PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in Patients With Colon Cancer

• Sponsor: Isofol Medical AB (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01681472
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 4
• Duration (Months): 11
• Patients Per Site Per Month: 2.9

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the concentration of four different metabolites in the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two different doses of Modufolin (arfolitixorin) and Levoleucovorin (Isovorin®), respectively (60 and 200 mg/m2).

Condition or Disease	Intervention/Treatment	Phase
Colonic Neoplasms	Drug: 6R-MTHF (arfolitixorin) 200 mg/m2; Drug: Levoleucovorin 200 mg/m2; Drug: 6R-MTHF (arfolitixorin) 60 mg/m2; Drug: Levoleucovorin 60 mg/m2	Phase 1/Phase 2

Detailed Description

The purpose of this study is to compare the concentration of [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF in the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two different does of Modufolin® and Levoleucovorin (Isovorin®), respectively (60 and 200 mg/m2).

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: A Single-Blind, Randomized Phase I/II Study of Pharmacokinetic and Pharmacodynamic Investigation of Modufolin® (60 or 200mg/m2) Compared to Levoleucovorin (60 or 200mg/m2) in Tumor, Adjacent Mucosa and Plasma for Patients With Colon Cancer
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Levoleucovorin 200 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: Levoleucovorin 200 mg/m2; i.v. bolus injection; Other Names: Isovorin®
Active Comparator: Levoleucovorin 60 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: Levoleucovorin 60 mg/m2; i.v. bolus injection; Other Names: Isovorin®
Experimental: 6R-MTHF 200 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: 6R-MTHF (arfolitixorin) 200 mg/m2; i.v. bolus injection; Other Names: Modufolin® ISO-901 [6R] 5,10-methylenetetrahydrofolate arfolitixorin
Experimental: 6R-MTHF 60 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: 6R-MTHF (arfolitixorin) 60 mg/m2; i.v. bolus injection; Other Names: Modufolin® ISO-901 [6R] 5,10-methylenetetrahydrofolate arfolitixorin

Outcome Measures

Primary Outcome Measures

1. Concentration of [6R]-5,10-methylene-THF in Tumor Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.

2. Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.

3. Concentration of [6S]-5-THF in Tumor Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.

4. Concentration of [6S]-5-THF in Adjacent Mucosa Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.

5. Concentration of [6S]-5-methyl-THF in Tumor Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.

6. Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.

7. Concentration of [6S]-5-formyl-THF in Tumor Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.

8. Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue [Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration]

   Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.

Secondary Outcome Measures

1. AUC(0-2h) of [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery)]

   Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: [6R]-5,10-methylene-THF

2. AUC(0-2h) of [6S]-5-THF [Samples taken Day 1 (Day of surgery)]

   Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-THF

3. AUC(0-2h) of [6S]-5-methyl-THF [Samples taken Day 1 (Day of surgery)]

   Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: [6S]-5-methyl-THF

4. AUC(0-2h) of [6SR]-5-formyl-THF [Samples taken Day 1 (Day of surgery)]

   Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-formyl-THF

5. AUC(Last) of [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery) and Day 2]

   Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: [6R]-5,10-methylene-THF

6. AUC(Last) of [6S]-5-THF [Samples taken Day 1 (Day of surgery) and Day 2]

   Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-THF

7. AUC(Last) of [6S]-5-methyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

   Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-methyl-THF

8. AUC(Last) of [6S]-5-formyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

   Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-formyl-THF

9. Cmax of [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery) and Day 2]

   Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R]-5,10-methylene-THF

10. Cmax of [6S]-5-THF in Plasma [Samples taken Day 1 (Day of surgery) and Day 2]

    Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF

11. Cmax of [6S]-5-methyl-THF in Plasma [Samples taken Day 1 (Day of surgery) and Day 2]

    Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF

12. Cmax of [6S]-5-formyl-THF in Plasma [Samples taken Day 1 (Day of surgery) and Day 2]

    Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R] 5,10- methylene-THF and the metabolites: [6S]-5-THF, [6S]-5-methyl-THF, and [6S]-5-formyl-THF

