A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.

BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. RESULTS: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. CONCLUSIONS: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Adding Water to the Mill: Olmesartan-Induced Collagenous Sprue-A Case Report and Brief Literature Review.

Collagenous sprue (CS) is a distinct clinicopathological disorder histologically defined by a thickened subepithelial band (Freeman, 2011). It is a rare condition which has been recently observed in a significant proportion of sprue-like enteropathy associated with olmesartan, a novel entity described by Rubio-Tapia et al. in 2012. CS is historically associated with a poor prognosis (Marthey et al., 2014). However, histological and clinical improvements have been described in most studies with concomitant usage of corticosteroids and/or gluten-free diet (Marthey et al., 2014). We report a unique case of olmesartan-induced collagenous sprue in a 79-year-old man that showed complete histological and clinical remission with the sole withdrawal of the incriminating drug. The literature on this topic is briefly reviewed.

Prophylaxis of Thromboembolism in Critical Care (PROTECT) Trial: a pilot study.

PURPOSE: There is no randomized trial comparing low-molecular weight heparin (LMWH) and unfractionated heparin (UFH) for thromboprophylaxis in medical-surgical ICU patients. The primary objective of this randomized pilot study on LMWH vs UFH was to assess the feasibility of conducting a large randomized trial with respect to timely enrollment and blinded study drug administration, practicality of twice-weekly lower limb ultrasounds to screen for deep venous thrombosis, LMWH bioaccumulation and dose adjustment in renal insufficiency, and recruitment rates for a future trial in medical-surgical intensive care unit (ICU) patients. Its additional goals were to evaluate the suitability of the exclusion criteria and to document the range of research activities that precede accrual of patients into a trial to plan multisite management. MATERIALS AND METHODS: By computerized telephone randomization, we allocated 129 medical-surgical ICU patients to treatment with dalteparin 5,000 IU QD SC or that with UFH 5,000 IU BID SC. Within each clinical center, only the study pharmacist was not blinded. We performed bilateral lower limb compression ultrasounds within 48 hours of ICU admission, twice weekly, on suspicion of deep venous thrombosis, and 7 days after ICU discharge. Research coordinators and investigators at 7 centers reported the time they engaged in all research activities before the first patient was randomized. RESULTS: Timely complete study drug administration occurred after enrollment. More than 99% of scheduled doses were administered in a blinded fashion. Scheduled ultrasounds were performed without exception. No bioaccumulation of dalteparin was observed when creatinine clearance decreased to lower than 30 mL/min. Average recruitment was 2 patients/center per month before the study exclusion criteria were modified. Study startup activities required, on average, 65.5 hours of combined investigator and research coordinator time at each center. Careful examination of the accrual in the pilot study led to a reexamination of the Prophylaxis of Thromboembolism in Critical Care Trial (PROTECT) study exclusion criteria. CONCLUSIONS: This pilot study suggests that a multicenter randomized clinical trial comparing LMWH with UFH in critically ill medical-surgical patients is feasible. Pilot studies can improve the design of larger trials and may enhance successful timely completion.

Heparin-induced thrombocytopenia in medical surgical critical illness.

BACKGROUND: In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3,746 critically ill patients, 17 patients (0.5%) developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to a lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (five vs 12 patients, P = .14), which was statistically significant (three vs 12 patients, P = .046) in a prespecified per-protocol analysis that excluded patients with DVT at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis may reduce HIT frequency in patients in the ICU. METHODS: In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to the study drug and other open-label heparin, to determine whether the study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT. RESULTS: HIT-associated thrombosis occurred in 10 of 17 patients (58.8%) (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P = .020), including less seroconversion (P = .058) and less breakthrough of thrombocytopenia/thrombosis (P = .032). Antiplatelet factor 4/heparin IgG antibodies by enzyme-linked immunosorbent assay were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%, P < .001). One patient with HIT-associated DVT died after UFH bolus (anaphylactoid reaction), whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH. CONCLUSIONS: The lower risk of HIT in patients in the ICU receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.