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    Clinical Trial Results:
    Randomised, double-blind, double-dummy, active-controlled, phase III clinical trial on the efficacy and safety of an 8-week add-on treatment with budesonide 9 mg capsules vs. budesonide 6 mg capsules vs. budesonide-MMX® 9 mg tablets in patients with ulcerative colitis refractory to standard treatment with mesalazine.

    Summary
    EudraCT number
    		 2017-004576-57
    Trial protocol
    		 DE   LV   HU   SK   LT   CZ   PL  
    Global end of trial date
    03 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jun 2024
    First version publication date
    05 Jun 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BUX-4/UCA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstr. 5, Freiburg, Germany, 79108
    Public contact
    Clinical Research and Development, Dr. Falk Pharma GmbH, +49 76115140, zentrale@drfalkpharma.de
    Scientific contact
    Clinical Research and Development, Dr. Falk Pharma GmbH, +49 76115140, zentrale@drfalkpharma.de
    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
    15 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to prove the non-inferiority of an 8-week add-on treatment with once-daily 9 mg budesonide capsules and 6 mg budesonide capsules, respectively, versus active comparator 9 mg budesonide-MMX® tablets, for the induction of remission in patients with ulcerative colitis (UC) refractory to standard treatment with mesalazine.
    Protection of trial subjects
    Close supervision of subjects by implementing interim visits every 14 days to guarantee their safety and well-being. Prior to recruitment of patients, all relevant documents of the clinical study were submitted and proved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient's consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
    Background therapy
    		 Patients enrolled in this trial had to be on treatment with approved oral mesalazine formulations for at least 6 weeks prior to baseline at a mesalazine dosage of ≥ 2.4 g/d, or therapeutic aminosalicylate equivalent, i.e. either olsalazine ≥ 2.4 g/d, or balsalazide ≥ 5.6 g/d, or sulfasalazine ≥ 6.2 g/d. The dose, formulation and intake regimen of oral mesalazine used prior to baseline had to be kept stable for 6 weeks until baseline. Alternatively, patients had to be on treatment with a combinatory treatment with approved oral mesalazine formulations at a dosage of ≥ 2.4 g/d (or therapeutic equivalent) and an approved rectal mesalazine formulation (in a registered dose for treatment of an acute episode of distal UC) for at least 10 days prior to baseline. The dose, formulation and intake regimen of combined (oral and rectal) mesalazine (if applicable) had to be kept stable for at least 10 days until baseline. The oral mesazaline treatment had to be continued. The dose, formulation and intake regimen of oral mesalazine treatment had to be kept stable from baseline throughout the trial until end of tapering phase. Rectal mesalazine treatment had to be stopped at baseline.
    Evidence for comparator
    		 Cortiment® MMX® (budesonide-MMX®) is the only approved budesonide formulation for the induction of remission in patients with active, mild to moderate UC refractory to mesalazine standard treatment.
    Actual start date of recruitment
    01 Mar 2019
    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
    Poland: 41
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Latvia: 27
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Russian Federation: 170
    Country: Number of subjects enrolled
    Türkiye: 14
    Country: Number of subjects enrolled
    Ukraine: 188
    Worldwide total number of subjects
    482
    EEA total number of subjects
    110
    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)
    448
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 482 patients were randomized and treated in the Czech Republic, Germany, Hungary, Latvia, Lithuania, Poland, the Russian Federation, Slovakia, Turkey and Ukraine.

    Pre-assignment
    Screening details
    		 Patients signing the informed consent form were screened for up to 2 weeks to evaluate eligibility for the study. A total of 648 patients was screened for enrollment into the study. One hundred and sixty-six patients were neither randomized nor treated. The most common reason for screening failure was violation of eligibility criteria.

    Period 1
    Period 1 title
    8-week double-blind treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The study was conducted using the double-dummy technique to guarantee the double-blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A (BUX-9 mg)
    Arm description
    		 8-week treatment with 1 budesonide 9 mg capsule and 1 placebo budesonide-MMX® tablet
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budenofalk® 9 mg capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule Budenofalk® 9 mg granules once daily in the morning

    Investigational medicinal product name
    Budesonide-MMX® placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 placebo budesonide-MMX® tablet per day in the morning

    Arm title
    		 Group B (BUX-6 mg)
    Arm description
    		 8-week treatment with 1 budesonide 6 mg capsule and 1 placebo budesonide-MMX® tablet
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budenofalk® 6 mg capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule Budenofalk® 6 mg granules once daily in the morning