13. Tmax of [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: [6R]-5,10-methylene-THF

14. Tmax of [6S]-5-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF

15. Tmax of [6S]-5-methyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF

16. Tmax of [6S]-5-formyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF

17. T(1/2) of [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Terminal plasma elimination half-life time for the active substance in Modufolin: [6R]-5,10-methylene-THF

18. T(1/2) of [6S]-5-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Terminal plasma elimination half-life time for the metabolite [6S]-5-THF

19. T(1/2) of [6S]-5-methyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF

20. T(1/2) of [6S]-5-formyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF

21. T(Last) of [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    The time-point for the last measurable concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF

22. T(Last) of [6S]-5-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    The time-point for the last measurable concentration for the metabolite [6S]-5-TH in plasma

23. T(Last) of [6S]-5-methyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    The time-point for the last measurable concentration for the metabolite [6S]-5-methyl-THF in plasma

24. T(Last) of [6S]-5-formyl-THF [Samples taken Day 1 (Day of surgery) and Day 2]

    The time-point for the last measurable concentration for the metabolite [6S]-5-formyl-THF in plasma

25. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF [Samples taken Day 1 (Day of surgery)]

    Correlation between the exposure of [6R]-5,10-methylene-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6R]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.

26. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF [Samples taken Day 1 (Day of surgery)]

    Correlation between the exposure of [6S]-5-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-THF in the tumor or adjacent mucosa at surgery.

27. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF [Samples taken Day 1 (Day of surgery)]

    Correlation between the exposure of [6S]-5-methyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-methyl-THF in the tumor or adjacent mucosa at surgery.

28. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF [Samples taken Day 1 (Day of surgery)]

    Correlation between the exposure of [6S]-5-formyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-formyl-THF in the tumor or adjacent mucosa at surgery.

29. Gene Expression Ratios (Mucosa:Tumor) [Sample taken Day 1 (Day of Surgery)]

    Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.

30. Correlation of Gene Expression in Tumor and Adjacent Mucosa [Sample taken Day 1 (Day of Surgery)]

    Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.

31. Homocystein Concentration [Samples taken at Screening visit, Day 2, and End of Study (Day 5)]

    Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).

32. S-Folate Concentration [Samples taken at Screening visit, Day 2 and End of Study (Day 5)]

    Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).

33. Change in Homocystein Concentration From Screening [Samples taken at Screening visit, Day 2 and End of Study (Day 5)]

    Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted. The criteria for assessment categories "normal", "low" and "high" were based on the reference ranges for plasma-Homocystein as follows: "low" <4,7 mcmol/L; "normal" => 4,7 and <=16 mcmol/L; "high" >16 mcmol/L. Values were applicable for both male and female adults.

34. Change in S-Folate Concentration From Screening [Samples taken at Screening visit, Day 2 and End of Study (Day 5)]

    Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.

35. Number of AEs Per Severity [Screening visit until end of study, Day 5]

    Number of reported AEs per treatment with respect to severity

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Main Inclusion Criteria:

• Operable colon cancer amenable to curative surgery.

• Performance status of 0 to 1

• Informed consent form

• Patients must be at least 18 years of age.

Main Exclusion Criteria:

• Any concurrent other anti-tumor therapy

• Any prohibited concomitant medication within 30 days of surgery

• Pregnancy or breast-feeding.

