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    Clinical Trial Results:
    A multicentre, double blind, randomised, placebo controlled, Phase II trial to evaluate Resminostat for maintenance treatment of patients with advanced stage (Stage IIB-IVB) mycosis fungoides (MF) or Sézary Syndrome (SS) that have achieved disease control with systemic therapy – the RESMAIN Study

    Summary
    EudraCT number
    		 2016-000807-99
    Trial protocol
    		 GB   DE   NL   ES   AT   BE   PL   GR   IT  
    Global end of trial date
    08 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2025
    First version publication date
    17 Jul 2025
    Other versions
    Summary report(s)
    		 CTR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    4SC-201-6-2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02953301
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    4SC AG
    Sponsor organisation address
    Fraunhoferstr. 22, Planegg, Germany, 82152
    Public contact
    Corporate Communications, 4SC AG, public@4sc.com
    Scientific contact
    Clinical Operations, 4SC AG, resmain@4sc.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
    08 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine if maintenance treatment with resminostat increases progression-free survival (PFS) compared to placebo in patients with advanced stage (Stage IIB-IVB) MF or SS that have achieved disease control (complete response [CR], partial response [PR] or stable disease [SD]) with previous systemic therapy.
    Protection of trial subjects
    The most recent systemic therapy had to have been completed as planned or stopped due to unacceptable tolerability prior to randomisation to prevent discontinuation of patients from treatments from which they derived benefit. All patients, including those randomised to treatment with placebo, were able to receive best supportive care at the discretion of the investigator. Patients randomised to treatment with placebo who had disease progression were offered to roll over to resminostat. Before the start of a new treatment cycle, subjects were assessed including adverse events, physical examination, and measurement of hematological and biochemical parameters. Depending on the observed toxicities, the dose of resminostat could be individually reduced by 1/3 of the total daily dose. Guidance was given in the study protocol concerning actions to be taken due to the observed toxicities (dose reduction, interruption, discontinuation). Subjects requiring more than one dose reduction had to be discontinued. A Data Safety Monitoring Board (DSMB) was implemented to independently safeguard the interests of patients in the study and to enhance the integrity and credibility of the study. The DSMB reviewed selected safety data across the study at regular, pre-defined intervals and made recommendations regarding continuation, modification or termination of the study for safety concerns.
    Background therapy
    		 -
    Evidence for comparator
    		 The use of placebo as a treatment arm was considered justified since medical guidelines did not give clear recommendations for maintenance treatment in advanced CTCL, as evidence-based information on maintenance treatment is missing. Furthermore, patients on placebo had the option to roll-over to open-label treatment with resminostat once progressive. The Sponsor's opinion on use of placebo was confirmed by the EMA (Scientific Advice: EMA/CHMP/SAWP/ 33911/2016, 28-Jan-2016).
    Actual start date of recruitment
    14 Dec 2016
    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
    Switzerland: 23
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 53
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Italy: 18
    Worldwide total number of subjects
    201
    EEA total number of subjects
    141
    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)
    104
    From 65 to 84 years
    96
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients were randomized to treatment with resminostat or placebo at a ratio of 1:1 using IWRS, from 09 Jan 2017 to 11 May 2022 at 55 sites in 12 countries. Randomization of patients to resminostat or placebo was stratified by disease stage prior to the last systemic therapy and remission status achieved with the last systemic therapy.

    Pre-assignment
    Screening details
    		 234 patients (including 11 patients who were re-screened and thus each counted twice) were screened for trial participation. Of these, 33 were screening failures due to eligibility criterion not met (n=18), patient withdrawal (n=4), adverse event (n=4), physician decision (n=1) or other reasons (n=6), but 11 were eligible upon re-screening.

    Period 1
    Period 1 title
    Randomized period (double-blind)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Randomization (including stratification) of an individual patient to resminostat or placebo treatment was performed according to an algorithm in the IWRS. Subsequently to stratification and randomization, the IWRS assigned a specific medication kit (per kit number) to each patient. The kit numbers were assigned to wallets, each containing one resminostat or placebo blister. Emergency unblinding for a patient was also performed via the IWRS by the investigator or authorized team members.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Resminostat - ITT
    Arm description
    		 Subjects who were randomized to treatment with resminostat and included in the Intention to Treat population.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Resminostat
    Investigational medicinal product code
    4SC-201
    Other name
    KINSELBY
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each treatment consisted of 3 tablets (600 mg), administered orally once daily, from Day 1 – Day 5 of each 14 day cycle. Tablets were to be taken together, preferably in the morning, with water, and could be administered with or without food. The tablets were not to be chewed and/or crushed but were to be swallowed whole.

