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    Clinical Trial Results:
    A randomized, placebo-controlled, double-blind, parallel-group, multicenter combined Phase 2a/2b study to assess the efficacy and safety of BAY 1817080 in patients with diabetic neuropathic pain

    Summary
    EudraCT number
    		 2020-002066-14
    Trial protocol
    		 DE   NO   CZ   FI   SE   HU   SK   DK   PL  
    Global end of trial date
    17 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Dec 2022
    First version publication date
    24 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1817080/20887
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04641273
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.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
    17 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This Phase 2 study had a dual objective: Part A (Phase 2a) aimed to reach proof of concept, i.e. show good efficacy and safety of Eliapixant in diabetic neuropathic pain (DNP) patients. Part B (Phase 2b) was planned to explore the dose response relationship and, thus, serve as a dose finding study. This study was terminated due to lack of efficacy after completion of Part A in line with the decision criteria pre-specified in the protocol. Part A: to evaluate the efficacy of BAY1817080 on the treatment of pain associated with DNP as compared with placebo
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2021
    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
    Finland: 11
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Czechia: 43
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Slovakia: 27
    Worldwide total number of subjects
    154
    EEA total number of subjects
    154
    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)
    80
    From 65 to 84 years
    72
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 42 centers in 10 countries with first subject first visit on 22-Jan-2021 and last subject last visit on 18-Oct-2021 for Part A. This study was terminated due to lack of efficacy after completion of Part A in line with the decision criteria pre-specified in the protocol.

    Pre-assignment
    Screening details
    		 Overall, 224 subjects were enrolled and 70 subjects failed screening. A total of 154 subjects were randomly assigned to treatment (77 in each treatment arm) and received at least 1 dose of study intervention.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eliapixant 150 mg BID
    Arm description
    		 Subjects were randomized to receive 150 mg oral doses of Eliapixant, administered twice daily over the course of 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eliapixant
    Investigational medicinal product code
    BAY1817080
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg twice daily (BID), administered orally for 8 weeks. The tablets were administered approximately at the same time each day 12 hours apart.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were randomized to receive matching placebo, administered twice daily over the course of 8 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets administered BID orally for 8 weeks. The tablets were administered approximately at the same time each day 12 hours apart.

    Number of subjects in period 1
    		Eliapixant 150 mg BID Placebo
    Started
    77
    77
    Completed
    67
    68
    Not completed
    10
    9
         COVID-19 pandemic
    2
    -
         Physician decision
    2
    -
         Adverse event, non-fatal
    4
    2
         Subject decision
    1
    5
         Other
    -
    1
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eliapixant 150 mg BID
    Reporting group description
    		 Subjects were randomized to receive 150 mg oral doses of Eliapixant, administered twice daily over the course of 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomized to receive matching placebo, administered twice daily over the course of 8 weeks

    Reporting group values
    		 Eliapixant 150 mg BID Placebo Total
    Number of subjects
    		 77 77 154
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.2 ( 9.2 ) 62.7 ( 9.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 26 54
        Male
    		 49 51 100
    Baseline weekly mean 24-hour average pain intensity score using the 11-point numeric rating scale
    NRS is an one-item assessment of average neuropathic pain intensity which is presented as an 11-point Likert scale with 0 as “no pain” and 10 as “worst imaginable pain” Used per protocol set (PPS): Eliapixant 150 mg BID (N=71), Placebo (N=73)
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 5.87 ( 1.21 ) 5.77 ( 1.05 ) -
    Baseline Neuropathic Pain Symptom Inventory (NPSI) score
    The NPSI was developed to evaluate different symptoms of neuropathic pain. It contained 12 items, of which five summary pain scores were calculated. The total score was summed over 100 by adding each of the five categories together. The 10 descriptive items used to derive the domain summary scores were each rated on an 11-point numeric rating scale. The remaining two items reported how consistently pain had been present and the number of pain episodes Used per protocol set (PPS): Eliapixant 150 mg BID (N=71), Placebo (N=73)
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 35.61 ( 14.39 ) 36.78 ( 15.99 ) -

    End points

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    End points reporting groups
    Reporting group title
    Eliapixant 150 mg BID
    Reporting group description
    		 Subjects were randomized to receive 150 mg oral doses of Eliapixant, administered twice daily over the course of 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomized to receive matching placebo, administered twice daily over the course of 8 weeks

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who were randomized to a treatment group and had at least one non-missing post-baseline measurement

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who were randomized to a treatment group and had taken at least one unit of the study medication

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included subjects had no validity findings affecting efficacy endpoints

    Primary: Change in weekly mean 24-hour average pain intensity score using the 11-point numeric rating scale (NRS) from baseline to the end of intervention (EOI)

