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Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus

Primary Purpose

Lithium Use, Nephrogenic Diabetes Insipidus

Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Atorvastatin
Sponsored by
Lady Davis Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lithium Use, Nephrogenic Diabetes Insipidus

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Individuals between 18 and 85 years of age
  • Individuals with any psychiatric disorder who are taking lithium

    o Patients will be recruited from the Douglas Mental Health University Institute, Jewish General Hospital and McGill University Health Centre.

  • Able and willing to give informed consent.
  • Chronic and current lithium users (at least 2 months of Lithium use).
  • Stable dose of lithium for the past 2 months.
  • Patients taking any lithium level will be included.
  • Patients with any psychiatric diagnosis will also be included.
  • NDI defined as a 10-hour water restriction UOsm <600mOsm/Kg.

Exclusion Criteria:

  • Patients allergic to Statins
  • Patients with statin use within 6 weeks prior to the study
  • Patients with a past history of severe adverse reaction to statins.
  • Patients with a baseline Low Density Lipoprotein (LDL) level <1.5.
  • Relative contraindications to statin use 42: pregnancy or lactation, concurrent use of fibrates, heavy ethanol consumption (>50 units/week).
  • Incapacity to consent
  • Deemed by the treating physician to have a severe cognitive or behavioural disturbance such as acute delirium or moderate-severe DSM5 Neurocognitive Disorder (dementia), preventing their ability to complete safely the study questionnaire and/or to provide blood and urine test.

Sites / Locations

  • McGill University Health Centre
  • Jewish General Hospital
  • Douglas Mental Health University Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Atorvastatin

Arm Description

Patients will be randomized to a placebo a day using simple 1:1 randomization using random.org, for 12 weeks.

Patients will be randomized to Atorvastatin 20mg/day for 12 weeks or pill placebo.

Outcomes

Primary Outcome Measures

Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline (UOsm in mOsm/Kg)
Urine Osmolality value at 12 week follow-up

Secondary Outcome Measures

Raw aquaporins-2 (AQP-2) values at 12 week follow-up, adjusted for baseline
aquaporins-2 measurement as adjusted for baseline
Raw Urine Volume (mL/24h) value at 12 week follow-up, adjusted for baseline
24h urine volume values measured as adjusted for baseline
Raw Self-Reported Fluid Intake value 12 week follow-up, adjusted for baseline
self-reported fluid intake #measurement as adjusted for baseline

Full Information

First Posted
November 15, 2016
Last Updated
September 11, 2020
Sponsor
Lady Davis Institute
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1. Study Identification

