Phase I Study in Healthy Volunteers to Evaluate ECG Effect
Conditions
Brief summary
The purpose of this study is to evaluating ECG effects, safety, tolerability and pharmacokinetics of single ascending dose of Modufolin® in healthy male volunteers
Detailed description
An adaptive randomised, double-blind, single-centre, placebo-controlled Phase I study evaluating ECG effects, safety, tolerability and PK of single ascending doses of Modufolin® for Injection, 100 mg in healthy male volunteers. Thirty-three (33) eligible and consenting subjects will be included in 3 cohorts, 11 subjects in each cohort. Within each cohort, subjects will be randomised to receive either placebo (3 subjects) or Modufolin® for Injection, 100 mg (8 subjects). There will be 3 pre-defined ascending dose-levels. Additional dose levels may be considered if recommended by the internal Safety Review cCommittee. There will be an interval between each dose level to allow time for safety data to be analyzed and evaluated by the iSRC. The iSRC will have the choice to decide to escalate the dose as planned, reduce or increase the dose escalation step, repeat the dose, reduce the dose or terminate the study. The total study duration for the subjects will be approximately 5 weeks and there will be in total 3 visits to the clinic. Subjects will be screened for eligibility according to study-specific inclusion/exclusion criteria within 4 weeks prior to start of stud treatment (Visit 1; Screening visit). The subjects will be confined to the research clinic from the evening before dosing (Day -1) until 24 hrs post dose (Days 1 and 2). The subjects should be fasting overnight (8 hrs) before IMP/placebo administration until 4 hrs post-dose. A Follow-up Visit will be performed 5 to 10 days after dose administration of for each cohort.
Interventions
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)
Sponsors
Isofol Medical AB
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
IMP (Modufolin® for Injection, 100 mg) and Placebo are not identical in appearance and all efforts will be made at the clinic in order to maintain the blind. Both the IMP and the placebo will be masked in such a way that study subjects and study staff will remain blinded during the study. An un-blinded study nurse will prepare the IMP/placebo for injection and will administer the IMP/placebo to the study subject. The un-blinded study nurse performing the dose administration will not be involved in any study-specific assessments or evaluations.
Intervention model description
An adaptive, randomized, double-blind, single-center, placebo-controlled
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Willing and able to provide a written informed consent for participation in the study. 2. Healthy male subject aged 18-60 years inclusive. 3. 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 4. Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. 5. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change-from-baseline QTcF (ΔQTcF) | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change-from-baseline Heart Rate (ΔHR) | 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. | 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. |
| Change-from-baseline PR (ΔPR) | 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. | 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. |
| Change-from-baseline QRS (ΔQRS) | 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. | 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. |
| Number of Participants With Categorical QTcF Outliers | 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. | QTcF outliers per absolute category across treatment groups and QTcF outliers per change-from-baseline category (ΔQTcF) |
| Categorical Outliers for HR, PR Interval, QRS Interval | 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. | Categorical Analysis of outliers for HR, PR, and QRS intervals |
| Categorical Analysis for T Wave Morphology | 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. | 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. |
| Physical Examination | At visit 1 (screening) and follow-up | 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). |
| Systolic Blood Pressure | 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). | Systolic and diastolic BP and pulse were measured in supine position after 10 min of rest. |
| Diastolic Blood Pressure | 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). | 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. |
| Vital Signs: Pulse | 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). | 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. |
| Safety Laboratory Measurements | 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) | 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. |
| Frequency, Seriousness and Intensity of AEs | From start of IMP administration to follow-up visit | An overall summary of AEs occurring after first administration of IMP (TEAE) is presented by treatment |
| Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5 minute post-dose time point | 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. |
| Plasma PK Characteristics: C5min | 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 | Measured concentration at 5 min post dose (C5min) of MTHF and 5-Formyl-THF |
| Plasma PK Characteristics: AUClast | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted |
| Plasma PK Characteristics: AUClast/Dose | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted. |
| Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted. |
| Plasma PK Characteristics: t1/2 | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted: |
| Plasma PK Characteristics: CL | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted. |
| Plasma PK Characteristics: Vss | 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 | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted |
| Plasma PK Characteristics: Cmax | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted |
| Plasma PK Characteristics: Tmax | 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. | Pharmacokinetic parameters were calculated for test item MTHF, and for the following metabolites: 5-Formyl-THF, 5-Methyl-THF, and THF, if data permitted |
| Plasma PK Characteristics: Cmax/Dose for Metabolite 5-Formyl-THF | 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 | 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. |
| Number of Subjects With AEs | From start of IMP administration to follow-up visit | 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 |
| Plasma PK Characteristics: C0 | 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 | The mean back-extrapolated concentration at time 0 h (C0) was calculated for MTHF |
Countries
Sweden
Participant flow
Recruitment details
Subjects were recruited from a database of healthy volunteers at CTC and from advertising in media, including social media.
Pre-assignment details
Subjects were screened for eligibility according to study-specific inclusion/exclusion criteria within four weeks prior to start of study treatment (Visit 1; Screening Visit).
Participants by arm
| Arm | Count |
|---|---|
| 200 mg/m2 of Modufolin® 8 subjects were treated with 200 mg/m2 of Modufolin® as an intravenous bolus injection. | 8 |
| 350 mg/m2 of Modufolin® 8 subjects were treated with 350 mg/m2 of Modufolin® as an intravenous bolus injection. | 8 |
| 500 mg/m2 of Modufolin® 8 subjects were treated with 500 mg/m2 of Modufolin® as an intravenous bolus injection. | 8 |
| Placebo 9 subjects were treated with placebo as an intravenous bolus injection. | 9 |
| Total | 33 |
Baseline characteristics
| Characteristic | 200 mg/m2 of Modufolin® | 350 mg/m2 of Modufolin® | 500 mg/m2 of Modufolin® | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 8 Participants | 8 Participants | 9 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 7 Participants | 9 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Sweden | 8 participants | 8 participants | 8 participants | 9 participants | 33 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 9 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 6 / 8 | 5 / 8 | 8 / 8 | 1 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 9 |
Outcome results
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.
Time frame: 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.