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    End point title
    		 Change in weekly mean 24-hour average pain intensity score using the 11-point numeric rating scale (NRS) from baseline to the end of intervention (EOI)
    End point description
    NRS was an one-item assessment of average neuropathic pain intensity which was presented as an 11-point Likert scale with 0 as “no pain” and 10 as “worst imaginable pain”
    End point type
    Primary
    End point timeframe
    At baseline (week 0) and at EOI (week 8)
    End point values
    		 Eliapixant 150 mg BID Placebo
    Number of subjects analysed
    71 [1]
    73 [2]
    Units: Scores of the scale
        arithmetic mean (standard deviation)
    -1.50 ( 1.94 )
    -2.18 ( 1.85 )
    Notes
    [1] - PPS
    [2] - PPS
    Statistical analysis title
    		 Bayesian Repeated measures ANCOVA
    Statistical analysis description
    Posterior mean, 90% credible interval and posterior probabilities were calculated based on a Bayesian repeated measures ANCOVA adjusting for the treatment (Eliapixant 150mg BID or placebo), timepoint (weeks 4, 6 and 8) and treatment-timepoint interaction as factors having fixed effects and baseline score as a continuous covariate, with an unstructured covariance matrix
    Comparison groups
    Eliapixant 150 mg BID v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.063
         upper limit
    		 1.141
    Notes
    [3] - Proof-of-Concept decision based on Bayesian criteria (based on posterior probability)

    Secondary: Change in Neuropathic Pain Symptom Inventory (NPSI) score from baseline to the EOI

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    End point title
    		 Change in Neuropathic Pain Symptom Inventory (NPSI) score from baseline to the EOI
    End point description
    The Neuropathic Pain Symptom Inventory (NPSI) was a Patient-reported outcome (PRO) developed to evaluate different symptoms of neuropathic pain. The NPSI contained 12 items, of which five summary pain scores were calculated. The total score was summed over 100 by adding each of the five categories together. The 10 descriptive items used to derive the domain summary scores were each rated on an 11-point numeric rating scale ( 0= “no (symptom)” and 10= “worst (symptom) imaginable”); each item had a recall period of the past 24 hours. The remaining two items reported how consistently pain had been present and the number of pain episodes
    End point type
    Secondary
    End point timeframe
    At baseline (week 0), weeks 2, 4 and at EOI (week 8)
    End point values
    		 Eliapixant 150 mg BID Placebo
    Number of subjects analysed
    71 [4]
    73 [5]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -9.38 ( 18.90 )
    -11.87 ( 18.05 )
    Notes
    [4] - PPS
    [5] - PPS
    Statistical analysis title
    		 Repeated measures ANCOVA
    Statistical analysis description
    Mean, 90% confidence interval and p-values are calculated based on a repeated measures ANCOVA adjusting for the treatment (Eliapixant 150mg BID or placebo), timepoint (weeks 2, 4, 8) and treatment-timepoint interaction as factors having fixed effects and baseline score as a continuous covariate, with an unstructured covariance matrix.
    Comparison groups
    Eliapixant 150 mg BID v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4648
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.498
         upper limit
    		 6.463
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7

    Secondary: Patient Global Impression of Change (PGI-C) at the EOI

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    End point title
    		 Patient Global Impression of Change (PGI-C) at the EOI
    End point description
    The PGI-C was an one-item, self-reported instrument used to assess patients’ impression of disease severity and change, with a 7-point scale response-option. Scores range from 1 (“very much better”) to 7 (“very much worse”) PGI-C responder was defined as very much better or much better on the PGI-C scale at EOI
    End point type
    Secondary
    End point timeframe
    At EOI (week 8)
    End point values
    		 Eliapixant 150 mg BID Placebo
    Number of subjects analysed
    65 [6]
    67 [7]
    Units: Number of subjects
        VERY MUCH BETTER
    4
    8
        MUCH BETTER
    11
    17
        A LITTLE BETTER
    21
    21
        NO CHANGE
    19
    15
        A LITTLE WORSE
    5
    3
        MUCH WORSE
    4
    3
        VERY MUCH WORSE
    1
    0
    Notes
    [6] - PPS
    [7] - PPS
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Odds ratio, 90% CI and p-value follow from a logistic regression adjusting for treatment as a fixed effects factor, based on multiple imputation (MI)-based approach for imputing missing PGIC responses at week 8 (MI performed using MCMC under MAR assumption).
    Comparison groups
    Eliapixant 150 mg BID v Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.96

    Secondary: The proportion of subjects achieving a ≥30% and a ≥50% reduction in weekly mean 24-hour average pain intensity score using NRS

