A Registry Study on Treatment of Patients with Acquired Protein C Deficiency with a Protein C Concentrate (Human)

The objective of this non-interventional, international registry was to collect and assess data on the indications, safety, and the outcomes of treatment of patients with acquired protein C deficiency with a plasma-derived, human non-activated protein C concentrate (Ceprotin, Baxalta/Shire).

Any patient who received treatment with protein C concentrate was eligible for the study; there were no exclusion criteria. This was an observational study with no required predefined visits, medical or laboratory tests, procedures or interventions either at enrollment or during the study. The study was conducted from June 2010 to June 2015. Management of patients was according to the discretion of the investigator. The primary endpoints were the medical diagnoses associated with protein C concentrate treatment, the protein C concentrate treatment regimens (dose, frequency), treatment outcomes and safety information. Here we report the results from 18 patients with severe acquired protein C deficiency (SAPCD - as judged by the treating physician) from 4 European (EU) investigative sites. Protein C concentrate is not currently approved for treatment of acquired protein C deficiency in the EU.

The median age at study entry was 1.9 years (range: birth to 73.1 years); 5 [27.8%] patients were <1 month, 4 (22%) from 1 month to <2 years of age, 2 (11.1%) from 2 to <12 years, 2 (11.1%) from 12 to <18 and 5 (27.8%) ≥18 years of age.

Eighteen patients were treated with protein C concentrate. At clinical presentation, 15/18 (83.3%) of these patients had sepsis, 2 had necrotizing enterocolitis and 1 had hemolytic uremic syndrome. Thromboembolic disease was present in 8/18 (25.8%) patients, all of whom had purpura fulminans. Of these 8 patients, 2 had disseminated intravascular coagulation (DIC) in addition to other conditions; 1 patient also had arterial thrombosis, and the other patient had macrovascular thrombosis and skin necrosis. The remaining 10 (74.2%) patients had no evidence of thromboembolic disease: of these, 7 patients had sepsis, 2 necrotizing enterocolitis and 1 hemolytic uremic syndrome.

Dose level and frequency were variable: the most common dosage was 100 IU/kg and the most common interval between doses was 6 hours. There were no infusions administered for surgical interventions or for prophylaxis.

At the time of final analysis 17/18 (94.4%) of patients had at least one follow-up visit. The median duration of study participation was 17.8 months (range 0.4-39.6 months). The mortality rate was 2/18 (11%) patients, including one case of fatal peritonitis, coinciding with protein C concentrate treatment in a 44 day-old, very low birthweight preterm infant and a case of multi-organ failure in a 19 year-old patient. Both deaths were considered not related to protein C concentrate.

Ten patients received anticoagulation therapies in addition to protein C including: 4 treatments with antithrombin concentrates, 1 with clopidogrel, 6 with low molecular weight heparin and 7 with unfractionated heparin. Data from historical protein C concentrate treatments which occurred prior to enrollment in the study were collected from 3 patients upon their enrollment into the study (all 3 treatments resulted in halting/reversal of coagulopathy).

During the entire study period, 13 adverse events (AEs) were reported in 5 patients with acquired deficiency; among these, 4 were serious adverse events (SAEs). During the period of treatment with protein C concentrate, there were 2 AEs including an SAE of gastroenteritis; neither were considered related AEs. The results of this registry demonstrate that in current clinical practice in the EU, treatment with protein C concentrate was safe with a mortality rate of 11% in patients with acute SAPCD and thrombotic episodes observed in association with sepsis and/or purpura fulminans in this study.