    Arm title
    		 Placebo - ITT
    Arm description
    		 Subjects who were randomized to treatment with placebo and included in the Intention to Treat population.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each treatment consisted of 3 tablets, administered orally once daily, from Day 1 – Day 5 of each 14 day cycle. Tablets were to be taken together, preferably in the morning, with water, and could be administered with or without food. The tablets were not to be chewed and/or crushed but were to be swallowed whole.

    Number of subjects in period 1
    		Resminostat - ITT Placebo - ITT
    Started
    100
    101
    Completed
    100
    101
    Period 2
    Period 2 title
    Rollover Period (open-label)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Patients randomized to treatment with placebo who progressed were offered to roll over to resminostat.

    Arms
    Arm title
    		 Open-label
    Arm description
    		 Subjects treated with placebo in the randomized period, who progressed and agreed to roll over to open-label treatment with resminostat.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Resminostat
    Investigational medicinal product code
    4SC-201
    Other name
    KINSELBY
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each treatment consisted of 3 tablets (600 mg), administered orally once daily, from Day 1 – Day 5 of each 14 day cycle. Tablets were to be taken together, preferably in the morning, with water, and could be administered with or without food. The tablets were not to be chewed and/or crushed but were to be swallowed whole.

    Number of subjects in period 2 [1]
    		Open-label
    Started
    80
    Completed
    80
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all patients had the option to enter the Rollover Period. Only patients on placebo who progressed during the double-blind phase, or patients on blinded treatment at trial termination had the option to roll-over to open-label treatment with resminostat (Rollover Period).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Resminostat - ITT
    Reporting group description
    		 Subjects who were randomized to treatment with resminostat and included in the Intention to Treat population.

    Reporting group title
    Placebo - ITT
    Reporting group description
    		 Subjects who were randomized to treatment with placebo and included in the Intention to Treat population.

    Reporting group values
    		 Resminostat - ITT Placebo - ITT Total
    Number of subjects
    		 100 101 201
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 53 51 104
        From 65-84 years
    		 46 50 96
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (standard deviation)
    		 63.5 ( 11.8 ) 64.0 ( 12.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 31 78
        Male
    		 53 70 123
    Diagnosis
    Units: Subjects
        Mycosis fungoides
    		 80 84 164
        Sezary Syndrome
    		 20 17 37
    Remission status
    Randomization of subjects to resminostat or placebo was stratified by disease stage prior to the last systemic therapy and remission status achieved with the last systemic therapy to ensure comparability of the populations in the two treatment arms.
    Units: Subjects
        Complete Response
    		 14 11 25
        Partial Response
    		 49 58 107
        Stable Disease
    		 37 32 69
    Stage of disease
    Subjects with advance stage (Stages IIB to IVB) Mycosis fungoides or Sézary syndrome were enrolled in this study.
    Units: Subjects
        IIB
    		 59 58 117
        IIIA
    		 8 4 12
        IIIB
    		 7 4 11
        IVA1
    		 10 16 26
        IVA2
    		 13 13 26
        IVB
    		 3 6 9
    Subject analysis sets

    Subject analysis set title
    Resminostat - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes all patients who were correctly randomised to resminostat and treated accordingly with at least one dose of the trial medication and who did not have any major protocol violations. Patients were analysed as treated.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes all patients who were correctly randomised to placebo and treated accordingly with at least one dose of the trial medication and who did not have any major protocol violations. Patients were analysed as treated.