    Investigational medicinal product name
    Budesonide-MMX® placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 placebo budesonide-MMX® tablet per day in the morning

    Arm title
    		 Group C (MMX-9 mg)
    Arm description
    		 8-week treatment with 1 placebo budesonide capsule and 1 budesonide-MMX® 9 mg tablet
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide placebo capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 placebo budesonide capsule once daily in the morning

    Investigational medicinal product name
    Budesonide-MMX® 9 mg tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 budesonide-MMX® 9 mg tablet once daily in the morning

    Number of subjects in period 1
    		Group A (BUX-9 mg) Group B (BUX-6 mg) Group C (MMX-9 mg)
    Started
    159
    164
    159
    Completed
    149
    158
    149
    Not completed
    10
    6
    10
         Adverse event, non-fatal
    2
    2
    2
         Other reasons
    3
    -
    2
         Lack of patient's cooperation
    1
    1
    2
         Lack of efficacy
    4
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A (BUX-9 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 9 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Group B (BUX-6 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 6 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Group C (MMX-9 mg)
    Reporting group description
    		 8-week treatment with 1 placebo budesonide capsule and 1 budesonide-MMX® 9 mg tablet

    Reporting group values
    		 Group A (BUX-9 mg) Group B (BUX-6 mg) Group C (MMX-9 mg) Total
    Number of subjects
    		 159 164 159 482
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 148 148 152 448
        From 65-84 years
    		 11 16 7 34
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.1 ( 12.86 ) 42.3 ( 13.87 ) 40.9 ( 12.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 69 78 73 220
        Male
    		 90 86 86 262

    End points

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    End points reporting groups
    Reporting group title
    Group A (BUX-9 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 9 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Group B (BUX-6 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 6 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Group C (MMX-9 mg)
    Reporting group description
    		 8-week treatment with 1 placebo budesonide capsule and 1 budesonide-MMX® 9 mg tablet

    Primary: Clinical and endoscopic remission at week 8 / EOT (PP final)

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    End point title
    		 Clinical and endoscopic remission at week 8 / EOT (PP final)
    End point description
    Percentage of patients being in clinical and endoscopic remission at week 8 / EOT. The primary efficacy variable was defined as an abbreviated mDAI total score ≤ 2 with • mDAI subscore for rectal bleeding = 0, • mDAI subscore for stool frequency ≤ 1, and • mDAI subscore for mucosal appearance ≤ 1. The analysis set is the per-protocol analysis set for the final analysis (N = 431).
    End point type
    Primary
    End point timeframe
    After 8-week treatment: week 8 / EOT
    End point values
    		 Group A (BUX-9 mg) Group B (BUX-6 mg) Group C (MMX-9 mg)
    Number of subjects analysed
    144
    145
    142
    Units: Subjects
        Yes
    76
    76
    78
        No
    68
    69
    64
    Statistical analysis title
    		 Non-inferiority test (BUX-9 mg vs. MMX-9 mg)
    Statistical analysis description
    For statistical testing a non-inferiority margin of 10% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated confidence interval for the treatment difference with respect to clinical and endoscopic remission (πBUX-9 mg – πMMX-9 mg) is above -10%. This corresponds to a local significance level of 0.0232 for the final analysis.
    Comparison groups
    Group A (BUX-9 mg) v Group C (MMX-9 mg)
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0905 [1]
    Method
    		 Farrington-Manning test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.7
         upper limit
    		 9.4
    Notes
    [1] - As the p-value is above the local significance level of 0.0232, non-inferiority has not been proven for the PP analysis set for the final analysis.
    Statistical analysis title
    		 Non-inferiority test (BUX-6 mg vs. MMX-9 mg)
    Comparison groups
    Group B (BUX-6 mg) v Group C (MMX-9 mg)
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.1007
    Method
    		 Farrington-Manning test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 9.1
    Notes
    [2] - For statistical testing a non-inferiority margin of 10% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated confidence interval for the treatment difference with respect to clinical and endoscopic remission (πBUX-6 mg – πMMX-9 mg) is above -10%. This corresponds to a local significance level of 0.0232 for the final analysis.

