<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02967653</url>
  </required_header>
  <id_info>
    <org_study_id>16/02</org_study_id>
    <nct_id>NCT02967653</nct_id>
  </id_info>
  <brief_title>Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus</brief_title>
  <official_title>Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus: A Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lady Davis Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lady Davis Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Lithium remains the gold-standard treatment for bipolar disorder, with 30-40% of patients&#xD;
      with responding preferentially to this medication. Additionally, lithium is commonly used in&#xD;
      treatment-resistant depression, and other psychiatric disorders (e.g. schizoaffective&#xD;
      disorder). Lithium is especially valuable considering the great difficulty in achieving and&#xD;
      maintaining symptomatic remission, the high rates of disability, as well as tremendous&#xD;
      personal, family, and societal costs associated with bipolar disorder and treatment-resistant&#xD;
      depression. Despite this, clinicians are increasingly avoiding lithium, largely due to fear&#xD;
      of irreversible chronic kidney disease (CKD), particularly in North America.&#xD;
&#xD;
      It is well known that lithium exposure, even when dosed safely (&lt;1.0mmol/L in adults 11 and&#xD;
      &lt;0.8mmol/L in geriatric patients 12,13), can increase the risk of CKD by 3 times, in large&#xD;
      part through Nephrogenic Diabetes Insipidus (NDI) 14-19. NDI itself has also been associated&#xD;
      with acute kidney injury 20, and life-threatening hypernatremia, which is an electrolyte&#xD;
      imbalance characterized by high levels of blood sodium. Aside from hypertension, diabetes&#xD;
      mellitus, aging, and other nonspecific CKD risk factors.&#xD;
&#xD;
      NDI is characterized by excessive thirst (polydipsia) due to increased production of dilute&#xD;
      urine (polyuria). In NDI, lithium is believed to interact with the inositol monophosphate and&#xD;
      protein kinase C pathways, thereby affecting calcium-related intracellular signaling, cyclic&#xD;
      AMP (cAMP), inhibition of Glycogen Synthase Kinase-3 Beta (GSK3Beta), activation of MAP&#xD;
      Kinase and many other pathways.&#xD;
&#xD;
      NDI occurs commonly in lithium users: 50% of chronic lithium users have urinary concentrating&#xD;
      difficulties, with 12-19% have decreased urine osmolality (UOsm) &lt;300mOsm/Kg).&#xD;
&#xD;
      To date, amiloride (5-20mg/day) is the only medication with prior evidence of therapeutic&#xD;
      effectiveness in NDI from randomized clinical trials. However as a potassium-sparing diuretic&#xD;
      31, amiloride can lead to lithium-level elevations, and can thereby theoretically increase&#xD;
      the risk of lithium-associated CNS and acute renal toxicity.&#xD;
&#xD;
      There is a need for novel, well-tolerated agents for the treatment of lithium-induced NDI.&#xD;
&#xD;
      We recently demonstrated that statins, which are well-tolerated and commonly used&#xD;
      medications, are associated with low lithium-induced NDI risk in the first and only previous&#xD;
      cross-sectional study examining statins and NDI in humans (n=71) 33. In this study we&#xD;
      examined current lithium users aged 20-95, who had a mean lithium duration and serum lithium&#xD;
      level of 10.6 years and 0.62mmol/L, respectively. Patients were assessed for UOsm following&#xD;
      10-hour water-restriction, a reliable measure of NDI. We found that 0% (0/17) of statin users&#xD;
      compared to 20.4% (11/54) on non-users had UOsm &lt;300mOsm/Kg following 10-hour&#xD;
      water-restriction (Fisher's Exact p=0.055). The main statin prescribed in our previous study&#xD;
      was atorvastatin 10-40mg/day (n=10) 33, which is the most widely used statin for&#xD;
      cardiovascular disease. Atorvastatin and other statins are well-tolerated and have not been&#xD;
      found to have adverse effects on mood, cognition, or renal function.&#xD;
&#xD;
      The mechanism by which statins may treat NDI is not yet known, but two independent mice&#xD;
      studies have demonstrated the effectiveness of statins in treating genetic forms of NDI. In&#xD;
      those mice models of genetic NDI, prostaglandin and intracellular cytoskeleton proteins&#xD;
      pathways were thought to explain statins' activity on NDI.&#xD;
&#xD;
