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    Clinical Trial Results:
    A Phase II Randomized, Double-Blind Trial of Immunotherapy with Nivolumab or Nivolumab plus Ipilimumab versus Double-Placebo Control as a Post-Surgical/Post-Radiation Treatment for Stage IV Melanoma with No Evidence of Disease

    Summary
    EudraCT number
    		 2014-001167-12
    Trial protocol
    		 DE   AT  
    Global end of trial date
    27 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Sep 2022
    First version publication date
    29 Sep 2022
    Other versions
    Summary report(s)
    		 Immuned_Synpsos

    Trial information

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    Trial identification
    Sponsor protocol code
    IMMUNED
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02523313
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Essen
    Sponsor organisation address
    Hufelandstraße 55, Essen, Germany, 45147
    Public contact
    Departement of Dermatology, University Hospital Essen, 0049 2017234342, dirk.schadendorf@uk-essen.de
    Scientific contact
    Departement of Dermatology, University Hospital Essen, 0049 2017234342, dirk.schadendorf@uk-essen.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to estimate the efficacy of adjuvant immunotherapy with nivolumab alone or in combination with ipilimumab therapy in stage IV melanoma patients with no evidence of disease, i.e. the primary endpoint is recurrence-free survival (RFS).
    Protection of trial subjects
    The treatment should be conducted exactly as described in the protocol. Any protocol deviations were reported. The recommendations of Good Clinical Practice (ICH-GCP: International Conference on Harmonisation - Good Clinical Practice), valid since 17.1.1997, were observed. The selection of patients occurred through the investigator according to the inclusion and exclusion criteria after informing the patient orally and in writing about the study and after the patient has signed the informed consent. There was no preferred enrolment of men or women within this study. However, pregnant or lactating female patients were excluded from study participation. Women of childbearing potential and male patients with partners of childbearing potential had to use a highly effective form ofcontraception according to Clinical Trials Facilitation Group.
    Background therapy
    		 Relevant prior and concomitant medications were documented in the eCRF. Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement) was not permitted. Prior radiotherapy had to be completed at least two weeks prior to study drug administration.
    Evidence for comparator
    		 Eligible patients were randomly assigned to one of the three treatment groups (1:1:1) using a central, interactive, online system. Both experimental treatment groups – i.e., nivolumab alone (arm A) and nivolumab plus ipilimumab (arm B) – were compared with a double-matching placebo group (arm C). Patients in arm A received nivolumab (3 mg/kg) plus ipilimumab-placebo (nivolumab montherapy). Patients in arm B received nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) (nivolumab-ipilimumab-combination therapy) Patients in arm C received nivolumab-placebo and ipilimumab-placebo (double placebo control)
    Actual start date of recruitment
    01 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 167
    Worldwide total number of subjects
    167
    EEA total number of subjects
    167
    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)
    123
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 After written informed consent, eligibility was confirmed and baseline data were obtained. Patients were randomzed 1 : 1 : 1 into the arms. Block randomization was used (block length of six) stratified according to PD-L1 status, site of metastasis, and trial site. Randomization period was from 02 SEP 2015 and 20 NOV 2018. Active German sites: 20

    Pre-assignment
    Screening details
    		 Selection of patients occurred by the investigators according to the inclusion / exclusion criteria. Baseline examinations should be performed within 3 weeks before first dose of study treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 237 [1]
    Intermediate milestone: Number of subjects
    Randomization: 167
    Number of subjects completed
    		 167

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 7
    Reason: Number of subjects
    		 patient's wish: 1
    Reason: Number of subjects
    		 not matching eligibility criteria: 62
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The screening period was defined as pre-assignment period. 237 patients were screened, but only 167 patients were randomized into the 3 study arms.
    Period 1
    Period 1 title
    Induction phase (12 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    The Sponsor, subjects, investigator and site staff were blinded to the study drug administered. matching Nivolumab and Ipilimumab-Placebos were used. In order to protect the blind in Arm B, the 1mg/kg Nivolumab administered in weeks 1, 4, 7 and 10 should be diluted to the same volume as 3 mg/kg Nivolumab-placebo prepared on weeks 3, 5, 9, 11. In general, all placebo infusions were diluted to the same volume of the corresponding study drug.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Nivolumab-monotherapy (plus Placebo) given as adjuvant therapy after surgery or radiation therapy: Patients received Nivolumab 3 mg/kg every 2 weeks for up to 12 weeks (+ Ipilimumab-Placebo on weeks 1, 4, 7 and 10 and Nivolumab-Placebo on weeks 4 and 10). Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was applied at a dose of 3 mg/kg given as IV infusion every 2 weeks (q2wx6): weeks 1, 3, 5, 7, 9, 11 during induction phase

    Investigational medicinal product name
    Nivolumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab-Placebo was administered at week 4 and 10 during induction phase.

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab-Placebo was administered at weeks 1, 4, 7 and 10 during induction phase.

    Arm title
    		 Arm B
    Arm description
    		 Nivolumab + ipilimumab combination therapy given as adjuvant therapy after surgery or radiation therapy: Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) were applied as IV infusion every 3 weeks for 4 doses. Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was applied at a dose of 1 mg/kg given as IV infusion every 3 weeks for 4 doses: weeks 1, 4, 7, 10 of induction phase.

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab (3 mg/kg) was administered as an IV infusion on the same day as the Nivolumab infusion every 3 weeks for 4 doses: weeks 1, 4, 7, 10 of induction phase.

    Investigational medicinal product name
    Nivolumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab-Placebo was administered on weeks 3, 5, 9 and 11.

    Arm title
    		 Arm C
    Arm description
    		 Double placebo control given as adjuvant therapy after surgery or radiation therapy. Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment. Patients in Arm C had a cross-over option: In case of documented recurrence of disease in the eCRF (confirmed via tumor assessment using radiologic imaging), subjects in Arm C could receive Nivolumab 3mg/kg monotherapy every 2 weeks until subsequent progression or for up to 1 year, whichever occurs first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Nivolumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab-Placebo was administered on weeks 1, 3, 4, 5, 7, 9, 10, 11 during induction phase.

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab-Placebo was administered at weeks 1, 4, 7 and 10 during induction phase.

    Number of subjects in period 1
    		Arm A Arm B Arm C
    Started
    59
    56
    52
    Completed
    56
    55
    51
    Not completed
    3
    1
    1
         Consent withdrawn by subject
    3
    1
    1
    Period 2
    Period 2 title
    Maintenance Phase (40 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Nivoluman-Placebo was diluted to the same volume as 3 mg/kg Nivolumab.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Nivolumab-Monotherapy as maintenance for up to 40 weeks or until recurrence of disease.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was applied at a dose of 3 mg/kg IV every 2 weeks for up to 40 weeks or until recurrence of disease, whichever occurred first.

    Arm title
    		 Arm B
    Arm description
    		 Nivolumab-Monotherapy as maintenance for up to 40 weeks or until recurrence of disease.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab was applied at a dose of 3 mg/kg IV every 2 weeks for up to 40 weeks or until recurrence of disease, whichever occurred first.

    Arm title
    		 Arm C
    Arm description
    		 Nivolumab-Placebo as maintenance for up to 40 weeks or until recurrence of disease.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Nivolumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab-Placebo was administered as IV infusion every 2 weeks for up to 40 weeks or occurrence of relapse/progress, whichever occurred first.

    Number of subjects in period 2
    		Arm A Arm B Arm C
    Started
    56
    55
    51
    Completed
    21
    11
    10
    Not completed
    35
    44
    41
         Consent withdrawn by subject
    -
    -
    1
         patient's wish
    1
    1
    1
         unknown
    -
    1
    -
         Adverse event, non-fatal
    7
    34
    2
         Relapse / Progress
    25
    7
    36
         Protocol deviation
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Nivolumab-monotherapy (plus Placebo) given as adjuvant therapy after surgery or radiation therapy: Patients received Nivolumab 3 mg/kg every 2 weeks for up to 12 weeks (+ Ipilimumab-Placebo on weeks 1, 4, 7 and 10 and Nivolumab-Placebo on weeks 4 and 10). Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment.

    Reporting group title
    Arm B
    Reporting group description
    		 Nivolumab + ipilimumab combination therapy given as adjuvant therapy after surgery or radiation therapy: Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) were applied as IV infusion every 3 weeks for 4 doses. Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment.

    Reporting group title
    Arm C
    Reporting group description
    		 Double placebo control given as adjuvant therapy after surgery or radiation therapy. Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment. Patients in Arm C had a cross-over option: In case of documented recurrence of disease in the eCRF (confirmed via tumor assessment using radiologic imaging), subjects in Arm C could receive Nivolumab 3mg/kg monotherapy every 2 weeks until subsequent progression or for up to 1 year, whichever occurs first.

    Reporting group values
    		 Arm A Arm B Arm C Total
    Number of subjects
    		 59 56 52 167
    Age categorical
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of randomization minus Year of birth.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 43 45 35 123
        From 65-84 years
    		 16 11 17 44
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 57.0 (48.0 to 65.0) 52.0 (44.5 to 59.0) 58.5 (46.0 to 65.5) -
    Gender categorical
    Units: Subjects
        Female
    		 28 25 19 72
        Male
    		 31 31 33 95
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat-set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who gave their informed consent and who were randomized.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients from the ITT population who received at least one single infusion of investigational agent and who did not have major disqualifying protocol violations. Definition of major disqualifying protocol violations: Patients with documented stage I-III melanoma as per AJCC staging / Documented/confirmed disease at baseline / The last intervention demonstrating that the subject is free of disease is more than 13 weeks before the first infusion / Incomplete baseline staging (missing CT chest or CT abdomen, pelvis or CT/MRT head) / Prior therapy with CTLA4 or PD1 antibodies / Subjects with uveal or mucosal melanoma. Disqualifying protocol violatiosn during study: Subjects who receive anti-cancer therapy other than study treatment while on study therapy / Subjects treated differently than as randomized (subjects who received the wrong treatment or who discontinued prematurely due to protocol violation)

    Subject analysis sets values
    		 Intent-to-treat-set Safety set
    Number of subjects
    167
    162
    Age categorical
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of randomization minus Year of birth.
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    123
    119
        From 65-84 years
    44
    43
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    55.0 (46.0 to 65.0)
    Gender categorical
    Units: Subjects
        Female
    72
    68
        Male
    95
    94

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Nivolumab-monotherapy (plus Placebo) given as adjuvant therapy after surgery or radiation therapy: Patients received Nivolumab 3 mg/kg every 2 weeks for up to 12 weeks (+ Ipilimumab-Placebo on weeks 1, 4, 7 and 10 and Nivolumab-Placebo on weeks 4 and 10). Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment.

    Reporting group title
    Arm B
    Reporting group description
    		 Nivolumab + ipilimumab combination therapy given as adjuvant therapy after surgery or radiation therapy: Nivolumab (1 mg/kg) and Ipilimumab (3 mg/kg) were applied as IV infusion every 3 weeks for 4 doses. Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment.

    Reporting group title
    Arm C
    Reporting group description
    		 Double placebo control given as adjuvant therapy after surgery or radiation therapy. Upon recurrence of disease and treatment discontinuation of each subject, investigators were unblinded to each subject’s treatment assignment to determine the appropriate subsequent treatment. Patients in Arm C had a cross-over option: In case of documented recurrence of disease in the eCRF (confirmed via tumor assessment using radiologic imaging), subjects in Arm C could receive Nivolumab 3mg/kg monotherapy every 2 weeks until subsequent progression or for up to 1 year, whichever occurs first.
    Reporting group title
    Arm A
    Reporting group description
    		 Nivolumab-Monotherapy as maintenance for up to 40 weeks or until recurrence of disease.

    Reporting group title
    Arm B
    Reporting group description
    		 Nivolumab-Monotherapy as maintenance for up to 40 weeks or until recurrence of disease.

    Reporting group title
    Arm C
    Reporting group description
    		 Nivolumab-Placebo as maintenance for up to 40 weeks or until recurrence of disease.

    Subject analysis set title
    Intent-to-treat-set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who gave their informed consent and who were randomized.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients from the ITT population who received at least one single infusion of investigational agent and who did not have major disqualifying protocol violations. Definition of major disqualifying protocol violations: Patients with documented stage I-III melanoma as per AJCC staging / Documented/confirmed disease at baseline / The last intervention demonstrating that the subject is free of disease is more than 13 weeks before the first infusion / Incomplete baseline staging (missing CT chest or CT abdomen, pelvis or CT/MRT head) / Prior therapy with CTLA4 or PD1 antibodies / Subjects with uveal or mucosal melanoma. Disqualifying protocol violatiosn during study: Subjects who receive anti-cancer therapy other than study treatment while on study therapy / Subjects treated differently than as randomized (subjects who received the wrong treatment or who discontinued prematurely due to protocol violation)

    Primary: Recurrence-free survival (RFS)

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    End point title
    		 Recurrence-free survival (RFS)
    End point description
    Since this study included patients with NED and investigated the adjuvant use of immunotherapy, RFS replaced progression-free survival as normally used in stage IV disease (the definitions of both surrogate endpoints are congruent). Tumor assessments using CT or MRI scans and classification of the response by the investigator according to RECIST v1.1 were performed at the beginning every 12 weeks during study treatment. During follow-up period, tumor assessment was performed every 3 months for the first 2 years after last infusion of study medication, therafter every 6 months. If recurrence/progression of disease was suspected for any reason at or between the 12-weekly evaluation visits, radiological confirmation was necessary.
    End point type
    Primary
    End point timeframe
    Time from randomization until first recurrence (local or distant metastasis), new primary melanoma or death from any cause, whichever occurred first. Patients without recurrence and patients who did not die were censored at the date of last contact.
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: months
        median (confidence interval 95%)
    12.3 (5.30 to 23.85)
    9999 (24.97 to 9999999999)
    6.3 (3.26 to 9.61)
    Statistical analysis title
    		 Hazard ratio for disease recurrence /Arm A - Arm C
    Comparison groups
    Arm A v Arm C
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0236
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1
    Statistical analysis title
    		 Hazard ratio for disease recurrence /Arm B - Arm C
    Comparison groups
    Arm B v Arm C
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.25
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.48

    Primary: 1-year RFS rate

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    End point title
    		 1-year RFS rate
    End point description
    Proportion of patients being alive or with unknown survival status and without recurrence (local or distant metastasis) or new primary melanoma or not known to show recurrence 12 months after randomization, derived by Kaplan-Meier.
    End point type
    Primary
    End point timeframe
    12 months after date of randomization
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: percent
        number (confidence interval 95%)
    51.7 (37.98 to 63.83)
    75.3 (61.10 to 84.88)
    32.2 (19.81 to 45.32)
    Statistical analysis title
    		 1 year RFS rate Arm A vs. Arm C
    Comparison groups
    Arm A v Arm C
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0506
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6034
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1
    Statistical analysis title
    		 1 year RFS rate Arm B vs. Arm C
    Comparison groups
    Arm B v Arm C
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.273
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.52

    Primary: 2-year RFS rate

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    End point title
    		 2-year RFS rate
    End point description
    Proportion of patients being alive or with unknown survival status and without recurrence (local or distant metastasis) or new primary melanoma or not known to show recurrence 24 months after randomization, derived by Kaplan-Meier.
    End point type
    Primary
    End point timeframe
    24 months after date of randomization
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: percent
        number (confidence interval 95%)
    36.9 (24.46 to 49.46)
    66.5 (51.58 to 77.81)
    15.0 (6.68 to 26.56)
    Statistical analysis title
    		 2 year RFS rate Arm A vs. Arm C
    Comparison groups
    Arm A v Arm C
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0141
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5677
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.89
    Statistical analysis title
    		 2 year RFS rate Arm B vs. Arm C
    Comparison groups
    Arm B v Arm C
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.2436
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.43

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as time from randomization until date of death. OS for patients who have not died were censored at the date of last contact. 19 patients of double-placebo arm C switched to arm A. The rank preserving structural failure time model (RPSFTM) was used to adjust survival time for treatment switching after disease progression from arm C to Nivolumab (Arm A) group. RPSFT estimates the survival time gained or lost by receiving active treatment. RPSFT splits the survival time in time off and on treatment and estimates the treatment effect (Ψ) using g-estimation (grid search from -1.0 to 1.0 with an interval of 0.001) (Here: Ψ = -0.00005, hence the factor is 1, i.e. there is no effect). Time to event for crossover patients were re-calculated based on the optimal Ψ. The method relies on the assumption that the only difference between randomized groups is the treatment received and the treatment effect is the same for all patients regardless of when treatment is received.
    End point type
    Secondary
    End point timeframe
    From date of randomization until end of study (= 2 years after last patient off treatment).
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: months
        median (confidence interval 95%)
    999999 (999999 to 999999)
    999999 (999999 to 999999)
    999999 (38.59 to 999999)
    No statistical analyses for this end point

