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Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine… Russell, James A; Vincent, Jean-Louis; Kjølbye, Anne L; Olsson, Håkan; Blemings, Allan; Spapen, Herbert; Carl, Peder; Laterre, Pierre-Francois; Grundemar, Lars Aug 15, 2017

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RESEARCH Open AccessSelepressin, a novel selective vasopressinV1A agonist, is an effective substitute fornorepinephrine in a phase IIa randomized,placebo-controlled trial in septic shockpatientsJames A. Russell1*, Jean-Louis Vincent2, Anne Louise Kjølbye3, Håkan Olsson3, Allan Blemings3, Herbert Spapen4,Peder Carl5, Pierre-Francois Laterre6 and Lars Grundemar3AbstractBackground: Vasopressin is widely used for vasopressor support in septic shock patients, but experimentalevidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics,and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septicshock patients.Methods: This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septicshock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or amaximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrinewas added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrinedose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days.Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.Results: A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHgwithout norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin andplacebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion wasweaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001),successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001).Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo(p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs.placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequentdiscontinuation of this dose group.(Continued on next page)* Correspondence: jim.russell@hli.ubc.ca1Centre for Heart Lung Innovation, Division of Critical Care Medicine, St.Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver,BC V6Z 1Y6, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Russell et al. Critical Care  (2017) 21:213 DOI 10.1186/s13054-017-1798-7(Continued from previous page)Conclusions: In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrinewhile maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.Trial registration: ClinicalTrials.gov, NCT01000649. Registered on September 30, 2009.Keywords: Selepressin, V1A agonist, Norepinephrine, Mechanical ventilation, Fluid balance, Septic shockBackgroundNorepinephrine has traditionally been the vasopressor ofchoice in the treatment of septic shock, recommendedas the first-line vasopressor in the Surviving SepsisGuidelines [1]. However, vasopressin infusion has beenused to replace norepinephrine to maintain adequatesystemic arterial pressure (e.g., in patients refractory tonorepinephrine) [2–4]. In a large, multicenter, random-ized, double-blind, norepinephrine-controlled trial (theVasopressin and Septic Shock Trial [VASST]), vasopres-sin decreased mortality compared with norepinephrinein patients with less severe septic shock, although theoverall mortality was not different [5]. The researchers inthe VAsopressin versus Noradrenaline as Initial therapy inSeptic sHock (VANISH) randomized controlled trial ofvasopressin vs. norepinephrine found no differences inrates of acute kidney injury, the primary endpoint [6].Vasopressin infusion is currently recommended as asecond-line vasopressor for septic shock in the SurvivingSepsis Guidelines [1] and is used clinically [7].Selepressin, a novel, selective vasopressin V1A receptoragonist, is a potent vasopressor, and it has also beenshown to reduce fluid requirements and limit edema for-mation in animal septic shock models [8–11] and is nowin clinical development for the treatment of septicshock. In a phase I first-in-human trial, selepressin infu-sion in 30 healthy subjects with infusion rates up to3.0 ng/kg/minute for 6 h showed V1A-agonistic vaso-pressor properties, was safe and well tolerated, andshowed no signs of vasopressin V2 activity (Ferring Phar-maceuticals A/S, unpublished data). In this first-in-patient pilot phase IIa randomized, placebo-controlledtrial, the hypothesis was that selepressin maintains ad-equate arterial pressure in the absence of norepinephrineand shortens the duration of organ dysfunction in pa-tients with early septic shock.MethodsStudy designThis was a multicenter, double-blind, randomized,placebo-controlled phase IIa trial investigating three as-cending doses of