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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2016-001714-14
    Trial protocol
    		 IT  
    Global end of trial date
    20 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Oct 2020
    First version publication date
    05 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    136PO15274
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03210480
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AZIENDE CHIMICHE RIUNITE ANGELII FRANCESCO ACRAF S.p.A.
    Sponsor organisation address
    Via Amelia 70, Rome, Italy, 00181
    Public contact
    CTAu@angelini.it, AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO ACRAF S.p.A. , 39 +390691045405, federica.pelacchi@angelinipharma.com
    Scientific contact
    CTAunit, AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO ACRAF S.p.A., 39 0691045335, ctaunit@angelini.it
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is the evaluation of the change in the lithium-induced tremor when switching from lithium IR formulation (Carbolithium®) to a new lithium Slow-Release (SR)/Prolonged Release (PR) formulation (Lithiofor®), after 1 week.
    Protection of trial subjects
    The present study has been conducted in accordance with the study protocol, GCPs, Declaration of Helsinki (including up-to-date versions) and the applicable regulatory requirements. Patients had written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects partecipating in the trial. No other specific measures were provided. In case of ineffective treatment the Investigator administered alternative drugs and the patients discontinued study.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Lithium has been a cornerstone of therapy for bipolar disorder for several decades and is effective in the management of both manic and depressive episodes. The effectiveness of lithium monotherapy in acute mania has been demonstrated in randomised active- and placebo-controlled trials and for this reason it is a first-line recommendation in the majority of the current clinical practice guidelines. Moreover, lithium salts have demonstrated efficacy in the prevention of mania, depression and suicidal behaviour and remain among the most commonly prescribed prophylactic medications for the maintenance phase of Bipolar Depression.
    Actual start date of recruitment
    01 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 85
    Worldwide total number of subjects
    85
    EEA total number of subjects
    85
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    84
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment of 138 patients was planned. 85 were screened and 73 patients were randomised to allocated intervention (37 in Lithium PR and 36 in Lithium IR) from 28 March 2017 (FPFV) to 20 September 2019 (LPLV).

    Pre-assignment
    Screening details
    		 85 patients were screened and evaluated for relevant medical and psychiatric history, current medical conditions, age, sex, race, weight and height, clinical chemistry, hematology and urinalysis screens, screening of substance abuse and a pregnancy test in female subjects. 12 patients resulted screening failure. 73 patients were randomised.

    Pre-assignment period milestones
    Number of subjects started
    		 85
    Number of subjects completed
    		 70

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Discontinued medication: 3
    Reason: Number of subjects
    		 Consent withdrawn by subject: 4
    Reason: Number of subjects
    		 Screening failure: 8
    Period 1
    Period 1 title
    PERIOD 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study. A blinded assessor performed the primary and secondary outcome evaluations, except for other safety evaluations, in order to limit bias due to the open-label conditions.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test: Lithium PR
    Arm description
    		 Lithium Sulphate Prolonged-Release 660 mg tablet (Lithiofor®) – Lithium PR
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lithium Sulphate Prolonged-Release 660 mg tablet
    Investigational medicinal product code
    136
    Other name
    Lithiofor®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients had to take orally 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).

    Arm title
    		 Reference: Lithium IR
    Arm description
    		 Lithium Carbonate Immediate-Release 150 mg and 300 mg capsules (Carbolithium®) – Lithium IR
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lithium Carbonate Immediate-Release 150 mg and 300 mg
    Investigational medicinal product code
    136
    Other name
    Carbolithium®
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients had to take orally 300-1800 mg daily divided into 2-6 doses daily.

    Number of subjects in period 1 [1]
    		Test: Lithium PR Reference: Lithium IR
    Started
    35
    35
    Completed
    27
    32
    Not completed
    8
    3
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    4
    -
         Protocol deviation
    2
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 85 patients were screened and evaluated. 73 patients were randomised.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Test: Lithium PR
    Reporting group description
    		 Lithium Sulphate Prolonged-Release 660 mg tablet (Lithiofor®) – Lithium PR

    Reporting group title
    Reference: Lithium IR
    Reporting group description
    		 Lithium Carbonate Immediate-Release 150 mg and 300 mg capsules (Carbolithium®) – Lithium IR

    Reporting group values
    		 Test: Lithium PR Reference: Lithium IR Total
    Number of subjects
    		 35 35 70
    Age categorical
    Patients aged 18-65 - m-ITT
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        From 18 to 65 years
    		 35 35 70
    Age continuous
    Subjects
    Units: years
        arithmetic mean (standard deviation)
    		 45.20 ± 11.71 45.54 ± 14.66 -
    Gender categorical
    Gender - mITT
    Units: Subjects
        female
    		 20 23 43
        male
    		 15 12 27
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population included all randomized subjects who took at least one dose of the study treatments and consisted of 72 patients (1 patient did not take any study medication).

