A Pilot Study of Hemin Therapy for Gastroparesis (Diabetes Mellitus)

Study Overview
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Brief Summary
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This study is designed to learn if hemin can increase the production of heme oxygenase 1 and improve gastric (stomach) emptying and symptoms in diabetic patients with slow gastric emptying (gastroparesis).

Detailed Description
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Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase 1 (HO1) leads to loss of interstitial cells of Cajal and delayed gastric emptying in diabetic non-obese diabetic mice. HO1 is an enzyme which protects cells from physical, chemical, and biologic stress. In mice with diabetes and slow gastric emptying, hemin increases HO-1 activity and improves gastric emptying. Hemin is produced from red blood cells and is approved by the Food and Drug Administration for treating acute porphyria, which is an inherited condition caused by an enzyme deficiency. Hemin is not approved by the Food and Drug Administration for treating gastroparesis. In this study subjects were randomized to intravenous hemin, prepared in albumin, or albumin alone. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 weeks. Assessments included blood tests for HO1 protein and enzyme activity levels, gastric emptying with 13^C-spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks.

Official Title
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A Pilot Study of Hemin Therapy for Gastroparesis

Conditions
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Gastroparesis, Diabetes Mellitus

Intervention / Treatment
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* Biological: Hemin
* Biological: Albumin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Where relevant (i.e., for ensuring safety), the inclusion and exclusion criteria are similar to those in a recently completed trial of hemin therapy for myelodysplastic syndrome at Rush University, Chicago (http://clinicaltrials.gov/ct2/show/NCT00467610). Upper gastrointestinal symptoms which satisfy criteria for postprandial distress syndrome or vomiting for the last 3 months with symptom onset at least 6 months prior to diagnosis At least moderately severe symptoms as manifest by a total symptom score of 2.5 or higher on the Gastroparesis Cardinal Symptom Index (GCSI)21 Delayed gastric emptying (i.e, < 40% emptying at 2 and/or < 90% emptying at 4 hours by scintigraphy) No structural cause for symptoms by endoscopy within the past 12 months Patient must have a platelet counts > 50,000/microliters and absolute neutrophil counts (ANC) >500/microliters. Patient must have adequate hepatic and renal functions, defined as serum bilirubin, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT) ≤ 2 times the upper limit of normal (ULN), and creatinine ≤ 1.5 times the ULN. Able to provide written informed consent before participating in the study If female: Either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or if of childbearing potential, must comply with an effective method of birth control acceptable to the investigator during the study (oral contraceptives, Depo-Provera, intra-uterine device or barrier methods) Patient is not breastfeeding. Patient of childbearing potential must have a negative urine or serum pregnancy test during the screening period. Exclusion Criteria: History of allergic reaction or significant sensitivity to Panhemantin ® Patients who have taken or used any investigational drug or device in the 30 days prior to screening Predominant symptoms of epigastric pain or rumination syndrome Structural cause for symptoms on recent endoscopy Patients with preexisting blood coagulation abnormalities Patients with previously documented renal impairment defined as above 150 mmol/L or 1.7 mg/dL serum creatinine Previous gastric or intestinal surgery - patients with enteral feeding tubes and/or venting/feeding gastrostomy will be eligible provided they can comply with study requirements. Tube feeding will be stopped 24 hours before the gastric emptying study Current use of narcotics, anticholinergic agents (e.g., hyoscyamine, belladonna), anticoagulants (e.g., warfarin) or erythromycin. Gastrointestinal prokinetic drugs (eg metoclopramide, or domperidone) may be continued at a stable dose throughout the study History of a pre-existing medical condition that, in the opinion of the investigator, will interfere with the participation in the study. History of venous thrombosis or hypercoagulable state Poor peripheral venous access, if central venous access is not available Uncontrolled active infection Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study. Known intolerance or allergy to eggs Screening weight greater than 130 kg

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hemin<br>Panhematin®, Ovation Pharmaceuticals, Deerfield, Illinois (IL). Hemin was diluted in 25% albumin to obtain a concentration of 2.4 mg/mL and administered at a dose of 1.25 mL/Kg and at a rate of 60 mL/hour. 10 iv infusions for 8 weeks | Biological: Hemin<br>* 10 iv infusions for 8 weeks<br>* Other names: Panhematin®, (Ovation Pharmaceuticals, Deerfield, IL);|
| Placebo Comparator: Albumin<br>10 iv infusions for 8 weeks | Biological: Albumin<br>* 10 iv infusions for 8 weeks<br>* Other names: Albumin (Human) 25% Solution manufactured by CSL Behring.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous Plasma Heme-oxygenase 1 (HO1) Protein Concentration | HO1 protein concentration levels in plasma were assessed with a HO1 (human) enzyme-linked immunosorbent assay (ELISA) kit. | baseline, day 3, day 7, day 56 | 
| Venous Monocyte HO1 Activity | HO1 activity in white blood cells was measured by an assay that measures bilirubin production as a marker of HO1 activity. | baseline, Day 3, Day 7, Day 56 | 
| Gastric Emptying Half-time | The time for half of the ingested solids or liquids to leave the stomach. Gastric emptying was assessed with ^13C Spirulina Breath Test. After an overnight fast, subjects consumed the test meal containing ^13C Spirulina. Breath samples were collected in duplicate glass tube using a straw to blow into the bottom of the tube to displace contained air. The ^13CO_2 content of the breath was determined by AB Diagnostics. The provide of ^13CO_2 excretion is used to estimate the half-time of gastric emptying. | baseline, day 3, day 7, day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastrointestinal Symptoms | Subjects recorded their GI symptoms every day in the validated Gastroparesis Cardinal Symptom Index (GCSI) - Daily Diary. For each subject, the daily GCSI data were averaged per week. Components coded 0 (no symptoms) to 5 (very severe). GCSI total score is the average of 9 components from the nausea/vomiting, fullness/early satiety, and bloating subscores. These individual subscores are averages of 3,4, and 2 components, respectively. Subscores for upper and lower abdominal pain, heartburn/regurgitation and FDA nausea, vomiting, fullness, and pain (NVFP) composite are averages of 2, 2, 7, and 4 components, respectively. | baseline, 8 weeks | 
| Autonomic Functions | Subjects completed a standardized autonomic symptom questionnaire, the Composite Autonomic Severity Score (CASS) which consists of 2 subscores: cardiovagal (CASS-vag; 0-3) and adrenergic (CASS-adr;0-3), where 0, 1, 2, 3 represent non, mild, moderate, and severe dysfunction, respectively. | baseline, Day 56 | 
| Serum Creatinine |  | baseline, Day 4, Day 7, Day 56 | 
| Prothrombin Time |  | baseline, Day 4, Day 7, Day 56 | 
| Activated Partial Thromboplastin Time (APTT) |  | baseline, Day 4, Day 7, Day 56 | 
| Hemoglobin | Measured by complete blood count | baseline, Day 4, Day 7, Day 56 | 
| Erythrocyte Count | Measured by complete blood count | baseline, Day 4, Day 7, Day 56 | 
| Leukocyte and Platelet Counts | Measured by complete blood count | baseline, Day 4, Day 7, Day 56 |