      In preparation for this project, our co-investigators Drs. Trepiccione and Christensen have&#xD;
      initiated a pilot study in mice to investigate whether atorvastatin treatment could improve&#xD;
      the lithium-induced NDI. NDI was induced in 10 mice by feeding mice with a LiCl-enriched diet&#xD;
      for 15 days. After induction of NDI, a group of mice received intraperitoneal injection of&#xD;
      atorvastatin (n=5) and a control group received vehicle (n=5) for additional 5 days in&#xD;
      parallel with continued lithium treatment. Although our small statistical sample do not allow&#xD;
      us to reach significance, (n=5 per group), the mice receiving atorvastatin showed a tendency&#xD;
      to reduce polyuria.&#xD;
&#xD;
      In line with this research, our present research protocol aims at conducting a randomized&#xD;
      controlled trial investigating a statin, such as atorvastatin, in the treatment of&#xD;
      lithium-induced NDI.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 13, 2017</start_date>
  <completion_date type="Actual">July 1, 2019</completion_date>
  <primary_completion_date type="Actual">July 1, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline (UOsm in mOsm/Kg)</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>Urine Osmolality value at 12 week follow-up</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Raw aquaporins-2 (AQP-2) values at 12 week follow-up, adjusted for baseline</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>aquaporins-2 measurement as adjusted for baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Raw Urine Volume (mL/24h) value at 12 week follow-up, adjusted for baseline</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>24h urine volume values measured as adjusted for baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Raw Self-Reported Fluid Intake value 12 week follow-up, adjusted for baseline</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>self-reported fluid intake #measurement as adjusted for baseline</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Raw value of Cognition in the domain of executive function at 12 week follow-up, adjusted for baseline</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>Using Screen for Cognitive Impairment in Psychiatry (SCIP), Stroop, Trials A/Trials B tests</description>
  </other_outcome>
  <other_outcome>
    <measure>Safety Measures</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>Creatine kinase (CK) and Low Density Lipoprotein (LDL) Liver function tests Thyroid function (TSH) Calcium levels eGFR</description>
  </other_outcome>
  <other_outcome>
    <measure>Subgroup Analyses - Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline in patients UOsm &lt;300mOsm/Kg</measure>
    <time_frame>12 weeks follow-up</time_frame>
    <description>Subgroup analyses</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Lithium Use, Nephrogenic Diabetes Insipidus</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will be randomized to a placebo a day using simple 1:1 randomization using random.org, for 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atorvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be randomized to Atorvastatin 20mg/day for 12 weeks or pill placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin</intervention_name>
    <description>Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease</description>
    <arm_group_label>Atorvastatin</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Lipitor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Individuals between 18 and 85 years of age&#xD;
&#xD;
          -  Individuals with any psychiatric disorder who are taking lithium&#xD;
&#xD;
             o Patients will be recruited from the Douglas Mental Health University Institute,&#xD;
             Jewish General Hospital and McGill University Health Centre.&#xD;
&#xD;
          -  Able and willing to give informed consent.&#xD;
&#xD;
          -  Chronic and current lithium users (at least 2 months of Lithium use).&#xD;
&#xD;
          -  Stable dose of lithium for the past 2 months.&#xD;
&#xD;
          -  Patients taking any lithium level will be included.&#xD;
&#xD;
          -  Patients with any psychiatric diagnosis will also be included.&#xD;
&#xD;
          -  NDI defined as a 10-hour water restriction UOsm &lt;600mOsm/Kg.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients allergic to Statins&#xD;
&#xD;
          -  Patients with statin use within 6 weeks prior to the study&#xD;