    Subject analysis sets values
    		 Resminostat - PP Placebo - PP
    Number of subjects
    90
    84
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    47
    39
        From 65-84 years
    42
    45
        85 years and over
    1
    0
    Age continuous
    Units: years
        median (standard deviation)
    63.5 ( 11.7 )
    65.0 ( 12.1 )
    Gender categorical
    Units: Subjects
        Female
    40
    29
        Male
    50
    55
    Diagnosis
    Units: Subjects
        Mycosis fungoides
    71
    68
        Sezary Syndrome
    19
    16
    Remission status
    Randomization of subjects to resminostat or placebo was stratified by disease stage prior to the last systemic therapy and remission status achieved with the last systemic therapy to ensure comparability of the populations in the two treatment arms.
    Units: Subjects
        Complete Response
    11
    10
        Partial Response
    46
    49
        Stable Disease
    33
    25
    Stage of disease
    Subjects with advance stage (Stages IIB to IVB) Mycosis fungoides or Sézary syndrome were enrolled in this study.
    Units: Subjects
        IIB
    53
    44
        IIIA
    7
    4
        IIIB
    7
    4
        IVA1
    9
    15
        IVA2
    11
    13
        IVB
    3
    4

    End points

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    End points reporting groups
    Reporting group title
    Resminostat - ITT
    Reporting group description
    		 Subjects who were randomized to treatment with resminostat and included in the Intention to Treat population.

    Reporting group title
    Placebo - ITT
    Reporting group description
    		 Subjects who were randomized to treatment with placebo and included in the Intention to Treat population.
    Reporting group title
    Open-label
    Reporting group description
    		 Subjects treated with placebo in the randomized period, who progressed and agreed to roll over to open-label treatment with resminostat.

    Subject analysis set title
    Resminostat - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes all patients who were correctly randomised to resminostat and treated accordingly with at least one dose of the trial medication and who did not have any major protocol violations. Patients were analysed as treated.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes all patients who were correctly randomised to placebo and treated accordingly with at least one dose of the trial medication and who did not have any major protocol violations. Patients were analysed as treated.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from date of randomisation to first date that criteria for progressive disease were met according to the global response score or death due to any cause in the absence of documented progressive disease.
    End point type
    Primary
    End point timeframe
    From date of randomisation to end of blinded treatment.
    End point values
    		 Resminostat - ITT Placebo - ITT Resminostat - PP Placebo - PP
    Number of subjects analysed
    100
    101
    90
    84
    Units: months
        median (confidence interval 95%)
    8.3 (4.2 to 15.7)
    4.2 (2.8 to 6.4)
    8.2 (4.2 to 15.2)
    3.7 (2.8 to 4.7)
    Statistical analysis title
    		 Analysis of the Primary Endpoint
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.623
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.424
         upper limit
    		 0.916

    Secondary: Time to Symptom (Pruritus) Worsening (TTSW)

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    End point title
    		 Time to Symptom (Pruritus) Worsening (TTSW)
    End point description
    TTSW (pruritus), the key secondary endpoint, is defined as the time from date of randomisation to first date that criteria for symptom (pruritus) worsening were met. Symptom worsening was defined as an increase of a minimum of 3 points on the visual analogue scale (VAS) itching score, confirmed by two consecutive VAS itching score assessments (total of four weeks/two cycles) by the subject.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of blinded treatment.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    72
    82
    Units: Subjects with event
    14
    11
    Statistical analysis title
    		 Analysis of the Secondary Endpoint TTSW
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.644
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.215
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.538
         upper limit
    		 2.742

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    TTP was defined as the time from date of randomisation to first date that criteria for progressive disease (per the global response score) were met.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of blinded treatment.
    End point values
    		 Resminostat - ITT Placebo - ITT Resminostat - PP Placebo - PP
    Number of subjects analysed
    100
    101
    90
    84
    Units: months
        median (confidence interval 95%)
    8.3 (4.2 to 15.7)
    4.2 (2.8 to 6.4)
    8.2 (4.2 to 15.2)
    3.7 (2.8 to 4.7)
    Statistical analysis title
    		 Analysis of the Secondary Endpoint TTP
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.623
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.424
         upper limit
    		 0.916

    Secondary: Time to Next Treatment (TTNT)

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    End point title
    		 Time to Next Treatment (TTNT)
    End point description
    TTNT was defined as the time from date of randomisation to first date that new treatment was received. For placebo patients, rollover to resminostat was considered as the next treatment.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of follow-up.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    100
    101
    Units: months
        median (confidence interval 95%)
    8.8 (7.4 to 13.8)
    4.2 (3.0 to 6.0)
    Statistical analysis title
    		 Analysis of the Secondary Endpoint TTNT
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.594
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.428
         upper limit
    		 0.825