    Subject analysis set title
    m-ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified ITT population consisted of all randomized patients who took at least one dose of study medication and had an evaluation of the primary endpoint (tremor) both at baseline and at 1 week of treatment. Following the Data Review Meeting, three patients (4003, 2009 and 7001) were excluded from the m-ITT that therefore it consisted of 70 patients.

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population consisted of all patients in m-ITT with no major protocol deviations and a treatment compliance ≥80% from baseline to 1-week treatment period.Following the Data Review Meeting, 20 additional patients were excluded from the PP population leaving 50 PP patients.

    Subject analysis sets values
    		 Safety population m-ITT population PP population
    Number of subjects
    72
    70
    50
    Age categorical
    Patients aged 18-65 - m-ITT
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
        From 18 to 65 years
    72
    70
    50
    Age continuous
    Subjects
    Units: years
        arithmetic mean (standard deviation)
    45.37 ± 13.17
    45.37 ± 13.17
    47.24 ± 13.44
    Gender categorical
    Gender - mITT
    Units: Subjects
        female
    43
    43
    31
        male
    27
    27
    19

    End points

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    End points reporting groups
    Reporting group title
    Test: Lithium PR
    Reporting group description
    		 Lithium Sulphate Prolonged-Release 660 mg tablet (Lithiofor®) – Lithium PR

    Reporting group title
    Reference: Lithium IR
    Reporting group description
    		 Lithium Carbonate Immediate-Release 150 mg and 300 mg capsules (Carbolithium®) – Lithium IR

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population included all randomized subjects who took at least one dose of the study treatments and consisted of 72 patients (1 patient did not take any study medication).

    Subject analysis set title
    m-ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified ITT population consisted of all randomized patients who took at least one dose of study medication and had an evaluation of the primary endpoint (tremor) both at baseline and at 1 week of treatment. Following the Data Review Meeting, three patients (4003, 2009 and 7001) were excluded from the m-ITT that therefore it consisted of 70 patients.

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population consisted of all patients in m-ITT with no major protocol deviations and a treatment compliance ≥80% from baseline to 1-week treatment period.Following the Data Review Meeting, 20 additional patients were excluded from the PP population leaving 50 PP patients.

    Primary: Proportion of patients with Improvement in tremor at 1 week

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    End point title
    		 Proportion of patients with Improvement in tremor at 1 week [1]
    End point description
    The primary endpoint was the evaluation of the proportion of patients with an improvement in tremor assessed by a single item (2.5 tremor, see section 9.5.1.1) of the UKU side-effect rating scale after 1-week treatment period compared to baseline. Improvement was defined as a difference ≥1 between scoring system at baseline and scoring system after 1 week of treatment. m-ITT. Statistical Analysis Fisher's exact test p-value (two-tail)
    End point type
    Primary
    End point timeframe
    After 1 week of treatment vs baseline.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoint was analyzed using a two tailed Fisher’s exact test with an alpha level of 0.05.
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        number (confidence interval 95%)
    62.9 (46.85 to 78.86)
    20 (6.75 to 33.25)
    No statistical analyses for this end point

    Secondary: Proportion of patients with Improvement in tremor at 4 weeks

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    End point title
    		 Proportion of patients with Improvement in tremor at 4 weeks
    End point description
    The evaluation of the proportion of patients with an improvement in tremor assessed using a single item of the UKU side-effect rating scale (item 2.5 tremor) at 4-weeks treatment period compared to baseline. m-ITT
    End point type
    Secondary
    End point timeframe
    After 4 weeks of treatment vs baseline.
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        number (confidence interval 95%)
    85.7 (72.75 to 98.68)
    48.6 (32.01 to 65.13)
    No statistical analyses for this end point

    Secondary: Proportion of patients with Improvement in tremor at 12 weeks

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    End point title
    		 Proportion of patients with Improvement in tremor at 12 weeks
    End point description
    The evaluation of the proportion of patients with an improvement in tremor assessed using a single item of the UKU side-effect rating scale (item 2.5 tremor) at 12-weeks treatment period compared to baseline. m-ITT
    End point type
    Secondary
    End point timeframe
    After 12 weeks of treatment vs baseline.
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        number (confidence interval 95%)
    92.6 (82.71 to 100)
    64.5 (47.67 to 81.36)
    No statistical analyses for this end point

