Study Evaluating ECG Effects, Safety, Tolerability and Ph... | NCT03203564

Status Module

Description Module

Label	Type	Description	Intervention Names
Modufolin® for injection, 200, 350 and 500 mg/m2	Active Comparator	Three cohorts, 8 subjects will be randomised to Modufolin ® for injection 100 mg	Drug: Modufolin (arfolitixorin)
0.9% NaCl sterile solution	Placebo Comparator	Three cohorts, 3 subjects will be randomised to placebo	Drug: Modufolin (arfolitixorin)

Name	Type	Description	Arm Group Labels	Other Names
Modufolin (arfolitixorin)	Drug	Thirty-three eligible and consenting subjects will be included in 3 cohorts, 11 subjects in each cohort, Within each cohort, subjects will be randomized to receive either placebo (3 subjects) or Modufolin® for injection, 100mg (8 subjects)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change-from-baseline QTcF (ΔQTcF)	At each nominal time point specified in the CSP, up to 10 ECG replicates were extracted with TQT Plus methods. TQT Plus ECG extraction technique: Twelve-lead ECGs were extracted from continuous recordings (Holter recordings) prior to and serially after IMP administration at time points as shown in the Schedule of events. Subjects were supinely resting for at least 10 min prior to time points for ECG recordings. The 12-lead Holter and ECG equipment were supplied and supported by iCardiac Technologies, Inc. For all ECG parameters, baseline is defined as the average of the measured ECG intervals from the three pre-dose time points (45, 30, and 15 min pre-dose) on Day 1.	Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

Secondary Outcomes

Measure	Description	Time Frame
Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations	Predicted ΔΔQTcF interval at geometric mean Cmax for 5,10-MTHF, THF, and 5-Formyl-THF and geometric mean concentration of 5-Methyl-THF observed at 5 minutes post-dose The relationship between plasma concentrations of 5,10-MTHF, THF, 5-Methyl-THF, and 5-Formyl-THF, and change-from-baseline QTcF (ΔQTcF) was quantified using a linear mixed-effects modeling approach with separate analyses for each of the analytes (5,10-MTHF, THF 5-Methyl-THF, and 5-Formyl-THF) initially, with ΔQTcF as the dependent variable, plasma concentration of 5,10-MTHF (or THF, 5-Methyl-THF, or 5-Formyl-THF) as a continuous covariate (i.e., 0 for placebo), centered baseline QTcF as an additional covariate, treatment (active = 1 or placebo = 0) and time (i.e., time point) as categorical factors, and a random intercept and slope per subject. The degrees of freedom estimates were determined by the Kenward-Roger method.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Willing and able to provide a written informed consent for participation in the study.
Healthy male subject aged 18-60 years inclusive.
Body Mass Index (BMI) ≥ 18 and ≤ 30 kg/m2 and weight at least 50 kg and no more than 100 kg at screening and body surface area ≤ 2 m2
Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator.
Willing to use condom and highly effective contraceptive methods with a failure rate of < 1% to prevent pregnancy1 and drug exposure to a partner and refrain from donating sperm from the date of dosing until 3 months after dosing of the IMP/placebo.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or subject´s ability to participate in the study.

2. Any clinically significant illness, medical/surgical procedure or trauma within four weeks of the first administration of IMP/placebo. 3. Any planned major surgery within the duration of the study. 4. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV). 5. After 10 minutes (min) supine rest at the time of screening, any vital signs values outside the following ranges:
- Systolic BP > 150 mm Hg
- Diastolic BP > 90 mm Hg
- Pulse < 40 or > 85 beats per min 6. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator.
  
  7. History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to Modufolin® (i.e., folate derivatives). 8. Regular use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals within two weeks prior to the administration of IMP/placebo, except occasional intake of paracetamol (maximum 2000 mg/day; and not exceeding 3 000 mg/week), at the discretion of the Investigator and nasal decongestants without cortisone or antihistamine for a maximum of 10 days, at the discretion of the Investigator. 9. Regular use of any prescribed or non-prescribed medication which could influence folate and vitamin B12 status within 30 days prior to the administration of IMP/placebo.
  