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was defined as the percentage of patients within each treatment group who achieved complete response or partial response during the randomised period. Therefore, patients with baseline remission status of complete response were excluded from this analysis. The response reported by the Investigator was used for the analysis. Only Global Response Scores that were based on all four components were considered for the evaluation of the ORR.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of blinded treatment.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    86
    90
    Units: subjects
        Complete Response
    3
    0
        Partial Response
    12
    9
    Statistical analysis title
    		 Analysis of the Secondary Endpoint ORR
    Statistical analysis description
    Odds Ratio and its related p-value from a Cochran-Mantel-Haenszel (CMH) test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.764
         upper limit
    		 5.565

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was defined as the time from date of complete response or partial response (whichever is first) until the criteria for progressive disease (per global response score) were met. For patients who achieved a partial response (PR) or complete response (CR) during the trial, DOR was calculated as the number of months from the date measurement criteria were first met for a PR or CR (whichever was recorded first) as determined by global response score assessment (based on four components) until the first date that PD was determined by global response score assessment. Patients with baseline remission status CR were excluded from this analysis. DOR was calculated as (date of first PD - date of PR/CR) + 1.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of blinded treatment.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    17
    12
    Units: months
        number (not applicable)
    19.4
    20.3
    Statistical analysis title
    		 Analysis of the Secondary Endpoint DOR
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.226
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.287
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.579
         upper limit
    		 9.024

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival is defined as the time from the day of randomisation to death from any cause. For patients who are known to be still alive at the time of trial analysis or who are lost to FU, survival time will be censored at the last recorded date that the patient is known to be alive (i.e. the date of last attended visit or the date of the follow-up phone call). Not only data from randomised period but also rollover and follow-up data will be taken into account for derivation of overall survival.
    End point type
    Secondary
    End point timeframe
    Time from the day of randomisation to end of follow-up.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    100
    101
    Units: months
        number (not applicable)
    70.8
    75.6
    Statistical analysis title
    		 Analysis of the Secondary Endpoint OS
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.982
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.606
         upper limit
    		 1.59

    Secondary: Progression Free Survival on Second Line Therapy (PFS2)

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    End point title
    		 Progression Free Survival on Second Line Therapy (PFS2)
    End point description
    PFS2 was defined as the time from date of randomisation to second objective disease progression or death from any cause (whichever comes first). If a patient started first subsequent treatment before first objective disease progression, then the first objective disease progression prior to start of the second subsequent treatment was considered as event. For the placebo treatment group, PFS2 was assessed in rollover period or (if no rollover took place) in follow-up period. For the resminostat treatment group, PFS2 was assessed in follow-up period.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of follow-up.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    100
    101
    Units: months
        median (confidence interval 95%)
    26.5 (20.0 to 48.3)
    23.2 (16.6 to 33.6)
    Statistical analysis title
    		 Analysis of the Secondary Endpoint PFS2
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.156
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.758
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.516
         upper limit
    		 1.113

    Secondary: Progression Free Survival on Third Line Therapy (PFS3)

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    End point title
    		 Progression Free Survival on Third Line Therapy (PFS3)
    End point description
    PFS3 was defined as the time from date of randomisation to third objective disease progression or death from any cause (whichever comes first). If a patient started second subsequent treatment before disease progression, then the first objective disease progression prior to the start of third subsequent treatment was considered as event. PFS3 was assessed in follow-up period.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of follow-up.
    End point values
    		 Resminostat - ITT Placebo - ITT
    Number of subjects analysed
    100
    101
    Units: months
        median (confidence interval 95%)
    37.6 (24.9 to 67.5)
    45.5 (32.3 to 59.7)
    Statistical analysis title
    		 Analysis of the Secondary Endpoint PFS3
    Statistical analysis description
    A two-sided stratified log-rank test with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata. Hazard Ratio from a Cox Proportional Hazards model with stage of disease (IIB/IIIA/IIIB/IVA1 vs IVA2/IVB) and remission status (CR/PR vs SD) as strata.
    Comparison groups
    Resminostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.921
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.674
         upper limit
    		 1.547

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent form up to completion of the 30th day after the last administration of trial drug.
    Adverse event reporting additional description
    Only treatment-emergent adverse events are shown here.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Resminostat
    Reporting group description
    		 Subjects who were treated with resminostat during the randomized or rollover period. This includes patients randomized to resminostat (N=100) and patients randomized to placebo who rolled over to open-label treatment with resminostat (N=80).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo during the randomised period.

