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

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ClinicalTrials.gov Identifier: NCT05044611
Recruitment Status : Not yet recruiting
First Posted : September 16, 2021
Last Update Posted : November 19, 2021
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Bipolar Disorder Drug: Anhydrous Amiloride Hydrochloride Drug: Placebo Phase 4

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, kalemia, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 148 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

Two-phased study:

1st phase: Double blind, placebo-controlled, randomized trial to demonstrate the efficacy of 2 months treatment with amiloride 5mg twice a day to increase urine osmolality in patients with BD treated with lithium for at least 5 years and with a urine concentration defect.

This double-blinded phase is followed by an open label phase (2nd phase) during 10 months to evaluate the long-term safety profile of the investigated drug and its potential nephroprotective role.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: AMIloride for the Treatment of Nephrogenic Diabetes Insipidus for Patients With Bipolar Disorder Treated With Lithium: a Randomized Controlled Trial
Estimated Study Start Date : April 1, 2022
Estimated Primary Completion Date : January 1, 2024
Estimated Study Completion Date : November 1, 2024


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




Primary Outcome Measures :
  1. 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. [ Time Frame: 2 month after randomization ]
    The primary endpoint is the percentage change in maximal urine osmolality before and after 2 months of treatment


Secondary Outcome Measures :
  1. Demonstrate the efficacy of amiloride to reduce nocturia [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in mean number of nocturnal voids

  2. Demonstrate the efficacy of amiloride to reduce the sensation of thirst [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in mean number of nocturnal voids

  3. Demonstrate the efficacy of amiloride to reduce polyuria [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Presence of polyuria (defined as a daily urine output > 3 L/day)

  4. Demonstrate the efficacy of amiloride to increase quality of life [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in Quality-of-life scale score (SF36)

  5. Demonstrate the efficacy of amiloride to reduce the decline of eGFR after one year of treatment [ Time Frame: 12 months after randomization ]
    Difference in eGFR (estimated by the CKD-EPI equation based on standardized serum creatinine measurement) before and after 12 months of treatment

  6. Evaluate the effect of amiloride in mood stability [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in Mood Scale scores YMRS

  7. Evaluate the effect of amiloride in circulating lithium levels stability [ Time Frame: 2 months after randomization ]
    Difference in residual plasma lithium levels before and after the 2 months treatment period

  8. Evaluate the effect of amiloride in mood stability [ Time Frame: 12 months after randomization ]
    Total number of hospital admission for maniac or depressive relapse during 12 months of treatment

  9. Evaluate the effect of amiloride in mood stability [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in Mood Scale MADRS

  10. Evaluate the effect of amiloride in mood stability [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in anxiety scale score (GAD7)

  11. Evaluate the effect of amiloride in mood stability [ Time Frame: 2 months after randomization and 12 months after randomization ]
    Difference in the Pittsburgh sleep score (PSQI)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults (age ≥ 18 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
  • Hyperkalemia > 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)
  • Acute phase of mood disorder
  • Previous use of amiloride (long term use ≥ 6 months or/and 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

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): NCT05044611


Contacts
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Contact: VRTOVSNIK Francois, Pr 01 40 25 71 01 francois.vrtovsnik@aphp.fr
Contact: FLAMANT Martin 01 40 25 88 00 martin.flamant@aphp.fr

Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Study Chair: DECHANET Aline, Mrs Assistance Publique - Hôpitaux de Paris (AP-HP)
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT05044611    
Other Study ID Numbers: APHP200042
First Posted: September 16, 2021    Key Record Dates
Last Update Posted: November 19, 2021
Last Verified: November 2021
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
Keywords provided by Assistance Publique - Hôpitaux de Paris:
lithium
urine concentration defect
Additional relevant MeSH terms:
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Diabetes Insipidus
Diabetes Insipidus, Nephrogenic
Bipolar Disorder
Bipolar and Related Disorders
Mental Disorders
Kidney Diseases
Urologic Diseases
Pituitary Diseases
Endocrine System Diseases
Amiloride
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Acid Sensing Ion Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Epithelial Sodium Channel Blockers
Diuretics, Potassium Sparing