  10. Administration of another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment with less than three months between administration of last dose and first dose of IMP/placebo in this study. Subjects consented and screened but not dosed in previous phase I studies are not excluded. 11. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit. 12. Positive screen for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the IMP/placebo. 13. Current or history of alcohol abuse and/or use of anabolic steroids or drugs of abuse.
  
  14. Intake of xanthine and/or taurine containing energy drinks within two days prior to screening.
  
  15. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to dosing. 16. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Facility	Status	City	State	ZIP	Country	Contacts
CTC Clinical Trial Consultants		Uppsala		75185	Sweden

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
FG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Jul 12, 2017	Dec 20, 2018

ID	Title	Description
BG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
BG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
BG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
BG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.
BG004	Total	Total of all reporting groups

Units	Counts
Participants	BG0008 BG0018 BG0028 BG0039 BG00433

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change-from-baseline QTcF (ΔQTcF)

At each nominal time point specified in the CSP, up to 10 ECG replicates were extracted with TQT Plus methods. TQT Plus ECG extraction technique: Twelve-lead ECGs were extracted from continuous recordings (Holter recordings) prior to and serially after IMP administration at time points as shown in the Schedule of events. Subjects were supinely resting for at least 10 min prior to time points for ECG recordings.

The 12-lead Holter and ECG equipment were supplied and supported by iCardiac Technologies, Inc.

For all ECG parameters, baseline is defined as the average of the measured ECG intervals from the three pre-dose time points (45, 30, and 15 min pre-dose) on Day 1.

The QT/QTc Analysis Set includes all subjects in the Safety Analysis Set with measurements at baseline as well as on-treatment with at least one post-dose time point with a valid ΔQTcF (change from baseline QTcF) value.

Posted

Least Squares Mean

Standard Error

msec

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Units	Counts
Participants	OG0008 OG0018 OG0028 OG003

Title	Denominators	Categories
End of infusion	ParticipantsOG0008 ParticipantsOG0018 ParticipantsOG0028 ParticipantsOG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001 OG002 OG003	The primary analysis of QTcF was based on a linear mixed-effects model with change-from-baseline QTcF as the dependent variable, time (categorical), treatment, and time-by-treatment interaction as fixed effects, and baseline QTcF as a covariate. The least-squares (LS) mean and 2-sided 90 % CIs have been calculated for the contrast "Modufolin® versus placebo" at each dose of Modufolin® and each post-dose time point.					Mean Difference (Final Values)	7.4			2-Sided	90	0.68	14.12			Parameter estimate is done for Placebo-corrected change-from baseline QTcF (ΔΔQTcF) for Modufolin 500 mg/m2 at end of infusion.

Secondary

Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations

Predicted ΔΔQTcF interval at geometric mean Cmax for 5,10-MTHF, THF, and 5-Formyl-THF and geometric mean concentration of 5-Methyl-THF observed at 5 minutes post-dose The relationship between plasma concentrations of 5,10-MTHF, THF, 5-Methyl-THF, and 5-Formyl-THF, and change-from-baseline QTcF (ΔQTcF) was quantified using a linear mixed-effects modeling approach with separate analyses for each of the analytes (5,10-MTHF, THF 5-Methyl-THF, and 5-Formyl-THF) initially, with ΔQTcF as the dependent variable, plasma concentration of 5,10-MTHF (or THF, 5-Methyl-THF, or 5-Formyl-THF) as a continuous covariate (i.e., 0 for placebo), centered baseline QTcF as an additional covariate, treatment (active = 1 or placebo = 0) and time (i.e., time point) as categorical factors, and a random intercept and slope per subject. The degrees of freedom estimates were determined by the Kenward-Roger method.

Posted

Geometric Mean

90% Confidence Interval

msec / ng/mL

5 minute post-dose time point

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®

Secondary

Change-from-baseline Heart Rate (ΔHR)

The analysis was based on the change-from-baseline post-dosing values. The same (by-time point analysis) model was used as described for QTcF. For all ECG parameters, baseline is defined as the average of the measured ECG intervals from the three pre-dose time points (45, 30, and 15 min predose) on Day 1.