    Serious adverse events
    		 Resminostat Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 180 (18.33%)
    12 / 101 (11.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: One SAE in the resminostat group was reported during the rollover period (open label).
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
    Additional description: One SAE was reported during the rollover period (open label).
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    Additional description: One SAE was reported during the rollover period (open label).
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (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
    Facial paralysis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
    Additional description: One SAE in the resminostat group was reported during the rollover period (open label).
         subjects affected / exposed
    2 / 180 (1.11%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ectropion
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain of skin
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin burning sensation
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: One SAE in the resminostat group was reported during the rollover period (open-label).
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
    Additional description: One SAE in the resminostat group was reported during the rollover period (open label).
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
    Additional description: One SAE in the resminostat group was reported during the rollover period (open label).
         subjects affected / exposed
    3 / 180 (1.67%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
    Additional description: SAE in the resminostat group reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
    Additional description: SAE in the resminostat group was reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe acute respiratory syndrome
    Additional description: SAE in the resminostat group was reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal oesophagitis
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
    Additional description: Reported during the rollover period (i.e. after unblinding).
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (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
    Decreased appetite
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Resminostat Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 180 (95.56%)
    81 / 101 (80.20%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 180 (7.22%)
    8 / 101 (7.92%)
         occurrences all number
    30
    9
    Flushing
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    12
    1
    Hot flush
         subjects affected / exposed
    4 / 180 (2.22%)
    0 / 101 (0.00%)
         occurrences all number
    5
    0
    Hypotension
         subjects affected / exposed
    5 / 180 (2.78%)
    0 / 101 (0.00%)
         occurrences all number
    17
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 180 (10.00%)
    4 / 101 (3.96%)
         occurrences all number
    30
    4
    Chills
         subjects affected / exposed
    10 / 180 (5.56%)
    1 / 101 (0.99%)
         occurrences all number
    15
    1
    Fatigue
         subjects affected / exposed
    60 / 180 (33.33%)
    15 / 101 (14.85%)
         occurrences all number
    119
    40
    Influenza like illness
         subjects affected / exposed
    14 / 180 (7.78%)
    6 / 101 (5.94%)
         occurrences all number
    24
    12
    Oedema peripheral
         subjects affected / exposed
    9 / 180 (5.00%)
    5 / 101 (4.95%)
         occurrences all number
    10
    5
    Pyrexia
         subjects affected / exposed
    16 / 180 (8.89%)
    8 / 101 (7.92%)
         occurrences all number
    22
    8
    Malaise
         subjects affected / exposed
    10 / 180 (5.56%)
    0 / 101 (0.00%)
         occurrences all number
    21
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 180 (8.33%)
    6 / 101 (5.94%)
         occurrences all number
    16
    6
    Dyspnoea
         subjects affected / exposed
    9 / 180 (5.00%)
    4 / 101 (3.96%)
         occurrences all number
    18
    5
    Oropharyngeal pain
         subjects affected / exposed
    6 / 180 (3.33%)
    2 / 101 (1.98%)
         occurrences all number
    7
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    32 / 180 (17.78%)
    4 / 101 (3.96%)
         occurrences all number
    53
    5
    Hallucination
         subjects affected / exposed
    5 / 180 (2.78%)
    0 / 101 (0.00%)
         occurrences all number
    6
    0
    Depression
         subjects affected / exposed
    3 / 180 (1.67%)
    3 / 101 (2.97%)
         occurrences all number
    3
    3
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    17 / 180 (9.44%)
