SALT Study (Switching to the Administration of Lithium Slow -Release Treatment)

Study Overview
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Brief Summary
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The aim of the study is to assess the tolerability, efficacy and safety of a new lithium sulphate prolonged release formulation (Lithiofor®) in patients affected by Bipolar Disorder poor tolerant to lithium immediate-release treatment in terms of lithium-induced tremor when switched from therapy with a lithium carbonate immediate release formulation (Carbolithium®) to a new lithium sulphate prolonged release formulation (Lithiofor®).

Detailed Description
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This is a phase IV, randomized, open, parallel groups, multicentre, prospective study. The main purpose of this clinical trial is to evaluate the change in the lithium induced tremor when switching from Lithium Immediate Release formulation (Carbolithium®) to Lithium Sulphate prolonged-release formulation (Lithiofor®) in Bipolar Disorder patients, poorly tolerant to the Lithium Immediate Release treatment. The primary end point will be the reduction of the lithium induced tremor. Patients in treatment with lithium carbonate immediate-release (Carbolithium®), will be enrolled in the study and, after 1 week of maintaining treatment, will be randomly switched to Lithium prolonged-release formulation or will continue the previous therapy.

Official Title
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Clinical Evaluation of Switching to Lithiofor® (Lithium Sulphate Slow -Release, Li-SR Tablets) From Carbolithium® (Lithium Carbonate Immediate-Release, Li-IR, Capsules) in Bipolar Patients, Poorly Tolerant to Lithium Immediate-release Treatment.

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Lithium sulphate prolonged-release 660 mg
* Drug: Lithium carbonate immediate-release 150 mg and 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 to 65 years (limits included), with no limitation of race. Female patients with childbearing potential should have a negative pregnancy test and should not be breastfeeding. Male and female patients should use an appropriate birth control method. Diagnosis of Bipolar disorder (BD) I or II (as per DSM-5), with or without rapid cycling. BD patients in treatment with lithium Carbolithium® immediate-release, presenting at the screening and baseline low tolerability in terms of tremor (tremor severity assessment ≥ 2 on single item of the UKU side-effect rating scale). MADRS score ≤ 10 and YMRS ≤ 12 at screening and baseline visits. Patients legally capable to give the consent to participate in the study and available to sign and date the written informed consent. Patient able to understand the study procedures and to comply with protocol requirements. Exclusion Criteria: Fulfilling criteria for the following disorders: schizophrenia, psychotic and schizoaffective disorders, unipolar depression; concomitant organic mental disorder or intellectual disability; history of dementia or cognitive disorders, any neurodegenerative diseases. Known hypersensitivity or allergy to lithium or to any components of the study medications. Pharmacological treatments affecting tremor, except for patients treated for at least 2 months before the screening visit (i.e. Beta-blockers; for further details). Known tremor due to irreversible lithium neurotoxicity. Patients at risk for suicidal behaviour. Immunocompromised patients. Acute, or chronic, or recurrent medical conditions that might affect/jeopardize the study results. Significant liver disease, defined as known active hepatitis or elevated liver enzymes > 3 times the upper boundary of the normal ranges. Value of creatinine outside the normal ranges and judged clinically relevant by Investigator. Any contraindication listed in the Summaries of Product Characteristics (SmPC) of Carbolithium® and lithium sulphate prolonged-release tablets (Lithiofor®). Positive history for drugs. Alcohol abuse. Positive urine drug screen for CNS-active drugs (cocaine, opioids, amphetamines and cannabinoids) at Visit 0 (screening). Clinically significant abnormalities on physical examination, vital signs, ECG, laboratory tests prior to screening visit. Inability to comply with the protocol requirements, instructions and study-related restrictions; e.g. uncooperative attitude, inability to return for study-visits, and improbability of completing the clinical study. Vulnerable subjects (e.g. persons kept in detention). Participation to an interventional clinical study within 3 months prior to the screening visit. If Subject is the Investigator or his(her) deputies, first grade relative, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, multicenter, prospective study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Lithium sulphate prolonged-release 660 mg | Drug: Lithium sulphate prolonged-release 660 mg<br>* Oral administration of one tablet once or twice daily (one tablet in the morning and one tablet in the evening) or two tablets in a single dose (two tablets in the evening) of Lithium sulphate 660 mg (Lithium sulphate dose will be individualised for each patient according to the relevant SmPC). Treatment duration: 3 months.<br>* Other names: LITHIOFOR®;|
| Active Comparator: Group 2<br>Lithium carbonate immediate-release 150 mg and 300 mg | Drug: Lithium carbonate immediate-release 150 mg and 300 mg<br>* Oral administration of 300-1800 mg daily divided into 2-6 doses of Lithium carbonate capsules (Lithium carbonate dose will be individualised for each patient according to the relevant SmPC). Treatment duration: 3 months.<br>* Other names: CARBOLITHIUM®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of item 2.5 (tremor) in Udvalg for Kliniske Undersøgelser (UKU) scale | Proportion of patients with an improvement in tremor assessed by the change from baseline of item 2.5 in UKU side-effect rating scale after 1-week treatment period. | Baseline - Week 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of item 2.5 (tremor) in Udvalg for Kliniske Undersøgelser (UKU) scale | Proportion of patients with an improvement in tremor assessed by the change from baseline of item 2.5 in UKU side-effect rating scale after 4- and 12-week treatment period. | Baseline - Weeks 4 and 12 | 
| Change of item 3.8 in Udvalg for Kliniske Undersøgelser (UKU) scale | Proportion of patients with a change from baseline of item 3.8 in UKU side-effect rating scale after 1-, 4- and 12-week treatment period. | Baseline - Weeks 1, 4 and 12 | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) | Change from baseline of total score in MADRS scale after 1-, 4- and 12-week treatment period. | Baseline - Weeks 1, 4 and 12 | 
| Change in Young Mania Rating Scale (YMRS) | Change from baseline of total score in YMRS scale after 1-, 4- and 12-week treatment period. | Baseline - Weeks 1, 4 and 12 | 
| Change in Treatment Satisfaction Questionnaire for Medication (TSQM) scale | Change from baseline in each sub-scale of TSQM after 1- and 12-week treatment period. | Baseline - Weeks 1 and 12 | 
| Change in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) | Change from baseline in Q-LES-Q-SF after 1- and 12-week treatment period. | Baseline - Weeks 1 and 12 | 
| Change in Clinical Global Impression (CGI) scale | Assessment by the physician of the overall efficacy by CGI scale after 1- and 12-week treatment period. | Baseline - Weeks 1 and 12 | 
| Frequency of treatment-related adverse events | Monitoring of the frequency of adverse events, physical examination, vital signs, ECG, laboratory analyses, plasma Lithium concentration. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tremor, Lithium Sulphate, Prolonged release formulation, Lithium carbonate, Immediate release formulation, Bipolar Disorder