Population: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 30 min post-dose | 1.2 msec | Standard Error 1.43 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 5 h post-dose | 5.4 msec | Standard Error 3.25 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 24 h post-dose | -5.9 msec | Standard Error 2.85 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 4 h post-dose | -3.3 msec | Standard Error 2.7 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 1 h post-dose | -1.2 msec | Standard Error 1.38 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 15 min post-dose | 3.1 msec | Standard Error 1.48 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 5 min post-dose | 11.2 msec | Standard Error 2.28 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 8 h post-dose | -5.5 msec | Standard Error 2.91 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 2 h post-dose | -3.5 msec | Standard Error 1.97 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 6 h post-dose | -0.8 msec | Standard Error 2.73 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 3 h post-dose | -2.8 msec | Standard Error 2.58 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | End of infusion | 2.8 msec | Standard Error 2.85 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 12 h post-dose | -4.5 msec | Standard Error 2.86 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 24 h post-dose | -8.1 msec | Standard Error 2.84 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | End of infusion | 9.2 msec | Standard Error 2.84 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 6 h post-dose | -2.5 msec | Standard Error 2.72 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 4 h post-dose | 0.7 msec | Standard Error 2.7 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 12 h post-dose | -6.6 msec | Standard Error 2.86 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 5 h post-dose | 2.6 msec | Standard Error 3.37 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 15 min post-dose | 7.5 msec | Standard Error 1.47 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 30 min post-dose | 2.5 msec | Standard Error 1.42 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 8 h post-dose | -5.5 msec | Standard Error 2.9 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 1 h post-dose | -0.7 msec | Standard Error 1.38 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 2 h post-dose | -1.7 msec | Standard Error 1.96 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 5 min post-dose | 9.1 msec | Standard Error 2.28 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 3 h post-dose | -0.8 msec | Standard Error 2.58 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 6 h post-dose | -6.7 msec | Standard Error 2.75 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | End of infusion | 8.5 msec | Standard Error 2.87 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 5 min post-dose | 22.4 msec | Standard Error 2.31 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 15 min post-dose | 12.4 msec | Standard Error 1.51 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 30 min post-dose | 4.2 msec | Standard Error 1.47 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 1 h post-dose | -0.9 msec | Standard Error 1.42 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 2 h post-dose | 1.0 msec | Standard Error 1.99 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 3 h post-dose | 0.9 msec | Standard Error 2.6 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 4 h post-dose | 0.0 msec | Standard Error 2.72 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 5 h post-dose | 0.8 msec | Standard Error 3.27 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 8 h post-dose | -7.7 msec | Standard Error 2.93 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 12 h post-dose | -4.1 msec | Standard Error 2.95 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QTcF (ΔQTcF) | 24 h post-dose | -4.6 msec | Standard Error 3.01 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 2 h post-dose | 0.7 msec | Standard Error 1.86 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 6 h post-dose | 6.4 msec | Standard Error 2.58 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 1 h post-dose | 1.4 msec | Standard Error 1.32 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 30 min post-dose | 0.8 msec | Standard Error 1.36 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | End of infusion | 1.1 msec | Standard Error 2.69 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 8 h post-dose | -0.9 msec | Standard Error 2.75 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 15 min post-dose | 0.2 msec | Standard Error 1.4 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 5 min post-dose | 0.0 msec | Standard Error 2.16 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 24 h post-dose | -1.3 msec | Standard Error 2.69 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 12 h post-dose | 2.8 msec | Standard Error 2.7 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 5 h post-dose | 11.5 msec | Standard Error 3.07 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 4 h post-dose | 2.6 msec | Standard Error 2.55 |
| Placebo | Change-from-baseline QTcF (ΔQTcF) | 3 h post-dose | 3.8 msec | Standard Error 2.44 |
Comparison: 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.90% CI: [0.68, 14.12]
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Notched (+) | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Flat | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Notched (-) | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | U wave presence | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Biphasic | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Normal (-) | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Normal (-) | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Biphasic | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Notched (+) | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Notched (-) | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Flat | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | U wave presence | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Flat | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Notched (+) | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Biphasic | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Normal (-) | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | Notched (-) | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Analysis for T Wave Morphology | U wave presence | 0 Participants |
| Placebo | Categorical Analysis for T Wave Morphology | Notched (+) | 0 Participants |
| Placebo | Categorical Analysis for T Wave Morphology | U wave presence | 0 Participants |
| Placebo | Categorical Analysis for T Wave Morphology | Normal (-) | 0 Participants |
| Placebo | Categorical Analysis for T Wave Morphology | Biphasic | 0 Participants |
| Placebo | Categorical Analysis for T Wave Morphology | Flat | 0 Participants |
| Placebo | Categorical Analysis for T Wave Morphology | Notched (-) | 0 Participants |
Secondary
Categorical Outliers for HR, PR Interval, QRS Interval
Categorical Analysis of outliers for HR, PR, and QRS intervals
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | QRS changes > 25% increase from baseline to >120ms | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | PR changes > 25% increase from baseline to >200ms | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% increase from baseline to >100bpm | 0 Participants |
| 200 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% decrease from baseline to <50 bpm | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% increase from baseline to >100bpm | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | PR changes > 25% increase from baseline to >200ms | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% decrease from baseline to <50 bpm | 0 Participants |
| 350 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | QRS changes > 25% increase from baseline to >120ms | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% decrease from baseline to <50 bpm | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% increase from baseline to >100bpm | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | PR changes > 25% increase from baseline to >200ms | 0 Participants |
| 500 mg/m2 of Modufolin® | Categorical Outliers for HR, PR Interval, QRS Interval | QRS changes > 25% increase from baseline to >120ms | 0 Participants |
| Placebo | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% decrease from baseline to <50 bpm | 0 Participants |
| Placebo | Categorical Outliers for HR, PR Interval, QRS Interval | QRS changes > 25% increase from baseline to >120ms | 0 Participants |
| Placebo | Categorical Outliers for HR, PR Interval, QRS Interval | HR changes >25% increase from baseline to >100bpm | 0 Participants |
| Placebo | Categorical Outliers for HR, PR Interval, QRS Interval | PR changes > 25% increase from baseline to >200ms | 0 Participants |
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.