    2 / 101 (1.98%)
         occurrences all number
    20
    2
    Blood creatinine increased
         subjects affected / exposed
    17 / 180 (9.44%)
    2 / 101 (1.98%)
         occurrences all number
    23
    2
    Neutrophil count decreased
         subjects affected / exposed
    9 / 180 (5.00%)
    1 / 101 (0.99%)
         occurrences all number
    58
    1
    Platelet count decreased
         subjects affected / exposed
    12 / 180 (6.67%)
    0 / 101 (0.00%)
         occurrences all number
    16
    0
    Weight decreased
         subjects affected / exposed
    10 / 180 (5.56%)
    2 / 101 (1.98%)
         occurrences all number
    10
    2
    White blood cell count decreased
         subjects affected / exposed
    10 / 180 (5.56%)
    1 / 101 (0.99%)
         occurrences all number
    39
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 180 (3.33%)
    3 / 101 (2.97%)
         occurrences all number
    9
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 180 (3.33%)
    3 / 101 (2.97%)
         occurrences all number
    12
    3
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 180 (3.89%)
    3 / 101 (2.97%)
         occurrences all number
    10
    4
    Monocyte count increased
         subjects affected / exposed
    5 / 180 (2.78%)
    0 / 101 (0.00%)
         occurrences all number
    6
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 180 (2.22%)
    2 / 101 (1.98%)
         occurrences all number
    4
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    4
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    7 / 180 (3.89%)
    0 / 101 (0.00%)
         occurrences all number
    9
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 180 (8.33%)
    3 / 101 (2.97%)
         occurrences all number
    18
    3
    Dysgeusia
         subjects affected / exposed
    46 / 180 (25.56%)
    2 / 101 (1.98%)
         occurrences all number
    167
    2
    Headache
         subjects affected / exposed
    31 / 180 (17.22%)
    10 / 101 (9.90%)
         occurrences all number
    103
    12
    Paraesthesia
         subjects affected / exposed
    10 / 180 (5.56%)
    3 / 101 (2.97%)
         occurrences all number
    12
    3
    Tremor
         subjects affected / exposed
    4 / 180 (2.22%)
    0 / 101 (0.00%)
         occurrences all number
    6
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 180 (5.56%)
    4 / 101 (3.96%)
         occurrences all number
    13
    4
    Neutropenia
         subjects affected / exposed
    9 / 180 (5.00%)
    0 / 101 (0.00%)
         occurrences all number
    24
    0
    Thrombocytopenia
         subjects affected / exposed
    7 / 180 (3.89%)
    1 / 101 (0.99%)
         occurrences all number
    12
    2
    Monocytosis
         subjects affected / exposed
    4 / 180 (2.22%)
    0 / 101 (0.00%)
         occurrences all number
    8
    0
    Lymphadenopathy
         subjects affected / exposed
    2 / 180 (1.11%)
    3 / 101 (2.97%)
         occurrences all number
    3
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 180 (3.89%)
    2 / 101 (1.98%)
         occurrences all number
    10
    6
    Eye disorders
    Dry eye
         subjects affected / exposed
    6 / 180 (3.33%)
    1 / 101 (0.99%)
         occurrences all number
    6
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 180 (11.11%)
    1 / 101 (0.99%)
         occurrences all number
    25
    1
    Abdominal pain upper
         subjects affected / exposed
    23 / 180 (12.78%)
    5 / 101 (4.95%)
         occurrences all number
    61
    5
    Constipation
         subjects affected / exposed
    15 / 180 (8.33%)
    5 / 101 (4.95%)
         occurrences all number
    18
    6
    Diarrhoea
         subjects affected / exposed
    75 / 180 (41.67%)
    17 / 101 (16.83%)
         occurrences all number
    264
    19
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 180 (5.56%)
    1 / 101 (0.99%)
         occurrences all number
    11
    1
    Nausea
         subjects affected / exposed
    120 / 180 (66.67%)
    10 / 101 (9.90%)
         occurrences all number
    414
    11
    Vomiting
         subjects affected / exposed
    59 / 180 (32.78%)
    3 / 101 (2.97%)
         occurrences all number
    120
    3
    Dyspepsia
         subjects affected / exposed
    10 / 180 (5.56%)
    3 / 101 (2.97%)
         occurrences all number
    11
    3
    Dry mouth
         subjects affected / exposed
    6 / 180 (3.33%)
    0 / 101 (0.00%)
         occurrences all number
    25
    0
    Toothache
         subjects affected / exposed
    6 / 180 (3.33%)
    3 / 101 (2.97%)
         occurrences all number
    6
    3
    Abdominal distension
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    7
    1
    Gastritis
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    4
