Clinical Trial: Pilot/Ph I Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

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 Ente

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 Summary:

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
Sponsor: Cantex Pharmaceuticals

Current Primary Outcome:

  • 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.


Original Primary Outcome:

  • 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 applied to study subjects to assess diarrhea and abdominal pain intensity. The sudy subject and the investigator will assess Global Impression of Improvement and the investigator will assess peripheral edema and ascitis.
  • Fecal apha 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.
  • Albumin plasma levels. [ Time Frame: Day 4 after 96 hours of continuous IV infusion of ODSH ]
    Plasma levels of albumin at Day 4 compared to Baseline. A plasma 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.


Current Secondary Outcome: 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


Original Secondary Outcome: Same as current

Information By: Cantex Pharmaceuticals

Dates:
Date Received: July 9, 2010
Date Started: July 2010
Date Completion:
Last Updated: August 5, 2015
Last Verified: August 2015