Fragmin for the Treatment of Acute VTE in Pediatric Cancer Patients

Prespecified therapeutic anti-factor Xa level was 0.5-1.0 international unit per milliliter (IU/mL). Cumulative data of Day 1 to 7 has been reported.

Time frame: 4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Population: The pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Heart rate and pulse rate of participants were measured in terms of beats per minute.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Respiratory rate was defined as the number of breaths per minute.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Time frame: Baseline, Day 1, Day 2, Day 30, Day 60, Day 90

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

Prespecified therapeutic anti-factor Xa level was 0.5-1.0 IU/mL. Cumulative data for day 1 to 7 has been reported.

Time frame: 4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Population: PD analysis set. Here, number analyzed signifies the number of participants analyzed at specific time points. Data for this OM was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

During dose adjustment phase, doses were adjusted according to prespecified therapeutic anti-Xa levels in order to achieve target prespecified therapeutic anti-factor Xa levels (0.5 to 1.0 IU/mL). Number of dose adjustments which were done within the specified time window of up to 4 hours post dose on all days (1 to 7) to achieve the prespecified therapeutic anti-Xa levels are reported.

Time frame: 4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Population: PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase. Data for this OM was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

Criteria:hematology:hemoglobin, hematocrit, erythrocytes less than(\<)0.8\*lower limit of normal(LLN), platelets \<0.5\*LLN \>1.75\*upper limit of normal (ULN),leukocytes \<0.6\* LLN \>1.5\* ULN, lymphocytes, lymphocytes/Leukocytes, neutrophils, neutrophils/leukocytes \<0.8\* LLN \>1.2\* ULN, basophils, basophils/leukocytes, eosinophils, eosinophils/leukocytes monocytes monocytes/leukocytes \>1.2\*ULN, activated partial thromboplastin time, prothrombin time, prothrombin international normalized ratio \>1.1\* ULN. Clinical chemistry: bilirubin \>1.5\*ULN, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase \>3.0\*ULN, protein, albumin \<0.8\* LLN \>1.2\* ULN, blood urea nitrogen, creatinine \>1.3\* ULN, sodium \<0.95\*LLN \>1.05\*ULN, potassium, chloride, calcium, magnesium \<0.9\* LLN \>1.1\* ULN, phosphate \<0.8\* LLN \>1.2\* ULN, glucose \<0.6\*LLN \>1.5\*ULN, estimated(est) creatinine clearance, est GFR modified and bedside schwartz, \>1.0\* ULN. Urinalysis: creatinine \>1.0\*ULN.

Time frame: Baseline up to 104 days

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here, Overall Number of Participants Analyzed signifies participants who were evaluable for this outcome measure.

Symptomatic VTE defined as new or progressive signs and symptoms as judged by the investigator including but not limited to: objective swelling, pain or tenderness, pitting edema, erythema or cyanosis. Progression of VTE: Progression of clot burden in terms of severity of occlusion, or involvement of new venous segments at any time after the initial diagnosis.

Time frame: Baseline up to 28 days after the last dose of study drug (up to Day 132)

Population: The PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase. Data for this outcome measure (OM) was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

Physical examinations included head, eyes, ears, nose, throat, neck, heart, chest, lungs, abdomen, extremities, skin, neurological status and general appearance. Abnormality in physical examination was based on investigator's discretion. Only those categories in which at least 1 participant had abnormality were reported.

Time frame: Screening, Visit 2 (Baseline), Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 30), Visit 6 (Day 60), Visit 7 (Day 90)

Population: The safety analysis set included all the participants who received at least 1 dose of study drug. Here number analyzed signifies the number of participants evaluable at specific time points.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after the last dose of study drug (up to Day 132) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs.

Time frame: Baseline up to 28 days after the last dose of study drug (up to Day 132)

Population: The safety analysis set included all the participants who received at least 1 dose of study drug.

Prespecified therapeutic anti-factor Xa level was 0.5-1.0 IU/mL. Percentage of participants who achieved the prespecified level during the dose adjustment phase were reported in this outcome measure.

Time frame: Day 1 to 7 in dose adjustment phase

Population: Analysis population included all the participants who received at least 1 dose of study drug.

Prespecified therapeutic anti-factor Xa level was 0.5-1.0 IU/mL. The percentage of participants who had anti factor-Xa levels within the prespecified therapeutic range at Day 30, 60 and 90 during the follow up phase were reported in this outcome measure.