    Primary: Clinical and endoscopic remission at week 8 / EOT (FAS final)

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    End point title
    		 Clinical and endoscopic remission at week 8 / EOT (FAS final)
    End point description
    Percentage of patients being in clinical and endoscopic remission at week 8 / EOT. The primary efficacy variable was defined as an abbreviated mDAI total score ≤ 2 with • mDAI subscore for rectal bleeding = 0, • mDAI subscore for stool frequency ≤ 1, and • mDAI subscore for mucosal appearance ≤ 1. The analysis set is the full analysis set for the final analysis (N = 482).
    End point type
    Primary
    End point timeframe
    After 8-week treatment: week 8 / EOT
    End point values
    		 Group A (BUX-9 mg) Group B (BUX-6 mg) Group C (MMX-9 mg)
    Number of subjects analysed
    159
    164
    159
    Units: Subjects
        Yes
    82
    82
    86
        No / missing
    77
    82
    73
    Statistical analysis title
    		 Non-inferiority test (BUX-9 mg vs. MMX-9 mg)
    Statistical analysis description
    For statistical testing a non-inferiority margin of 10% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated confidence interval for the treatment difference with respect to clinical and endoscopic remission (πBUX-9 mg – πMMX-9 mg) is above -10%. This corresponds to a local significance level of 0.0232 for the final analysis.
    Comparison groups
    Group A (BUX-9 mg) v Group C (MMX-9 mg)
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0896 [3]
    Method
    		 Farrington-Manning test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.5
         upper limit
    		 8.5
    Notes
    [3] - As the p-value is above the local significance level of 0.0232, non-inferiority has not been proven for the FAS analysis set for final analysis.
    Statistical analysis title
    		 Non-inferiority test (BUX-6 mg vs. MMX-9 mg)
    Statistical analysis description
    For statistical testing a non-inferiority margin of 10% was defined. Hence, non-inferiority is shown if the lower bound of the 95% repeated confidence interval for the treatment difference with respect to clinical and endoscopic remission (πBUX-6 mg – πMMX-9 mg) is above -10%. This corresponds to a local significance level of 0.0232 for the final analysis.
    Comparison groups
    Group B (BUX-6 mg) v Group C (MMX-9 mg)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1426 [4]
    Method
    		 Farrington-Manning test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 6.8
    Notes
    [4] - As the p-value is above the local significance level of 0.0232, non-inferiority has not been proven for the FAS analysis set for final analysis.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Period 1: 8-week double-blind treatment phase Period 2: 2-week double-blind tapering phase Period 3: 2-week follow-up phase
    Adverse event reporting additional description
    Period 1: Group A, Group B, Group C (safety analysis set) Period 2: Group A1, Group A2, Group B1, Group B2, Group C1, Group C2 (safety analysis set) Period 3: Former Group A, Former Group B, Former Group C (safety analysis set)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Group A (BUX-9 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 9 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Group B (BUX-6 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 6 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Group C (MMX-9 mg)
    Reporting group description
    		 8-week treatment with 1 placebo budesonide capsule and 1 budesonide-MMX® 9 mg tablet

    Reporting group title
    Group A1 (BUX-9 mg-V)
    Reporting group description
    		 2-week double-blind treatment with 1 budesonide 9 mg capsule every other day and 1 placebo budesonide-MMX® tablet every other day

    Reporting group title
    Group A2 (BUX-9 mg-P)
    Reporting group description
    		 2-week double-blind treatment with 1 placebo budesonide capsule every other day and 1 placebo budesonide-MMX® tablet every other day

    Reporting group title
    Group B1 (BUX-6 mg-V)
    Reporting group description
    		 2-week double-blind treatment with 1 budesonide 6 mg capsule every other day and 1 placebo budesonide-MMX® tablet every other day

    Reporting group title
    Group B2 (BUX-6 mg-P)
    Reporting group description
    		 2-week double-blind treatment with 1 placebo budesonide capsule every other day and 1 placebo budesonide-MMX® tablet every other day

    Reporting group title
    Group C1 (MMX-9 mg-V)
    Reporting group description
    		 2-week double-blind treatment with 1 placebo budesonide capsule every other day and 1 budesonide-MMX® tablet every other day

    Reporting group title
    Group C2 (MMX-9 mg-P)
    Reporting group description
    		 2-week double-blind treatment with 1 placebo budesonide capsule every other day and 1 placebo budesonide-MMX® tablet every other day

    Reporting group title
    Former Group A (BUX-9 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 9 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Former Group B (BUX-6 mg)
    Reporting group description
    		 8-week treatment with 1 budesonide 6 mg capsule and 1 placebo budesonide-MMX® tablet

    Reporting group title
    Former Group C (MMX-9 mg)
    Reporting group description
    		 8-week treatment with 1 placebo budesonide capsule and 1 budesonide-MMX® 9 mg tablet