• Second primary malignancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sahlgrenska University Hospital	Gothenburg		Sweden	461 85

Sponsors and Collaborators

• Isofol Medical AB

Investigators

• Principal Investigator: Kristoffer Derwinger, MD PhD, Sahlgrenska University Hospital, Sweden

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Isofol Medical AB
• ClinicalTrials.gov Identifier: NCT01681472
• Other Study ID Numbers: ISO-CC-002; 2012-000522-22
• First Posted: Sep 10, 2012
• Last Update Posted: Sep 25, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Isofol Medical AB: Colon cancer; 5,10-methylenetetrahydrofolate; Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Therapeutic Uses; Pharmacokinetics; Pharmacodynamics
• Additional relevant MeSH terms: Neoplasms; Colonic Neoplasms; Leucovorin; Tetrahydrofolates; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	6R-MTHF 200 mg/m2	6R-MTHF 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Period Title: Overall Study
STARTED	8	8	8	8
COMPLETED	8	7	8	8
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2	Total
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	Total of all reporting groups
Overall Participants	8	8	8	8	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	3 37.5%	2 25%	2 25%	7 21.9%
>=65 years	8 100%	5 62.5%	6 75%	6 75%	25 78.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	80.5 (9.15)	66.71 (16.89)	72 (15)	71.75 (11.25)	72.74 (13.07)
Sex: Female, Male (Count of Participants)
Female	4 50%	5 62.5%	3 37.5%	4 50%	16 50%
Male	4 50%	3 37.5%	5 62.5%	4 50%	16 50%
Region of Enrollment (Count of Participants)
Sweden	8 100%	8 100%	8 100%	8 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Concentration of [6R]-5,10-methylene-THF in Tumor Tissue
Description	Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	1871 (1159)	959 (417)	4725 (2210)	2393 (1920)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0323
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1336
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8622
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1752
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue
Description	Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	1333 (852)	626 (439)	5099 (3927)	3481 (3926)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1480
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0177
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6R]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Primary Outcome

Title	Concentration of [6S]-5-THF in Tumor Tissue
Description	Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	1329 (720)	933 (598)	4175 (3127)	2219 (1995)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1182
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0538
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5244
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0081
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0313
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4777
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Primary Outcome

Title	Concentration of [6S]-5-THF in Adjacent Mucosa Tissue
Description	Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	1333 (852)	626 (439)	5099 (3927)	3481 (3926)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2716
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0728
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0039
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0454
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Primary Outcome

Title	Concentration of [6S]-5-methyl-THF in Tumor Tissue
Description	Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	3574 (2415)	1904 (918)	4396 (1858)	1882 (1204)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0092
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8303
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1182
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0081
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3184
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1752
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Primary Outcome

Title	Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue
Description	Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	3667 (2043)	1216 (455)	2494 (765)	2066 (1517)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0728
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2246
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0428
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4309
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Primary Outcome

Title	Concentration of [6S]-5-formyl-THF in Tumor Tissue
Description	Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	3611 (3899)	512 (259)	100 (47)	57 (48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0728
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Primary Outcome

Title	Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue
Description	Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.
Time Frame	Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Mean (Standard Deviation) [pmol/g]	5456 (3963)	1403 (640)	82 (77)	42 (18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0240
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of [6S]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0338
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	AUC(0-2h) of [6R]-5,10-methylene-THF
Description	Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: [6R]-5,10-methylene-THF
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	326.40261 (61.98416)	239.90076 (0)	7734.09113 (1557.76552)	0 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	AUC(0-2h) of [6S]-5-THF
Description	Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-THF
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	827.1083 (178.23243)	640.0489 (0)	19408.1712 (3000.64794)	5639.2700 (885.82223)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	AUC(0-2h) of [6S]-5-methyl-THF
Description	Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: [6S]-5-methyl-THF
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	2336.24432 (829.18634)	1258.60184 (247.51353)	2277.89290 (1132.95603)	997.74091 (413.68052)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0728
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2246
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0166
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1752
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9581
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	AUC(0-2h) of [6SR]-5-formyl-THF
Description	Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite [6S]-5-formyl-THF
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	29911.9184 (6924.78031)	7595.4599 (764.27650)	0 (0)	0 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

