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    Clinical Trial Results:
    A multicentre double blind placebo controlled clinical trial to assess efficacy and safety of Alvalin® (cathine hydrochloride) vs. placebo in 265 obese patients/group with a body mass index (BMI) between 30 and 45 kg/m2

    Summary
    EudraCT number
    2012-003426-24
    Trial protocol
    DE  
    Global end of trial date
    05 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jul 2022
    First version publication date
    01 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTU079G
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Riemser Pharma GmbH
    Sponsor organisation address
    An der Wiek 7, Greifswald - Insel Riems, Germany, 17493
    Public contact
    Medical Science & Operations, RIEMSER Pharma GmbH, +49 38351760, info.germany@esteve.com
    Scientific contact
    Medical Science & Operations, RIEMSER Pharma GmbH, +49 38351760, info.germany@esteve.com
    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
    13 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of the efficacy and safety of 32 mg of Alvalin® compared to placebo given intermittently over 52 weeks (three treatment periods interrupted by two periods with basal therapy only) in the treatment of diet-related obesity in patients with a BMI of 30 to 45 kg/m². Primary endpoint is the weight reduction of at least 10% overall in the treatment group with at least 5% greater weight reduction than in the placebo group) after 52 weeks of treatment.
    Protection of trial subjects
    This study will be conducted in accordance with the following: • Federal Ministry of Health (2005). ""Arzneimittelgesetz in der Fassung der Bekanntmachung vom 12. Dezember 2005 (BGBl. I S. 3394), das zuletzt durch Artikel 1 der Verordnung vom 19. Juli 2011 (BGBl. I S. 1398) geändert worden ist" • 6. Bekanntmachung zur Anzeige von Nebenwirkungen und Arzneimittelmissbrauch nach §63b Abs. 1 bis 8 des Arzneimittelgesetzes (AMG) vom 19.1.2010 ; . [6. Announcement Concerning the Reporting of Side Effects and Drug Abuse in Accordance with § 63b Abs. 1 to 8 AMG)]. • WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI. Revidierte Deklaration von Helsinki (Somerset West 2004) [Revised Declaration Somerset West (South Africa, 1996)] • ICH Topic E 6 (R1) Guideline for Good Clinical Practice (2002) • General insurance conditions for the clinical trials of medicinal products (subject insurance). • GCP-Verordnung [GCP-Regulation] – GCP-V: Verordnung über die Anwendung der Guten Klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen vom 9. August 2004 • 3. Bekanntmachung zur klinischen Prüfung von Arzneimitteln am Menschen. Gemeinsame Bekanntmachung des Bundesinstituts für Arzneimittel und Medizinprodukte und des Paul-Ehrlich- Instituts vom 10. August 2006 • RIEMSER Arzneimittel AG: Standard Operating Procedures (SOP)
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 529
    Worldwide total number of subjects
    529
    EEA total number of subjects
    529
    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)
    529
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Multi-center study: 18 centers Planned sample size was 265 patients / group, including an expected drop-out rate of 40%. Patients who drop out will not be replaced. At least 56.700 applications of Alvalin® will have to be observed, to reach a sufficient accuracy for the detection of very rare adverse drug reactions.

    Pre-assignment
    Screening details
    In case of AE, investigator can interrupt or reduce medication. If the same AE occurs again after rechallenging, the medical therapy is reduced or stopped. Individuals who want to discontinue due to lack of efficiency should be encouraged to remain in the study and to attend their study visits.

    Period 1
    Period 1 title
    Period 1(overall study) - enhancedSafety
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The investigator obtained sealed emergency envelopes containing a letter with the individual treatment (test or reference drug) of the patient. The patient specific envelope was only opened if the medical condition of the patient and the adverse event required this. Reason, signature and date for opening had to be noted on the letter and the project manager at the sponsor had to be informed immediately. Normally, decoding only could have been performed after database closure.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test Preparation
    Arm description
    The study medication has to be applied every morning after breakfast. 32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.
    Arm type
    Experimental

    Investigational medicinal product name
    cathine hydrochloride (Alvalin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only.

    Arm title
    Placebo Preparation
    Arm description
    The study medication / placebo has to be applied every morning after breakfast. 0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Local use
    Dosage and administration details
    0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks.

    Number of subjects in period 1
    Test Preparation Placebo Preparation
    Started
    264
    265
    Completed
    251
    245
    Not completed
    13
    20
         No visit 2
    7
    11
         Lost to follow-up
    6
    9
    Period 2
    Period 2 title
    Period 2 - eITT
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test Preparation
    Arm description
    The study medication has to be applied every morning after breakfast. 32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.
    Arm type
    Experimental

    Investigational medicinal product name
    cathine hydrochloride (Alvalin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only.

    Arm title
    Placebo Preparation
    Arm description
    The study medication / placebo has to be applied every morning after breakfast. 0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Local use
    Dosage and administration details
    0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks.

