Protein Losing EnteropathyPhase 1NCT01161641
Pilot/Ph I Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery
A Phase 1 study testing ODSH at 0.125 mg/kg/h, ODSH at 0.375 mg/kg/h and ODSH at 0.250 mg/kg/h in people with Protein Losing Enteropathy, run by Jazz Pharmaceuticals at 4 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 years and older
- Conditions the study is for
- Protein Losing Enteropathy
- What is being tested?
- ODSH at 0.125 mg/kg/h, ODSH at 0.375 mg/kg/h and ODSH at 0.250 mg/kg/h
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 4 sitesUnited States
- Study dates
- Jul 2010to Feb 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
Division of Pediatric Cardiology, University of Michigan Health System
Ann Arbor, Michigan, 48109-5204
Department of Cardiology, Children's Hospital Boston
Boston, Massachusetts, 02115
Children's Hospital Los Angeles ( Gastroenterology & Nutrition)
Los Angeles, California, 20027-6016
Sanford Children's ( Sanford Research / USD)
Sioux Falls, South Dakota, 57104-4707
About this study
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"
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.
Read the 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.
- Conditions
- Protein Losing Enteropathy
- Being tested
- ODSH at 0.125 mg/kg/h, ODSH at 0.375 mg/kg/h, ODSH at 0.250 mg/kg/h
- Keywords
- Protein Losing Enteropathy
- Medical subject headings
- Protein-Losing Enteropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ODSH at 0.125 mg/kg/hDrug
Also called 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 1 of 0.125 mg/kg/h.
ODSH at 0.375 mg/kg/hDrug
Also called 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 3 of 0.375 mg/kg/h.
ODSH at 0.250 mg/kg/hDrug
Also called Cohort 2
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.
| Study group | Role | What they receive |
|---|---|---|
| ODSH at 0.125 mg/kg/h | Experimental | First cohort of 3 subjects to be administered the lowest dose of ODSH. Receives: Drug: ODSH at 0.125 mg/kg/h |
| ODSH at 0.250 mg/kg/h | Experimental | Second cohort of 3 subjects to receive the medium dose of ODSH Receives: Drug: ODSH at 0.250 mg/kg/h |
| ODSH at 0.375 mg/kg/h | Experimental | Third and last cohort of subject to receive the high dose of ODSH. Receives: Drug: ODSH at 0.375 mg/kg/h |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 1, 2, 3 and 4
Secondary outcomes (1)
PK: ODSH plasma blood levels at steady state
Assess the plasma levels of ODSH at steady state
Measured: Day 3 (during Day 3 of ODSH IV continuous infusion)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jul 2010 (estimated)
- Study startJul 2010
- Primary completionFeb 2012
- Study completionFeb 2012
Why it stopped: Extremely slow accural due to rarity of medical condition studied.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Protein Losing EnteropathyStudies of the same condition, open and under way.
- More trials run by Jazz PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jazz Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Mark Russell, MD, Principal investigator, Division of Pediatric Cardiology, University of Michigan Health System
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01161641
- Sponsor's protocol ID
- PGX-ODSH-2009-PLE
- Status last verified
- Aug 2015
- First submitted
- 9 Jul 2010
- Last updated
- 2 Dec 2021
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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"
- ClinicalTrials.gov ID
- NCT01161641
- Acronym / sponsor ID
- PGX-ODSH-2009-PLE
- Conditions
- Protein Losing Enteropathy
- Keywords
- Protein Losing Enteropathy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Extremely slow accural due to rarity of medical condition studied.
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Jazz PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Jul 2010
- Primary completion
- Feb 2012 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 13 Jul 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| ODSH at 0.125 mg/kg/h | Experimental | Drug: ODSH at 0.125 mg/kg/hFirst cohort of 3 subjects to be administered the lowest dose of ODSH. |
| ODSH at 0.250 mg/kg/h | Experimental | Drug: ODSH at 0.250 mg/kg/hSecond cohort of 3 subjects to receive the medium dose of ODSH |
| ODSH at 0.375 mg/kg/h | Experimental | Drug: ODSH at 0.375 mg/kg/hThird and last cohort of subject to receive the high dose of ODSH. |
Who may qualify
- Ages
- 6 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (8 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ODSH at 0.125 mg/kg/hAlso: Cohort 1ODSH 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. | Drug | ODSH at 0.125 mg/kg/h |
| ODSH at 0.375 mg/kg/hAlso: Cohort 3ODSH 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. | Drug | ODSH at 0.375 mg/kg/h |
| ODSH at 0.250 mg/kg/hAlso: Cohort 2ODSH 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. | Drug | ODSH at 0.250 mg/kg/h |
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.
1 secondary outcome
PK: ODSH plasma blood levels at steady state
Time frame: Day 3 (during Day 3 of ODSH IV continuous infusion)
Results and safety
The study was stopped early (reason given: Extremely slow accural due to rarity of medical condition studied.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark Russell, MD principal investigator
Division of Pediatric Cardiology, University of Michigan Health System
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing ODSH at 0.125 mg/kg/h, ODSH at 0.375 mg/kg/h and ODSH at 0.250 mg/kg/h in people with Protein Losing Enteropathy, run by Jazz Pharmaceuticals at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 2 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Extremely slow accural due to rarity of medical condition studied.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical improvement of PLE symptoms and signs. (time frame: Day 4 after 96 hours of IV continuous infusion of ODSH). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2021.