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Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus

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ClinicalTrials.gov Identifier: NCT02967653
Recruitment Status : Recruiting
First Posted : November 18, 2016
Last Update Posted : October 16, 2017
Sponsor:
Information provided by (Responsible Party):
Dr. Karl Looper, Lady Davis Institute

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.


Condition or disease Intervention/treatment Phase
Lithium Use, Nephrogenic Diabetes Insipidus Drug: Atorvastatin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus: A Randomized Controlled Trial
Actual Study Start Date : July 13, 2017
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2020


Arm Intervention/treatment
Placebo Comparator: Placebo
Patients will be randomized to a placebo a day using simple 1:1 randomization using random.org, for 12 weeks.
Drug: Atorvastatin
Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease
Other Name: Lipitor

Experimental: Atorvastatin
Patients will be randomized to Atorvastatin 20mg/day for 12 weeks or pill placebo.
Drug: Atorvastatin
Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease
Other Name: Lipitor




Primary Outcome Measures :
  1. Change in Urine Osmolality (UOsm in mOsm/Kg) [ Time Frame: 12 weeks follow-up ]

Secondary Outcome Measures :
  1. Change in aquaporins-2 (AQP-2) [ Time Frame: 12 weeks follow-up ]
  2. Change in Urine Volume (mL/24h) [ Time Frame: 12 weeks follow-up ]
  3. Change in Self-Reported Fluid Intake [ Time Frame: 12 weeks follow-up ]

Other Outcome Measures:
  1. Change in Cognition in the domain of executive function [ Time Frame: 12 weeks follow-up ]
    Using Screen for Cognitive Impairment in Psychiatry (SCIP), Stroop, Trials A/Trials B tests

  2. Safety Measures [ Time Frame: 12 weeks follow-up ]
    Creatine kinase (CK) and Low Density Lipoprotein (LDL) Liver function tests Thyroid function (TSH) Calcium levels eGFR

  3. Subgroup Analyses - Change in Urine Osmolality in patients with baseline UOSm <300mOsm/Kg [ Time Frame: 12 weeks follow-up ]
    Subgroup analyses



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02967653


Contacts
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Contact: Jocelyn Fotso Soh, M.Sc. 5143408222 ext 25205 jfs702@mun.ca

Locations
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Canada, Quebec
McGill University Health Centre Not yet recruiting
Montréal, Quebec, Canada, H3A1A1
Contact: Jocelyn Fotso Soh, MSc    514-340-8222 ext 25205    jfs702@mun.ca   
Principal Investigator: Pablo Cervantes, MD         
Jewish General Hospital Not yet recruiting
Montréal, Quebec, Canada, H3T1E4
Contact: Jocelyn Fotso Soh, MSc    514-340-8222 ext 25025    jfs702@mun.ca   
Principal Investigator: Soham Rej, MD, MSc         
Douglas Mental Health University Institute Recruiting
Montréal, Quebec, Canada, H4H1R3
Contact: Soham Rej, MD, MSc    514-340-8222 ext 25205    soham.rej@gmail.mcgill.ca   
Contact: Jocelyn Fotso Soh, MSc    5147156942    jfs702@mun.ca   
Principal Investigator: Soham Rej, MD, MSc         
Sponsors and Collaborators
Lady Davis Institute
Investigators
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Principal Investigator: Soham F Rej, MD, M.Sc. Jewish General Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Dr. Karl Looper, Psychiatrist-in-Chief, Associate Professor, Dept. of Psychiatry, McGill University; Co-Lead, Geri-PARTy Research Group, Lady Davis Institute
ClinicalTrials.gov Identifier: NCT02967653     History of Changes
Other Study ID Numbers: 16/02
First Posted: November 18, 2016    Key Record Dates
Last Update Posted: October 16, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Insipidus
Diabetes Insipidus, Nephrogenic
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Kidney Diseases
Urologic Diseases
Pituitary Diseases
Atorvastatin
Arginine Vasopressin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Hemostatics
Coagulants
Vasoconstrictor Agents
Antidiuretic Agents
Natriuretic Agents
Physiological Effects of Drugs