Back to resultsPilot/Ph I Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery
Primary Purpose
Protein Losing Enteropathy
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ODSH at 0.125 mg/kg/h
ODSH at 0.375 mg/kg/h
ODSH at 0.250 mg/kg/h
Sponsored by
About this trial
This is an interventional treatment trial for Protein Losing Enteropathy focused on measuring Protein Losing Enteropathy
Eligibility Criteria
Inclusion Criteria:
- Male or female ≥ 6 years old.
- History of single ventricle palliative surgery.
Anticipated need for four or more days of hospitalization, in the investigator's judgment, for the treatment of exacerbation of PLE.
Clinically significant PLE is defined as the presence of clinically significant symptoms (including, but not limited to, diarrhea, abdominal pain, peripheral edema and/or ascites), AND increased fecal alpha 1-antitrypsin (FA1AT; > 200 mg/dl) OR hypoalbuminemia of < 3 gr/dL; requiring supplemental albumin infusions.
- Prothrombin time (PT) and activated partial thromboplastin time (aPTT) not higher than 1.25 times the ULN for age.
- Platelet count of > 80,000 per mm3, hemoglobin of > 9.5 g/dL.
- The adult subject or the underage subject/legal guardian is willing to provide informed consent and to comply with the study procedures.
- Female subject of childbearing potential who is not pregnant, and is not lactating and is not planning to become pregnant during the study and will use medically acceptable contraception method for the duration of the study.
Exclusion Criteria:
- Has congenital or acquired hematologic disease or coagulation disorder.
- Has other type of PLE not associated with single ventricle palliative surgery e.g. subjects with congenital defects of glycation or with Crohn's disease; congenital trypsinogen or enterokinase deficiency;
- Has a clinical need for prophylactic or therapeutic treatment with oral or parenteral anticoagulant medications within 72 hours from the start of ODSH treatment or during the study. [The use of antithrombotic agents such as acetyl salicylic acid for cardiovascular prophylaxis or clopidogrel (or similar drug class agents) is permitted].
- Has documented liver failure or a serum ALT or AST greater than 1.5 times the upper limit of normal, or total bilirubin greater than 1.5 the upper limit of normal;
- Has clinically significant proteinuria or severe renal failure based on a creatinine clearance < 30 mL/min calculated from plasma creatinine (Appendix B) with the Cockcroft-Gault formula for adults or with any of the recommended formulas for subjects 6 to 18 years old;
- Has active gastrointestinal ulcer disease or evidence of gastrointestinal bleeding or urinary tract bleeding or any other source of bleeding within 60 days of the Screening visit.
- History of HIV, hepatitis B or hepatitis C; and
- Major surgery, stroke or myocardial infarction within the past 60 days from screening. Subjects with recent minor surgery can be enrolled in the study.
Sites / Locations
- Children's Hospital Los Angeles ( Gastroenterology & Nutrition)
- Department of Cardiology, Children's Hospital Boston
- Division of Pediatric Cardiology, University of Michigan Health System
- Sanford Children's ( Sanford Research / USD)
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
ODSH at 0.125 mg/kg/h
ODSH at 0.250 mg/kg/h
ODSH at 0.375 mg/kg/h
Arm Description
First cohort of 3 subjects to be administered the lowest dose of ODSH.
Second cohort of 3 subjects to receive the medium dose of ODSH
Third and last cohort of subject to receive the high dose of ODSH.
Outcomes
Primary Outcome Measures
Clinical improvement of PLE symptoms and signs.
Clinical Improvement of signs & symptoms of PLE such as diarrhea, abdominal pain, peripheral edema, and ascites. Visual/categorical scales will be used by the study subjects and the investigators to assess diarrhea/abdominal pain intensity as well as The Global Impression of Improvement. The investigator will assess peripheral edema and ascites.
Fecal alpha 1 antitrypsin (FA1AT)
Decrease of Fecal alpha 1 antitrypsin level at Day 4 compared to baseline.
Serum albumin levels.
Serum albumin levels at Day 4 compared to Baseline. A serum albumin level of 3 or more mg/dL or at least an increase of 25% from baseline at Day 4 or the reduction in the need for additional albumin infusions will be considered as clinically significant.
ODSH safety
aPTT as a measure of coagulation effect from ODSH will be measured every day. If the aPTT value is 8 or more seconds higher than the upper limit of normal value of aPTT for the study site then the ODSH infusion rate will be decreased as recommended in the protocol. Coagulation and bleeding abnormalities will be monitored closely by the investigator. Liver enzymes will also be monitored during the study.
