Fragmin for the Treatment of Acute VTE in Pediatric Cancer Patients

A THREE MONTH PROSPECTIVE OPEN LABEL STUDY OF THERAPY WITH FRAGMIN(REGISTERED) (DALTEPARIN SODIUM INJECTION) IN CHILDREN WITH VENOUS THROMBOEMBOLISM WITH OR WITHOUT MALIGNANCIES

Three month treatment of acute VTE with Fragmin in pediatric cancer patients

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: dalteparin

Detailed Description

Primary study objectives include are to determine the pharmacodynamic (PD) profiles for treatment doses of dalteparin in pediatric subjects of different ages with cancer and venous thromboembolism (VTE), using anti-Xa (Xa) levels and a population PD analysis methodology, and to determine the median dose required to achieve therapeutic anti- Xa levels (0.5 to 1.0 International Units [IU]/mL) based on subject age and weight.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0372
    • Sykehusapoteket Oslo
  • Oslo, Norway, 0424
    • Oslo universitetssykehus HF
• Russian Federation
  • Moscow, Russian Federation, 119049
    • SBHI of Moscow city Morozovskaya Children City Clinical Hospital of Moscow city
  • Republic Tatarstan
    • Kazan, Republic Tatarstan, Russian Federation, 420012
      • FSBEI HE Kazan SMU of Minzdrav Russia
    • Kazan, Republic Tatarstan, Russian Federation, 420138
      • SAHI "Children's Republican Clinical Hospital of the Ministry of
• Slovenia
  • Ljubljana, Slovenia, SI-1000
    • Lekarna, Univerzitetni klinicni center Ljubljana
  • Ljubljana, Slovenia, SI-1000
    • Pediatricna klinika, Univerzitetni Klinicni Center Ljubljana
• Spain
  • Madrid
    • Boadilla del Monte, Madrid, Spain, 28660
      • Hospital HM Universitario Monteprincipe Servicio de Farmacia
    • Boadilla del Monte, Madrid, Spain, 28660
      • Hospital HM Universitario Monteprincipe
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Jacksonville, Florida, United States, 32207
      • Wolfson Children's Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
    • Tampa, Florida, United States, 33606
      • University of South Florida
    • Tampa, Florida, United States, 33607
      • St. Joseph's Children's Hospital of Tampa
    • Tampa, Florida, United States, 33606
      • Investigational Drug Service Tampa General Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital Center of Research Excellence
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • El Paso, Texas, United States, 79905
      • El Paso Children's Hospital
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center El Paso
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer and Hematology Centers
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital Investigational Pharmacy Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

-

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: Single Arm; Single arm open-label	Drug: dalteparin; dalteparin subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Dose of Dalteparin Required to Achieve Prespecified Therapeutic Anti- Factor Xa Level	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.	4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Prespecified Therapeutic Anti- Factor Xa Levels	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.	Day 1 to 7 in dose adjustment phase
Number of Participants With New or Progressive Symptomatic Venous Thromboembolism (VTE)	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.	Baseline up to 28 days after the last dose of study drug (up to Day 132)
Time to First Occurrence of Symptomatic Recurrent Venous Thromboembolism (VTE)	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.	Baseline up to 28 days after the last dose of study drug (up to Day 132)
Percentage of Participants With Clinical Response of Progression, Regression, Resolution and No Change in Venous Thromboembolism (VTE)	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.	Baseline up to 28 days after the last dose of study drug (up to Day 132)
Percentage of Participants With Major and Minor 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 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).	Baseline up to 28 days after the last dose of study drug (up to Day 132)
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Baseline up to 28 days after the last dose of study drug (up to Day 132)
Number of Participants With Laboratory Abnormalities	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.	Baseline up to 104 days
Absolute Values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSBP) in Participants		Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Absolute Values of Heart Rate (HR) and Pulse Rate (PR) of Participants	Heart rate and pulse rate of participants were measured in terms of beats per minute.	Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Absolute Values of Height of Participants		Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Absolute Values of Weight of Participants		Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Absolute Values of Respiratory Rate of Participants	Respiratory rate was defined as the number of breaths per minute.	Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Absolute Values of Body Temperature of Participants		Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Absolute Values of Body Length of Participants		Baseline, Day 1, Day 2, Day 30, Day 60, Day 90
Number of Participants With Physical Examination Abnormalities of Participants	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.	Screening, Visit 2 (Baseline), Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 30), Visit 6 (Day 60), Visit 7 (Day 90)
Time to First Occurrence of Major Bleeding Event	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).	Baseline up to 28 days after the last dose of study drug (up to Day 132)
Percentage of Participants Who Remained Within Prespecified Therapeutic Anti-Factor Xa Levels at Day 30, 60 and 90 in Follow up Phase	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.	Day 30, Day 60, Day 90 in follow up phase
Percentage of Participants With Anti-Factor Xa Levels Outside the Prespecified Range at Day 30, 60 and 90 in Follow up Phase	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.	Day 30, Day 60, Day 90 in follow-up phase
Maintenance Dose of Dalteparin Required to Achieve Prespecified Therapeutic Anti- Factor Xa Levels	Prespecified therapeutic anti-factor Xa level was 0.5-1.0 IU/mL. Cumulative data for day 1 to 7 has been reported.	4 hours post-dose at each Day 1 to 7 in dose adjustment phase
Time to Achieve Prespecified Therapeutic Anti- Factor Xa Levels	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.	Day 1 to 7 in dose adjustment phase
Number of Dose Adjustments Required to Achieve Prespecified Therapeutic Anti-Xa Levels	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.	4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Body Clearance of Dalteparin	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.	4 hours post-dose at each Day 1 to 7 in dose adjustment phase
Volume of Distribution of Dalteparin	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.	4 hours post-dose at each Day 1 to 7 in dose adjustment phase
Absorption Rate Constant (Ka) of Dalteparin		4 hours post-dose at each Day 1 to 7 in dose adjustment phase

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Hartman LR, Nurmeev I, Svirin P, Wolter KD, Yan JL, Jani D, Goldenberg NA, Sherman N. A phase 2 pharmacodynamic dose-finding, safety, and efficacy study of dalteparin for pediatric venous thromboembolism treatment in children with and without cancer. Pediatr Blood Cancer. 2022 Aug;69(8):e29764. doi: 10.1002/pbc.29764. Epub 2022 Jun 9.
• Damle B, Jen F, Sherman N, Jani D, Sweeney K. Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism. J Clin Pharmacol. 2021 Feb;61(2):172-180. doi: 10.1002/jcph.1716. Epub 2020 Aug 21.

Helpful Links

• To obtain contact information for a study center near you, click here.
• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2009
• Primary Completion (ACTUAL): March 1, 2018
• Study Completion (ACTUAL): March 1, 2018

Study Registration Dates

• First Submitted: August 4, 2009
• First Submitted That Met QC Criteria: August 4, 2009
• First Posted (ESTIMATE): August 6, 2009

Study Record Updates

• Last Update Posted (ACTUAL): April 16, 2019
• Last Update Submitted That Met QC Criteria: March 19, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: VTE
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: FRAG-A001-201; A6301094 (OTHER: Alias Study Number); 2016-000394-21 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.