Efficacy of Amiloride in Treating Nephrogenic Diabetes Insipidus in Bipolar Disorder Patients on Long-term Lithium Therapy: A Randomized Controlled Trial

The primary objective of this study is to demonstrate the efficacy of **amiloride** in reducing the urine concentration defect in patients with nephrogenic diabetes insipidus who are treated with lithium for bipolar disorder. This is clinically relevant as it addresses a common side effect of lithium therapy, which can significantly impact patient quality of life and treatment adherence.

The secondary objectives of the study include evaluating the efficacy of amiloride to:

• Reduce the urine concentration defect
• Reduce nocturia
• Reduce the sensation of thirst
• Reduce polyuria
• Increase quality of life
• Reduce the decline of estimated glomerular filtration rate (eGFR) after one year of treatment
• Evaluate the effect on mood stability
• Stabilize circulating lithium levels
• Demonstrate the tolerance of amiloride in the short term (after 2 months) and long term (6 months and 12 months)

The clinical trial involves a study population comprising **adults** aged between 18 and 70 years, inclusive of both male and female participants. The participants are individuals diagnosed with **bipolar disorder** who have been undergoing treatment with lithium carbonate for a minimum duration of five years. These individuals also present with a urine concentration defect, specifically defined by a maximal urine osmolality of less than 600 mOsm/kg, indicative of nephrogenic diabetes insipidus. The trial includes women of childbearing age who have agreed to use an efficient contraceptive method for 12 months. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, ensuring that the participants meet the necessary health and treatment conditions relevant to the study's objectives. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial also involves a vulnerable population, as indicated by the inclusion of individuals with a chronic mental health condition.

The clinical trial is designed to evaluate the efficacy of **amiloride** in reducing urine concentration defects in patients with **nephrogenic diabetes insipidus** who are undergoing treatment with lithium for bipolar disorder. This study is a **randomized, controlled trial** with a double-blind design to ensure unbiased results. The trial is expected to last approximately three years, with an estimated recruitment start date of January 11, 2023, and an estimated end date of January 11, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-70 years), diagnosis of bipolar disorder, and a history of lithium treatment for at least five years. The primary endpoint is the percentage change in maximal urine osmolality after a two-month treatment period. Secondary endpoints include changes in urine osmolality at six and twelve months, nocturnal voids, thirst intensity, polyuria presence, quality of life, and various mood and anxiety scales.

Study visits will occur at baseline, and at two, six, and twelve months to assess these endpoints. The end-of-study visit will evaluate the long-term effects and tolerability of the treatment. Participants are expected to be involved in the study for up to twelve months, with conditions for early termination including unacceptable toxicity (defined as a grade ≥ 3 on the Common Terminology Criteria for Adverse Events) or withdrawal of consent.

The trial will utilize **amiloride** tablets and a placebo, both administered orally. The maximum daily dose of amiloride is set at 20 mg, with a total treatment period of up to 65 days. The study aims to provide valuable insights into the therapeutic potential of amiloride for patients with nephrogenic diabetes insipidus secondary to lithium treatment.

The clinical trial involves the administration of **AMILORIDE**, an experimental medication, for the treatment of **nephrogenic diabetes insipidus** in patients with bipolar disorder who are treated with lithium. **AMILORIDE** is provided in tablet form and is administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 6000 mg over a treatment period of up to 10 days. In another regimen, the maximum daily dose is 10 mg, with a total maximum dose of 650 mg over a treatment period of up to 65 days. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring participant compliance through regular assessments.

The study also includes the use of a **placebo** as a comparator treatment. The **Placebo d'amiloride** is designed to match the experimental medication in appearance and administration route, which is oral. The placebo is utilized to maintain the integrity of the double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This approach allows for an unbiased evaluation of the efficacy of **AMILORIDE** in reducing the urine concentration defect associated with nephrogenic diabetes insipidus.

The efficacy of **amiloride** in the treatment of nephrogenic diabetes insipidus in patients with bipolar disorder treated with lithium will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage change in maximal urine osmolality before and after a 2-month treatment period. This will be measured to evaluate the improvement in the urine concentration defect.

Secondary endpoints include a variety of parameters measured at baseline and at 2, 6, and 12 months. These include the percentage change in maximal urine osmolality, self-reported mean number of nocturnal voids, thirst intensity and distress scale scores, presence of polyuria (defined as a daily urine output greater than 3 liters per day), and quality-of-life scale scores (SF36). Additionally, the estimated glomerular filtration rate (eGFR) will be calculated using the CKD-EPI equation based on standardized serum creatinine measurements. Mood scale scores (YMRS and MADRS), anxiety scale score (GAD7), and the Pittsburgh sleep score (PSQI) will also be assessed. The total number of hospital admissions for manic or depressive relapse during the 12-month treatment period will be recorded, along with the difference in residual plasma lithium levels before and after the 2-month treatment period. Short- and long-term tolerances will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), with an unacceptable toxicity defined as a grade of 3 or higher at 2, 6, and 12 months.