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

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.

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