Unique Protocol Identification Number
NCT02967653
Brief Title
Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus
Official Title
Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus: A Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
July 13, 2017 (Actual)
Primary Completion Date
July 1, 2019 (Actual)
Study Completion Date
July 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Lady Davis Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Lithium remains the gold-standard treatment for bipolar disorder, with 30-40% of patients with responding preferentially to this medication. Additionally, lithium is commonly used in treatment-resistant depression, and other psychiatric disorders (e.g. schizoaffective disorder). Lithium is especially valuable considering the great difficulty in achieving and maintaining symptomatic remission, the high rates of disability, as well as tremendous personal, family, and societal costs associated with bipolar disorder and treatment-resistant depression. Despite this, clinicians are increasingly avoiding lithium, largely due to fear of irreversible chronic kidney disease (CKD), particularly in North America. It is well known that lithium exposure, even when dosed safely (<1.0mmol/L in adults 11 and <0.8mmol/L in geriatric patients 12,13), can increase the risk of CKD by 3 times, in large part through Nephrogenic Diabetes Insipidus (NDI) 14-19. NDI itself has also been associated with acute kidney injury 20, and life-threatening hypernatremia, which is an electrolyte imbalance characterized by high levels of blood sodium. Aside from hypertension, diabetes mellitus, aging, and other nonspecific CKD risk factors. NDI is characterized by excessive thirst (polydipsia) due to increased production of dilute urine (polyuria). In NDI, lithium is believed to interact with the inositol monophosphate and protein kinase C pathways, thereby affecting calcium-related intracellular signaling, cyclic AMP (cAMP), inhibition of Glycogen Synthase Kinase-3 Beta (GSK3Beta), activation of MAP Kinase and many other pathways. NDI occurs commonly in lithium users: 50% of chronic lithium users have urinary concentrating difficulties, with 12-19% have decreased urine osmolality (UOsm) <300mOsm/Kg). To date, amiloride (5-20mg/day) is the only medication with prior evidence of therapeutic effectiveness in NDI from randomized clinical trials. However as a potassium-sparing diuretic 31, amiloride can lead to lithium-level elevations, and can thereby theoretically increase the risk of lithium-associated CNS and acute renal toxicity. There is a need for novel, well-tolerated agents for the treatment of lithium-induced NDI. We recently demonstrated that statins, which are well-tolerated and commonly used medications, are associated with low lithium-induced NDI risk in the first and only previous cross-sectional study examining statins and NDI in humans (n=71) 33. In this study we examined current lithium users aged 20-95, who had a mean lithium duration and serum lithium level of 10.6 years and 0.62mmol/L, respectively. Patients were assessed for UOsm following 10-hour water-restriction, a reliable measure of NDI. We found that 0% (0/17) of statin users compared to 20.4% (11/54) on non-users had UOsm <300mOsm/Kg following 10-hour water-restriction (Fisher's Exact p=0.055). The main statin prescribed in our previous study was atorvastatin 10-40mg/day (n=10) 33, which is the most widely used statin for cardiovascular disease. Atorvastatin and other statins are well-tolerated and have not been found to have adverse effects on mood, cognition, or renal function. The mechanism by which statins may treat NDI is not yet known, but two independent mice studies have demonstrated the effectiveness of statins in treating genetic forms of NDI. In those mice models of genetic NDI, prostaglandin and intracellular cytoskeleton proteins pathways were thought to explain statins' activity on NDI. In preparation for this project, our co-investigators Drs. Trepiccione and Christensen have initiated a pilot study in mice to investigate whether atorvastatin treatment could improve the lithium-induced NDI. NDI was induced in 10 mice by feeding mice with a LiCl-enriched diet for 15 days. After induction of NDI, a group of mice received intraperitoneal injection of atorvastatin (n=5) and a control group received vehicle (n=5) for additional 5 days in parallel with continued lithium treatment. Although our small statistical sample do not allow us to reach significance, (n=5 per group), the mice receiving atorvastatin showed a tendency to reduce polyuria. In line with this research, our present research protocol aims at conducting a randomized controlled trial investigating a statin, such as atorvastatin, in the treatment of lithium-induced NDI.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lithium Use, Nephrogenic Diabetes Insipidus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will be randomized to a placebo a day using simple 1:1 randomization using random.org, for 12 weeks.
Arm Title
Atorvastatin
Arm Type
Experimental
Arm Description
Patients will be randomized to Atorvastatin 20mg/day for 12 weeks or pill placebo.
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Other Intervention Name(s)
Lipitor
Intervention Description
Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease
Primary Outcome Measure Information:
Title
Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline (UOsm in mOsm/Kg)
Description
Urine Osmolality value at 12 week follow-up
Time Frame
12 weeks follow-up
Secondary Outcome Measure Information:
Title
Raw aquaporins-2 (AQP-2) values at 12 week follow-up, adjusted for baseline
Description
aquaporins-2 measurement as adjusted for baseline
Time Frame
12 weeks follow-up
Title
Raw Urine Volume (mL/24h) value at 12 week follow-up, adjusted for baseline
Description
24h urine volume values measured as adjusted for baseline
Time Frame
12 weeks follow-up
Title
Raw Self-Reported Fluid Intake value 12 week follow-up, adjusted for baseline
Description
self-reported fluid intake #measurement as adjusted for baseline
Time Frame
12 weeks follow-up
Other Pre-specified Outcome Measures:
Title
Raw value of Cognition in the domain of executive function at 12 week follow-up, adjusted for baseline
Description
Using Screen for Cognitive Impairment in Psychiatry (SCIP), Stroop, Trials A/Trials B tests
Time Frame
12 weeks follow-up
Title
Safety Measures
Description
Creatine kinase (CK) and Low Density Lipoprotein (LDL) Liver function tests Thyroid function (TSH) Calcium levels eGFR
Time Frame
12 weeks follow-up
Title
Subgroup Analyses - Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline in patients UOsm <300mOsm/Kg
Description
Subgroup analyses
Time Frame
12 weeks follow-up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Individuals between 18 and 85 years of age Individuals with any psychiatric disorder who are taking lithium o Patients will be recruited from the Douglas Mental Health University Institute, Jewish General Hospital and McGill University Health Centre. Able and willing to give informed consent. Chronic and current lithium users (at least 2 months of Lithium use). Stable dose of lithium for the past 2 months. Patients taking any lithium level will be included. Patients with any psychiatric diagnosis will also be included. NDI defined as a 10-hour water restriction UOsm <600mOsm/Kg. Exclusion Criteria: Patients allergic to Statins Patients with statin use within 6 weeks prior to the study Patients with a past history of severe adverse reaction to statins. Patients with a baseline Low Density Lipoprotein (LDL) level <1.5. Relative contraindications to statin use 42: pregnancy or lactation, concurrent use of fibrates, heavy ethanol consumption (>50 units/week). Incapacity to consent Deemed by the treating physician to have a severe cognitive or behavioural disturbance such as acute delirium or moderate-severe DSM5 Neurocognitive Disorder (dementia), preventing their ability to complete safely the study questionnaire and/or to provide blood and urine test.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Soham F Rej, MD, M.Sc.
Organizational Affiliation
Jewish General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
McGill University Health Centre
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H3A1A1
Country
Canada
Facility Name
Jewish General Hospital
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H3T1E4
Country
Canada
Facility Name
Douglas Mental Health University Institute
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H4H1R3
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
32621644
Citation
Fotso Soh J, Beaulieu S, Trepiccione F, Linnaranta O, Torres-Platas G, Platt RW, Renaud S, Su CL, Mucsi I, D'Apolito L, Mulsant BH, Levinson A, Saury S, Muller D, Schaffer A, Dols A, Low N, Cervantes P, Christensen BM, Herrmann N, Rajji T, Rej S. A double-blind, randomized, placebo-controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users. Bipolar Disord. 2021 Feb;23(1):66-75. doi: 10.1111/bdi.12973. Epub 2020 Jul 16.
Results Reference
derived
PubMed Identifier
30012135
Citation
Fotso Soh J, Torres-Platas SG, Beaulieu S, Mantere O, Platt R, Mucsi I, Saury S, Renaud S, Levinson A, Andreazza AC, Mulsant BH, Muller D, Schaffer A, Dols A, Cervantes P, Low NC, Herrmann N, Christensen BM, Trepiccione F, Rajji T, Rej S. Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial. BMC Psychiatry. 2018 Jul 16;18(1):227. doi: 10.1186/s12888-018-1793-9.
Results Reference
derived

Learn more about this trial

Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus

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