AMIloride for the Treatment of Nephrogenic Diabetes Insipidus for Patients With Bipolar Disorder Treated With Lithium (AMIND)

AMIloride for the Treatment of Nephrogenic Diabetes Insipidus for Patients With Bipolar Disorder Treated With Lithium: a Randomized Controlled Trial

Lithium (Li) is the leading treatment for BD, protecting against both maniac and depressive relapse, and reducing the risk of suicide and mortality. However, despite this major clinical efficacy, the use of lithium is limited by its narrow therapeutic index and by its side effects. Li induces a vasopressin-resistant urinary concentration defect, with resulting nephrogenic diabetes insipidus (NDI) in 12-50 % of patients. This feature is more frequent after 5 years of treatment with lithium. Polyuria and subsequent thirst might affect patients' quality of life, but also cause potentially life-threatening hypernatremia if free access to water is impaired. Thus, we aim at evaluating the efficacy of amiloride on urine concentrating ability in patients with nephrogenic diabetes insipidus due to chronic lithium treatment.

Study Overview

• Status: Recruiting
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: Anhydrous Amiloride Hydrochloride; Drug: Placebo

Detailed Description

Patients will be referred to the nephrology or the renal physiology department for the usual follow-up of the lithium treatment. After verification of eligilibity criteria, information and collection of consent, patient will be randomized.

During the first phase, patients will be randomized in two parallel groups: the experimental arm will receive 5mg of amiloride twice daily during 2 months and the control arm will receive a placebo twice daily during 2 months.

Measures of fasting urine osmolality will be performed at baseline, 2 months, at 6 months and at 12 months, in order to compare the difference of urine osmolality before and after treatment between the two-randomization arms. Other baseline explorations are as follows: mean number of nocturnal voids, SF-36 questionnaire, thirst intensity and distress scales, YMRS/MADRS mood scale, GAD7 anxiety scale, PSQI sleep scale, GFR measurement and estimation, 24h urine for the quantification of the polyuria and osmolality, plasma and erythrocyte lithium level, serum osmolality, natremia, kaliemia, urea, chlore level, complete blood count, plasma copeptine and vasopressin.

A nephrologist visit will take place 15 days after the initiation of the treatment along with a new measure of plasma lithium level.

Patients will be evaluated at 1 month only if a change in posology is required after the first measurement at day 15 and then at 2, 6 and 12 months.

In parallel, patients will be evaluated by at the psychiatry clinic at 1 month, 2, 6 and 12 months, and in any condition requiring additional visit as usual in standard care (follow-up of anxiety, sleepiness, suicidal ideation, depression).

After the completion of this first phase, the open label second phase will begin. Unblinding the trial will allow the treatment allocation being available for the participants and health care professionals. Amiloride will be continued in participants in the experimental group, and the remaining participants will be followed-up without treatment. This phase will last for 10 months (total trial duration: 12 months).

At one year, renal functions (GFR, urine concentration and 24h urine production) will be assessed along with report of events including hospital admission.

The safety of the experimental treatment will be assessed by regular evaluations of plasma lithium and potassium level, beginning at 2 weeks after treatment initiation and after 2 months. The main risk of amiloride is hyperkalemia, which occurs in patients with severe renal insufficiency. These patients will not be included in our study. Otherwise, the treatment is generally safe and well-tolerated. Plasma lithium level will be measured at the first month clinical evaluation if a change in posology is required after the first measurement at day 15.

• Study Type: Interventional
• Enrollment (Estimated): 148
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: VRTOVSNIK Francois, Pr; Phone Number: 01 40 25 71 01; Email: francois.vrtovsnik@aphp.fr
• Study Contact Backup: Name: FLAMANT Martin; Phone Number: 01 40 25 88 00; Email: martin.flamant@aphp.fr

Study Locations

• France
  • Créteil, France
    • Recruiting
    • Néphrologie, Hôpital Henri-Mondor
    • Contact: STEHLE Thomas; Email: thomas.sethle@aphp.fr
  • Paris, France
    • Active, not recruiting
    • Néphrologie, Hopital Bichat
  • Paris, France
    • Recruiting
    • Physiologie Explorations fonctionnelles multidisciplinaires, Hôpital Bichat
    • Contact: LAHENS Alexandre; Email: alexandre.lahens@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults between 18 and 70 years (age ≥ 18 years and <70 years)
• Patient with bipolar disorder
• Patient treated with lithium for at least 5 years
• Patient with a urine concentration defect defined by a maximal urine osmolality < 600 mOsm/kg
• Woman of childbearing age agreeing to use an efficient contraceptive method for 12 months

