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

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.

Inclusion Criteria:

1. Male or female ≥ 6 years old.

2. History of single ventricle palliative surgery.

3. 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.

4. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) not higher
than 1.25 times the ULN for age.

5. Platelet count of > 80,000 per mm3, hemoglobin of > 9.5 g/dL.

6. The adult subject or the underage subject/legal guardian is willing to provide
informed consent and to comply with the study procedures.

7. 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:

1. Has congenital or acquired hematologic disease or coagulation disorder.

2. 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;

3. 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].

4. 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;

5. 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;

6. 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.

7. History of HIV, hepatitis B or hepatitis C; and

8. Major surgery, stroke or myocardial infarction within the past 60 days from
screening. Subjects with recent minor surgery can be enrolled in the study.