Phase I Study of Alpha-Melanocyte Stimulating Hormone in Patients With Acute Renal Failure

PROTOCOL OUTLINE: This is a dose escalation, double blind, placebo controlled, multicenter
study.

Group 1: Patients are infused with alpha-melanocyte stimulating hormone (alpha-MSH) or
placebo over 5 minutes. A cohort of 5 patients is infused at each dose level of alpha-MSH
until the minimum effective dose (MED) and the maximum tolerated dose (MTD) are determined.

Group 2: Patients receive a single dose of the MED of alpha-MSH IV over 5 minutes at the
time anastomoses are complete. Other patients receive alpha-MSH at the MTD. Cohorts of 5
patients each are treated at the MED and the MTD.

Group 3: Patients receive alpha-MSH as in group 2. Additional dose levels are also tested.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Group 1: Patients on chronic hemodialysis

Group 2: Patients at high risk of developing acute renal failure (ARF) after cadaveric
renal transplantation Received high risk allograft Cadaveric kidneys with greater than 24
hours of cold ischemia time Donor had rising creatinine before organ procurement Donor
over 60 years

Group 3: Patients with ischemic ARF due to hypotension, surgery, or trauma ARF severity
index 20-60% Creatinine clearance 12-14 mL/min Rising creatinine of at least 0.5 mg/dL per
day for 2 days without evidence of recovery despite standard supportive care No drug or
contrast induced renal failure No oliguric renal failure (creatinine clearance 3-4 mL/min)
No prior chronic renal failure Baseline creatinine greater than 2.5 mg/dL (males) or 2.0
mg/dL (females) No ARF due to bacterial or fungal sepsis, nephrotoxins, acute
tubulointerstitial nephritis, cyclosporine toxicity, bilateral renal vascular disease, or
systemic diseases (hepatorenal syndrome, glomerulonephritis, renal vasculitis, etc.)

--Prior/Concurrent Therapy--

Group 1: No recent immunosuppressive therapy Group 2 and 3: No prior renal
transplantation No prior alpha-MSH Group 3: No prior dialysis for this episode of ARF No
anticipated need for dialysis for at least 24 hours At least 12 hours since prior
diuretics, mannitol, or dopamine At least 14 days since prior immunosuppressive drugs

--Patient Characteristics--

No recent infection No known reaction to Terumo T175 dialyzer Not a prisoner Not pregnant
or nursing No allergy to drugs used in study Not mentally impaired Group 3: No severe
nonrenal medical condition that would interfere with the study (e.g., terminal cancer)