    Serious adverse events
    		 Group A (BUX-9 mg) Group B (BUX-6 mg) Group C (MMX-9 mg) Group A1 (BUX-9 mg-V) Group A2 (BUX-9 mg-P) Group B1 (BUX-6 mg-V) Group B2 (BUX-6 mg-P) Group C1 (MMX-9 mg-V) Group C2 (MMX-9 mg-P) Former Group A (BUX-9 mg) Former Group B (BUX-6 mg) Former Group C (MMX-9 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 159 (2.52%)
    4 / 164 (2.44%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    1 / 82 (1.22%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    2 / 159 (1.26%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 164 (0.61%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 164 (0.61%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 164 (0.61%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    1 / 82 (1.22%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 164 (0.61%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Group A (BUX-9 mg) Group B (BUX-6 mg) Group C (MMX-9 mg) Group A1 (BUX-9 mg-V) Group A2 (BUX-9 mg-P) Group B1 (BUX-6 mg-V) Group B2 (BUX-6 mg-P) Group C1 (MMX-9 mg-V) Group C2 (MMX-9 mg-P) Former Group A (BUX-9 mg) Former Group B (BUX-6 mg) Former Group C (MMX-9 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 159 (15.72%)
    31 / 164 (18.90%)
    32 / 159 (20.13%)
    0 / 77 (0.00%)
    2 / 82 (2.44%)
    1 / 86 (1.16%)
    2 / 78 (2.56%)
    1 / 81 (1.23%)
    0 / 78 (0.00%)
    6 / 159 (3.77%)
    3 / 164 (1.83%)
    13 / 159 (8.18%)
    Investigations
    Cortisol decreased
         subjects affected / exposed
    8 / 159 (5.03%)
    6 / 164 (3.66%)
    24 / 159 (15.09%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    1 / 164 (0.61%)
    3 / 159 (1.89%)
         occurrences all number
    9
    7
    27
    0
    0
    0
    0
    0
    0
    0
    1
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 159 (2.52%)
    4 / 164 (2.44%)
    3 / 159 (1.89%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    4
    4
    3
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Lipase increased
         subjects affected / exposed
    5 / 159 (3.14%)
    3 / 164 (1.83%)
    3 / 159 (1.89%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    1 / 164 (0.61%)
    3 / 159 (1.89%)
         occurrences all number
    5
    3
    3
    0
    0
    0
    0
    0
    0
    0
    1
    3
    White blood cell count increased
         subjects affected / exposed
    3 / 159 (1.89%)
    4 / 164 (2.44%)
    2 / 159 (1.26%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    3
    5
    3
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 159 (1.26%)
    4 / 164 (2.44%)
    1 / 159 (0.63%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    3 / 159 (1.89%)
         occurrences all number
    2
    4
    1
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 159 (0.63%)
    4 / 164 (2.44%)
    0 / 159 (0.00%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    0 / 159 (0.00%)
    0 / 164 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    1
    6
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 159 (6.92%)
    10 / 164 (6.10%)
    7 / 159 (4.40%)
    0 / 77 (0.00%)
    2 / 82 (2.44%)
    1 / 86 (1.16%)
    2 / 78 (2.56%)
    1 / 81 (1.23%)
    0 / 78 (0.00%)
    5 / 159 (3.14%)
    0 / 164 (0.00%)
    4 / 159 (2.52%)
         occurrences all number
    17
    10
    12
    0
    2
    1
    2
    3
    0
    8
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    4 / 164 (2.44%)
    1 / 159 (0.63%)
    0 / 77 (0.00%)
    0 / 82 (0.00%)
    0 / 86 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 159 (0.63%)
    1 / 164 (0.61%)
    0 / 159 (0.00%)
         occurrences all number
    1
    4
    1
    0
    0
    0
    0
    0
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2019
    The amendment includes clarifications to verbalize more detailed guidance as per the current status quo.
    21 Apr 2020
    The amendment was introduced due to the COVID-19 pandemic and its impact on the national health systems and public restrictions. The sponsor amended the clinical trial protocol for the duration of this pandemic. The aim of this amendment was to introduce mitigation measures for the negative effects of the COVID-19 pandemic on this clinical trial to ensure safety and well-being of the patients and health care staff at the trial sites. This amendment implied an addendum to the patient information sheet and informed consent form.

    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.
    This trial was partially disrupted by the COVID-19 pandemic and the Russia/Ukraine conflict. Mitigation measures were implemented to minimize the impact on study data. Supportive analyses do not indicate any problems with the reliability of the data.
    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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