    Number of subjects in period 2
    Test Preparation Placebo Preparation
    Started
    251
    245
    Completed
    101
    83
    Not completed
    150
    162
         Protocol deviation
    13
    7
         Other
    66
    45
         Lack of efficacy
    6
    20
         Adverse event, non-fatal
    6
    7
         Consent withdrawn by subject
    39
    55
         Lost to follow-up
    20
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Test Preparation
    Reporting group description
    The study medication has to be applied every morning after breakfast. 32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.

    Reporting group title
    Placebo Preparation
    Reporting group description
    The study medication / placebo has to be applied every morning after breakfast. 0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.

    Reporting group values
    Test Preparation Placebo Preparation Total
    Number of subjects
    264 265 529
    Age categorical
    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)
    264 265 529
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Calculated for Safety Population (n=514)
    Units: years
        arithmetic mean (standard deviation)
    46.44 ± 11.78 45.82 ± 12.02 -
    Gender categorical
    Gender of Safety population (n=514)
    Units: Subjects
        Female
    218 209 427
        Male
    46 56 102

    End points

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    End points reporting groups
    Reporting group title
    Test Preparation
    Reporting group description
    The study medication has to be applied every morning after breakfast. 32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.

    Reporting group title
    Placebo Preparation
    Reporting group description
    The study medication / placebo has to be applied every morning after breakfast. 0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.
    Reporting group title
    Test Preparation
    Reporting group description
    The study medication has to be applied every morning after breakfast. 32 mg cathine hydrochloride per day, i.e. 12 drops of Alvalin® intermittent for thrice 12 weeks separated by 2 periods of eight weeks with basal therapy only. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.

    Reporting group title
    Placebo Preparation
    Reporting group description
    The study medication / placebo has to be applied every morning after breakfast. 0 mg cathine hydrochloride per day 12 drops of Alvalin® placebo for 52 weeks. Patients receive basal therapy throughout the study and in addition during 52 weeks an active treatment / placebo therapy which is separated in: • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy • 08 weeks of basal therapy only • 12 weeks of active treatment or placebo therapy The basal therapy in this trial was standardised according to the programme established in the study of Hauner et al. (2004): Basal therapy comprised education, a moderately hypocaloric diet, and an increase in physical activity.

    Primary: Change of weight in total

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    End point title
    Change of weight in total
    End point description
    Primary endpoint is the weight reduction of at least 10% overall in the treatment group with at least 5% greater weight reduction than in the placebo group) after 52 weeks of treatment. Following the EMA Guideline on Clinical Evaluation of Medicinal Products used in Weight Control [Guideline on Weight Control (2007)], administering Alvalin®, a weight reduction of at least 10% compared to baseline and a superiority in weight reduction of at least 5% compared to placebo after a period of 12 months of therapy are necessary to fulfil the primary criterion.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: percentage of weight
        arithmetic mean (standard deviation)
    6.29 ± 6.74
    2.72 ± 5.63
    Statistical analysis title
    Hypothesis 1 (eITT)
    Statistical analysis description
    A two sided t-test was used for analysis of the reduction of body weight with a global α level of 0.05. Because there were two hypotheses, the α level for H1 is 0.025 (one sample t-test) and for H2 α is also 0.025 (two sample t-test)
    Comparison groups
    Placebo Preparation v Test Preparation
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Percentage of patients with weight loss >10%

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    End point title
    Percentage of patients with weight loss >10%
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: patients
    60
    24
    No statistical analyses for this end point

    Secondary: Percentage of patients with weight loss > 5 %

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    End point title
    Percentage of patients with weight loss > 5 %
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: patients
    127
    58
    No statistical analyses for this end point

    Secondary: Weight loss during the trial(V1-V13)

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    End point title
    Weight loss during the trial(V1-V13)
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: kg
        arithmetic mean (standard deviation)
    6.41 ± 6.99
    2.86 ± 5.75
    No statistical analyses for this end point

    Secondary: Change in waist circumference (WC)

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    End point title
    Change in waist circumference (WC)
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: cm
        arithmetic mean (standard deviation)
    6.26 ± 7.93
    3.09 ± 6.58
    No statistical analyses for this end point

    Secondary: Change in waist-hip ratio (WHR)

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    End point title
    Change in waist-hip ratio (WHR)
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: ratio
        arithmetic mean (standard deviation)
    0.0108 ± 0.0670
    -0.0012 ± 0.0630
    No statistical analyses for this end point

    Secondary: Change in BMI

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    End point title
    Change in BMI
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: kg/m^2
        arithmetic mean (standard deviation)
    2.28 ± 2.48
    1.01 ± 2.05
    No statistical analyses for this end point

    Secondary: Phisicians assessment of efficacy

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    End point title
    Phisicians assessment of efficacy
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: patients
        Very good
    51
    26
        Good
    54
    29
        Moderate
    25
    22
        Poor
    15
    11
        Very poor
    37
    60
    No statistical analyses for this end point