Secondary Outcome Measures
PK: ODSH plasma blood levels at steady state
Assess the plasma levels of ODSH at steady state
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01161641
Brief Title
Pilot/Ph I Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery
Official Title
" An Open Label Pilot Study Evaluating Safety and Evidence of Therapeutic Effect of IV Admin of 2-0, 3-0 Desulfated Heparin, Treatment of Exacerbation of Protein Losing Enteropathy (PLE) Associated With Single Ventricle Palliative Surgery"
Study Type
Interventional
2. Study Status
Record Verification Date
August 2015
Overall Recruitment Status
Terminated
Why Stopped
Extremely slow accural due to rarity of medical condition studied.
Study Start Date
July 2010 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Chimerix
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Protein Losing Enteropathy (PLE) is a serious medical condition that may develop in children and adults with congenital heart disease for which a palliative procedure known as the "Fontan procedure" has been performed. The loss of serum proteins into the gastrointestinal tract that is associated with PLE can cause serious symptoms and life-threatening complications. A number of clinical studies have suggested that heparin administration can have clinical benefit in children with PLE, however the risk of bleeding associated with the administration of heparin is an important concern and commonly limits its administration. ODSH is a desulfated heparin with minimal anticoagulation properties but which, in pre-clinical studies, appears to have the potential to replace heparin and greatly reduce the risk of bleeding. This open label study is to assess the safety and evidence of therapeutic effect of the administration of ODSH as a 4-day continuous intravenous infusion in patients with an exacerbation of their PLE.
Detailed Description
Protein Losing Enteropathy (PLE)is a serious and sometimes fatal condition that develops in approximately 10% of children who have undergone the single ventricle palliative surgery known as the Fontan procedure. The mechanisms by which PLE develops are not fully understood, however a recent mechanism has been proposed consistent with the specific loss of heparan sulfate proteoglycans from the basolateral surface of the intestinal epithelial cells resulting in the loss of serum protein including albumin and immunoglobulins into the gastrointestinal tract that is associated with protein losing enteropathy. A number of clinical studies have suggested that heparin administration can have clinical benefit in children with PLE, however the risk of bleeding as a consequence of treatment is an important concern and commonly limits its administration. ODSH (2-0, 3-0 desulfated heparin) is a modified heparin that preserves the anti-inflammatory properties of heparin with minimal or no anticoagulation effects. ODSH has been studied in the rodent model of PLE an has shown improvement of PLE in this model due to restoration of heparan sulfate and Syndecan 1 with stabilization of the cell matrix of the capillary endothelium.
This open label clinical study will enroll 9 subjects with a dose escalation (3 doses) study design. Three subjects will be treated with the lower dose of ODSH then an ad hoc safety committee will assess the safety information to make a recommendation regarding advancing to the next higher dose of ODSH until, if appropriate, the 3 dose cohorts have been completed. Plasma albumin and fecal alpha 1 antitrypsin which are both biological markers of protein loss through the intestinal lumen in this condition, are the primary variables that will be evaluated as evidence of a therapeutic effect together with the improvement of PLE signs and symptoms. The effect of ODSH on the associated diarrhea, abdominal pain, and peripheral edema or ascites will be evaluated using visual/categorical scales for the patients to assess symptoms and clinical evaluation by the investigator.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Protein Losing Enteropathy
Keywords
Protein Losing Enteropathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
5 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ODSH at 0.125 mg/kg/h
Arm Type
Experimental
Arm Description
First cohort of 3 subjects to be administered the lowest dose of ODSH.
Arm Title
ODSH at 0.250 mg/kg/h
Arm Type
Experimental
Arm Description
Second cohort of 3 subjects to receive the medium dose of ODSH
Arm Title
ODSH at 0.375 mg/kg/h
Arm Type
Experimental
Arm Description
Third and last cohort of subject to receive the high dose of ODSH.
Intervention Type
Drug
Intervention Name(s)
ODSH at 0.125 mg/kg/h
Other Intervention Name(s)
Cohort 1
Intervention Description
ODSH 1000 mg vials containing 20 cc of normal saline (50 mg/ml) to be prepared for 96-h IV infusion with normal saline based on subject's weight and dose assigned by Study Cohort 1 of 0.125 mg/kg/h.
Intervention Type
Drug
Intervention Name(s)
ODSH at 0.375 mg/kg/h
Other Intervention Name(s)
Cohort 3
Intervention Description
ODSH 1000 mg vials containing 20 cc of normal saline (50 mg/ml) to be prepared for 96-h IV infusion with normal saline based on subject's weight and dose assigned by Study Cohort 3 of 0.375 mg/kg/h.
Intervention Type
Drug
Intervention Name(s)
ODSH at 0.250 mg/kg/h
Other Intervention Name(s)
Cohort 2
Intervention Description
ODSH 1000 mg vials containing 20 cc of normal saline (50 mg/ml) to be prepared for 96-h IV infusion with normal saline based on subject's weight and dose assigned by Study Cohort 2 of 0.250 mg/kg/h.