Time frame: 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.
Population: QT/QTc population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 3 h post-dose | 2.2 bpm | Standard Error 1.47 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 5 min post-dose | 8.2 bpm | Standard Error 2.56 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 6 h post-dose | 8.3 bpm | Standard Error 2.52 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 5 h post-dose | 11.9 bpm | Standard Error 2.06 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | End of infusion | 2.6 bpm | Standard Error 1.91 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 24 h post-dose | 6.0 bpm | Standard Error 2.8 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 15 min post-dose | 3.9 bpm | Standard Error 1.63 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 12 h post-dose | 7.6 bpm | Standard Error 2.41 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 30 min post-dose | 3.3 bpm | Standard Error 2 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 1 h post-dose | 5.0 bpm | Standard Error 1.9 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 4 h post-dose | 1.7 bpm | Standard Error 1.82 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 2 h post-dose | 3.2 bpm | Standard Error 1.52 |
| 200 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 8 h post-dose | 8.1 bpm | Standard Error 2.24 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 24 h post-dose | 5.7 bpm | Standard Error 2.8 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 3 h post-dose | 0.3 bpm | Standard Error 1.46 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 6 h post-dose | 12.5 bpm | Standard Error 2.52 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 4 h post-dose | 2.0 bpm | Standard Error 1.82 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 5 min post-dose | 7.4 bpm | Standard Error 2.55 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 30 min post-dose | 1.3 bpm | Standard Error 2 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | End of infusion | 2.7 bpm | Standard Error 1.91 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 5 h post-dose | 12.4 bpm | Standard Error 2.12 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 8 h post-dose | 8.0 bpm | Standard Error 2.23 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 2 h post-dose | -0.1 bpm | Standard Error 1.52 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 1 h post-dose | 0.0 bpm | Standard Error 1.9 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 15 min post-dose | 3.6 bpm | Standard Error 1.63 |
| 350 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 12 h post-dose | 5.3 bpm | Standard Error 2.41 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 15 min post-dose | 2.6 bpm | Standard Error 1.64 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | End of infusion | 2.0 bpm | Standard Error 1.92 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 5 min post-dose | 13.3 bpm | Standard Error 2.56 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 30 min post-dose | 3.0 bpm | Standard Error 2 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 1 h post-dose | -0.9 bpm | Standard Error 1.91 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 2 h post-dose | -2.6 bpm | Standard Error 1.53 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 3 h post-dose | 0.3 bpm | Standard Error 1.47 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 4 h post-dose | 0.2 bpm | Standard Error 1.83 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 5 h post-dose | 8.9 bpm | Standard Error 2.06 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 6 h post-dose | 6.2 bpm | Standard Error 2.53 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 8 h post-dose | 2.5 bpm | Standard Error 2.24 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 12 h post-dose | 3.6 bpm | Standard Error 2.54 |
| 500 mg/m2 of Modufolin® | Change-from-baseline Heart Rate (ΔHR) | 24 h post-dose | 8.0 bpm | Standard Error 3 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 6 h post-dose | 5.4 bpm | Standard Error 2.38 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 2 h post-dose | -1.8 bpm | Standard Error 1.43 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 30 min post-dose | -0.7 bpm | Standard Error 1.88 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | End of infusion | -2.1 bpm | Standard Error 1.8 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 8 h post-dose | 2.1 bpm | Standard Error 2.11 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 15 min post-dose | -1.6 bpm | Standard Error 1.53 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 1 h post-dose | -1.3 bpm | Standard Error 1.79 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 24 h post-dose | 8.6 bpm | Standard Error 2.64 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 12 h post-dose | 0.6 bpm | Standard Error 2.27 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 5 h post-dose | 9.5 bpm | Standard Error 1.94 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 4 h post-dose | -3.3 bpm | Standard Error 1.72 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 3 h post-dose | -2.3 bpm | Standard Error 1.38 |
| Placebo | Change-from-baseline Heart Rate (ΔHR) | 5 min post-dose | 0.0 bpm | Standard Error 2.41 |
Secondary
Change-from-baseline PR (ΔPR)
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.
Time frame: 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.
Population: QT/QTc population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 5 min post-dose | -1.5 msec | Standard Error 2.07 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 4 h post-dose | -5.2 msec | Standard Error 1.84 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 6 h post-dose | -9.4 msec | Standard Error 2.04 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 5 h post-dose | -8.8 msec | Standard Error 2.59 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | End of infusion | -1.6 msec | Standard Error 2.08 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 24 h post-dose | -5.9 msec | Standard Error 2.77 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 15 min post-dose | -2.3 msec | Standard Error 2.61 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 12 h post-dose | -7.9 msec | Standard Error 3.12 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 30 min post-dose | -1.7 msec | Standard Error 2.11 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 1 h post-dose | -5.2 msec | Standard Error 1.89 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 3 h post-dose | -5.3 msec | Standard Error 2.14 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 8 h post-dose | -8.6 msec | Standard Error 2.62 |
| 200 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 2 h post-dose | -4.1 msec | Standard Error 2.13 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 2 h post-dose | -4.1 msec | Standard Error 2.13 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 6 h post-dose | -8.4 msec | Standard Error 2.04 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 24 h post-dose | -5.6 msec | Standard Error 2.77 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 4 h post-dose | -4.6 msec | Standard Error 1.84 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 5 min post-dose | -4.5 msec | Standard Error 2.07 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 30 min post-dose | -3.7 msec | Standard Error 2.11 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | End of infusion | -4.4 msec | Standard Error 2.08 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 5 h post-dose | -7.1 msec | Standard Error 2.71 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 8 h post-dose | -7.2 msec | Standard Error 2.62 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 3 h post-dose | -4.2 msec | Standard Error 2.14 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 1 h post-dose | -3.6 msec | Standard Error 1.89 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 15 min post-dose | -1.2 msec | Standard Error 2.61 |