13. Secondary Outcome

Title	AUC(Last) of [6R]-5,10-methylene-THF
Description	Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: [6R]-5,10-methylene-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	462.10746 (221.85761)	239.90076 (0)	7910.61038 (1623.24300)	2272.78010 (448.01407)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	AUC(Last) of [6S]-5-THF
Description	Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	2231.1443 (1051.06650)	640.0489 (0)	28466.5389 (5303.28705)	6766.9104 (1484.91243)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	AUC(Last) of [6S]-5-methyl-THF
Description	Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-methyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	32206.2771 (9121.1818)	7689.0921 (5164.6098)	21737.2428 (21757.1545)	5495.1924 (6110.0065)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0240
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1336
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2725
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1893
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Secondary Outcome

Title	AUC(Last) of [6S]-5-formyl-THF
Description	Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite [6S]-5-formyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [mcg*h/L]	43429.1885 (12411.2844)	9637.0308 (1637.2118)	75.6174 (69.2176)	50.1858 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0142
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

17. Secondary Outcome

Title	Cmax of [6R]-5,10-methylene-THF
Description	Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R]-5,10-methylene-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [µg/L]	195.0000 (40.76763)	123.0000 (0)	22087.5000 (5635.45853)	6452.8571 (559.18477)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

18. Secondary Outcome

Title	Cmax of [6S]-5-THF in Plasma
Description	Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [µg/L]	577.6250 (190.74436)	335.0000 (0)	13372.5000 (2108.15932)	5015.7143 (427.35064)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

19. Secondary Outcome

Title	Cmax of [6S]-5-methyl-THF in Plasma
Description	Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [µg/L]	2786.25000 (822.6253)	1078.00000 (275.26206)	2020.50000 (1142.25116)	800.42857 (396.41849)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0240
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1336
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1551
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1563
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

20. Secondary Outcome

Title	Cmax of [6S]-5-formyl-THF in Plasma
Description	Maximum concentration (Cmax) in plasma of the active substance in Modufolin: [6R] 5,10- methylene-THF and the metabolites: [6S]-5-THF, [6S]-5-methyl-THF, and [6S]-5-formyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [µg/L]	32962.5000 (8594.17369)	10168.3333 (2271.47896)	252.7500 (141.51178)	261.0000 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0142
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

21. Secondary Outcome

Title	Tmax of [6R]-5,10-methylene-THF
Description	Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: [6R]-5,10-methylene-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	1.14285857 (0.53079605)	1.00000000 (0)	0.08333000 (0.00000000)	0.08333000 (0.00000000)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

22. Secondary Outcome

Title	Tmax of [6S]-5-THF
Description	Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	2.02083375 (1.03677360)	1.50000000 (0)	0.38541750 (0.24775936)	0.09523571 (0.03149956)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0056
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

23. Secondary Outcome

Title	Tmax of [6S]-5-methyl-THF
Description	Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	4.75000000 (1.38873015)	2.41666667 (0.66458007)	3.75000000 (1.16496475)	2.92857143 (0.93222724)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1796
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3243
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0263
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0268
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2041
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

24. Secondary Outcome

Title	Tmax of [6S]-5-formyl-THF
Description	Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	0.12499750 (0.08908753)	0.08333000 (0.00000000)	0.10416500 (0.04167000)	0.08333000 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

25. Secondary Outcome

Title	T(1/2) of [6R]-5,10-methylene-THF
Description	Terminal plasma elimination half-life time for the active substance in Modufolin: [6R]-5,10-methylene-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	3.07069184 (2.48958159)	9.12204918 (0)	0.90893994 (0.62586420)	0.34368840 (0.06725217)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0268
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0227
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0933
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

26. Secondary Outcome

Title	T(1/2) of [6S]-5-THF
Description	Terminal plasma elimination half-life time for the metabolite [6S]-5-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	5.59459251 (1.76982092)	0 (0)	1.24808943 (0.23995973)	0.96378070 (0.19174152)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0177
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