selepressin in patients with early septicshock. Patients were recruited into the trial between2009 and 2011 in Belgium, Denmark, and the UnitedStates in accordance with the Declaration of Helsinkiand the principles of good clinical practice. The studyprotocol and informed consent documents were ap-proved by the independent ethics committees or re-search ethics boards of all participating institutions, andwritten informed consent was obtained from all patients,their next of kin, or another surrogate decision maker asappropriate prior to enrollment. The study was approvedby the competent regulatory authorities of each countryparticipating in the trial. An independent data safety andmonitoring committee evaluated the safety of the doseregimens prior to escalating to the next dose level.At each dose level, patients were randomized to con-stant intravenous infusion of selepressin or placebo in aratio of 2:1. Open-label norepinephrine was concomi-tantly administered to maintain the treatment targetMAP of ≥65 mmHg. Study drug infusion continued aslong as arterial pressure support was deemed necessary,but no longer than 7 days. Patients needing vasopressorsupport after 7 days were switched from study drug infu-sion to norepinephrine or another vasopressor. Assess-ments were performed during study drug treatment andup to 4 weeks after study drug initiation.Study populationPatients with hypotension in early septic shock, definedas hypotension not responding to infusion of fluid andrequiring at least 0.1 μg/kg/minute norepinephrine forat least 2 h, with a proven or suspected site of infectionand at least one sign of tissue hypoperfusion (oliguria,decreased Glasgow Coma Scale score, decreased ratio ofpartial pressure arterial oxygen to fraction of inspiredoxygen, or increased arterial blood lactate) could be in-cluded. To be eligible, patients had to be shifted to theopen-label norepinephrine and randomized to a constantintravenous infusion of selepressin or placebo within24 h of meeting the inclusion criteria. Briefly, exclusioncriteria (see Additional file 1: Table S1 for details) wereacute coronary syndrome; hypovolemia suspected onclinical grounds; cardiac failure; pregnancy or breast-feeding; hypotension other than septic shock; use ofvasopressin or terlipressin during the current hospitaladmission; acute mesenteric ischemia; episode of septicshock within 1 month; death anticipated within 24 h;chronic heart disease, including heart failure and sec-ond- and third-degree atrioventricular block withoutpacemaker; hyponatremia; brain injury; burn; peripheralvascular disease; previously randomized in this trial;Russell et al. Critical Care  (2017) 21:213 Page 2 of 10intake of an investigational drug within the last 3 months;participation in another clinical trial; and considered un-suitable to participate in the trial for any other reason.Sample size and randomizationThe study design comprised four treatment cohorts atthree ascending infusion rate levels, the first three co-horts with ten receiving active treatment and five receiv-ing placebo. The last cohort comprised active andplacebo to finally reach 20 patients at the maximum tol-erated infusion level and 20 patients receiving placebo.The randomization process was a computer-generatedrandom listing of the treatment allocations, stratified bycenter and in variable permuted blocks of 2, 4, or 6.Infusion of study drug and norepinephrineThe investigated starting and maximal infusion rates ofselepressin were 1.25 ng/kg/minute, 2.5 ng/kg/minute,and 3.75 ng/kg/minute, with the patient’s body weightbeing measured or estimated. Selepressin or placebo wasinfused via a central venous catheter at the constant ini-tial rate in addition to open-label norepinephrine target-ing a mean arterial pressure (MAP) of ≥65 mmHg.When patients were hemodynamically stable, open-labelnorepinephrine was tapered while maintaining targetMAP with study drug. When the MAP was stable for4 h without norepinephrine, study drug was weanedstepwise according to the protocol (Additional file 1:Table S2). If weaning resulted in hemodynamic instabil-ity, the study drug was reinstituted, and, if needed,open-label norepinephrine was restarted. Open-label nor-epinephrine was adjusted to maintain the MAP≥65 mmHg if blinded study drug was insufficient. Patientsreceived study drug until shock resolution (i.e., no vaso-pressor support) or a maximum of 7 days unless discon-tinued for safety reasons (Additional file 1: Table S3).Open-label norepinephrine was supplied in the UnitedStates and Canada as norepinephrine