| 350 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 12 h post-dose | -1.5 msec | Standard Error 3.12 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 15 min post-dose | 0.2 msec | Standard Error 2.61 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | End of infusion | -2.1 msec | Standard Error 2.08 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 5 min post-dose | -3.1 msec | Standard Error 2.07 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 30 min post-dose | 1.3 msec | Standard Error 2.11 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 1 h post-dose | -0.3 msec | Standard Error 1.89 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 2 h post-dose | 1.1 msec | Standard Error 2.13 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 3 h post-dose | -1.6 msec | Standard Error 2.14 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 4 h post-dose | -2.1 msec | Standard Error 1.84 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 5 h post-dose | -7.8 msec | Standard Error 2.59 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 6 h post-dose | -5.8 msec | Standard Error 2.04 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 8 h post-dose | -4.3 msec | Standard Error 2.62 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 12 h post-dose | -6.9 msec | Standard Error 3.22 |
| 500 mg/m2 of Modufolin® | Change-from-baseline PR (ΔPR) | 24 h post-dose | -6.4 msec | Standard Error 2.88 |
| Placebo | Change-from-baseline PR (ΔPR) | 6 h post-dose | -3.9 msec | Standard Error 1.93 |
| Placebo | Change-from-baseline PR (ΔPR) | 1 h post-dose | 0.4 msec | Standard Error 1.79 |
| Placebo | Change-from-baseline PR (ΔPR) | 30 min post-dose | 2.9 msec | Standard Error 1.99 |
| Placebo | Change-from-baseline PR (ΔPR) | End of infusion | -1.6 msec | Standard Error 1.96 |
| Placebo | Change-from-baseline PR (ΔPR) | 8 h post-dose | -5.6 msec | Standard Error 2.47 |
| Placebo | Change-from-baseline PR (ΔPR) | 15 min post-dose | 3.8 msec | Standard Error 2.46 |
| Placebo | Change-from-baseline PR (ΔPR) | 2 h post-dose | 3.1 msec | Standard Error 2.01 |
| Placebo | Change-from-baseline PR (ΔPR) | 24 h post-dose | -6.8 msec | Standard Error 2.61 |
| Placebo | Change-from-baseline PR (ΔPR) | 12 h post-dose | -1.7 msec | Standard Error 2.94 |
| Placebo | Change-from-baseline PR (ΔPR) | 5 h post-dose | -3.5 msec | Standard Error 2.44 |
| Placebo | Change-from-baseline PR (ΔPR) | 4 h post-dose | 1.4 msec | Standard Error 1.74 |
| Placebo | Change-from-baseline PR (ΔPR) | 3 h post-dose | 1.2 msec | Standard Error 2.02 |
| Placebo | Change-from-baseline PR (ΔPR) | 5 min post-dose | -0.1 msec | Standard Error 1.96 |
Secondary
Change-from-baseline QRS (ΔQRS)
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.
Time frame: 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.
Population: QT/QTc population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 5 h post-dose | 0.4 msec | Standard Error 0.47 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 2 h post-dose | -0.2 msec | Standard Error 0.22 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 4 h post-dose | 0.1 msec | Standard Error 0.39 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 3 h post-dose | 0.0 msec | Standard Error 0.3 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 24 h post-dose | 0.0 msec | Standard Error 0.45 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | End of infusion | -0.1 msec | Standard Error 0.27 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 8 h post-dose | -0.3 msec | Standard Error 0.53 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 5 min post-dose | -0.7 msec | Standard Error 0.28 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 6 h post-dose | -0.3 msec | Standard Error 0.52 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 15 min post-dose | -0.2 msec | Standard Error 0.25 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 12 h post-dose | 0.5 msec | Standard Error 0.56 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 30 min post-dose | -0.7 msec | Standard Error 0.27 |
| 200 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 1 h post-dose | -0.2 msec | Standard Error 0.26 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 15 min post-dose | -0.3 msec | Standard Error 0.25 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 1 h post-dose | 0.1 msec | Standard Error 0.26 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 6 h post-dose | -0.4 msec | Standard Error 0.52 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 3 h post-dose | -0.1 msec | Standard Error 0.31 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 30 min post-dose | 0.0 msec | Standard Error 0.27 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 2 h post-dose | 0.0 msec | Standard Error 0.22 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 5 min post-dose | -0.8 msec | Standard Error 0.28 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 24 h post-dose | 0.4 msec | Standard Error 0.45 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 8 h post-dose | -0.3 msec | Standard Error 0.53 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 5 h post-dose | 0.4 msec | Standard Error 0.49 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 12 h post-dose | 0.3 msec | Standard Error 0.56 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | End of infusion | -0.2 msec | Standard Error 0.27 |
| 350 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 4 h post-dose | -0.5 msec | Standard Error 0.39 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 2 h post-dose | -0.1 msec | Standard Error 0.22 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 6 h post-dose | -0.8 msec | Standard Error 0.52 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 12 h post-dose | -0.6 msec | Standard Error 0.58 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | End of infusion | -0.1 msec | Standard Error 0.27 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 5 min post-dose | -1.2 msec | Standard Error 0.28 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 15 min post-dose | -0.1 msec | Standard Error 0.25 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 30 min post-dose | -0.5 msec | Standard Error 0.27 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 1 h post-dose | 0.2 msec | Standard Error 0.26 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 3 h post-dose | -0.4 msec | Standard Error 0.3 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 4 h post-dose | 0.2 msec | Standard Error 0.38 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 5 h post-dose | 0.1 msec | Standard Error 0.47 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 8 h post-dose | -0.5 msec | Standard Error 0.53 |
| 500 mg/m2 of Modufolin® | Change-from-baseline QRS (ΔQRS) | 24 h post-dose | -0.9 msec | Standard Error 0.47 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 4 h post-dose | 0.9 msec | Standard Error 0.36 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 30 min post-dose | 0.0 msec | Standard Error 0.26 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 15 min post-dose | 0.0 msec | Standard Error 0.24 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 8 h post-dose | -0.6 msec | Standard Error 0.5 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 5 h post-dose | 0.2 msec | Standard Error 0.45 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 5 min post-dose | 0.0 msec | Standard Error 0.26 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 6 h post-dose | -0.7 msec | Standard Error 0.49 |
| Placebo | Change-from-baseline QRS (ΔQRS) | End of infusion | 0.5 msec | Standard Error 0.25 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 2 h post-dose | -0.1 msec | Standard Error 0.21 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 1 h post-dose | 0.0 msec | Standard Error 0.24 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 12 h post-dose | -1.0 msec | Standard Error 0.53 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 3 h post-dose | 0.2 msec | Standard Error 0.29 |
| Placebo | Change-from-baseline QRS (ΔQRS) | 24 h post-dose | -0.9 msec | Standard Error 0.42 |
