The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617001339347p
Ethics application status
Submitted, not yet approved
Date submitted
20/08/2017
Date registered
21/09/2017
Date last updated
20/11/2018
Date data sharing statement initially provided
20/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of lithium and fampridine on electroencephalography profiles in healthy volunteers
Scientific title
Effects of lithium and fampridine on electroencephalography profiles in healthy volunteers
Secondary ID [1] 292588 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Li 4AP EEG
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bipolar Disorder 304389 0
Condition category
Condition code
Mental Health 303722 303722 0 0
Depression
Mental Health 303729 303729 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase 1 - Pilot Study
Oral tablet lithium carbonate (750mg) or fampridine (20mg) single dose, once daily for 7 days.
Results from Phase 1 will dictate whether participants will receive single or multiple dose regimens in Phase 2. The decision will be based on whether EEG changes are evident after single or multiple doses in Phase 1. The decision will be made by senior study personnel in consultation with the Principal Investigator.

Phase 2 - Single dose
Participants will receive 4 oral study treatments: placebo, lithium carbonate (750mg), fampridine (two of three possible doses of 10, 15 or 20mg; i.e. 10 and 15mg, 10 and 20mg, or 15 and 20mg). Each participant will receive only two of the three fampridine doses, with each combination received by 8 participants. Allocation to a fampridine dose regimen will be carried out by a computer generated random code. Single doses of one of the 4 treatments will be administered at start of each treatment week, with 6 days of no treatment in between doses.

Phase 2 - Multiple Dose
Participants will receive 4 oral study treatments: placebo, lithium carbonate (750mg), fampridine (two of three possible doses of 10, 15 or 20mg; i.e. 10 and 15mg, 10 and 20mg, or 15 and 20mg). Each participant will receive only two of the three fampridine doses, with each combination received by 8 participants. Allocation to a fampridine dose regimen will be carried out by a computer generated random code. Daily doses of one of the 4 treatments will be administered for 7 days, with 7 days of no treatment in between doses. Dosing will occur days 1-7, 16-22, 30-36 and 43-47.

Adherence will be monitored by checking participants' drug containers at the end of each dosing week, and also sending daily text messages to participants to remind them to take their study treatments.
Intervention code [1] 298889 0
Treatment: Drugs
Comparator / control treatment
The placebo capsule will contain lactose.
Control group
Placebo

Outcomes
Primary outcome [1] 303092 0
Composite primary outcome.
Statistically significant differences in activity in infraslow (<1Hz), delta (1-4Hz), theta (4-7
Hz), alpha (8-13Hz), beta (13-30Hz) and gamma (>30Hz) bands in EEG data in response to drug treatments (versus placebo control and normative EEG database).
Timepoint [1] 303092 0
Baseline and end of each treatment period (Phase 2 single dose - 90 minutes post-dose, Phase 2 Multiple dose - 90 minutes post dose on day 7 of each treatment week).
Primary outcome [2] 303250 0
Composite primary outcome.
Statistically significant differences in functional connectivity in infraslow (<1Hz), delta (1-4Hz), theta (4-7
Hz), alpha (8-13Hz), beta (13-30Hz) and gamma (>30Hz) bands in EEG data in response to drug treatments (versus placebo control and normative EEG database).
Timepoint [2] 303250 0
Baseline and end of each treatment period (Phase 2 single dose - 90 minutes post-dose, Phase 2 Multiple dose - 90 minutes post dose on day 7 of each treatment week).
Secondary outcome [1] 337864 0
Changes in visual analogue mood scale scores.
Self rated mood (happy, sad, calm, tense, energetic, sleepy) rated from 0 (not at all) to 100 (extremely)
Timepoint [1] 337864 0
Immediately prior to EEG recording (Phase 2 single dose - 90 minutes post-dose, Phase 2 Multiple dose - 90 minutes post dose on day 7 of each treatment week).
Secondary outcome [2] 337974 0
Safety and tolerability. Endpoints include: vital signs (blood pressure, heart rate), reported adverse events.
Timepoint [2] 337974 0
Pre-dose to 2h post-dose (continuous) on clinic visit days (Phase 1 - D2,8, Phase 2 Single dose - D1,8,15,22, Phase 2 Multi-dose - D1,15,29,43).
Secondary outcome [3] 338646 0
Pharmacokinetics of lithium and fampridine.
The pharmacokinetic parameter for lithium and fampridine is C2h (drug concentrations at the time the EEG is being recorded).
This is a composite secondary outcome.
Timepoint [3] 338646 0
Two hours after dosing on days when EEGs are performed (Phase 1- Days 2 and 8. Phase 2 Single dose - Days 1, 8, 15, 22. Phase 2 Multiple dose - Days 7, 21, 35, 49)