    Secondary: Patient's assessment of efficacy

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    End point title
    Patient's assessment of efficacy
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Test Preparation Placebo Preparation
    Number of subjects analysed
    251
    245
    Units: patients
        Very good
    49
    21
        Good
    56
    37
        Moderate
    31
    22
        Poor
    12
    8
        Very poor
    34
    60
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed during the 52 weeks of study, additionally at follow-up visit 1 (3 months after end of treatment) and follow-up visit 2 (12 months after end of treatment).
    Adverse event reporting additional description
    15 randomised patients (2.3 %) had no intake of study medication and therefore 514 patients (79.9 %) were valid for the safety analysis. In 349/514 patients (67.9%) 959 AEs occurred: in 182 patients (52.1%) treated with Alvalin®, and in 167 patients (47.9%) receiving placebo.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Safety Placebo Preparation
    Reporting group description
    All persons with documented intake of trial medication in the course of the clinical trial were valid for the safety analysis.

    Reporting group title
    Safety Test preparation
    Reporting group description
    All persons with documented intake of trial medication in the course of the clinical trial were valid for the safety analysis.

    Serious adverse events
    Safety Placebo Preparation Safety Test preparation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 256 (8.20%)
    19 / 258 (7.36%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Surgical and medicinal procedures
         subjects affected / exposed
    9 / 256 (3.52%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer tumor
         subjects affected / exposed
    0 / 256 (0.00%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Prothesis dislocation
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast
         subjects affected / exposed
    2 / 256 (0.78%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    3 / 256 (1.17%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Crystal urine present
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal septum deviation
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
    Additional description: Sciatica, Dizziness, Restlessness, VIIth nerve paralysis
         subjects affected / exposed
    2 / 256 (0.78%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Inner ear disorder
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gatrointestinal
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal calculus
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muskuloskeletal and connective tissue
         subjects affected / exposed
    1 / 256 (0.39%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goiter
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism
    Additional description: hypercalcaemia, periarthritis calcarea
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Safety Placebo Preparation Safety Test preparation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 256 (65.23%)
    182 / 258 (70.54%)
    Vascular disorders
    Cardiovascular disorder, Flushing,Hypertension
         subjects affected / exposed
    9 / 256 (3.52%)
    10 / 258 (3.88%)
         occurrences all number
    9
    11
    General disorders and administration site conditions
    General disorders and administration site conditions
    Additional description: withdrawal syndrome, fatigue, malaise, irritability, thirst
         subjects affected / exposed
    5 / 256 (1.95%)
    27 / 258 (10.47%)
         occurrences all number
    5
    37
    Psychiatric disorders
    Psychiatric disorders
    Additional description: sleep disorder, middle insomnia, depression, nervousness, emotional distress, burnout syndrome, stress, depressed mood, anxiety, mood swings, anxiety disorder
         subjects affected / exposed
    16 / 256 (6.25%)
    23 / 258 (8.91%)
         occurrences all number
    17
    32
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 258 (0.39%)
         occurrences all number
    0
    1
    Investigations
    Investigations
    Additional description: Blood preassure increased, Blood preassure decreased, skin test positive, EKG abnormal
         subjects affected / exposed
    6 / 256 (2.34%)
    2 / 258 (0.78%)
         occurrences all number
    6
    2
    Cardiac disorders
    Tachycardia, Heart valve incompetence, Extrasystoles, Bundle branch block right
         subjects affected / exposed
    2 / 256 (0.78%)
    8 / 258 (3.10%)
         occurrences all number
    2
    10
    Nervous system disorders
    Nervous system disorders
    Additional description: Headache, restlessness, restless legs syndrome, dizziness, migraine, vertigo, agitation, somnolence, abnormal dreams
         subjects affected / exposed
    31 / 256 (12.11%)
    46 / 258 (17.83%)
         occurrences all number
    39
    54
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 258 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 258 (0.39%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    0 / 256 (0.00%)
    17 / 258 (6.59%)
         occurrences all number
    0
    21
    Nausea, Tongue disorder
         subjects affected / exposed
    1 / 256 (0.39%)
    3 / 258 (1.16%)
         occurrences all number
    1
    3
    Diarrhoea, Pulpitis dental, Toothache, Abdominal discomfort
         subjects affected / exposed
    26 / 256 (10.16%)
    16 / 258 (6.20%)
         occurrences all number
    26
    16
    Skin and subcutaneous tissue disorders
    Urticaria, Hyperhidrosis, Alopecia
         subjects affected / exposed
    2 / 256 (0.78%)
    2 / 258 (0.78%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    9 / 256 (3.52%)
    22 / 258 (8.53%)
         occurrences all number
    11
    28
    Glucose tolerance impaired, Hyperuricaemia
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 258 (0.39%)
         occurrences all number
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    51 / 256 (19.92%)
    67 / 258 (25.97%)
         occurrences all number
    51
    67
    Bronchitis
         subjects affected / exposed
    6 / 256 (2.34%)
    4 / 258 (1.55%)
         occurrences all number
    6
    4
    Urinary tract infection
         subjects affected / exposed
    5 / 256 (1.95%)
    5 / 258 (1.94%)
         occurrences all number
    5
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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