QT/QTc population.

Posted

Least Squares Mean

Standard Error

bpm

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo

Secondary

Change-from-baseline PR (ΔPR)

QT/QTc population

Posted

Least Squares Mean

Standard Error

msec

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo

Secondary

Change-from-baseline QRS (ΔQRS)

QT/QTc population

Posted

Least Squares Mean

Standard Error

msec

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo

Secondary

Number of Participants With Categorical QTcF Outliers

QTcF outliers per absolute category across treatment groups and QTcF outliers per change-from-baseline category (ΔQTcF)

Posted

Count of Participants

Participants

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Categorical Outliers for HR, PR Interval, QRS Interval

Categorical Analysis of outliers for HR, PR, and QRS intervals

Posted

Count of Participants

Participants

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Categorical Analysis for T Wave Morphology

Categorical T-wave morphology analysis and measurement of PR and QRS intervals were fully performed manually in three of the 10 ECG replicates at each time point. Final quality control and diagnostic interpretations were performed by the study cardiologist. When the results for each time point were compiled in the final data set, the comparison was made between ECG parameters from the three manually reviewed ECGs versus the 10 ECG replicates for quality control purposes. No treatment emergent T wave morphology changes were observed. In addition to the T-wave categorical analysis, the presence of abnormal U-waves was noted.

Posted

Count of Participants

Participants

Pre-dose at following timepoints -2 h, -45 min, -30 min, -15 min. Then at following timepoints; 0, 5 min, 15 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h post-dose.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.

Secondary

Physical Examination

A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities.

Physical examination findings were categorized as Normal, Abnormal non-clinical significant (NCS), and Abnormal clinical significant (CS).

Posted

Count of Participants

Participants

At visit 1 (screening) and follow-up

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Systolic Blood Pressure

Systolic and diastolic BP and pulse were measured in supine position after 10 min of rest.

Posted

Mean

Standard Deviation

mmHg

Predose at following timepoints: At screening (visit 1) and at -15 min (visit 2). Postdose at following timepoints: 3h, 5h, 8 h and 24h (visit 2) and at visit 3 (follow-up visit).

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Diastolic Blood Pressure

Systolic and diastolic BP and pulse were measured in supine position after 10 min of rest.

There were no clinically relevant mean changes over time or any individual changes assessed as clinically significant with regards to any of the vital signs parameters.

Posted

Mean

Standard Deviation

mmHg

Predose at following timepoints: At screening (visit 1) and at -15 min (visit 2). Postdose at following timepoints: 3h, 5h, 8 h and 24h (visit 2) and at visit 3 (follow-up visit).

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Vital Signs: Pulse

Systolic and diastolic BP and pulse were measured in supine position after 10 min of rest.

There were no clinically relevant mean changes over time or any individual changes assessed as clinically significant with regards to any of the vital signs parameters.

Posted

Mean

Standard Deviation

bpm

Predose at following timepoints: At screening (visit 1) and at -15 min (visit 2). Postdose at following timepoints: 3h, 5h, 8 h and 24h (visit 2) and at visit 3 (follow-up visit).

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Safety Laboratory Measurements

The following safety laboratory parameters were assessed:

Clinical Chemistry: Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Albumin, Aspartate aminotransferase (AST), Bilirubin (total and conjugated), Calcium, Chloride, Creatinine, Magnesium, Phosphorous, Potassium, Sodium, Urea nitrogen, Uric acid. Haematology: Haematocrit, Haemoglobin (Hb), Platelet count, Red blood cell (RBC) count, White blood cell (WBC) count with differential count. Urinalysis (dip stick):Glucose, Erythrocytes, Nitrite, Protein, Specific gravity, pH.