27. Secondary Outcome

Title	T(1/2) of [6S]-5-methyl-THF
Description	Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	7.0955575 (1.18981597)	10.7281060 (8.80812064)	9.0743346 (3.84317226)	8.5121573 (2.80644764)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

28. Secondary Outcome

Title	T(1/2) of [6S]-5-formyl-THF
Description	Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	1.51328500 (0.34108131)	0.98944069 (0.20217367)	0.23180085 (0.13438901)	0 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0668
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0502
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0081
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

29. Secondary Outcome

Title	T(Last) of [6R]-5,10-methylene-THF
Description	The time-point for the last measurable concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	3.00000000 (1.41421356)	2.00000000 (0)	3.25000000 (1.38873015)	1.35714286 (0.24397502)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6691
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

30. Secondary Outcome

Title	T(Last) of [6S]-5-THF
Description	The time-point for the last measurable concentration for the metabolite [6S]-5-TH in plasma
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	4.75000000 (1.48804762)	2.00000000 (0)	5.75000000 (0.70710678)	3.42857143 (0.78679579)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0640
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1213
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

31. Secondary Outcome

Title	T(Last) of [6S]-5-methyl-THF
Description	The time-point for the last measurable concentration for the metabolite [6S]-5-methyl-THF in plasma
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	24.0000000 (0.00000000)	12.0000000 (9.29516003)	15.0000000 (9.62140471)	8.5714286 (6.80336051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1791
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4945
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5990
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0303
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0107
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

32. Secondary Outcome

Title	T(Last) of [6S]-5-formyl-THF
Description	The time-point for the last measurable concentration for the metabolite [6S]-5-formyl-THF in plasma
Time Frame	Samples taken Day 1 (Day of surgery) and Day 2

Outcome Measure Data

Analysis Population Description

Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.

Arm/Group Title	L-LV(200)	L-LV(60)	Mod(200)	Mod(60)
Arm/Group Description	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Measure Participants	8	6	8	7
Mean (Standard Deviation) [h]	6.00000000 (0.00000000)	8.33333333 (7.73735528)	0.33333500 (0.23570226)	0.16667000 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0125
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Modufolin 200 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2, Levoleucovorin 60 mg/m2
	Comments	The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5286
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

33. Secondary Outcome

Title	Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF
Description	Correlation between the exposure of [6R]-5,10-methylene-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6R]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
AUC(0-2h) vs. conc in tumor	0.54039	NA	-0.21666
AUC(0-2h) vs. conc in adjacent mucosa	0.68223	NA	0.27618

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6063
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.21666
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2105
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.54039
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5079
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.27618
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0913
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.68223
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

34. Secondary Outcome

Title	Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF
Description	Correlation between the exposure of [6S]-5-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-THF in the tumor or adjacent mucosa at surgery.
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
AUC(0-2h) vs. conc in tumor	-0.02188	NA	0.27018	0.38298
AUC(0-2h) vs. conc in adjacent mucosa	0.07937	NA	0.34905	0.45404

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	AUC(0-2h) vs. concentration in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3964
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.38298
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5175
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.27018
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9590
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.02188
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3061
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.45404
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3967
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.34905
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8518
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.07937
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

35. Secondary Outcome

Title	Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF
Description	Correlation between the exposure of [6S]-5-methyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-methyl-THF in the tumor or adjacent mucosa at surgery.
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
AUC(0-2h) vs. conc in tumor	0.73743	0.44757	0.03292	0.09033
AUC(0-2h) vs. conc in adjacent mucosa	0.76502	0.34496	-0.66295	0.36854

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	AUC(0-2h) vs. conc in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0586
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.73743
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	AUC(0-2h) vs. conc in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2661
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.44757
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	AUC(0-2h) vs. conc in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9506
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.03292
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. conc in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8315
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.09033
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	AUC(0-2h) vs. conc in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0451
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.76502
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4027
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.34496
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1513
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.66295
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3690
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.36854
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

