Ignite Creation Date:
2024-05-06 @ 9:23 AM
Last Modification Date:
2024-10-26 @ 12:13 PM
Study NCT ID:
NCT02967653
Status:
COMPLETED
Last Update Posted:
2020-09-16
First Post:
2016-11-15
Brief Title:
Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus
Sponsor:
Lady Davis Institute
Organization:
Lady Davis Institute
Study Overview
Official Title:
Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus A Randomized Controlled Trial
Status:
COMPLETED
Status Verified Date:
2020-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 eg 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 10mmolL in adults 11 and 08mmolL in geriatric patients 1213 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 300mOsmKg
To date amiloride 5-20mgday 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 n71 33 In this study we examined current lithium users aged 20-95 who had a mean lithium duration and serum lithium level of 106 years and 062mmolL respectively Patients were assessed for UOsm following 10-hour water-restriction a reliable measure of NDI We found that 0 017 of statin users compared to 204 1154 on non-users had UOsm 300mOsmKg following 10-hour water-restriction Fishers Exact p0055 The main statin prescribed in our previous study was atorvastatin 10-40mgday n10 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 n5 and a control group received vehicle n5 for additional 5 days in parallel with continued lithium treatment Although our small statistical sample do not allow us to reach significance n5 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
It is well known that lithium exposure even when dosed safely 10mmolL in adults 11 and 08mmolL in geriatric patients 1213 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 300mOsmKg
To date amiloride 5-20mgday 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 n71 33 In this study we examined current lithium users aged 20-95 who had a mean lithium duration and serum lithium level of 106 years and 062mmolL respectively Patients were assessed for UOsm following 10-hour water-restriction a reliable measure of NDI We found that 0 017 of statin users compared to 204 1154 on non-users had UOsm 300mOsmKg following 10-hour water-restriction Fishers Exact p0055 The main statin prescribed in our previous study was atorvastatin 10-40mgday n10 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 n5 and a control group received vehicle n5 for additional 5 days in parallel with continued lithium treatment Although our small statistical sample do not allow us to reach significance n5 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
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None