code will be held in a sealed envelope by the sponsor.
All INvestigators have a qualification in psychology and have received training to conduct the relevant tests.
Audit of their practice will be on-going throughout the duration of the trial to ensure the methods used are consistent, reducing the effect of assessor bias. The same assessor will conduct pre and post assessments on any particular cohort of individuals to avoid introducing assessor variability.
Potential volunteers, after contacting the study team, will be given an information pack comprising:
· Volunteer information sheet
· Consent document
· Participant data collection sheet, together with screening questions.
· Instruction sheet
After receiving these documents, after 1 week they will be contacted by a member of the research team to ascertain if they wish to participate. If the individual wishes to participate in the trial, an appointment at a mutually convenient time will be made for the volunteer to be seen. The initial screening interview will be conducted by a CPN (CV attached). At this appointment the investigator will explain the details of the trial and offer an opportunity for the volunteer to ask questions. The consent document will then be completed by the volunteer, and countersigned by the researcher.
a. The volunteer will have several days to decide whether they wish to participate in the trial as they will have received the information pack in the mail previously. The volunteer would have the option of speaking to the Investigator directly before enrolling.
b. The volunteer will have an opportunity to ask questions and have any points of concern clarified.
c. Informed consent will be obtained from the volunteer.
d. The volunteer will be interviewed and a detailed history taken. Base line information regarding the volunteer’s circumstance will be gathered, including confirming the MMSE score is >28 (a score of <28 is an exclusion criterion).
e. The volunteer will complete a self-assessment cognitive questionnaire to obtain a score (appendix IV)
f. The volunteer will we offered a choice of appointment times and will be seen on three separate occasions for assessment of their executive function and memory. Three tests are necessary to average the day-to-day variation present in cognitive functioning.
g. Testing will be rescheduled if the volunteer has a minor inter-current illness eg. Flu, minor viral infection.
h. After the third series of tests the volunteer will be allocated a number, all numbers being issued sequentially commencing at the lowest.
i. Intervention procedure: Once allocated to either active or placebo group each individual will be given a trans-cranial intervention device to take home with them. They will be shown how to use the device, which should be used for 6 minutes twice daily every day of the week.
j. Telephone contact will be made by a researcher with the participant every 2 weeks throughout the intervention period to make the following verbal observations:
a. has there been any change in the health of the participant which could influence their capacity. If yes, then reassessment by the CPN is indicated.
b. What is the counter number on the device, this should increase by 28 every 2 weeks if compliance is 100%.
c. Are there any problems with the device or the intervention?
k. After 42 days of twice daily intervention a post intervention assessment will be conducted
l. At this interview, the researcher will enquire if there have been health events which would impair capacity. In the event of such an occurrence, the intervention will be withdrawn and the individual excluded from the trial.
m. After 56 days of twice daily intervention, the intervention will be withdrawn.
n. The last post-intervention tests (three) will be conducted between 2 and 7 days after the last intervention session and another self-assessment cognitive questionnaire will be completed.
The NIR applicator is a trans-cranial light applicator and is CE approved for its intended use.
The Cognitolite has been in use in the USA and the EU for the last several years without any recorded adverse events.
A trained assistant will demonstrate to the volunteer the method of applying of the NIR applicator.
The NIR applicator will be applied twice daily for 84 days. The intervention time is 6 minutes on each occasion. The volunteer will be encouraged to notify the team of any untoward effect of the intervention and the volunteer will be contacted by telephone weekly to ascertain if there are any concerns regarding the intervention.
The volunteer will be reviewed 42 days after the commencement of the intervention.
The final 3 assessments will be conducted between 2 and 7 days after the conclusion of the final intervention.
Three assessments prior to commencement and after the conclusion of intervention is to reduce the effect upon the data collected of normal day to day variation in intellectual performance.
The participants will be contacted by telephone every 2 weeks by a research assistant to ascertain if there are any issues of concern.
Assessment of efficacy
Efficacy will be defined by an improvement in the scores of the measurable end points from base line:
1. Improvement of primary outcome measures from baseline
2. Improvement of secondary outcome measures from baseline.
For each cognitive test, and each secondary outcome measure, the frequency distribution and summary statistics of score improvement will be calculated. Score improvements will be compared between the active and placebo groups. Statistical significance of differences between the groups will be assessed using the Wilcoxon test, with due awareness of the chance of spurious significance arising from the relatively large number of statistical tests involved. Confidence intervals will be computed for mean score improvements.
Agreement between the various cognitive tests will be investigated by computing correlation coefficients on the test scores.
Assessment of Safety
The NIR applicator is CE approved and is safe for its intended use.
The self-reported feedback form requests that the volunteer contact Dr Dougal directly to report any perceived untoward events.
The definition of an adverse event is defined by Article 10 of the Directive:
“any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to the death of a volunteer or user or to a serious deterioration in his state of health;”
This will occur under the following conditions:
1. The volunteer develops a local reaction at the site of intervention with the trans-cranial phototherapy device. This will most likely be due to a local allergic reaction to the plastic used in the construction of the trans-cranial phototherapy device.
2. The volunteer experiences an adverse reaction to the phototherapy intervention.
3. The volunteer declines to continue with the intervention.
The paper-based data will be kept in a locked cupboard and any electronic data will be stored on CD, which will be kept in a locked cupboard. Computers used to create this storage medium are password protected and are virus protected with McAfee virus and network software. No information will be stored on laptops or memory sticks.
Quality control/ Quality assurance
The manufacturer of the NIR applicator has IEC13485 quality management systems are in place. All adverse incidents will be evaluated in accordance with the IEC13485 quality management systems.