36. Secondary Outcome

Title	Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF
Description	Correlation between the exposure of [6S]-5-formyl-THF following 2 hours after dosing (AUC[0-2h]) and the concentration of [6S]-5-formyl-THF in the tumor or adjacent mucosa at surgery.
Time Frame	Samples taken Day 1 (Day of surgery)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
AUC(0-2h) vs. conc in tumor	0.68778	0.11512
AUC(0-2h) vs. conc in adjacent mucosa	0.23512	0.02576

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5751
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.23512
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	AUC(0-2h) vs. concentration in adjacent mucosa
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9672
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.02576
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	AUC(0-2h) vs. conc in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0594
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.68778
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	AUC(0-2h) vs. conc in tumor
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8281
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.11512
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

37. Secondary Outcome

Title	Gene Expression Ratios (Mucosa:Tumor)
Description	Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.
Time Frame	Sample taken Day 1 (Day of Surgery)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Modufolin 60 mg/m2	Modufolin 200 mg/m2	Levoleucovorin 60 mg/m2	Levoleucovorin 200 mg/m2
Arm/Group Description	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection
Measure Participants	7	8	6	8
AMT	1.35	5.60	1.86	3.33
PCFT	2.03	2.75	2.92	2.45
FPGS	0.47	0.70	0.63	0.83
MTHFS	0.51	0.87	0.83	0.72
ABCC3	1.83	3.37	2.48	4.15
GGH	0.50	0.47	0.35	0.31
ABCC1	0.41	0.55	0.77	0.43
MTHFD1L	0.15	0.24	0.29	0.35
SHMT1	0.89	1.13	0.72	2.26
SHMT2	0.31	0.34	0.38	0.48
RFC-1	0.48	0.66	0.53	1.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0451
	Comments
	Method	pearson
	Comments

38. Secondary Outcome

Title	Correlation of Gene Expression in Tumor and Adjacent Mucosa
Description	Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.
Time Frame	Sample taken Day 1 (Day of Surgery)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
AMT	-0.47193	-0.70730	0.75404	0.42972
PCFT	0.11497	0.89976	0.58502	0.88128
FPGS	0.17664	-0.64743	0.88682	0.97624
MTHFS	0.95840	0.58419	0.43194	0.94364
ABCC3	0.00322	0.77700	-0.25891	-0.38987
GGH	0.78928	-0.09737	0.46883	0.93711
ABCC1	0.74757	0.14436	-0.16724	0.82963
MTHFD1L	0.74459	0.20955	0.37160	0.32113
SHMT1	0.59183	0.05531	0.67853	0.50966
SHMT2	0.55508	-0.71666	0.86266	0.81040
RFC-1	0.64565	-0.02450	0.23312	0.31800

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for AMT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3359
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.42972
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for AMT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0307
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.75404
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for AMT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1160
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.70730
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for AMT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2377
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.47193
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for PCFT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0087
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.88128
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for PCFT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1277
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.58502
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for PCFT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0146
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.89976
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for PCFT gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7863
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.11497
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for FPGS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.97624
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for FPGS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.88682
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for FPGS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1645
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.64743
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for FPGS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6756
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.17664
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for MTHFS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.94364
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for MTHFS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2852
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.43194
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for MTHFS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2234
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.58419
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for MTHFS gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.95840
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for ABCC3 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3873
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.38987
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for ABCC3 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5358
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.25891
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for ABCC3 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0691
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.77700
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for ABCC3 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9940
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.00322
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for GGH gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.93711
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for GGH gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2413
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.46883
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for GGH gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8544
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.09737
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for GGH gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0199
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.78928
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for ABCC1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0209
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.82963
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for ABCC1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6922
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.16724
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for ABCC1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7850
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.14436
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for ABCC1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0330
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.74757
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for MTHFD1L gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4825
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.32113
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for MTHFD1L gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3647
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.37160
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for MTHFD1L gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6903
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.20955
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for MTHFD1L gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0341
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.74459
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for SHMT1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2426
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.50966
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for SHMT1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0643
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.67853
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for SHMT1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9171
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.05531
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for SHMT1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1222
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.59183
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for SHMT2 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0271
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.81040
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for SHMT2 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.86266
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for SHMT2 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1090
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.71666
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for SHMT2 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1533
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.55508
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Modufolin 60 mg/m2
	Comments	Correlation for RFC-1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4870
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.31800
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Modufolin 200 mg/m2
	Comments	Correlation for RFC-1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5785
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.23312
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 60 mg/m2
	Comments	Correlation for RFC-1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9632
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	-0.02450
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Levoleucovorin 200 mg/m2
	Comments	Correlation for RFC-1 gene expression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0838
	Comments
	Method	Pearson Correlation
	Comments
Method of Estimation	Estimation Parameter	Correlation factor
	Estimated Value	0.64565
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