&#xD;
          -  Patients with a past history of severe adverse reaction to statins.&#xD;
&#xD;
          -  Patients with a baseline Low Density Lipoprotein (LDL) level &lt;1.5.&#xD;
&#xD;
          -  Relative contraindications to statin use 42: pregnancy or lactation, concurrent use of&#xD;
             fibrates, heavy ethanol consumption (&gt;50 units/week).&#xD;
&#xD;
          -  Incapacity to consent&#xD;
&#xD;
          -  Deemed by the treating physician to have a severe cognitive or behavioural disturbance&#xD;
             such as acute delirium or moderate-severe DSM5 Neurocognitive Disorder (dementia),&#xD;
             preventing their ability to complete safely the study questionnaire and/or to provide&#xD;
             blood and urine test.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Soham F Rej, MD, M.Sc.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Jewish General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>McGill University Health Centre</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H3A1A1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H3T1E4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Douglas Mental Health University Institute</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H4H1R3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>November 15, 2016</study_first_submitted>
  <study_first_submitted_qc>November 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 18, 2016</study_first_posted>
  <last_update_submitted>September 11, 2020</last_update_submitted>
  <last_update_submitted_qc>September 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lady Davis Institute</investigator_affiliation>
    <investigator_full_name>Dr. Karl Looper</investigator_full_name>
    <investigator_title>Psychiatrist-in-Chief, Associate Professor, Dept. of Psychiatry, McGill University; Co-Lead, Geri-PARTy Research Group</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Insipidus</mesh_term>
    <mesh_term>Diabetes Insipidus, Nephrogenic</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02967653
org study id: 16/02
nct id: NCT02967653
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline (UOsm in mOsm/Kg)
time frame: 12 weeks follow-up
description: Urine Osmolality value at 12 week follow-up
measure: Raw aquaporins-2 (AQP-2) values at 12 week follow-up, adjusted for baseline
time frame: 12 weeks follow-up
description: aquaporins-2 measurement as adjusted for baseline
measure: Raw Urine Volume (mL/24h) value at 12 week follow-up, adjusted for baseline
time frame: 12 weeks follow-up
description: 24h urine volume values measured as adjusted for baseline
measure: Raw Self-Reported Fluid Intake value 12 week follow-up, adjusted for baseline
time frame: 12 weeks follow-up
description: self-reported fluid intake #measurement as adjusted for baseline
measure: Raw value of Cognition in the domain of executive function at 12 week follow-up, adjusted for baseline
time frame: 12 weeks follow-up
description: Using Screen for Cognitive Impairment in Psychiatry (SCIP), Stroop, Trials A/Trials B tests
measure: Safety Measures
time frame: 12 weeks follow-up
description: Creatine kinase (CK) and Low Density Lipoprotein (LDL) Liver function tests Thyroid function (TSH) Calcium levels eGFR
measure: Subgroup Analyses - Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline in patients UOsm <300mOsm/Kg
time frame: 12 weeks follow-up
description: Subgroup analyses
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients will be randomized to a placebo a day using simple 1:1 randomization using random.org, for 12 weeks.
arm group label: Atorvastatin
arm group type: Experimental
description: Patients will be randomized to Atorvastatin 20mg/day for 12 weeks or pill placebo.
intervention type: Drug
intervention name: Atorvastatin
description: Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease
arm group label: Atorvastatin
arm group label: Placebo
other name: Lipitor
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Soham F Rej, MD, M.Sc.
role: Principal Investigator
affiliation: Jewish General Hospital
facility: 
facility: 
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Lady Davis Institute
investigator full name: Dr. Karl Looper
investigator title: Psychiatrist-in-Chief, Associate Professor, Dept. of Psychiatry, McGill University; Co-Lead, Geri-PARTy Research Group
mesh term: Diabetes Insipidus
mesh term: Diabetes Insipidus, Nephrogenic
mesh term: Diabetes Mellitus
mesh term: Atorvastatin
sharing ipd: Undecided