A Phase 1 interventional study of ODSH at 0.125 mg/kg/h and ODSH at 0.375 mg/kg/h in Protein Losing Enteropathy, sponsored by Chimerix. Terminated at 4 sites in United States. Open to participants aged 6 Years and older. Per ClinicalTrials.gov, last updated 2021-12-02.
Sponsored by Chimerix · Phase 1, Interventional, and Treatment
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.
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.
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This study's enrollment of 5 is below the median of 70 across 552 interventional studies indexed under Intestinal Diseases.
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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.
Exclusion Criteria:
First cohort of 3 subjects to be administered the lowest dose of ODSH.
Drug: ODSH at 0.125 mg/kg/h
Second cohort of 3 subjects to receive the medium dose of ODSH
Drug: ODSH at 0.250 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 1 of 0.125 mg/kg/h.
Also known as: Cohort 1
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.
Also known as: Cohort 3
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.
Also known as: Cohort 2
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.
Time frame: Day 4 after 96 hours of IV continuous infusion of ODSH
Fecal alpha 1 antitrypsin (FA1AT)
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
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.
Time frame: Day 4 after 96 hours of continuous IV infusion of ODSH
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.
Time frame: Day 1, 2, 3 and 4
PK: ODSH plasma blood levels at steady state
Assess the plasma levels of ODSH at steady state
Time frame: Day 3 (during Day 3 of ODSH IV continuous infusion)
This study is terminated, as verified in Aug 2015. You cannot join it, but the record below documents what was studied.
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