Bipolar DisorderPhase 4AMINDNCT05044611
AMIloride for the Treatment of Nephrogenic Diabetes Insipidus for Patients With Bipolar Disorder Treated With Lithium
A Phase 4 study testing Anhydrous Amiloride Hydrochloride in people with Bipolar Disorder, run by Assistance Publique - Hôpitaux de Paris at 2 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Bipolar Disorder
- What is being tested?
- Anhydrous Amiloride Hydrochloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 148 participants
- Where
- 2 sitesFrance
- Study dates
- 11 Jan 2023to 11 Jan 2026
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 23Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
France2 sites
Néphrologie, Hôpital Henri-Mondor
Créteil
Physiologie Explorations fonctionnelles multidisciplinaires, Hôpital Bichat
Paris
About this study
Official title: 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.
Read the 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.
- Conditions
- Bipolar Disorder
- Being tested
- Anhydrous Amiloride Hydrochloride, Placebo
- Keywords
- lithium, urine concentration defect
- Medical subject headings
- Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anhydrous Amiloride HydrochlorideDrug
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
PlaceboDrug
Route of administration : oral the control arm will receive a placebo twice daily during 2 months
| Study group | Role | What they receive |
|---|---|---|
| Amiloride | Experimental | the experimental arm will receive 5mg of amiloride twice daily during 2 months Receives: Drug: Anhydrous Amiloride Hydrochloride |
| Placebo | Placebo comparator | the control arm will receive a placebo twice daily during 2 months Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 2 month after randomization
Secondary outcomes (11)
Demonstrate the efficacy of amiloride to reduce nocturia
Difference in mean number of nocturnal voids
Measured: 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
Measured: 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)
Measured: 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)
Measured: 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
Measured: 12 months after randomization
Evaluate the effect of amiloride in mood stability
Difference in Mood Scale scores YMRS
Measured: 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
Measured: 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
Measured: 12 months after randomization
Evaluate the effect of amiloride in mood stability
Difference in Mood Scale MADRS
Measured: 2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in mood stability
Difference in anxiety scale score (GAD7)
Measured: 2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in mood stability
Difference in the Pittsburgh sleep score (PSQI)
Measured: 2 months after randomization and 12 months after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2021
- Study start11 Jan 2023
- Primary completion3 Mar 2025
- Study completion11 Jan 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 148 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- DECHANET Aline, Mrs, Study chair, Assistance Publique - Hôpitaux de Paris (AP-HP)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05044611
- Sponsor's protocol ID
- APHP200042
- Acronym
- AMIND
- Status last verified
- May 2025
- First submitted
- 27 Aug 2021
- Last updated
- 9 May 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Krishnan N, Perazella MA. Diagnosis and Management of Acute and Chronic Lithium-Associated Nephrotoxicity. J Am Soc Nephrol. 2026 Aug 1;37(8):1789-1801. doi: 10.1681/ASN.0000001172. Epub 2026 Jun 5.
PubMed 42247265
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- AMIloride for the Treatment of Nephrogenic Diabetes Insipidus for Patients With Bipolar Disorder Treated With Lithium: a Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT05044611
- Acronym / sponsor ID
- AMIND / APHP200042
- Conditions
- Bipolar Disorder
- Keywords
- lithium, urine concentration defect
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 148 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 11 Jan 2023 (actual)
- Primary completion
- 3 Mar 2025 (actual)
- Study completion
- 11 Jan 2026 (estimated)
- First posted
- 16 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Amiloride | Experimental | Drug: Anhydrous Amiloride Hydrochloridethe experimental arm will receive 5mg of amiloride twice daily during 2 months |
| Placebo | Placebo comparator | Drug: Placebothe control arm will receive a placebo twice daily during 2 months |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (23 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anhydrous Amiloride HydrochlorideAmiloride 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 | Drug | Amiloride |
| PlaceboRoute of administration : oral the control arm will receive a placebo twice daily during 2 months | Drug | Placebo |
Primary outcome
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
11 secondary outcomes
Demonstrate the efficacy of amiloride to reduce nocturia
Time frame: 2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to reduce the sensation of thirst
Time frame: 2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to reduce polyuria
Time frame: 2 months after randomization and 12 months after randomization
Demonstrate the efficacy of amiloride to increase quality of life
Time frame: 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
Time frame: 12 months after randomization
Evaluate the effect of amiloride in mood stability
Time frame: 2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in circulating lithium levels stability
Time frame: 2 months after randomization
Evaluate the effect of amiloride in mood stability
Time frame: 12 months after randomization
Evaluate the effect of amiloride in mood stability
Time frame: 2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in mood stability
Time frame: 2 months after randomization and 12 months after randomization
Evaluate the effect of amiloride in mood stability
Time frame: 2 months after randomization and 12 months after randomization
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2025.
- Derived from this study: PubMed 42247265Krishnan N, Perazella MA. Diagnosis and Management of Acute and Chronic Lithium-Associated Nephrotoxicity. J Am Soc Nephrol. 2026 Aug 1;37(8):1789-1801. doi: 10.1681/ASN.0000001172. Epub 2026 Jun 5.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
DECHANET Aline, Mrs study chair
Assistance Publique - Hôpitaux de Paris (AP-HP)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Anhydrous Amiloride Hydrochloride in people with Bipolar Disorder, run by Assistance Publique - Hôpitaux de Paris at 2 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 9 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05044611, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2025.