Eligibility
Key inclusion criteria
To be included in the study, participants must meet all of the following inclusion criteria:
1. Capable of understanding and signing an informed consent.
2. Aged >18 years on the day of consent.
3. Good general health.
4. Suitable venous access.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
To be included in the study, participants must meet none of the following exclusion criteria:
1. Females who are or intend to become pregnant, or are lactating.
2. Participants who, in the opinion of the investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
3. Any participant for whom the investigator believes, for any reason, that participation would not be an acceptable risk.
4. Regular use of any drug that alters mood or is used to treat mental disorder, including daily use of alcohol or use of alcohol within 24 hours of testing.
5. Subjects with a prior history of seizures; susceptibility to photosensitivity; or a history of allergic skin reactions.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone/fax/computer
Prof Glue will create the random codes. All study personnel involved with recruitment, dosing, data collection and analysis will have no access to the random codes until the databases are locked.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Allocation to blinded study treatment (placebo, lithium, fampridine) is by random code with administration sequence balanced, and includes gender as a stratification factor.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9146 0
New Zealand
State/province [1] 9146 0
Otago

Funding & Sponsors
Funding source category [1] 297164 0
University
Name [1] 297164 0
University of Otago
Address [1] 297164 0
PO Box 56
Dunedin, 9054
Country [1] 297164 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin, 9054
Country
New Zealand
Secondary sponsor category [1] 296183 0
None
Name [1] 296183 0
Address [1] 296183 0
Country [1] 296183 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 298332 0
Northern A HDEC
Ethics committee address [1] 298332 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 298332 0
New Zealand
Date submitted for ethics approval [1] 298332 0
01/03/2018
Approval date [1] 298332 0
Ethics approval number [1] 298332 0

Summary
Brief summary
Lithium is the first line treatment for bipolar disorder (BD), a disorder characterised by cyclic perturbations in mood, correlated with aberrant patterns of brain connectivity and rhythmicity in distributed brain networks. These patterns of activity, reflecting the intrinsic electrophysiological properties of constituent neurons, are dependent upon membrane ion channel function. BD is strongly associated with disturbances in genes responsible for ion channel expression, localisation and structure and can be treated with some antiepileptic drugs, acting directly on ion channels. Thus, ion channel dysfunction is strongly implicated in BD, however, lithium has had no known effect on ion channels.
Recently, we found that lithium selectively blocks a specific K+ current, the delay current (ID), found in several types of brain neuron. ID can influence action potential threshold and output timing, how inputs from different synaptic sources are integrated, and network synchrony and rhythmicity. Output timing (gating) and synchrony are important variables in brain network function, contributing to the formation and dissolution of functional brain networks over time. Modulation of ID, including by lithium, may influence patterns of connectivity and rhythmicity in the brain and could explain the effectiveness of lithium in BD.
We have found, additionally, that Fampridine (4AP), a prescription treatment for multiple sclerosis, blocks ID in cortical projection neurons in vitro. We therefore hypothesise, that Fampridine may act as an adjunctive or replacement therapy for lithium in BD. In order to assess this hypothesis, we aim to examine EEG recordings of infraslow (<1Hz) network function of healthy volunteers in the presence of lithium, Fampridine and placebo control.

The specific objectives of the study are:
• To examine the early and late effects of dose (Fampridine) and dose timing of lithium and Fampridine on EEG changes in healthy volunteers.
• To evaluate the magnitude and duration of affective changes following administration of lithium, Fampridine or placebo in healthy volunteers. Blood testing will also show any associations of cognitive changes with levels of Li+ / Fampridine and its metabolites in the participant’s bloodstream.
Trial website
None
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76746 0
Prof Paul Glue
Address 76746 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 76746 0
New Zealand
Phone 76746 0
+64 21 243 3372
Fax 76746 0
Email 76746 0
paul.glue@otago.ac.nz
Contact person for public queries
Name 76747 0
Prof Paul Glue
Address 76747 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 76747 0
New Zealand
Phone 76747 0
+64 3 4709451
Fax 76747 0
Email 76747 0
paul.glue@otago.ac.nz
Contact person for scientific queries
Name 76748 0
Prof Paul Glue
Address 76748 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 76748 0
New Zealand
Phone 76748 0
+64 21 243 3372
Fax 76748 0
Email 76748 0
paul.glue@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Not applicable