    Secondary: Proportion of patients with an improvement in polyuria/polydipsia after 1 week

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    End point title
    		 Proportion of patients with an improvement in polyuria/polydipsia after 1 week
    End point description
    Proportion of patients with an improvement in polyuria/polydipsia; assessed by single item of the UKU side-effect rating scale (item 3.8 polyuria/polydipsia) after 1-week treatment periods compared to baseline; m-ITT
    End point type
    Secondary
    End point timeframe
    After 1-week treatment periods compared to baseline;
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: Percent
        number (confidence interval 95%)
    2.9 (0.00 to 8.38)
    17.1 (4.66 to 29.63)
    No statistical analyses for this end point

    Secondary: Proportion of patients with an improvement in polyuria/polydipsia after 4 weeks

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    End point title
    		 Proportion of patients with an improvement in polyuria/polydipsia after 4 weeks
    End point description
    Proportion of patients with an improvement in polyuria/polydipsia; assessed by single item of the UKU side-effect rating scale (item 3.8 polyuria/polydipsia) after 4-weeks treatment periods compared to baseline; m-ITT
    End point type
    Secondary
    End point timeframe
    After 4-weeks treatment periods compared to baseline;
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        number (confidence interval 95%)
    21.4 (6.23 to 36.6)
    17.1 (4.66 to 29.6)
    No statistical analyses for this end point

    Secondary: Proportion of patients with an improvement in polyuria/polydipsia after 12 weeks

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    End point title
    		 Proportion of patients with an improvement in polyuria/polydipsia after 12 weeks
    End point description
    Proportion of patients with an improvement in polyuria/polydipsia; assessed by single item of the UKU side-effect rating scale (item 3.8 polyuria/polydipsia) after 12-weeks treatment periods compared to baseline; m-ITT
    End point type
    Secondary
    End point timeframe
    After 12-weeks treatment periods compared to baseline;
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        number (confidence interval 95%)
    22.2 (6.54 to 37.90)
    22.6 (7.86 to 37.30)
    No statistical analyses for this end point

    Secondary: Changes in manic and depressive symptoms (MADRS scale) from baseline after 1-week

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    End point title
    		 Changes in manic and depressive symptoms (MADRS scale) from baseline after 1-week
    End point description
    Changes in manic and depressive symptoms were assessed from baseline after 1-week of treatment according to the rating scale MADRS and YMRS scales.
    End point type
    Secondary
    End point timeframe
    After 1-week of treatment
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    9.19 ± 131.12
    18.6 ± 131.12
    No statistical analyses for this end point

    Secondary: Changes in manic and depressive symptoms (MADRS scale) from baseline after 4-weeks

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    End point title
    		 Changes in manic and depressive symptoms (MADRS scale) from baseline after 4-weeks
    End point description
    Changes in manic and depressive symptoms from baseline after 4-weeks of treatment. The manic and depressive symptoms assessment will be performed according to the rating scale MADRS and YMRS scales.
    End point type
    Secondary
    End point timeframe
    After 4-weeks of treatment
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    -0.30 ± 95.44
    50 ± 175.63
    No statistical analyses for this end point

    Secondary: Changes in manic and depressive symptoms (MADRS scale) from baseline after 12-weeks

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    End point title
    		 Changes in manic and depressive symptoms (MADRS scale) from baseline after 12-weeks
    End point description
    Changes in manic and depressive symptoms from baseline after 12-weeks of treatment. The manic and depressive symptoms assessment will be performed according to the rating scale MADRS and YMRS scales.
    End point type
    Secondary
    End point timeframe
    After 12-weeks of treatment
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    13.94 ± 96.24
    46.55 ± 201.67
    No statistical analyses for this end point

    Secondary: Changes in manic and depressive symptoms (YMRS scale) after 1-week

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    End point title
    		 Changes in manic and depressive symptoms (YMRS scale) after 1-week
    End point description
    Changes in manic and depressive symptoms were assessed from baseline after 1-week of treatment according to the rating scale MADRS and YMRS scales.
    End point type
    Secondary
    End point timeframe
    After 1-week of treatment
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    -12.75 ± 66.74
    -19.21 ± 49.12
    No statistical analyses for this end point

    Secondary: Changes in manic and depressive symptoms (YMRS scale) after 4-weeks

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    End point title
    		 Changes in manic and depressive symptoms (YMRS scale) after 4-weeks
    End point description
    Changes in manic and depressive symptoms were assessed from baseline after 4-weeks of treatment according to the rating scale MADRS and YMRS scales.
    End point type
    Secondary
    End point timeframe
    After 4-weeks of treatment
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    -43.14 ± 74.37
    15.87 ± 153.97
    No statistical analyses for this end point