Primary Outcome Measure Information:
Title
Clinical improvement of PLE symptoms and signs.
Description
Clinical Improvement of signs & symptoms of PLE such as diarrhea, abdominal pain, peripheral edema, and ascites. Visual/categorical scales will be used by the study subjects and the investigators to assess diarrhea/abdominal pain intensity as well as The Global Impression of Improvement. The investigator will assess peripheral edema and ascites.
Time Frame
Day 4 after 96 hours of IV continuous infusion of ODSH
Title
Fecal alpha 1 antitrypsin (FA1AT)
Description
Decrease of Fecal alpha 1 antitrypsin level at Day 4 compared to baseline.
Time Frame
Day 4 after 96 hours of ODSH IV continuous infusion
Title
Serum albumin levels.
Description
Serum albumin levels at Day 4 compared to Baseline. A serum albumin level of 3 or more mg/dL or at least an increase of 25% from baseline at Day 4 or the reduction in the need for additional albumin infusions will be considered as clinically significant.
Time Frame
Day 4 after 96 hours of continuous IV infusion of ODSH
Title
ODSH safety
Description
aPTT as a measure of coagulation effect from ODSH will be measured every day. If the aPTT value is 8 or more seconds higher than the upper limit of normal value of aPTT for the study site then the ODSH infusion rate will be decreased as recommended in the protocol. Coagulation and bleeding abnormalities will be monitored closely by the investigator. Liver enzymes will also be monitored during the study.
Time Frame
Day 1, 2, 3 and 4
Secondary Outcome Measure Information:
Title
PK: ODSH plasma blood levels at steady state
Description
Assess the plasma levels of ODSH at steady state
Time Frame
Day 3 (during Day 3 of ODSH IV continuous infusion)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female ≥ 6 years old.
History of single ventricle palliative surgery.
Anticipated need for four or more days of hospitalization, in the investigator's judgment, for the treatment of exacerbation of PLE.
Clinically significant PLE is defined as the presence of clinically significant symptoms (including, but not limited to, diarrhea, abdominal pain, peripheral edema and/or ascites), AND increased fecal alpha 1-antitrypsin (FA1AT; > 200 mg/dl) OR hypoalbuminemia of < 3 gr/dL; requiring supplemental albumin infusions.
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) not higher than 1.25 times the ULN for age.
Platelet count of > 80,000 per mm3, hemoglobin of > 9.5 g/dL.
The adult subject or the underage subject/legal guardian is willing to provide informed consent and to comply with the study procedures.
Female subject of childbearing potential who is not pregnant, and is not lactating and is not planning to become pregnant during the study and will use medically acceptable contraception method for the duration of the study.
Exclusion Criteria:
Has congenital or acquired hematologic disease or coagulation disorder.
Has other type of PLE not associated with single ventricle palliative surgery e.g. subjects with congenital defects of glycation or with Crohn's disease; congenital trypsinogen or enterokinase deficiency;
Has a clinical need for prophylactic or therapeutic treatment with oral or parenteral anticoagulant medications within 72 hours from the start of ODSH treatment or during the study. [The use of antithrombotic agents such as acetyl salicylic acid for cardiovascular prophylaxis or clopidogrel (or similar drug class agents) is permitted].
Has documented liver failure or a serum ALT or AST greater than 1.5 times the upper limit of normal, or total bilirubin greater than 1.5 the upper limit of normal;
Has clinically significant proteinuria or severe renal failure based on a creatinine clearance < 30 mL/min calculated from plasma creatinine (Appendix B) with the Cockcroft-Gault formula for adults or with any of the recommended formulas for subjects 6 to 18 years old;
Has active gastrointestinal ulcer disease or evidence of gastrointestinal bleeding or urinary tract bleeding or any other source of bleeding within 60 days of the Screening visit.
History of HIV, hepatitis B or hepatitis C; and
Major surgery, stroke or myocardial infarction within the past 60 days from screening. Subjects with recent minor surgery can be enrolled in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Russell, MD
Organizational Affiliation
Division of Pediatric Cardiology, University of Michigan Health System
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Los Angeles ( Gastroenterology & Nutrition)
City
Los Angeles
State/Province
California
ZIP/Postal Code
20027-6016
Country
United States
Facility Name
Department of Cardiology, Children's Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Division of Pediatric Cardiology, University of Michigan Health System
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-5204
Country
United States
Facility Name
Sanford Children's ( Sanford Research / USD)
City
Sioux Falls
State/Province
South Dakota
ZIP/Postal Code
57104-4707
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Pilot/Ph I Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery
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