39. Secondary Outcome

Title	Homocystein Concentration
Description	Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).
Time Frame	Samples taken at Screening visit, Day 2, and End of Study (Day 5)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Concentration at Screening	12.59 (4.28)	11.27 (3.98)	14.53 (6.22)	13.80 (3.83)
Concentration at Day 2	6.41 (2.32)	6.40 (3.10)	7.06 (1.97)	8.14 (2.63)
Concentration at Day 5	9.04 (2.53)	9.18 (4.65)	10.20 (3.34)	10.10 (2.64)

40. Secondary Outcome

Title	S-Folate Concentration
Description	Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).
Time Frame	Samples taken at Screening visit, Day 2 and End of Study (Day 5)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	6	8	7
Concentration at Screening	21.75 (8.88)	21.00 (6.54)	15.03 (5.20)	18.71 (7.65)
Concentration at Day 2	45.00 (0.00)	45.00 (0.00)	45.00 (0.00)	45.00 (0.00)
Concentration at Day 5	44.75 (0.71)	40.80 (9.39)	44.14 (2.27)	40.29 (3.73)

41. Secondary Outcome

Title	Change in Homocystein Concentration From Screening
Description	Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted. The criteria for assessment categories "normal", "low" and "high" were based on the reference ranges for plasma-Homocystein as follows: "low" <4,7 mcmol/L; "normal" => 4,7 and <=16 mcmol/L; "high" >16 mcmol/L. Values were applicable for both male and female adults.
Time Frame	Samples taken at Screening visit, Day 2 and End of Study (Day 5)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Modufolin 60 mg/m2	Modufolin 200 mg/m2	Levoleucovorin 60 mg/m2	Levoleucovorin 200 mg/m2
Arm/Group Description	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection
Measure Participants	7	8	6	8
Normal at Screen and Normal at Day 2	5 62.5%	4 50%	4 50%	4 50%
Shift from Normal at Screen to Low at Day 2	0 0%	1 12.5%	2 25%	2 25%
Shift from High at Screen to Normal at Day 2	2 25%	3 37.5%	0 0%	2 25%
Normal at Screen and Normal at Day 5	5 62.5%	5 62.5%	4 50%	6 75%
Shift from Normal at Screen to Low at Day 5	0 0%	0 0%	1 12.5%	0 0%
Shift from High at Screen and Normal at Day 5	2 25%	3 37.5%	0 0%	2 25%
Missing data Screen to Day 5	0 0%	0 0%	1 12.5%	0 0%

42. Secondary Outcome

Title	Change in S-Folate Concentration From Screening
Description	Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.
Time Frame	Samples taken at Screening visit, Day 2 and End of Study (Day 5)

Outcome Measure Data

Analysis Population Description

The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.

