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Trial registered on ANZCTR


Registration number
ACTRN12617001157369
Ethics application status
Approved
Date submitted
2/08/2017
Date registered
8/08/2017
Date last updated
12/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Renal pharmacodynamics of lithium and amiloride in healthy volunteers
Scientific title
Renal pharmacodynamics of lithium and amiloride in healthy volunteers
Secondary ID [1] 292582 0
none
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Bipolar affective disorder 304252 0
Condition category
Condition code
Mental Health 303601 303601 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
From day 2, volunteers will receive either oral tablets of lithium 250mg or 500mg/day for 8 weeks. In addition, during weeks 5-6, they will also receive oral tablets of amiloride 5mg/day, and during weeks 7-8, they will receive amiloride 10mg/day. The volunteers will be seen weekly to assess adherence by tablet count.
Intervention code [1] 298786 0
Treatment: Drugs
Comparator / control treatment
Fixed sequence design, in which the first 4 weeks, participants will receive lithium alone; in the subsequent 4 weeks, they will have 2 ascending doses of amiloride added to lithium. The objective of the study is to evaluate the pharmacodynamic interaction between 2 dose levels of lithium (250 and 500mg/day) and 2 ascending dose levels of amiloride (5mg and 10mg day).
Control group
Dose comparison

Outcomes
Primary outcome [1] 302954 0
Change in urinary concentrating ability, as assessed over 6 hours after administration of 40mcg desmopressin intranasally after overnight fluid deprivation. This will be determined based on plasma and urine osmolality measurements.
Timepoint [1] 302954 0
6 hour urine collections post desmopressin dosing on Days 1, 29, 43 and 57
Plasma osmolality on days 1, 29, 43 and 57 at t= o and 240 mins post desmopressin administration.
Secondary outcome [1] 337551 0
Safety and tolerability, as assessed by safety laboratory tests, vital signs and reported adverse events
Timepoint [1] 337551 0
Safety laboratory tests - Screening, days 15, 29, 43 and 57.
Lithium blood concentrations days 15, 29, 43 and 57
Vital signs and reported adverse events: continuously pre-study through Day 57
Secondary outcome [2] 337552 0
Resting EEG - 10 minutes recording
Timepoint [2] 337552 0
Days 1 and 29

Eligibility
Key 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
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key 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. Alcohol abuse, or regular use of cannabis or other recreational drugs.
5. Patients established on diuretics or regularly taking NSAIDs.

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)
None
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerized random code, with block of 4, stratifying by gender
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This is a randomized (for lithium dose), open-label, fixed sequence study in 12 healthy volunteers. From Day 2 to Day 57, subjects will take lithium 250mg capsules at night, either one or two daily (allocation to lithium dose will be via computer generated random code, stratified by gender). From Days 30- 43, all subjects will take one amiloride 5mg tablet at night. From Days 44- 57, all subjects will take two amiloride 5mg tablets at night.
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
1. Demographic and Background Characteristics: Demographic, background characteristics and trial data will be descriptively summarized for all subjects.
2. Plasma lithium concentrations: summary statistics by study week.
3. Urine osmolality: Effect of lithium alone and in combination with 2 amiloride dose levels on changes in urinary concentrating ability by analysis of variance (ANOVA)
4. PKPD analyses: Modelling of the relationship between plasma lithium concentrations, plasma amiloride concentrations, urinary amiloride concentrations, and change in urinary concentrating ability, to identify Lithium:amiloride dose ratio that minimizes lithium-induced changes in urinary concentrating ability. This will be performed using nonlinear mixed effects modelling techniques.
5. EEG: log Fourier power will be calculated for eyes open and eyes closed periods separately for all electrodes. Frontal midline power, left-right alpha asymmetry, and frontal-posterior alpha asymmetry will be extracted as separate measures and each subjected to repeated measures ANOVA with effect of Lithium and eyes open/closed as factors.
6. A statistically significant 5% reduction in arginine vasopressin (AVP) -stimulated urine osmolality was reported after 4 weeks of lithium treatment in 11 healthy volunteers (Walker 2005).

Recruitment
Recruitment status
Active, not 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] 9119 0
New Zealand
State/province [1] 9119 0
Otago

Funding & Sponsors
Funding source category [1] 297158 0
University
Name [1] 297158 0
University of Otago
Address [1] 297158 0
PO Box 56
Dunedin 9054
Country [1] 297158 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 296173 0
None
Name [1] 296173 0
Address [1] 296173 0
Country [1] 296173 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298325 0
Southern HDEC
Ethics committee address [1] 298325 0
Ministry of Health
Ethics Dept
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 298325 0
New Zealand
Date submitted for ethics approval [1] 298325 0
14/08/2017
Approval date [1] 298325 0
10/01/2018
Ethics approval number [1] 298325 0

Summary
Brief summary
Lithium is first line treatment for acute and maintenance of bipolar affective disorder, and as augmentation for refractory major depression. The most prevalent renal effect of lithium is impairment of renal concentrating ability, which may affect at least half of all patients on chronic lithium treatment. Up to 20% of patients will report polydipsia and polyuria as a result of this change. If lithium is stopped early on, the decreased urinary concentrating ability is largely reversible. However some patients who remain on lithium long term, will develop a progressive impairment of urinary concentrating ability [nephrogenic diabetes insipidus]. This functional lesion is not usually reversible and is associated with a chronic focal interstitial fibrosis in renal biopsy, which may be progressive and lead to end-stage renal failure.

Amiloride is a potassium-sparing diuretic that in clinical case series can reverse lithium-induced polyuria and improve renal concentrating ability. Mechanistically, amiloride blocks the renal epithelial sodium channel, which is the major entry site for lithium in collecting duct cells. Although combining amiloride with lithium could reduce development of lithium-induced renal toxicity, it is unclear what the optimal dose of both drugs might be. Earlier studies have used 10mg/day (Bedford 2008), or 10-20mg/day (Batlle 1985, Kosten 1986). The objective of this study is to evaluate the pharmacodynamic interaction between 2 dose levels of amiloride (5 and 10mg/day) and 2 dose levels of lithium (250 and 500mg/day), based on changes in renal concentrating ability.
Trial website
None
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76726 0
Prof Rob Walker
Address 76726 0
University of Otago
PO Box 56
Dunedin 9054
Country 76726 0
New Zealand
Phone 76726 0
+64 3 4740999
Fax 76726 0
Email 76726 0
rob.walker@otago.ac.nz
Contact person for public queries
Name 76727 0
Dr Shona Neehoff
Address 76727 0
University of Otago
PO Box 56
Dunedin 9054
Country 76727 0
New Zealand
Phone 76727 0
+64 3 4740999 extn 57388
Fax 76727 0
Email 76727 0
shona.neehoff@otago.ac.nz
Contact person for scientific queries
Name 76728 0
Prof Paul Glue
Address 76728 0
University of Otago
PO Box 56
Dunedin 9054
Country 76728 0
New Zealand
Phone 76728 0
+64 21 243 3372
Fax 76728 0
Email 76728 0
paul.glue@otago.ac.nz

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary