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    Clinical Trial Results:
    A Single-blind, Randomized Phase I/II study of Pharmacokinetic and Pharmacodynamic investigation of Modufolin® (60 or 200 mg/m2) compared to Levoleucovorin (60 or 200 mg/m2) in tumour, adjacent mucosa and plasma for patients with colon cancer.

    Summary
    EudraCT number
    		 2012-000522-22
    Trial protocol
    		 SE  
    Global end of trial date
    05 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jul 2016
    First version publication date
    23 Nov 2014
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISO-CC-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01681472
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Isofol Medical AB
    Sponsor organisation address
    Biotech Center, Arvid Wallgrens Backe 20, Gothenburg, Sweden, SE-413 46
    Public contact
    Chief Scientific Officer, Isofol Medical AB, +46 (0)70 876 15 70, anders.vedin@isofolmedical.com
    Scientific contact
    Chief Scientific Officer, Isofol Medical AB , +46 (0)70 876 15 70, anders.vedin@isofolmedical.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 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF concentration in the tumor tissue and adjacent mucosa for the different treatment groups
    Protection of trial subjects
    The patients were treated as in routine care. No trial specific measures were put in place to protect the patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    6
    From 65 to 84 years
    18
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: Start: 06 September 2012 Stop: 20 June 2013

    Pre-assignment
    Screening details
    		 Potential patients were identified at various outpatient departments that refers patients to the study site. 35 patients had to be screened in order to identify 32 eligible patients. The reasons for screening failure were; performance status not fullfilled, presence of second primary malignancy, and medication intake not approved by the protocol.

    Pre-assignment period milestones
    Number of subjects started
    		 32
    Number of subjects completed
    		 32

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All roles in the study was blinded except the study nurse designated to prepare the study drug for the bolus injection who could not be blinded due to practical reasons. Study drug accountability and compliance was checked on regular basis by a monitor solely appointed for this check.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Modufolin 60 mg/m2
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Modufolin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Study nurses trained in the Modufolin® reconstitution procedures prepared the study drug. Modufolin® was administered as an IV bolus injection after the patient was anesthetized for surgery. The study nurse obtained dose information for each patient from the randomization envelope. The dose was specified in the unit [mg/m2] and was converted into number of milligrams using an automatic calculator for patient’s body surface.

    Arm title
    		 Modufolin 200 mg/m2
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Modufolin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Study nurses trained in the Modufolin® reconstitution procedures prepared the study drug. Modufolin® was administered as an IV bolus injection after the patient was anesthetized for surgery. The study nurse obtained dose information for each patient from the randomization envelope. The dose was specified in the unit [mg/m2] and was converted into number of milligrams using an automatic calculator for patient’s body surface.

    Arm title
    		 L-LV 60 mg/m2
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Isovorin
    Investigational medicinal product code
    Other name
    Levoleucovorin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    L-LV was administered as an IV bolus injection after the patient was anesthetized for surgery. The study nurse obtained dose information for each patient from the randomization envelope. The dose was specified in the unit [mg/m2] and was converted into number of milligrams using an automatic calculator for patient’s body surface.

    Arm title
    		 L-LV 200 mg/m2
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Isovorin
    Investigational medicinal product code
    Other name
    Levoleucovorin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    L-LV was administered as an IV bolus injection after the patient was anesthetized for surgery. The study nurse obtained dose information for each patient from the randomization envelope. The dose was specified in the unit [mg/m2] and was converted into number of milligrams using an automatic calculator for patient’s body surface.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: All roles in the study was blinded except the study nurse designated to prepare the study drug for the bolus injection who could not be blinded due to practical reasons. Modufolin is a powder for solution for injection and Isovorin a solution for injection. Study drug accountability and compliance was checked on regular basis by a monitor solely appointed for this check.
    Number of subjects in period 1
    		Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2
    Started
    8
    8
    8
    8
    Completed
    8
    8
    7
    8
    Not completed
    0
    0
    1
    0
         Adverse event, non-fatal
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All randomized patients

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 32 32
    Age categorical
    Safety population
    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)
    		 6 6
        From 65-84 years
    		 18 18
        85 years and over
    		 8 8
    Gender categorical
    Units: Subjects
        Female
    		 16 16
        Male
    		 16 16
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who have received trial medication and from whom at least one (1) measurement has been obtained. Intention-to-treat population was equal to Safety Population (SP) in this study

    Subject analysis set title
    Per protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients who completed the trial without any major deviations from the protocol procedures.

    Subject analysis sets values
    		 Safety population Per protocol population
    Number of subjects
    31
    29
    Age categorical
    Safety population
    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)
    6
    6
        From 65-84 years
    17
    16
        85 years and over
    8
    7
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    15
    13
        Male
    16
    16

    End points

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    End points reporting groups
    Reporting group title
    Modufolin 60 mg/m2
    Reporting group description
    		 -

    Reporting group title
    Modufolin 200 mg/m2
    Reporting group description
    		 -

    Reporting group title
    L-LV 60 mg/m2
    Reporting group description
    		 -

    Reporting group title
    L-LV 200 mg/m2
    Reporting group description
    		 -

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who have received trial medication and from whom at least one (1) measurement has been obtained. Intention-to-treat population was equal to Safety Population (SP) in this study

    Subject analysis set title
    Per protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients who completed the trial without any major deviations from the protocol procedures.

    Primary: Tissue concentration of [6R]-5,10-methylene-THF in adjacent mucosa

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    End point title
    		 Tissue concentration of [6R]-5,10-methylene-THF in adjacent mucosa
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    3241 ( 2137 )
    5606 ( 4441 )
    816 ( 218 )
    1535 ( 527 )
    2921 ( 3094 )
    Statistical analysis title
    		 Comparison of Methylene-THF conc. mucosa-60mg/m2
    Statistical analysis description
    An exploratory evaluation of the mucosa concentrations of [6R]-5,10-methylene-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0034
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Exploratory
    Statistical analysis title
    		 Comparison of Methylene-THF conc. mucosa-200mg/m2
    Statistical analysis description
    An exploratory evaluation of the mucosa concentrations of [6R]-5,10-methylene-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0019
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Exploratory

    Primary: Tissue concentration of [6S]-5-THF in tumor

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    End point title
    		 Tissue concentration of [6S]-5-THF in tumor
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    2219 ( 1995 )
    4175 ( 3127 )
    933 ( 598 )
    1329 ( 720 )
    2247 ( 2273 )
    Statistical analysis title
    		 Comparison of THF concentration in tumor-60mg/m2
    Statistical analysis description
    An exploratory evaluation of tumor concentrations of [6S]-5-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0538
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Exploratory
    Statistical analysis title
    		 Comparison of THF concentration in tumor-200mg/m2
    Statistical analysis description
    An exploratory evaluation of tumor concentrations of [6S]-5-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0313
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Exploratory

    Primary: Tissue concentration of [6S]-5-THF in adjacent mucosa

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    End point title
    		 Tissue concentration of [6S]-5-THF in adjacent mucosa
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    3481 ( 3926 )
    5099 ( 3927 )
    626 ( 439 )
    1333 ( 852 )
    2744 ( 3260 )
    Statistical analysis title
    		 Comparison of THF conc in adjacent mucosa-60mg/m2
    Statistical analysis description
    An exploratory evaluation of mucosa concentrations of [6S]-5-THF was done respectively for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0124
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Exploratory
    Statistical analysis title
    		 Comparison of THF conc in adjacent mucosa-200mg/m2
    Statistical analysis description
    An exploratory evaluation of mucosa concentrations of [6S]-5-THF was done respectively for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0039
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Exploratory

    Primary: Tissue concentration of [6S]-5-methyl-THF in tumor

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    End point title
    		 Tissue concentration of [6S]-5-methyl-THF in tumor
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    1882 ( 1204 )
    4396 ( 1858 )
    1904 ( 918 )
    3574 ( 2415 )
    3047 ( 2000 )
    Statistical analysis title
    		 Comparison of Methyl-THF conc in tumor-60mg/m2
    Statistical analysis description
    An exploratory evaluation of the tumor concentrations of [6S]-5-methyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.8303
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Exploratory
    Statistical analysis title
    		 Comparison of Methyl-THF conc in tumor-200mg/m2
    Statistical analysis description
    An exploratory evaluation of the tumor concentrations of [6S]-5-methyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.3184
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Exploratory

    Primary: Tissue concentration of [6S]-5-methyl-THF in adjacent mucosa

    		 Close Top of page
    End point title
    		 Tissue concentration of [6S]-5-methyl-THF in adjacent mucosa
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    2066 ( 1517 )
    2494 ( 765 )
    1216 ( 455 )
    3667 ( 2043 )
    2450 ( 1583 )
    Statistical analysis title
    		 Comparison of Methyl-THF conc. in mucosa-60mg/m2
    Statistical analysis description
    An exploratory evaluation of the mucosa concentrations of [6S]-5-methyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.2246
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - Exploratory
    Statistical analysis title
    		 Comparison of Methyl-THF conc. in mucosa-200mg/m2
    Statistical analysis description
    An exploratory evaluation of the mucosa concentrations of [6S]-5-methyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.4309
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - Exploratory