    Secondary: 1-year OS rate

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    End point title
    		 1-year OS rate
    End point description
    Proportion of patients being alive 12 months after randomization, derived by Kaplan-Meier.
    End point type
    Secondary
    End point timeframe
    12 months after date of randomization
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: percent
        number (confidence interval 95%)
    92.2 (80.44 to 96.98)
    95.7 (84.02 to 98.92)
    93.9 (82.31 to 98.00)
    No statistical analyses for this end point

    Secondary: 2-year OS rate

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    End point title
    		 2-year OS rate
    End point description
    Proportion of patients being alive 24 months after randomization, derived by Kaplan-Meier.
    End point type
    Secondary
    End point timeframe
    24 months after date of randomization
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: percent
        number (confidence interval 95%)
    81.7 (67.81 to 90.07)
    91.2 (78.16 to 96.60)
    87.3 (73.87 to 94.10)
    No statistical analyses for this end point

    Secondary: Time to recurrence (TTR)

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    End point title
    		 Time to recurrence (TTR)
    End point description
    TTR of a patient was defined as the time from randomization until disease recurrence (local or distant metastasis) or melanoma-related death. TTR for patients without recurrence or melanoma-related death were censored at the date of last contact. TTR replaced here consistently time to progression (TTP) as normally used in stage IV disease.
    End point type
    Secondary
    End point timeframe
    From date of randomization until end of study (= defined as 2 years after last patient off treatment)
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: months
        median (confidence interval 95%)
    15.2 (5.30 to 33.26)
    999999 (24.97 to 999999)
    6.3 (4.87 to 9.61)
    Statistical analysis title
    		 HR (arm A vs. double placebo (Arm C))
    Statistical analysis description
    Risk of disease recurrence (local or distant metastasis) or melanoma-related death
    Comparison groups
    Arm A v Arm C
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0137
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.9
    Statistical analysis title
    		 HR (arm B vs. double placebo (Arm C))
    Statistical analysis description
    Risk of disease recurrence (local or distant metastasis) or melanoma-related death
    Comparison groups
    Arm A v Arm C
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.45

    Secondary: 1-year TTR rate

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    End point title
    		 1-year TTR rate
    End point description
    Proportion of patients alive without disease recurrence (local or distant metastasis) 12 months after randomization, derived by Kaplan-Meier.
    End point type
    Secondary
    End point timeframe
    12 months after date of randomization
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59
    56
    52
    Units: percent
        number (confidence interval 95%)
    55.2 (41.25 to 67.09)
    75.3 (61.10 to 84.88)
    32.2 (19.81 to 45.32)
    No statistical analyses for this end point

    Secondary: Progression/recurrence free survival 2 (PRFS2)

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    End point title
    		 Progression/recurrence free survival 2 (PRFS2) [1]
    End point description
    For crossover patients (arm C into arm A) the PRFS2 was defined as time from randomization until the earliest of the following: - date of first disease progression per RECIST 1.1 or new primary melanoma beyond the initial unresectable disease recurrence, - date of second recurrence in patients without evidence of disease after surgery of a resectable first recurrence or - death. For patients who remained alive and whose disease has not recurred, or disease has recurred but subsequent disease progression or recurrence has not occurred, PRFS2 was censored on the date of last contact.
    End point type
    Secondary
    End point timeframe
    From date of randomization until end of study (= 2 years after last patient off study treatment)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression/recurrence free survival 2 is only calculated for crossover patients. Crossover was only allowed for patients randomized to arm C (double placebo arm). Therefore only results for arm C patients are presented.
    End point values
    		 Arm C
    Number of subjects analysed
    19 [2]
    Units: month
        median (confidence interval 95%)
    999999 (21.18 to 999999)
    Notes
    [2] - 19 patients of 52 patients randomized into arm C crossed over.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs that occurred from the patient’s written consent until 90 days after discontinuation of study treatment were reported, except in cases where a study participant had started a new anti-neoplastic therapy.
    Adverse event reporting additional description
    Any SAE occurring after the start of a new anti-neoplastic therapy that was suspected to be related to study treatment by the investigator had to be reported. AEs associated with the disease under study or its relapse or progression did not have to be reported, because recurrence/progression was assessed as outcome da
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Safety set_Arm A
    Reporting group description
    		 All patients of the ITT set who received at least one single infusion of investigational agent.