Exclusion Criteria:

• Renal failure defined as eGFR < 30 ml/min/1.73m² estimated by the CKD-EPI equation
• Kalemia > 5 mmol/l
• Hypersensitivity or known allergy to amiloride
• Hypersensitivity to lactose
• Known adrenal insufficiency
• Concomitant use of other potassium-sparing treatment (e.g. spironolactone, angiotensin converting enzyme inhibitors (ACE), angiotensin II receptor (AT2R) antagonists, calcineurin inhibitors tacrolimus and ciclosporin)
• Acute ongoing infection (less than 3 days before inclusion)
• Severe heart failure (NYHA > II)
• Rhythm, conduction or repolarisation disorder present on an ECG done within 12 months prior to inclusion
• Acute phase of mood disorder
• Uncontrolled diabetes mellitus or diabetes with hyporeninism hypoaldosteronism
• Potassium supplements
• Use of heparins
• Use of trimethoprim
• Cirrhosis
• Oedemas
• Previous use of amiloride use in the 6 months prior to randomisation)
• Pregnant or breastfeeding women
• Participation in another clinical study involving investigational medicinal product or patient being in the exclusion period at the end of a previous study
• Patient refusal to participate
• Non-affiliation to a social security regimen or CMU
• Patient under State Medical Aid
• Subject deprived of freedom, subject under a legal protective measure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amiloride; the experimental arm will receive 5mg of amiloride twice daily during 2 months	Drug: Anhydrous Amiloride Hydrochloride; Amiloride is a blocker of ENaC that is administered patients with various disorders, such as primary or secondary hyperaldosteronism. It does not have the market authorization in the indication of lithium-induced NDI. Dose : 5 mg Pharmaceutical form: Tablets Daily Posology : 10 mg Route of administration : oral Procedures and duration of treatment: 2 months during the double blinded phase and 10 additional months for the open label phase
Placebo Comparator: Placebo; the control arm will receive a placebo twice daily during 2 months	Drug: Placebo; Route of administration : oral the control arm will receive a placebo twice daily during 2 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The main objective of this study is demonstrating the efficacy of amiloride to reduce the urine concentration defect in patients treated by lithium and presenting a nephrogenic diabetes insipidus after 2 months of treatment.	The primary endpoint is the percentage change in maximal urine osmolality before and after 2 months of treatment	2 month after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demonstrate the efficacy of amiloride to reduce nocturia	Difference in mean number of nocturnal voids	2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to reduce the sensation of thirst	Difference in mean number of nocturnal voids	2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to reduce polyuria	Presence of polyuria (defined as a daily urine output > 3 L/day)	2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to increase quality of life	Difference in Quality-of-life scale score (SF36)	2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to reduce the decline of eGFR after one year of treatment	Difference in eGFR (estimated by the CKD-EPI equation based on standardized serum creatinine measurement) before and after 12 months of treatment	12 months after randomization
Evaluate the effect of amiloride in mood stability	Difference in Mood Scale scores YMRS	2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in circulating lithium levels stability	Difference in residual plasma lithium levels before and after the 2 months treatment period	2 months after randomization
Evaluate the effect of amiloride in mood stability	Total number of hospital admission for maniac or depressive relapse during 12 months of treatment	12 months after randomization
Evaluate the effect of amiloride in mood stability	Difference in Mood Scale MADRS	2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in mood stability	Difference in anxiety scale score (GAD7)	2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in mood stability	Difference in the Pittsburgh sleep score (PSQI)	2 months after randomization and 12 months after randomization

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: DECHANET Aline, Mrs, Assistance Publique - Hôpitaux de Paris (AP-HP)

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2023
• Primary Completion (Estimated): January 11, 2025
• Study Completion (Estimated): November 11, 2025

Study Registration Dates

• First Submitted: August 27, 2021
• First Submitted That Met QC Criteria: September 9, 2021
• First Posted (Actual): September 16, 2021

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: lithium; urine concentration defect
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Kidney Diseases; Urologic Diseases; Endocrine System Diseases; Bipolar and Related Disorders; Pituitary Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Bipolar Disorder; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Channel Blockers; Diuretics, Potassium Sparing; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Amiloride
• Other Study ID Numbers: APHP200042

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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