SAFETY, TOLERANCE, AND CLINICAL EFFICACY OF RPR 109413 AND GAMIMUNE-N

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Purpose: This is a randomized, double-blind study comparing the safety, patient acceptability and efficacy of RPR 109413 to a licensed IVIG product, Gamimune-N. Background: Intravenous gammaglobulin (IVIG) preparations have been tested in the US since 1975; ten have been licensed since 1981, seven of which are currently available. The efficacy of IVIG in preventing infections in patients with primary disorders of humoral immunity is well accepted, though it has never been subjected to a controlled double-blind study. A study comparing IVIG to placebo would be considered unethical, though it is possible to compare new products to those that have been licensed for use. In the past several years efforts have focused on developing products with increased safety, especially with regard to the risk of transmitting viral infections such as Hepatitis C. This study proposes to compare the safety, efficacy, and patient acceptability of a new, heat-pasteurized IVIG preparation (RPR 109413) to a licensed preparation, Gamimune-N. RPR 109413 is a sterile, preservative-free, liquid preparation of unmodified human polyvalent immunoglobulins manufactured by Armour Division of Rhtne-Poulenc Rorer Pharmaceutical. It is prepared from ISG made from a pool of at least 1000 donors. Donors are tested for HIV, HBsAg, Hepatitis C antibody, and increased levels of ALT before being accepted into the pool. The ISG is prepared by the same Cohn fractionation process used for all of the currently licensed products. The Cohn fraction III supernatant is subjected to a viral inactivation step consisting of treatment at 60 C. This treatment was shown to inactivate several surrogate viruses. It is not practical to test inactivation of Hepatitis C directly since the only test system is non-human primates, but these other viruses have been shown to have similar sensitivity to viruses known to be human pathogens. The IgG is adsorbed to reduce the concentration of isoagglutinins, polyethylene glycol is added to precipitate complexes, and the solution is dialyzed to remove the PEG and reduce the sodium concentration. Five percent mannitol is added to enhance stability. The final preparation is at least 98% IgG with trace amounts of IgA and IgM. The amount of IgA is estimated to be < 5 5g/ml, which is comparable to the other low IgA preparation, Gammagard. Methods: This is a randomized, double-blind study comparing the safety, patient acceptability and efficacy of RPR 109413 to a licensed IVIG product, Gamimune-N. It is a multicenter phase II study intended to enroll approximately 80 patients. Each center will enroll up to 10 patients. All patients have well characterized disorders of humoral immunity and require gammaglobulin infusions for infection prophylaxis. All patients have received at least six infusions of IVIG and are known to tolerate the currently available preparations. IgA deficient patients who are at risk for making anti-IgA antibodies will be excluded. Patients will come to the research ward for a screening visit within one month of entering the study. If they meet the entry requirements they will be entered to receive six infusions at the dose and frequency given during the three months preceding the study. They will receive either RPR 109413 or Gamimune-N which will be put in IV bags by the pharmacy so that neither the patient nor the investigators will know which preparation is used. The IVIG will be infused at an initial rate of 0.01 cc/kg/min and the rate increased to 0.02 then 0.04 and finally a maximum of 0.06 cc/kg/min at 15 minute intervals unless adverse reactions occur. These rates are standard for the infusion of IVIG and below those commonly used for infusions of non-investigational IVIG.