    Primary: Tissue concentration of [6S]-5-formyl-THF in tumor

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    End point title
    		 Tissue concentration of [6S]-5-formyl-THF in tumor
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    57 ( 48 )
    100 ( 47 )
    512 ( 259 )
    3611 ( 3899 )
    1144 ( 2499 )
    Statistical analysis title
    		 Comparison of Formyl-THF in tumor-60mg/m2
    Statistical analysis description
    An exploratory evaluation of the tumor concentrations of [6S]-5-formyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0034
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Exploratory
    Statistical analysis title
    		 Comparison of Formyl-THF in tumor-200mg/m2
    Statistical analysis description
    An exploratory evaluation of the tumor concentrations of [6S]-5-formyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.0009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - Exploratory

    Primary: Tissue concentration of [6S]-5-formyl-THF in adjacent mucosa

    		 Close Top of page
    End point title
    		 Tissue concentration of [6S]-5-formyl-THF in adjacent mucosa
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard deviation)
    42 ( 18 )
    82 ( 77 )
    1403 ( 640 )
    5456 ( 3963 )
    1843 ( 3130 )
    Statistical analysis title
    		 Comparison of Formyl-THF conc. in mucosa-60mg/m2
    Statistical analysis description
    An exploratory evaluation of mucosa concentrations of [6S]-5-formyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.0058
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - Exploratory
    Statistical analysis title
    		 Comparison of Formyl-THF conc. in mucosa-200mg/m2
    Statistical analysis description
    An exploratory evaluation of mucosa concentrations of [6S]-5-formyl-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.0014
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - Exploratory

    Primary: Tissue concentration of [6R]-5,10-methylene-THF in the tumor

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    End point title
    		 Tissue concentration of [6R]-5,10-methylene-THF in the tumor
    End point description
    End point type
    Primary
    End point timeframe
    Biopsies for analysis were collected at one time-point, i.e. during surgery.
    End point values
    		 Modufolin 60 mg/m2 Modufolin 200 mg/m2 L-LV 60 mg/m2 L-LV 200 mg/m2 Per protocol population
    Number of subjects analysed
    7
    8
    6
    8
    29
    Units: pmol/g
        arithmetic mean (standard error)
    2393 ( 1920 )
    4725 ( 2210 )
    959 ( 417 )
    1871 ( 1159 )
    2596 ( 2100 )
    Statistical analysis title
    		 Comparison of Methylene-THF conc in tumor-60 mg/m2
    Statistical analysis description
    An exploratory evaluation of the tumor concentrations of [6R]-5,10-methylene-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 60 mg/m2 v L-LV 60 mg/m2
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.1336
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - Exploratory
    Statistical analysis title
    		 Comparison of Methylene-THF conc in tumor-200mg/m2
    Statistical analysis description
    An exploratory evaluation of the tumor concentrations of [6R]-5,10-methylene-THF was done for differences between treatments using Kruskal-Wallis and Wilcoxon tests as it was found that the assumption of normality was violated. Differences in variability between treatment groups were assessed using Proc GLM and Levene’s test.
    Comparison groups
    Modufolin 200 mg/m2 v L-LV 200 mg/m2
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0074
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - Exploratory

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The recording of AEs started in connection with the start of the treatment and continued until the patient had completed the end of study visit.
    Adverse event reporting additional description
    SAEs occurring after the end of study visit at day 5 were to be reported if a relationship to study drug was suspected.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 31 (16.13%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.03%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 31 (38.71%)
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 31 (12.90%)
         occurrences all number
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Mouth haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jul 2012
    Initially two strata (one morning stratum and one afternoon stratum) were defined in the protocol. Prior to enrollment of first patient in the trial the protocol was amended and the afternoon stratum was deleted due to logistic reasons in order to optimize the recruitment rate and consequently the overall trial duration.
    09 Oct 2012
    The initial protocol defined and interim analysis after 16 patients had completed the protocol. An additional interim analysis after 32 patients was added.
    28 Jun 2013
    The list of genes to be analyzed was updated. Recent litterature data (post study start) indicated that the initial list of genes had to be updated in order to include all specific genes with the highest probability of impact on the metabolism of LV and methylene-THF.

    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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