Posted

Number

Clinically relevant changes

Pre-dose at screening (visit 1) and -2h (visit 2). Post-dose at following timepoints: 24 h (visit 2) and at follow-up (visit 3)

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003

Secondary

Frequency, Seriousness and Intensity of AEs

An overall summary of AEs occurring after first administration of IMP (TEAE) is presented by treatment

FAS

Posted

Number

Adverse events

From start of IMP administration to follow-up visit

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: C0

The mean back-extrapolated concentration at time 0 h (C0) was calculated for MTHF

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

ng/mL

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h. pre-dose to 24 h post-dose

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: C5min

Measured concentration at 5 min post dose (C5min) of MTHF and 5-Formyl-THF

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

ng/mL

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: AUClast

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

h*ng/mL

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: AUClast/Dose

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted.

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

(h*ng/mL)/mg

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast)

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted.

All samples analysed from the subjects given placebo were below Lower Limit of Quantification (LLOQ).

Posted

Mean

Standard Deviation

hour

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: t1/2

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted:

All samples analysed from the subjects given placebo were below Lower Limit of Quantification

Posted

Mean

Standard Deviation

hour

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: CL

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted.

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

L/h

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: Vss

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

litre

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: Cmax

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

ng/mL

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: Tmax

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

hour

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h.

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Secondary

Plasma PK Characteristics: Cmax/Dose for Metabolite 5-Formyl-THF

Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted. Only the metabolite 5-Formyl-THF has values above LLOQ and are presented below.

All samples analysed from the subjects given placebo were below Lower Limit of Quantification.

Posted

Mean

Standard Deviation

ng/mL/mg

Pre-dose at -15 min and post-dose at following timepoints: 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo

Secondary

Number of Subjects With AEs

An overall summary of subjects with AEs occurring after first administration of IMP (TEAE), number of related TEAEs and number of withdrawals due to TEAEs are presented by treatment

FAS

Posted

Number

Subjects

From start of IMP administration to follow-up visit

ID	Title	Description
OG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.
OG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.
OG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.
OG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0011 events1 affected8 at risk EG0023 events3 affected8 at risk EG0030 events0 affected9 at risk
Sneezing	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0010 events0 affected8 at risk EG0021 events1 affected8 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0010 events0 affected8 at risk EG0022 events2 affected8 at risk EG003
Headache	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 events1 affected8 at risk EG0011 events1 affected8 at risk EG0021 events1 affected8 at risk EG003
Hypoaesthesia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0011 events1 affected8 at risk EG0020 events0 affected8 at risk EG003
Hypoaesthesia oral	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0010 events0 affected8 at risk EG0021 events1 affected8 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 events1 affected8 at risk EG0010 events0 affected8 at risk EG0022 events2 affected8 at risk EG003
Paraesthesia oral	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0002 events2 affected8 at risk EG0011 events1 affected8 at risk EG0020 events0 affected8 at risk EG003
Chills	General disorders	MedDRA (19.0)	Systematic Assessment	EG0001 events1 affected8 at risk EG0010 events0 affected8 at risk EG0020 events0 affected8 at risk EG003
Fatigue	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0010 events0 affected8 at risk EG0020 events0 affected8 at risk EG003
Flushing	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0010 events0 affected8 at risk EG0021 events1 affected8 at risk EG003
Injection site pain	General disorders	MedDRA (19.0)	Systematic Assessment	EG0001 events1 affected8 at risk EG0010 events0 affected8 at risk EG0020 events0 affected8 at risk EG003
Pain	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0010 events0 affected8 at risk EG0021 events1 affected8 at risk EG003
Dysgeusia	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 events0 affected8 at risk EG0011 events1 affected8 at risk EG0020 events0 affected8 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 events1 affected8 at risk EG0012 events2 affected8 at risk EG0024 events4 affected8 at risk EG003
Paraesthesia oral	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 events1 affected8 at risk EG0010 events0 affected8 at risk EG0020 events0 affected8 at risk EG003

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	200 mg/m2 of Modufolin®	8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection.	8	8	6	8
EG001	350 mg/m2 of Modufolin®	8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection.	8	8	5	8
EG002	500 mg/m2 of Modufolin®	8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection.	8	8	8	8
EG003	Placebo	9 subjects were treated with placebo as an intravenous bolus injection.	9	9	1	9