    1
    Stomatitis
         subjects affected / exposed
    5 / 180 (2.78%)
    1 / 101 (0.99%)
         occurrences all number
    7
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    14 / 180 (7.78%)
    2 / 101 (1.98%)
         occurrences all number
    15
    2
    Pruritus
         subjects affected / exposed
    24 / 180 (13.33%)
    13 / 101 (12.87%)
         occurrences all number
    28
    19
    Rash
         subjects affected / exposed
    10 / 180 (5.56%)
    2 / 101 (1.98%)
         occurrences all number
    19
    2
    Dry skin
         subjects affected / exposed
    7 / 180 (3.89%)
    2 / 101 (1.98%)
         occurrences all number
    7
    2
    Dermatitis acneiform
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    5
    1
    Erythema
         subjects affected / exposed
    5 / 180 (2.78%)
    1 / 101 (0.99%)
         occurrences all number
    5
    1
    Skin ulcer
         subjects affected / exposed
    5 / 180 (2.78%)
    0 / 101 (0.00%)
         occurrences all number
    6
    0
    Eczema
         subjects affected / exposed
    3 / 180 (1.67%)
    4 / 101 (3.96%)
         occurrences all number
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 180 (8.33%)
    6 / 101 (5.94%)
         occurrences all number
    17
    6
    Back pain
         subjects affected / exposed
    13 / 180 (7.22%)
    8 / 101 (7.92%)
         occurrences all number
    23
    10
    Muscle spasms
         subjects affected / exposed
    36 / 180 (20.00%)
    5 / 101 (4.95%)
         occurrences all number
    52
    8
    Myalgia
         subjects affected / exposed
    14 / 180 (7.78%)
    1 / 101 (0.99%)
         occurrences all number
    16
    1
    Pain in extremity
         subjects affected / exposed
    15 / 180 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    16
    1
    Musculoskeletal pain
         subjects affected / exposed
    6 / 180 (3.33%)
    4 / 101 (3.96%)
         occurrences all number
    6
    4
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    11 / 180 (6.11%)
    6 / 101 (5.94%)
         occurrences all number
    11
    6
    Nasopharyngitis
         subjects affected / exposed
    21 / 180 (11.67%)
    17 / 101 (16.83%)
         occurrences all number
    29
    22
    Influenza
         subjects affected / exposed
    8 / 180 (4.44%)
    0 / 101 (0.00%)
         occurrences all number
    10
    0
    Skin infection
         subjects affected / exposed
    7 / 180 (3.89%)
    1 / 101 (0.99%)
         occurrences all number
    8
    1
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 180 (4.44%)
    2 / 101 (1.98%)
         occurrences all number
    13
    2
    Bronchitis
         subjects affected / exposed
    5 / 180 (2.78%)
    4 / 101 (3.96%)
         occurrences all number
    7
    4
    Folliculitis
         subjects affected / exposed
    4 / 180 (2.22%)
    2 / 101 (1.98%)
         occurrences all number
    4
    2
    Sinusitis
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    5
    1
    Tinea pedis
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    4
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 180 (2.22%)
    3 / 101 (2.97%)
         occurrences all number
    4
    4
    Pharyngitis
         subjects affected / exposed
    0 / 180 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    0
    3
    Rhinitis
         subjects affected / exposed
    3 / 180 (1.67%)
    3 / 101 (2.97%)
         occurrences all number
    3
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    37 / 180 (20.56%)
    2 / 101 (1.98%)
         occurrences all number
    64
    2
    Hyperuricaemia
         subjects affected / exposed
    4 / 180 (2.22%)
    4 / 101 (3.96%)
         occurrences all number
    4
    4
    Hypokalaemia
         subjects affected / exposed
    4 / 180 (2.22%)
    1 / 101 (0.99%)
         occurrences all number
    6
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 180 (1.11%)
    3 / 101 (2.97%)
         occurrences all number
    2
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jul 2016
    The changes introduced by this Amendment (Protocol Version 2.0) were made to add the definition of abstinence from heterosexual intercourse (inclusion criteria #6, Protocol Section 16.6.1 contraception), clarify the process for emergency unblinding, clarify submission and approval of substantial amendments to the competent regulatory authorities and correct minor typos in the Schedule of Assessments.
    24 Oct 2016
    The changes introduced by this Amendment (Protocol Version 3.0) were made to include changes in the accepted contraceptive measures, to specify the use of highly effective contraceptive measures according to the Clinical Trials Facilitation and Coordination Group (CTFG) Guideline and to add serum pregnancy tests every other cycle starting from Cycle 3.