    Secondary: Changes in manic and depressive symptoms (YMRS scale) after 12 -weeks

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    End point title
    		 Changes in manic and depressive symptoms (YMRS scale) after 12 -weeks
    End point description
    Changes in manic and depressive symptoms were assessed from baseline after 12 -weeks of treatment according to the rating scale MADRS and YMRS scales.
    End point type
    Secondary
    End point timeframe
    After 12 -weeks
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    -15.20 ± 83.81
    -42.06 ± 91.23
    No statistical analyses for this end point

    Secondary: Changes in patient’s satisfaction from baseline at 1 week (TSQM)

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    End point title
    		 Changes in patient’s satisfaction from baseline at 1 week (TSQM)
    End point description
    Patient’s satisfaction to the assigned treatment from baseline to 1 week of treatment was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) Version II.
    End point type
    Secondary
    End point timeframe
    After 1 week
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    22.18 ± 93.66
    -2.78 ± 27.85
    No statistical analyses for this end point

    Secondary: Changes in patient’s satisfaction from baseline at 12 weeks (TSQM)

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    End point title
    		 Changes in patient’s satisfaction from baseline at 12 weeks (TSQM)
    End point description
    Patient’s satisfaction to the assigned treatment from baseline to 12 weeks of treatment was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) Version II.
    End point type
    Secondary
    End point timeframe
    After 12 weeks
    End point values
    		 Test: Lithium PR Reference: Lithium IR
    Number of subjects analysed
    35
    35
    Units: percent
        arithmetic mean (standard deviation)
    8.80 ± 83.70
    1.68 ± 30.69
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The timeframe for reporting adverse events is from informed Consent signature up to the last visit scheduled in the study (12 weeks after Visit 1)
    Adverse event reporting additional description
    The adverse events seen in the study were as expected for this population and this class of drugs. They were mostly mild and transient, did not seem to be dose-related and gave no indication of target organ toxicity or unexpected findings.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Test: Lithium PR
    Reporting group description
    		 Lithium sulphate prolonged-release 660 mg tablet (Lithiofor). Patients took orally 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). 1 patient never took study medication.

    Reporting group title
    Reference: Lithium IR
    Reporting group description
    		 Lithium carbonate immediate-release 150 mg and 300 mg capsules (Carbolithium®). Patients took orally 300-1800 mg daily divided into 2-6 doses.

    Serious adverse events
    		 Test: Lithium PR Reference: Lithium IR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
    Additional description: Patient relatives informed directly the Investigators that the patient had committed suicide.
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Test: Lithium PR Reference: Lithium IR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 36 (52.78%)
    16 / 36 (44.44%)
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoe
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Psychiatric symptom
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Depression
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Elevated mood
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Bipolar disorder
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Panic attack
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Thyroid function test
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Medication error
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Foot fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Overdose
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Tremor
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 36 (8.33%)
         occurrences all number
    4
    3
    Headache
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    4 / 36 (11.11%)
    5 / 36 (13.89%)
         occurrences all number
    5
    7
    Leukocyturia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Prostatitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Herpes ophthalmic
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Polydipsia
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 36 (11.11%)
         occurrences all number
    4
    6
    Dyslipidaemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2017
    Amendment no. 1 of 15-May 2017, (protocol version 3.0 dated 15/05/2017) was issued after the completion of the Italian commercialization procedure, in order to include the reference to the prolonged-release formulation marketed by Angelini S.p.A., with the commercial brand name Resilient™.
    20 Feb 2018
    Amendment no. 2 of 6 February 2018 issued to include two additional sites (Azienda Sanitaria dell’Alto Adige Servizio Psichiatrico del Comprensorio Sanitario di Bolzano and Ospedale San Giovanni di Dio di Orbetello Unità Funzionale Salute Mentale). Azienda Sanitaria dell’Alto Adige Servizio Psichiatrico del Comprensorio Sanitario di Bolzano later asked to be excluded from participation and did not randomize any patient.
    17 Aug 2018
    Amendment no. 4 of 19 April 2018 (protocol version 4.0 dated 19.04.2018), to introduce: • Changes in the Sponsor’s personnel, due to internal reorganization, • Updated safety information and updated SPC of Carbolithium®, • Modification of the informed consent form following the entry into force of the Regulation 2016/679 EU (GDPR).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the objective difficulties in patient recruitment (after the availability of Lithium PR -Resilient ™ on the Italian market), the Sponsor decided to terminate the study early in June 2019, including 85 patients out of 138 expected.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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