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    End point title
    		 The proportion of subjects achieving a ≥30% and a ≥50% reduction in weekly mean 24-hour average pain intensity score using NRS
    End point description
    Percentage number was based on number of subjects in the analysis set with non-missing weekly mean pain NRS at the timepoint.
    End point type
    Secondary
    End point timeframe
    From baseline (Week 0) to EOI (Week 8)
    End point values
    		 Eliapixant 150 mg BID Placebo
    Number of subjects analysed
    71 [8]
    73 [9]
    Units: Percentage of subjects
    number (not applicable)
        >=30% improvement in pain (n=50;58)
    40.0
    58.6
        >=50% improvement in pain (n=50;58)
    28.0
    36.2
    Notes
    [8] - PPS
    [9] - PPS
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Odds ratio, 90% CI and p-value follow from a logistic regression adjusting for treatment as a fixed effects factor, based on multiple imputation (MI)-based approach for imputing missing NRS responses at week 8 (MI performed using MCMC under MAR assumption).
    Comparison groups
    Eliapixant 150 mg BID v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.53
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.95
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Odds ratio, 90% CI and p-value follow from a logistic regression adjusting for treatment as a fixed effects factor, based on multiple imputation (MI)-based approach for imputing missing NRS responses at week 8 (MI performed using MCMC under MAR assumption).
    Comparison groups
    Eliapixant 150 mg BID v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.69
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.3

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs)

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a patient or clinical study subject, that occurred after providing written informed consent, whether or not considered related to the study intervention Treatment-emergent adverse event (TEAE) was defined as any adverse event arising or worsening after the start of study intervention administration until 14 days after the last intake of study intervention
    End point type
    Secondary
    End point timeframe
    Start of intervention to 14 days after stop of treatment
    End point values
    		 Eliapixant 150 mg BID Placebo
    Number of subjects analysed
    77 [10]
    77 [11]
    Units: Subjects
        Any TEAE
    39
    37
        Any study drug-related TEAE
    20
    11
        Any serious TEAE
    3
    1
        Any TEAE with permanent stop of study drug
    6
    3
    Notes
    [10] - SAF
    [11] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study intervention administration until 14 days after the last study medication intake. Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Eliapixant 150 mg BID
    Reporting group description
    		 Subjects were randomized to receive 150 mg oral doses of Eliapixant, administered twice daily over the course of 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomized to receive matching placebo, administered twice daily over the course of 8 weeks.

    Serious adverse events
    		 Eliapixant 150 mg BID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 77 (1.30%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    IIIrd nerve disorder
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Eliapixant 150 mg BID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 77 (49.35%)
    37 / 77 (48.05%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 77 (2.60%)
         occurrences all number
    1
    2
    Malaise
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    Pyrexia
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    2
    Hiccups
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Blood fibrinogen increased
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 77 (1.30%)
         occurrences all number
    4
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Heart rate increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Cystatin C increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Muscle rupture
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Rib fracture
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    Thermal burn
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Inflammation of wound
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 77 (2.60%)
         occurrences all number
    4
    2
    Anosmia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Diabetic neuropathy
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    8 / 77 (10.39%)
    0 / 77 (0.00%)
         occurrences all number
    8
    0
    Headache
         subjects affected / exposed
    5 / 77 (6.49%)
    8 / 77 (10.39%)
         occurrences all number
    11
    8
    Hypoaesthesia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Hypogeusia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Parosmia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Hyperfibrinogenaemia
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 77 (1.30%)
         occurrences all number
    4
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    2
    Vision blurred
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    1 / 77 (1.30%)
    3 / 77 (3.90%)
         occurrences all number
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 77 (2.60%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 77 (1.30%)
         occurrences all number
    4
    1
    Dry mouth
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    Flatulence
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    Oesophageal pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Rash macular
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 77 (5.19%)
         occurrences all number
    3
    6
    Back pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    Muscular weakness
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Limb discomfort
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Spinal pain
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Sacroiliac joint dysfunction
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Osteomyelitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Periodontitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Skin bacterial infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Diabetic foot infection
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Oral fungal infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Herpes dermatitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    Weight fluctuation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    2
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (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
    22 Jun 2021
    Protocol amendment 1 (global), dated 22 JUN 2021: • Visit schedule was adapted to allow for testing of liver parameters every 2 weeks during the treatment period as precautionary measure • Adaptation of exclusion criterion 6 with addition of an example for extremely low body weight to support the investigator decisions on subject selection
    22 Oct 2021
    Protocol amendment 2 (global), dated 22 OCT 2021, key modifications for Part A: • Coronavirus disease 2019 (COVID-19) tests to be performed at every onsite visit • Update of visit numbering to facilitate programming by the use of an integer number for all visits • The potential risk of phototoxicity was removed and a liver safety monitoring board was implemented according to newly available data • The endpoint definitions were updated as EOI visit • Inclusion criteria were separated for Part A and Part B • Exclusion criteria were adapted to clarify that the normal ranges provided by the central laboratory should be followed • Clarification was added that no special lifestyle considerations have to be taken based on newly available data • The use of rescue medication including the allowed daily dose was updated • General statement was included to further clarify the trial termination • Additional hematology and blood chemistry parameters were added • The definition of the serious adverse events (SAE) reporting timelines was revised to provide a clear guidance for the investigator for the SAE reporting in order to meet a general requirement provided by the German health authority to other protocols

    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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