    Reporting group title
    Safety set_Arm B
    Reporting group description
    		 -

    Reporting group title
    Safety set_Arm C
    Reporting group description
    		 -

    Serious adverse events
    		 Safety set_Arm A Safety set_Arm B Safety set_Arm C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 56 (33.93%)
    36 / 55 (65.45%)
    16 / 51 (31.37%)
         number of deaths (all causes)
    13
    7
    16
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 56 (1.79%)
    8 / 55 (14.55%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety set_Arm A Safety set_Arm B Safety set_Arm C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 56 (94.64%)
    55 / 55 (100.00%)
    46 / 51 (90.20%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    0
    3
    Melanocytic naevus
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    2
    3
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 55 (1.82%)
    0 / 51 (0.00%)
         occurrences all number
    3
    1
    0
    Hypertension
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    6 / 51 (11.76%)
         occurrences all number
    4
    2
    7
    Lymphoedema
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    2 / 51 (3.92%)
         occurrences all number
    5
    1
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    3 / 56 (5.36%)
    8 / 55 (14.55%)
    2 / 51 (3.92%)
         occurrences all number
    3
    9
    2
    Fatigue
         subjects affected / exposed
    16 / 56 (28.57%)
    25 / 55 (45.45%)
    14 / 51 (27.45%)
         occurrences all number
    19
    28
    16
    Influenza like illness
         subjects affected / exposed
    15 / 56 (26.79%)
    10 / 55 (18.18%)
    4 / 51 (7.84%)
         occurrences all number
    18
    13
    5
    Oedema peripheral
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Pain
         subjects affected / exposed
    4 / 56 (7.14%)
    4 / 55 (7.27%)
    4 / 51 (7.84%)
         occurrences all number
    5
    5
    4
    Pyrexia
         subjects affected / exposed
    9 / 56 (16.07%)
    11 / 55 (20.00%)
    1 / 51 (1.96%)
         occurrences all number
    11
    13
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 56 (23.21%)
    7 / 55 (12.73%)
    10 / 51 (19.61%)
         occurrences all number
    14
    8
    10
    Dyspnoea
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 55 (7.27%)
    3 / 51 (5.88%)
         occurrences all number
    4
    5
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 56 (1.79%)
    4 / 55 (7.27%)
    3 / 51 (5.88%)
         occurrences all number
    1
    4
    3
    Pneumonitis
         subjects affected / exposed
    0 / 56 (0.00%)
    5 / 55 (9.09%)
    0 / 51 (0.00%)
         occurrences all number
    0
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    3
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 56 (10.71%)
    22 / 55 (40.00%)
    2 / 51 (3.92%)
         occurrences all number
    6
    24
    2
    Amylase increased
         subjects affected / exposed
    8 / 56 (14.29%)
    9 / 55 (16.36%)
    5 / 51 (9.80%)
         occurrences all number
    11
    9
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 56 (5.36%)
    6 / 55 (10.91%)
    1 / 51 (1.96%)
         occurrences all number
    3
    6
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences all number
    1
    4
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 56 (8.93%)
    9 / 55 (16.36%)
    1 / 51 (1.96%)
         occurrences all number
    5
    9
    1
    Lipase increased
         subjects affected / exposed
    9 / 56 (16.07%)
    15 / 55 (27.27%)
    7 / 51 (13.73%)
         occurrences all number
    14
    19
    11
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    5 / 51 (9.80%)
         occurrences all number
    2
    4
    9
    Tri-iodothyronine free decreased
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Weight decreased
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 55 (1.82%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    1
    White blood cell count decreased
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 55 (3.64%)
    3 / 51 (5.88%)
         occurrences all number
    2
    2
    6
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 56 (1.79%)
    4 / 55 (7.27%)
    3 / 51 (5.88%)
         occurrences all number
    1
    4
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 55 (5.45%)
    2 / 51 (3.92%)
         occurrences all number
    4
    3
    2
    Headache
         subjects affected / exposed
    14 / 56 (25.00%)
    11 / 55 (20.00%)
    11 / 51 (21.57%)
         occurrences all number
    18
    11
    18
    Paraesthesia
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 55 (7.27%)
    2 / 51 (3.92%)
         occurrences all number
    4
    4
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 55 (5.45%)
    4 / 51 (7.84%)