Time frame: Day 30, Day 60, Day 90 in follow up phase

Population: PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase. Here, number analyzed signifies number of participants analyzed at specific time points. Data for this OM was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

Prespecified therapeutic anti-factor Xa range was 0.5-1.0 IU/mL. The percentage of participants who had anti-factor Xa levels outside the prespecified therapeutic range at Day 30, 60 and 90 during the follow up phase were reported in this outcome measure.

Time frame: Day 30, Day 60, Day 90 in follow-up phase

Population: PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase. Here, number analyzed signifies number of participants analyzed at specific time points. Data for this OM was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

VTEs included both DVT and PE. DVT is a blood clot in the deep veins of the leg. PE is a blood clot in the lungs. Clinical response of progression was defined as progression of clot burden in terms of severity of occlusion, or involvement of new venous segments at any time after the initial diagnosis. Clinical response of regression: Regressed clot burden utilizing the same imaging modality as the screening visit. Clinical response of resolution: Thrombus resolution of the qualifying event measured by repeat imaging at the end of study (EOS) visit.

Time frame: Baseline up to 28 days after the last dose of study drug (up to Day 132)

Population: The PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase. Data for this OM was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

A bleeding event was considered as major if it was clinically overt and satisfies 1 or more of the following criteria: fatal bleeding, bleeding accompanied by a decrease in hemoglobin of at least 2 grams per deciliter 24 hours, Overt bleeding deemed by the attending physician to necessitate permanent discontinuation of trial medication, Overt bleeding deemed by the attending physician to be unrelated to the participant's underlying condition and accompanied by blood product administration or bleeding occurred at a critical site (intraocular, intracranial, retroperitoneal). A bleeding event was considered as minor if it was clinically overt but not meeting the criteria for major or clinically relevant no major bleeding (bleeding resulting in any medical or surgical interventions but which did not meet the criteria for major bleeding).

Time frame: Baseline up to 28 days after the last dose of study drug (up to Day 132)

Population: The safety analysis set included all the participants who received at least 1 dose of study drug.

Time to achieve the target range (prespecified therapeutic anti- factor Xa levels) was defined as the number of days from the first dose of study drug to the final dose that achieves the target anti-factor Xa level. Prespecified therapeutic anti-factor Xa level was 0.5-1.0 IU/mL. Cumulative data of Day 1 to 7 is reported.

Time frame: Day 1 to 7 in dose adjustment phase

Population: PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase. Data for this OM was not planned to be collected and analyzed for age group of \>=0 to \<8 weeks.

Time to first occurrence of major bleeding event was defined as the time interval (in days) between date of first study treatment and date of documentation of first major bleeding event. A bleeding event was considered as major if it was clinically overt and satisfies 1 or more of the following criteria: fatal bleeding, bleeding accompanied by a decrease in hemoglobin of at least 2 grams per deciliter, overt bleeding deemed by the attending physician to necessitate permanent discontinuation of trial medication, overt bleeding deemed by the attending physician to be unrelated to the participant's underlying condition and accompanied by blood product administration, bleeding occurred at a critical site (intraocular, intracranial, retroperitoneal or intraspinal).

Time frame: Baseline up to 28 days after the last dose of study drug (up to Day 132)

Population: The safety analysis set included all the participants who received at least 1 dose of study drug.

It was defined as the time interval (in days) between date of first study treatment and date of documentation of first VTE. VTEs included both DVT and PE. DVT is a blood clot in the deep veins of the leg. If a DVT clot breaks off from a vein wall and flows towards the lungs and blocks some or all of the blood supply, it becomes PE. When a blood clot breaks, loose and travels in the blood, this is called VTE. VTE was confirmed by at least one radiographic test and was defined as any new or progressive VTE whose signs and symptoms (identified by the investigator) included: objective swelling or tenderness, pitting edema, erythema or cyanosis.

Time frame: Baseline up to 28 days after the last dose of study drug (up to Day 132)

Population: The PD analysis set included all participants who received at least 1 dose of study drug and achieved therapeutic range of anti-factor Xa during dose adjustment phase.

Time frame: 4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Population: Data not reported for the endpoint, since the PK data was collected and analyzed in a pooled analysis, together with data from two external studies; the results of this pooled analysis will be reported separately.

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). Clearance obtained after intravenous infusion dose (apparent clearance) is influenced by the fraction of the dose absorbed.

Time frame: 4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Population: Data not reported for the endpoint, since the PK data was collected and analyzed in a pooled analysis, together with data from two external studies; the results of this pooled analysis will be reported separately.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.

Time frame: 4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Population: Data not reported for the endpoint, since the PK data was collected and analyzed in a pooled analysis, together with data from two external studies; the results of this pooled analysis will be reported separately.