Treatment of Patients with Severe Congenital Protein C Deficiency in a Registry Study of Protein C Concentrate (Human)
Authors: Manco-Johnson Marilyn , Hertfelder Hans-Joerg , Kalfa Theodosia A. , Broxson Emmett H. , Bomgaars Lisa , Shapiro Amy D. , Jacqueline Dyck-Jones , Ehrle Sandra , Finnerty Maureen , Gelmont David , Yel Leman , Loghman-Adham Mahmoud 
Published: October 2019

Abstract
The objective of this non-interventional, international registry was to collect and assess safety and outcomes of all treatment with protein C concentrate for patients with protein C deficiency in Europe and the United States. Here we report the results from 25 patients with severe congenital protein C deficiency (SCPCD).
Any patient who received treatment with protein C concentrate was eligible for the study; there were no exclusion criteria. There were no predefined visits, laboratory tests and/or procedures, or interventions at enrollment or during the study. Management of patients was at the discretion of the investigator. Clinical data collected during the treatment course of these patients are reported here.
Twenty-five patients with congenital protein C deficiency from 10 US study sites and 10 study sites in the EU were enrolled into the study. The median age at study entry was 11.12 years (range: 1.3- 43.7 years). No patient was <1 month old, 2 (8.0%) patients were 1 month to <2 years old, 12 (48.0%) patients were 2 to <12 years old, 3 (12%) patients were 12 to <18 and 8 (32%) patients were ≥18 years old. The median duration of study participation was 39.7 months (range: 0.9 to 59.9 months). Thirteen (52%) patients were male and 12 (48%) were female.
The initial clinical presentation that led to the diagnosis of SCPCD occurred prior to enrollment into the study (years in some cases). The initial presentations included primarily thromboembolic events (18 [52.9%]) or purpura fulminans (16 [47.1%]).
During the study there were 259 treatment regimens with protein C concentrate, including 113 (43.6%) for acute episodes, 29 (11.2%) for short term replacement for surgical procedures, and 117 (45.2%) for long term prophylaxis. There were large variations in protein C treatments prescribed. The most common dose and frequency in patients treated for acute episodes was 60 IU/kg administered once a day.
Protein C concentrate was administered at enrollment either intravenously or subcutaneously (SQ). During the study, 217/259 (83.8%) treatment regimens of protein C concentrate were administered intravenously and 42 (16.2%) were administered SQ. Nine patients received SQ infusions prophylactically and three of these 9 patients also used SQ infusions for treatment of an acute episode.
Of 25 acute episodes in 7 patients treated with protein C concentrate, 22 (88.0%) resulted in recovery, 2 (8.0%) showed improvement and 1 (4.0%) was unchanged; there was no instance of worsening of an acute episode.
Protein C concentrate was effective in prevention of coagulopathy and thrombosis in 23 (100%) short-term replacement treatments for surgery/invasive procedures performed in 13 patients with SCPCD.
The median protein C activity level increased from 2.5% (range: 0.0 to 40.0%) at diagnosis (unaugmented) to 41.0% (range: 1.0% to 264.0%) following protein C concentrate infusion.
One patient (4.0%) with congenital heart disease died of congestive heart failure, assessed as not related to protein C concentrate. Of 111 AEs in 22 patients, 83 AEs in 17 patients occurred during treatment with protein C concentrate. Of these 83 AEs, only 3 were considered related to protein C concentrate: a single patient had 2 SAEs (abdominal pain and pain in extremity) and 1 nonserious AE (purpura fulminans) that were considered by the investigator to be possibly related to administration of protein C concentrate.
The results of this registry provide additional evidence for the use of protein C concentrate as an effective and safe short-term replacement therapy for surgery/invasive procedures and for acute episodes in patients with congenital protein C deficiency. No new safety concerns were identified.

Disclosures
Manco-Johnson: Bayer: Honoraria, Research Funding; Baxter/Baxalta/Shire: Honoraria; Biogen: Honoraria; NovoNordisk: Honoraria; CSL Behring: Honoraria. Hertfelder:Bayer Healthcare: Consultancy, Honoraria, Other: Support of Congress, Educational and Scientific Meeting Participations; Baxter/Baxalta/Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of Congress Participation; Pfizer: Consultancy, Honoraria, Other: Support of Congress, Educational and Scientific Meeting Participations; Daiichi-Sankyo Germany: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of Congress Participations; NovoNordisc: Other: Support of Congress Participations; Sanofi Aventis: Honoraria, Other: Educational meeting Participations, Speakers Bureau; Octapharma Germany: Other: Support of Congress Participations. Kalfa:Baxter/Baxalta/Shire: Research Funding. Bomgaars:Boeringer Ingleheim: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Membership on DSMB. Shapiro:National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; OPKO: Other: Clinical research protocols; Octopharma: Other: Clinical research protocols; PTC Therapeutics: Other: Clinical research protocols; Bayer healthcare Pharmaceuticals: Other: International network on pediatric hemophilia; Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Daiichi Sankyo: Other: Clinical research protocols; Biogen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Consultancy; ProMetic Life Sciences: Consultancy; American Thrombosis and Hemostasis Network: Other: Medical Director; Selexys: Other: Clinical research protocols; Novartis: Other: Clinical research protocols; CSL Behring: Other: Clinical research protocols. Jacqueline:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Ehrle:Baxter/Baxalta/Shire: Employment, Equity Ownership. Finnerty:Baxalta/Baxter: Employment. Gelmont:Baxter/Baxalta/Shire: Employment, Equity Ownership. Yel:Baxter/Baxalta/Shire: Employment, Equity Ownership. Loghman-Adham:Baxter/Baxalta/Shire: Employment, Equity Ownership.