Pilot/Ph I Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery
|Protein Losing Enteropathy||Drug: ODSH at 0.125 mg/kg/h Drug: ODSH at 0.375 mg/kg/h Drug: ODSH at 0.250 mg/kg/h||Phase 1|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|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"|
- Clinical improvement of PLE symptoms and signs. [ Time Frame: Day 4 after 96 hours of IV continuous infusion of ODSH ]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) [ Time Frame: Day 4 after 96 hours of ODSH IV continuous infusion ]Decrease of Fecal alpha 1 antitrypsin level at Day 4 compared to baseline.
- Serum albumin levels. [ Time Frame: Day 4 after 96 hours of continuous IV infusion of ODSH ]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 [ Time Frame: Day 1, 2, 3 and 4 ]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.
- PK: ODSH plasma blood levels at steady state [ Time Frame: Day 3 (during Day 3 of ODSH IV continuous infusion) ]Assess the plasma levels of ODSH at steady state
|Study Start Date:||July 2010|
|Study Completion Date:||February 2012|
|Primary Completion Date:||February 2012 (Final data collection date for primary outcome measure)|
Experimental: ODSH at 0.125 mg/kg/h
First cohort of 3 subjects to be administered the lowest dose of ODSH.
Drug: ODSH at 0.125 mg/kg/h
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.
Other Name: Cohort 1
Experimental: ODSH at 0.250 mg/kg/h
Second cohort of 3 subjects to receive the medium dose of ODSH
Drug: ODSH at 0.250 mg/kg/h
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.
Other Name: Cohort 2
Experimental: ODSH at 0.375 mg/kg/h
Third and last cohort of subject to receive the high dose of ODSH.
Drug: ODSH at 0.375 mg/kg/h
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.
Other Name: Cohort 3
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01161641
|United States, California|
|Children's Hospital Los Angeles ( Gastroenterology & Nutrition)|
|Los Angeles, California, United States, 20027-6016|
|United States, Massachusetts|
|Department of Cardiology, Children's Hospital Boston|
|Boston, Massachusetts, United States, 02115|
|United States, Michigan|
|Division of Pediatric Cardiology, University of Michigan Health System|
|Ann Arbor, Michigan, United States, 48109-5204|
|United States, South Dakota|
|Sanford Children's ( Sanford Research / USD)|
|Sioux Falls, South Dakota, United States, 57104-4707|
|Principal Investigator:||Mark Russell, MD||Division of Pediatric Cardiology, University of Michigan Health System|