         occurrences all number
    4
    3
    4
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    4
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 56 (16.07%)
    5 / 55 (9.09%)
    6 / 51 (11.76%)
         occurrences all number
    9
    5
    7
    Abdominal pain upper
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    3
    Constipation
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    3
    2
    1
    Diarrhoea
         subjects affected / exposed
    15 / 56 (26.79%)
    17 / 55 (30.91%)
    4 / 51 (7.84%)
         occurrences all number
    19
    20
    4
    Gastritis
         subjects affected / exposed
    1 / 56 (1.79%)
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences all number
    1
    4
    0
    Nausea
         subjects affected / exposed
    9 / 56 (16.07%)
    12 / 55 (21.82%)
    6 / 51 (11.76%)
         occurrences all number
    15
    15
    10
    Vomiting
         subjects affected / exposed
    5 / 56 (8.93%)
    3 / 55 (5.45%)
    2 / 51 (3.92%)
         occurrences all number
    7
    4
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 56 (3.57%)
    5 / 55 (9.09%)
    1 / 51 (1.96%)
         occurrences all number
    2
    6
    1
    Dry skin
         subjects affected / exposed
    6 / 56 (10.71%)
    2 / 55 (3.64%)
    2 / 51 (3.92%)
         occurrences all number
    6
    3
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 56 (0.00%)
    7 / 55 (12.73%)
    1 / 51 (1.96%)
         occurrences all number
    0
    7
    1
    Night sweats
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    1
    3
    1
    Pruritus
         subjects affected / exposed
    8 / 56 (14.29%)
    14 / 55 (25.45%)
    4 / 51 (7.84%)
         occurrences all number
    8
    19
    5
    Rash
         subjects affected / exposed
    2 / 56 (3.57%)
    6 / 55 (10.91%)
    0 / 51 (0.00%)
         occurrences all number
    2
    6
    0
    Rash maculo-papular
         subjects affected / exposed
    4 / 56 (7.14%)
    15 / 55 (27.27%)
    0 / 51 (0.00%)
         occurrences all number
    4
    17
    0
    Pash pustular
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    6 / 56 (10.71%)
    19 / 55 (34.55%)
    1 / 51 (1.96%)
         occurrences all number
    6
    19
    1
    Hypothyroidism
         subjects affected / exposed
    8 / 56 (14.29%)
    11 / 55 (20.00%)
    1 / 51 (1.96%)
         occurrences all number
    10
    12
    1
    Thyroiditis
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 56 (19.64%)
    7 / 55 (12.73%)
    4 / 51 (7.84%)
         occurrences all number
    11
    8
    5
    Back pain
         subjects affected / exposed
    8 / 56 (14.29%)
    6 / 55 (10.91%)
    5 / 51 (9.80%)
         occurrences all number
    11
    6
    6
    Bone pain
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    4 / 51 (7.84%)
         occurrences all number
    2
    5
    4
    Hyperglycaemia
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    0
    3
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    4
    0
    Myalgia
         subjects affected / exposed
    4 / 56 (7.14%)
    4 / 55 (7.27%)
    1 / 51 (1.96%)
         occurrences all number
    4
    4
    1
    Pain in extremitiy
         subjects affected / exposed
    7 / 56 (12.50%)
    10 / 55 (18.18%)
    5 / 51 (9.80%)
         occurrences all number
    8
    10
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    2
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 56 (12.50%)
    7 / 55 (12.73%)
    6 / 51 (11.76%)
         occurrences all number
    10
    8
    8
    Rhinitis
         subjects affected / exposed
    1 / 56 (1.79%)
    4 / 55 (7.27%)
    1 / 51 (1.96%)
         occurrences all number
    2
    4
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 56 (1.79%)
    6 / 55 (10.91%)
    1 / 51 (1.96%)
         occurrences all number
    1
    6
    1
    Hyperuricaemia
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    3
    2
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    5 / 55 (9.09%)
    0 / 51 (0.00%)
         occurrences all number
    2
    5
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2018
    Recruitment period was extended by three months, and the number of planned patients was adapted according to a new calculation based on recent findings from study CA209-238.
    05 Sep 2019
    Amendment included an extension of the follow-up period (after the treatment period of approx. one year, all patients are followed-up for a maximum of 5 years or until end of study, i.e. 24 months after end of treatment of last patient), an addition of two more secondary objectives (TTR, PFS2/RFS2 for crossover patients of arm C), further explanations on AE reporting, and statistical adaptions.

    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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