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 2 | 71.50 mmHg | Standard Deviation 10.23 |
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (-00:15) | 69.63 mmHg | Standard Deviation 3.74 |
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (03:00) | 69.00 mmHg | Standard Deviation 6.89 |
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Follow-up | 68.25 mmHg | Standard Deviation 4.53 |
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (08:00) | 69.00 mmHg | Standard Deviation 7.29 |
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (05:00) | 65.63 mmHg | Standard Deviation 5.88 |
| 200 mg/m2 of Modufolin® | Diastolic Blood Pressure | Screening | 68.63 mmHg | Standard Deviation 5.21 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (05:00) | 62.38 mmHg | Standard Deviation 5.04 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (08:00) | 64.50 mmHg | Standard Deviation 3.89 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (-00:15) | 65.88 mmHg | Standard Deviation 6.42 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Follow-up | 70.25 mmHg | Standard Deviation 7.81 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 2 | 69.38 mmHg | Standard Deviation 4.5 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (03:00) | 64.38 mmHg | Standard Deviation 7.37 |
| 350 mg/m2 of Modufolin® | Diastolic Blood Pressure | Screening | 69.75 mmHg | Standard Deviation 8.51 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (05:00) | 72.25 mmHg | Standard Deviation 7.15 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Screening | 72.25 mmHg | Standard Deviation 8.01 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (-00:15) | 75.38 mmHg | Standard Deviation 2.77 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (03:00) | 72.63 mmHg | Standard Deviation 5.71 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 1 (08:00) | 70.25 mmHg | Standard Deviation 6.36 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Visit 2 Day 2 | 74.25 mmHg | Standard Deviation 5.47 |
| 500 mg/m2 of Modufolin® | Diastolic Blood Pressure | Follow-up | 71.00 mmHg | Standard Deviation 8.07 |
| Placebo | Diastolic Blood Pressure | Visit 2 Day 1 (-00:15) | 69.56 mmHg | Standard Deviation 9.06 |
| Placebo | Diastolic Blood Pressure | Follow-up | 70.11 mmHg | Standard Deviation 7.99 |
| Placebo | Diastolic Blood Pressure | Visit 2 Day 2 | 71.11 mmHg | Standard Deviation 8.15 |
| Placebo | Diastolic Blood Pressure | Screening | 73.56 mmHg | Standard Deviation 11.75 |
| Placebo | Diastolic Blood Pressure | Visit 2 Day 1 (03:00) | 65.56 mmHg | Standard Deviation 11.2 |
| Placebo | Diastolic Blood Pressure | Visit 2 Day 1 (08:00) | 66.22 mmHg | Standard Deviation 9.59 |
| Placebo | Diastolic Blood Pressure | Visit 2 Day 1 (05:00) | 67.00 mmHg | Standard Deviation 11.16 |
Secondary
Frequency, Seriousness and Intensity of AEs
An overall summary of AEs occurring after first administration of IMP (TEAE) is presented by treatment
Time frame: From start of IMP administration to follow-up visit
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | Subject-unique related TEAEs | 7 Adverse events |
| 200 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | SAEs | 0 Adverse events |
| 200 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | No. of TEAEs | 8 Adverse events |
| 200 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | No. of subject-unique TEAEs | 8 Adverse events |
| 350 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | No. of TEAEs | 8 Adverse events |
| 350 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | Subject-unique related TEAEs | 4 Adverse events |
| 350 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | SAEs | 0 Adverse events |
| 350 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | No. of subject-unique TEAEs | 7 Adverse events |
| 500 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | No. of TEAEs | 16 Adverse events |
| 500 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | No. of subject-unique TEAEs | 16 Adverse events |
| 500 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | SAEs | 0 Adverse events |
| 500 mg/m2 of Modufolin® | Frequency, Seriousness and Intensity of AEs | Subject-unique related TEAEs | 14 Adverse events |
| Placebo | Frequency, Seriousness and Intensity of AEs | No. of TEAEs | 2 Adverse events |
| Placebo | Frequency, Seriousness and Intensity of AEs | SAEs | 0 Adverse events |
| Placebo | Frequency, Seriousness and Intensity of AEs | Subject-unique related TEAEs | 0 Adverse events |
| Placebo | Frequency, Seriousness and Intensity of AEs | No. of subject-unique TEAEs | 2 Adverse events |
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)
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF > 60 msec | 0 Participants |
| 200 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 500 msec | 0 Participants |
| 200 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 480 and ≤ 500 msec | 0 Participants |
| 200 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF of > 30 and ≤ 60 msec | 0 Participants |
| 200 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 450 and ≤ 480 msec | 0 Participants |
| 350 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 450 and ≤ 480 msec | 0 Participants |
| 350 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 480 and ≤ 500 msec | 0 Participants |
| 350 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF of > 30 and ≤ 60 msec | 0 Participants |
| 350 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 500 msec | 0 Participants |
| 350 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF > 60 msec | 0 Participants |
| 500 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 500 msec | 0 Participants |
| 500 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF > 60 msec | 0 Participants |
| 500 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF of > 30 and ≤ 60 msec | 2 Participants |
| 500 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 450 and ≤ 480 msec | 1 Participants |
| 500 mg/m2 of Modufolin® | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 480 and ≤ 500 msec | 0 Participants |
| Placebo | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF > 60 msec | 0 Participants |
| Placebo | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 500 msec | 0 Participants |
| Placebo | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 480 and ≤ 500 msec | 0 Participants |
| Placebo | Number of Participants With Categorical QTcF Outliers | No. participants with ΔQTcF of > 30 and ≤ 60 msec | 0 Participants |
| Placebo | Number of Participants With Categorical QTcF Outliers | No. participants with QTcF > 450 and ≤ 480 msec | 0 Participants |
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
Time frame: From start of IMP administration to follow-up visit
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Number of Subjects With AEs | Subjects with at least one related TEAE | 5 Subjects |
| 200 mg/m2 of Modufolin® | Number of Subjects With AEs | Withdrawals due to TEAE | 0 Subjects |
| 200 mg/m2 of Modufolin® | Number of Subjects With AEs | Subjects with at least one TEAE | 6 Subjects |
| 350 mg/m2 of Modufolin® | Number of Subjects With AEs | Subjects with at least one TEAE | 5 Subjects |
| 350 mg/m2 of Modufolin® | Number of Subjects With AEs | Withdrawals due to TEAE | 0 Subjects |
| 350 mg/m2 of Modufolin® | Number of Subjects With AEs | Subjects with at least one related TEAE | 3 Subjects |
| 500 mg/m2 of Modufolin® | Number of Subjects With AEs | Subjects with at least one related TEAE | 8 Subjects |
| 500 mg/m2 of Modufolin® | Number of Subjects With AEs | Withdrawals due to TEAE | 0 Subjects |
| 500 mg/m2 of Modufolin® | Number of Subjects With AEs | Subjects with at least one TEAE | 8 Subjects |
| Placebo | Number of Subjects With AEs | Subjects with at least one TEAE | 1 Subjects |
| Placebo | Number of Subjects With AEs | Withdrawals due to TEAE | 0 Subjects |
| Placebo | Number of Subjects With AEs | Subjects with at least one related TEAE | 0 Subjects |
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).