    09 Mar 2017
    This Amendment (Protocol Version 4.0) incorporated the changes of the previous two Amendments for all participating countries. In addition, it clarified the response assessment of skin disease (adaptation of the GRS, Olsen et al 2011) and the prior therapy qualifying for inclusion criterion #1, modified the allowed window between completion of prior treatment and randomization (from 8 weeks to 12 weeks), added evaluation of changes in the VAS itching score and updated the new address of the sponsor. Furthermore, the amendment clarified that serum pregnancy tests were mandatory only at screening and EOT; at all other visits requiring pregnancy testing, test in serum or urine was allowed.
    23 Jul 2018
    The changes introduced by this Amendment (Protocol Version 5.0) were made to update information regarding clinical trials with resminostat, clarify the disease stage used for stratification, modify exclusion criterion #8 (history of prior cancers), add systemic steroids as anti-itching medication to the list of prohibited medication (also restricted for other indications), clarify and modify the procedures for rollover, clarify response assessments, modify the requirements to start a new treatment cycle (alignment with toxicity guidelines, administration of trial medication before safety laboratory results are available), allow reescalation of the dose to 600 mg/day if the dose was reduced due to nausea, vomiting or similar gastrointestinal events, remove Chief Development Officer from list of sponsor signatories and correct minor inconsistencies and typos.
    28 Feb 2019
    The changes introduced by this Amendment (Protocol Version 6.0) were made to recalculate the sample size based on the observed patient dropout rate of up to 30% (prior assumption: 10%). The number of patients required to observe 125 PFS events was increased to 95 patients per treatment arm (total number of patients: 190). Furthermore, the changes introduced by Amendment No. 4 concerning requirements to start a new treatment cycle were updated in several other sections of the protocol. A Protocol Version 6.1 (applicable in Germany only) was set up at the request of the German regulatory authority (Bundesministerium fuer Arzneimittel und Medizinprodukte, BfArM) to reinstall the requirement to check safety laboratory analyses on Day 1 of each new treatment cycle before administration of trial medication. An Addendum (Protocol Version 6.2; applicable in Belgium only) was set up based on concerns of the IEC in Belgium that patients with progressing tumors not meeting the defined criteria for PD could stay on trial treatment although a different treatment would be warranted. Therefore, exclusion criterion #15 was added to exclude patients with tumoral stage MF lacking involvement of the skin.
    15 Nov 2021
    The changes introduced by this Amendment (Protocol Version 7.0) were made to recalculate the sample size based on the observed patient dropout rate of 33% (prior assumption: up to 30%). The number of patients required to observe 125 PFS events for the main data analysis was increased to 100 patients per treatment arm (total number of patients: 200). In case 125 events were not reached upon randomization of 200 patients, the main analysis had to be performed 10 months after randomization of the last patient. Furthermore, patients on CR, PR or SD and without any AE of Grade ≥ 2 or any AE considered clinically relevant and related to trial medication during the last 6 cycles were allowed to skip site visits scheduled between the visits of intermediate and complete response assessments. The same changes were introduced to the current protocol in Germany (leading to Protocol Version 7.1) and Belgium (leading to Protocol Version 7.2).
    21 Dec 2022
    The changes introduced by this Amendment (Protocol Version 8.0) were made to specify communication of trial results (primary endpoint) to participating investigators and patients upon the main statistical data analysis. Accordingly, participants were to be informed of their treatment allocation (unblinding). In case of positive results, patients on placebo were to be offered to roll-over to resminostat therapy and patients on resminostat could continue openlabel treatment with resminostat. In case of negative results, all patients were to be discontinued from trial treatment and the trial was to be terminated. Furthermore, performance of skin biopsy and blood sampling for biomarkers and PK were no longer required. The same changes were introduced to the current protocol in Germany (leading to Protocol Version 8.1) and Belgium (leading to Protocol Version 8.2).

    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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