Arm/Group Title	Modufolin 60 mg/m2	Modufolin 200 mg/m2	Levoleucovorin 60 mg/m2	Levoleucovorin 200 mg/m2
Arm/Group Description	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection
Measure Participants	7	8	6	8
Shift from Normal at Screen to High at Day 2	7 87.5%	8 100%	5 62.5%	8 100%
Missing data Screen to Day 2	0 0%	0 0%	1 12.5%	0 0%
Normal at Screening and Normal at Day 5	3 37.5%	1 12.5%	1 12.5%	0 0%
Shift from Normal at Screen to High at Day 5	4 50%	6 75%	4 50%	8 100%
Missing data Screen to Day 5	0 0%	1 12.5%	1 12.5%	0 0%

43. Secondary Outcome

Title	Number of AEs Per Severity
Description	Number of reported AEs per treatment with respect to severity
Time Frame	Screening visit until end of study, Day 5

Outcome Measure Data

Analysis Population Description

The safety population contained 31 of the 32 enrolled patients. One patient randomized to L-LV 60 mg/m2 was withdrawn prior to study drug administration and thus excluded from the safety analysis set.

Arm/Group Title	Levoleucovorin 200 mg/m2	Levoleucovorin 60 mg/m2	Modufolin 200 mg/m2	Modufolin mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection	Levoleucovorin: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection	[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
Measure Participants	8	7	8	8
AEs of mild severity	1	0	1	5
AEs of moderate severity	3	0	7	2
AEs of severe severity	0	1	2	2

Adverse Events

Arm/Group Title	Levoleucovorin 200 mg/m2		Levoleucovorin 60 mg/m2		6R-MTHF 200 mg/m2		6R-MTHF 60 mg/m2
Arm/Group Description	Levoleucovorin: i.v. bolus injection		Levoleucovorin: i.v. bolus injection		[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection		[6R] 5,10-methylenetetrahydrofolate: i.v. bolus injection
All Cause Mortality
	Levoleucovorin 200 mg/m2		Levoleucovorin 60 mg/m2		6R-MTHF 200 mg/m2		6R-MTHF 60 mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Levoleucovorin 200 mg/m2		Levoleucovorin 60 mg/m2		6R-MTHF 200 mg/m2		6R-MTHF 60 mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		1/7 (14.3%)		2/8 (25%)		2/8 (25%)
Cardiac disorders
Acute mycardial infarction	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Cardiac arrest	0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/8 (0%)
Injury, poisoning and procedural complications
Postoperative wound complication	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Anastomotic leak	0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/8 (0%)		0/7 (0%)		0/8 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Levoleucovorin 200 mg/m2		Levoleucovorin 60 mg/m2		6R-MTHF 200 mg/m2		6R-MTHF 60 mg/m2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/8 (50%)		2/7 (28.6%)		4/8 (50%)		5/8 (62.5%)
Cardiac disorders
Atrial fibrillation	2/8 (25%)	2	0/7 (0%)	0	2/8 (25%)	2	0/8 (0%)	0
Gastrointestinal disorders
Dyspepsia	0/8 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	2/8 (25%)	2
Vomiting	0/8 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	1/8 (12.5%)	1
Nausea	0/8 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Abdominal pain	0/8 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Mouth haemorrhage	1/8 (12.5%)	1	0/7 (0%)	0	0/8 (0%)	0	0/8 (0%)	0
General disorders
Pyrexia	0/8 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Infections and infestations
Pneumonia	0/8 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	1/8 (12.5%)	1
Injury, poisoning and procedural complications
Hepatic enzyme increased	0/8 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Nervous system disorders
Paralysis	0/8 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/8 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/8 (12.5%)	1
Dysphonia	0/8 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/8 (0%)	0
Dyspnoea	1/8 (12.5%)	1	0/7 (0%)	0	0/8 (0%)	0	0/8 (0%)	0
Vascular disorders
Flushing	0/8 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/8 (12.5%)	1
Hypotension	0/8 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/8 (12.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.