Time frame: At visit 1 (screening) and follow-up
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Physical Examination | Abnormal CS - Visit 1 | 0 Participants |
| 200 mg/m2 of Modufolin® | Physical Examination | Abnormal CS - Follow-up | 0 Participants |
| 200 mg/m2 of Modufolin® | Physical Examination | Abnormal NCS - Visit 1 | 0 Participants |
| 200 mg/m2 of Modufolin® | Physical Examination | Abnormal NCS - Follow-up | 0 Participants |
| 350 mg/m2 of Modufolin® | Physical Examination | Abnormal NCS - Visit 1 | 0 Participants |
| 350 mg/m2 of Modufolin® | Physical Examination | Abnormal CS - Follow-up | 0 Participants |
| 350 mg/m2 of Modufolin® | Physical Examination | Abnormal CS - Visit 1 | 0 Participants |
| 350 mg/m2 of Modufolin® | Physical Examination | Abnormal NCS - Follow-up | 0 Participants |
| 500 mg/m2 of Modufolin® | Physical Examination | Abnormal NCS - Visit 1 | 1 Participants |
| 500 mg/m2 of Modufolin® | Physical Examination | Abnormal CS - Follow-up | 0 Participants |
| 500 mg/m2 of Modufolin® | Physical Examination | Abnormal NCS - Follow-up | 0 Participants |
| 500 mg/m2 of Modufolin® | Physical Examination | Abnormal CS - Visit 1 | 0 Participants |
| Placebo | Physical Examination | Abnormal CS - Follow-up | 0 Participants |
| Placebo | Physical Examination | Abnormal CS - Visit 1 | 0 Participants |
| Placebo | Physical Examination | Abnormal NCS - Follow-up | 0 Participants |
| Placebo | Physical Examination | Abnormal NCS - Visit 1 | 0 Participants |
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
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | THF | 31800 h*ng/mL | Standard Deviation 3780 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | MTHF | 10900 h*ng/mL | Standard Deviation 1680 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | 5-Methyl-THF | 23400 h*ng/mL | Standard Deviation 4470 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | THF | 53100 h*ng/mL | Standard Deviation 10000 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | MTHF | 19700 h*ng/mL | Standard Deviation 1990 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | 5-Methyl-THF | 38500 h*ng/mL | Standard Deviation 6380 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | MTHF | 31100 h*ng/mL | Standard Deviation 3210 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | 5-Methyl-THF | 47400 h*ng/mL | Standard Deviation 7540 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast | THF | 90100 h*ng/mL | Standard Deviation 17500 |
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.
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | THF | 85.0 (h*ng/mL)/mg | Standard Deviation 11.8 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | 5-Formyl-THF | 2.33 (h*ng/mL)/mg | Standard Deviation 1.97 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | 5-Methyl-THF | 62.7 (h*ng/mL)/mg | Standard Deviation 12.5 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | MTHF | 29.2 (h*ng/mL)/mg | Standard Deviation 5.27 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | THF | 80.1 (h*ng/mL)/mg | Standard Deviation 14 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | MTHF | 29.8 (h*ng/mL)/mg | Standard Deviation 2.74 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | 5-Formyl-THF | 1.24 (h*ng/mL)/mg | Standard Deviation 1.22 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | 5-Methyl-THF | 58.3 (h*ng/mL)/mg | Standard Deviation 9.87 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | 5-Formyl-THF | 0.343 (h*ng/mL)/mg | Standard Deviation 0.58 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | 5-Methyl-THF | 49.9 (h*ng/mL)/mg | Standard Deviation 7.91 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | MTHF | 32.9 (h*ng/mL)/mg | Standard Deviation 4.93 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: AUClast/Dose | THF | 95.0 (h*ng/mL)/mg | Standard Deviation 19.2 |
Secondary
Plasma PK Characteristics: C0
The mean back-extrapolated concentration at time 0 h (C0) was calculated for MTHF
Time frame: 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
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: C0 | 34200 ng/mL | Standard Deviation 10300 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: C0 | 78300 ng/mL | Standard Deviation 12600 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: C0 | 99000 ng/mL | Standard Deviation 23100 |
Secondary
Plasma PK Characteristics: C5min
Measured concentration at 5 min post dose (C5min) of MTHF and 5-Formyl-THF
Time frame: 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
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: C5min | MTHF | 24600 ng/mL | Standard Deviation 6480 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: C5min | 5-Formyl-THF | 443 ng/mL | Standard Deviation 432 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: C5min | MTHF | 52200 ng/mL | Standard Deviation 8530 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: C5min | 5-Formyl-THF | 609 ng/mL | Standard Deviation 240 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: C5min | MTHF | 70100 ng/mL | Standard Deviation 13100 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: C5min | 5-Formyl-THF | 374 ng/mL | Standard Deviation 83.2 |
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.
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | THF | 11.6 L/h | Standard Deviation 1.47 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | 5-Methyl-THF | 15.6 L/h | Standard Deviation 3.11 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | MTHF | 38.6 L/h | Standard Deviation 1.84 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | MTHF | 35.5 L/h | Standard Deviation 3.05 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | THF | 12.6 L/h | Standard Deviation 2.58 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | 5-Methyl-THF | 16.5 L/h | Standard Deviation 2.63 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | 5-Methyl-THF | 19.1 L/h | Standard Deviation 3.49 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | THF | 10.7 L/h | Standard Deviation 2.37 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: CL | MTHF | 30.6 L/h | Standard Deviation 5.14 |
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
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | 5-Methyl-THF | 2490 ng/mL | Standard Deviation 450 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | THF | 16400 ng/mL | Standard Deviation 3610 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | 5-Formyl-THF | 642 ng/mL | Standard Deviation 474 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | 5-Methyl-THF | 3950 ng/mL | Standard Deviation 755 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | THF | 29600 ng/mL | Standard Deviation 3970 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | 5-Formyl-THF | 619 ng/mL | Standard Deviation 257 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | THF | 44400 ng/mL | Standard Deviation 6090 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | 5-Formyl-THF | 386 ng/mL | Standard Deviation 75.3 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax | 5-Methyl-THF | 4740 ng/mL | Standard Deviation 484 |
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.
Time frame: 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
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax/Dose for Metabolite 5-Formyl-THF | 1.73 ng/mL/mg | Standard Deviation 1.33 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax/Dose for Metabolite 5-Formyl-THF | 0.934 ng/mL/mg | Standard Deviation 0.379 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Cmax/Dose for Metabolite 5-Formyl-THF | 0.407 ng/mL/mg | Standard Deviation 0.0826 |
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:
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | THF | 1.35 hour | Standard Deviation 0.211 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | MTHF | 0.989 hour | Standard Deviation 0.936 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | 5-Methyl-THF | 5.54 hour | Standard Deviation 0.714 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | THF | 1.51 hour | Standard Deviation 0.267 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | MTHF | 1.87 hour | Standard Deviation 0.634 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | 5-Methyl-THF | 5.66 hour | Standard Deviation 0.644 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | MTHF | 2.03 hour | Standard Deviation 0.78 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | 5-Methyl-THF | 5.84 hour | Standard Deviation 0.634 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: t1/2 | THF | 1.59 hour | Standard Deviation 0.37 |
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.
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification (LLOQ).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 5-Formyl-THF | 3.41 hour | Standard Deviation 2.94 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 5-Methyl-THF | 24.0 hour | Standard Deviation 0.0339 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | THF | 7.01 hour | Standard Deviation 1.52 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | MTHF | 4.38 hour | Standard Deviation 1.95 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | MTHF | 5.37 hour | Standard Deviation 1.3 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | THF | 8.01 hour | Standard Deviation 0.0178 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 5-Methyl-THF | 24.0 hour | Standard Deviation 0.098 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 5-Formyl-THF | 3.00 hour | Standard Deviation 2.92 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 5-Methyl-THF | 23.8 hour | Standard Deviation 0.135 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | MTHF | 6.75 hour | Standard Deviation 2.31 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | THF | 8.75 hour | Standard Deviation 2.12 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Timepoint for Last Measured Plasma Concentration (Tlast) | 5-Formyl-THF | 1.40 hour | Standard Deviation 2.67 |
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
Time frame: 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.
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | 5-Formyl-THF | 0.0778 hour | Standard Deviation 0.0255 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | 5-Methyl-THF | 3.12 hour | Standard Deviation 0.835 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | THF | 0.267 hour | Standard Deviation 0.334 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | 5-Formyl-THF | 0.102 hour | Standard Deviation 0.0601 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | THF | 0.123 hour | Standard Deviation 0.0786 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | 5-Methyl-THF | 3.50 hour | Standard Deviation 1.07 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | 5-Formyl-THF | 0.142 hour | Standard Deviation 0.145 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | 5-Methyl-THF | 3.63 hour | Standard Deviation 0.519 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Tmax | THF | 0.300 hour | Standard Deviation 0.179 |
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
Time frame: 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
Population: All samples analysed from the subjects given placebo were below Lower Limit of Quantification.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | THF | 21.8 litre | Standard Deviation 3.3 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | MTHF | 18.1 litre | Standard Deviation 9.38 |
| 200 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | 5-Methyl-THF | 138 litre | Standard Deviation 28.4 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | THF | 24.9 litre | Standard Deviation 4.17 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | MTHF | 20.4 litre | Standard Deviation 6.1 |
| 350 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | 5-Methyl-THF | 153 litre | Standard Deviation 27.4 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | MTHF | 18.5 litre | Standard Deviation 6.07 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | 5-Methyl-THF | 181 litre | Standard Deviation 27.9 |
| 500 mg/m2 of Modufolin® | Plasma PK Characteristics: Vss | THF | 21.6 litre | Standard Deviation 4.43 |
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.
Time frame: 5 minute post-dose time point
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| 200 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5-Formyl-THF | 296.43 msec / ng/mL |
| 200 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5-Methyl-THF | 218.18 msec / ng/mL |
| 200 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5,10-MTHF | 24111.78 msec / ng/mL |
| 200 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | THF | 15995.29 msec / ng/mL |
| 200 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | ΔΔQTcF | 4.15 msec / ng/mL |
| 350 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5-Methyl-THF | 544.01 msec / ng/mL |
| 350 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5,10-MTHF | 51566.94 msec / ng/mL |
| 350 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | THF | 29386.77 msec / ng/mL |
| 350 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5-Formyl-THF | 567.17 msec / ng/mL |
| 350 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | ΔΔQTcF | 13.25 msec / ng/mL |
| 500 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | ΔΔQTcF | 19.88 msec / ng/mL |
| 500 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5-Formyl-THF | 379.33 msec / ng/mL |
| 500 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5,10-MTHF | 69012.28 msec / ng/mL |
| 500 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | 5-Methyl-THF | 333.09 msec / ng/mL |
| 500 mg/m2 of Modufolin® | Relationship Between ΔΔQTc and Modufolin® (and Metabolites) Plasma Concentrations | THF | 44018.37 msec / ng/mL |
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.
Time frame: 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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 200 mg/m2 of Modufolin® | Safety Laboratory Measurements | 0 Clinically relevant changes |
| 350 mg/m2 of Modufolin® | Safety Laboratory Measurements | 0 Clinically relevant changes |
| 500 mg/m2 of Modufolin® | Safety Laboratory Measurements | 0 Clinically relevant changes |
| Placebo | Safety Laboratory Measurements | 0 Clinically relevant changes |
Secondary
Systolic Blood Pressure
Systolic and diastolic BP and pulse were measured in supine position after 10 min of rest.
Time frame: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (-00:15) | 111.38 mmHg | Standard Deviation 10.94 |
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (08:00) | 118.50 mmHg | Standard Deviation 9.06 |
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 2 | 117.75 mmHg | Standard Deviation 9.29 |
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Screening | 115.50 mmHg | Standard Deviation 7.6 |
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (03:00) | 108.88 mmHg | Standard Deviation 7.12 |
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (05:00) | 115.50 mmHg | Standard Deviation 5.61 |
| 200 mg/m2 of Modufolin® | Systolic Blood Pressure | Follow-up | 121.38 mmHg | Standard Deviation 8.93 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (08:00) | 113.88 mmHg | Standard Deviation 6.75 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Screening | 121.25 mmHg | Standard Deviation 7.07 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Follow-up | 115.63 mmHg | Standard Deviation 11.03 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (-00:15) | 109.38 mmHg | Standard Deviation 9.36 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (03:00) | 105.00 mmHg | Standard Deviation 6.89 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 2 | 114.13 mmHg | Standard Deviation 5.77 |
| 350 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (05:00) | 115.00 mmHg | Standard Deviation 8.5 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (08:00) | 115.63 mmHg | Standard Deviation 5.83 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Follow-up | 119.38 mmHg | Standard Deviation 10.21 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Screening | 116.63 mmHg | Standard Deviation 9.56 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 2 | 120.88 mmHg | Standard Deviation 8.46 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (-00:15) | 117.38 mmHg | Standard Deviation 8.11 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (03:00) | 112.50 mmHg | Standard Deviation 9.29 |
| 500 mg/m2 of Modufolin® | Systolic Blood Pressure | Visit 2 Day 1 (05:00) | 120.88 mmHg | Standard Deviation 7.94 |
| Placebo | Systolic Blood Pressure | Visit 2 Day 1 (03:00) | 111.22 mmHg | Standard Deviation 7.87 |
| Placebo | Systolic Blood Pressure | Visit 2 Day 1 (-00:15) | 123.67 mmHg | Standard Deviation 24.63 |
| Placebo | Systolic Blood Pressure | Screening | 125.56 mmHg | Standard Deviation 14.82 |
| Placebo | Systolic Blood Pressure | Visit 2 Day 1 (08:00) | 114.89 mmHg | Standard Deviation 10.61 |
| Placebo | Systolic Blood Pressure | Visit 2 Day 1 (05:00) | 113.00 mmHg | Standard Deviation 13.32 |
| Placebo | Systolic Blood Pressure | Visit 2 Day 2 | 119.00 mmHg | Standard Deviation 10.02 |
| Placebo | Systolic Blood Pressure | Follow-up | 122.11 mmHg | Standard Deviation 12.24 |
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Screening | 59.50 bpm | Standard Deviation 5.21 |
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 2 | 59.38 bpm | Standard Deviation 9.53 |
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (08:00) | 60.25 bpm | Standard Deviation 6.82 |
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (-00:15) | 55.25 bpm | Standard Deviation 5.44 |
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Follow-up | 66.25 bpm | Standard Deviation 9.04 |
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 03:00) | 56.25 bpm | Standard Deviation 5.5 |
| 200 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (05:00) | 65.38 bpm | Standard Deviation 4 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 2 | 57.63 bpm | Standard Deviation 8.91 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (05:00) | 65.25 bpm | Standard Deviation 9.66 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 03:00) | 53.13 bpm | Standard Deviation 11.01 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (08:00) | 59.00 bpm | Standard Deviation 5.83 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Follow-up | 67.88 bpm | Standard Deviation 12.91 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (-00:15) | 52.00 bpm | Standard Deviation 8.6 |
| 350 mg/m2 of Modufolin® | Vital Signs: Pulse | Screening | 66.50 bpm | Standard Deviation 9.38 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (05:00) | 66.00 bpm | Standard Deviation 11.6 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Screening | 62.00 bpm | Standard Deviation 11.24 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (-00:15) | 56.38 bpm | Standard Deviation 5.58 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 03:00) | 53.75 bpm | Standard Deviation 4.95 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 1 (08:00) | 56.75 bpm | Standard Deviation 7.21 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Visit 2 Day 2 | 61.75 bpm | Standard Deviation 13.48 |
| 500 mg/m2 of Modufolin® | Vital Signs: Pulse | Follow-up | 69.25 bpm | Standard Deviation 16.26 |
| Placebo | Vital Signs: Pulse | Visit 2 Day 1 03:00) | 50.33 bpm | Standard Deviation 6.6 |
| Placebo | Vital Signs: Pulse | Follow-up | 67.44 bpm | Standard Deviation 14.47 |
| Placebo | Vital Signs: Pulse | Visit 2 Day 2 | 61.22 bpm | Standard Deviation 11.31 |
| Placebo | Vital Signs: Pulse | Visit 2 Day 1 (-00:15) | 54.44 bpm | Standard Deviation 11.34 |
| Placebo | Vital Signs: Pulse | Screening | 63.22 bpm | Standard Deviation 12.88 |
| Placebo | Vital Signs: Pulse | Visit 2 Day 1 (08:00) | 55.67 bpm | Standard Deviation 7.23 |
| Placebo | Vital Signs: Pulse | Visit 2 Day 1 (05:00) | 61.44 bpm | Standard Deviation 8.92 |