bitartrate 1 mg/ml(Levophed, norepinephrine base; Hospira, Lake Forest,IL, USA) diluted in 5% dextrose and in Europe asNorepinephrine 1:1000 (norepinephrine tartrate;(Cardinal Health Ltd., Basingstoke, UK) 2 mg/ml (1 mg/ml norepinephrine base) diluted in 5% glucose. A tightprotocol and accurate pumps (Braun Perfusor® Space; B.Braun Melsungen AG, Melsungen, Germany) were usedto calculate open-label norepinephrine delivered.Study outcomesThe co-primary endpoints were stabilization of MAP asdetermined by proportion of patients maintaining aMAP >60 mmHg without open-label norepinephrine at12, 24, 48, and 96 h, and day 7; infusion rates and cumu-lative dose of open-label norepinephrine; and proportionof patients maintaining a MAP >60 mmHg at 12, 24, 48,and 96 h, and day 7, regardless of open-label norepin-ephrine administration. The limit for maintained MAPwas defined as 60 mmHg to prevent small variationsaround the clinical treatment target of 65 mmHg havingdisproportional impact on the overall evaluation.Secondary endpoints included pharmacodynamics,pharmacokinetics, safety (vital signs, central venouspressure, central venous oxygen saturation, electrocar-diographic and cardiac function, respiratory function,clinical chemistry, hematology, hemostasis, and urinaly-sis), organ dysfunction, an indirect measure of vascularleakage (i.e., fluid balance), and morbidity. Treatment-emergent adverse events (occurrence from start of studydrug to 48 h after infusion was stopped) were collatedand evaluated. Morbidity and organ dysfunction wereevaluated by time course of Sequential Organ FailureAssessment (SOFA) scores; days alive and free of organdysfunction (using SOFA); proportion of patients off allvasopressors; days alive and out of intensive care unit(ICU); days alive and free of vasopressors; corticoste-roids for sepsis treatment, dialysis, or mechanical venti-lation at days 7, 14, and 28; ICU and hospital (up to day28) lengths of stay; and plasma C-reactive protein (CRP),tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10,and IL-1ra levels.PharmacokineticsBecause the study drug infusion was administered ac-cording to need, the pharmacokinetic parameters steady-state concentration, total systemic clearance, distributionvolume at steady state, and half-life were calculated bymodeling using a two-compartment population pharma-cokinetic model with random subject effects on clear-ance and distribution volume using WinNonlin®Pro(Pharsight Corp., Cary, NC, USA). Actual blood sam-pling time points were used for the calculations.Statistical analysisAll statistical analyses were performed using SAS version9.2 for Windows software (SAS Institute Inc., Cary, NC,USA). The first two co-primary endpoints were comparedusing a logistic regression model. The rates and cumula-tive amounts of open-label norepinephrine administeredwere compared between treatment groups by using a re-peated measures analysis of covariance (ANCOVA) modelwith treatment, time, and treatment by time interaction asfactors; baseline rate of norepinephrine as a covariate; andsubject as the experimental unit. The analyses were donefor both the full analysis set and the per-protocol analysisset. For both analysis sets, the analyses were presented forthe whole analysis set and those alive (and not discontin-ued) at the time of the measurement. The selepressingroups were compared individually with the placebogroup in an analysis of variance model.Russell et al. Critical Care  (2017) 21:213 Page 3 of 10Changes in vascular leakage endpoints (i.e., fluid bal-ance), as well as changes from baseline in cytokines andSOFA scores, were compared between treatment groupsusing the same ANCOVA model as for norepinephrine.Patients were categorized as free of organ dysfunction ifall six individual SOFA scores were 0. Percentage daysalive and free of organ dysfunction/ICU/hospital (i.e.,number of days/7 observation days × 100) were analyzedbetween treatment groups using nonparametricWilcoxon tests. The treatment differences between theselepressin groups and placebo were estimated using theHodges-Lehmann estimator for independent samples. Theproportions of patients alive were analyzed between treat-ment groups on days 7, 14, and 28 using a logistic regres-sion model. Confidence intervals (Clopper-Pearson) werecalculated for mortality rates and for the ORs of mortalityrates.ResultsStudy populationFifty-three patients were randomized, and 52 subjectswere dosed; 10 subjects received 1.25 ng/kg/minute, 19subjects received 2.5 ng/kg/minute, 2 subjects received3.75 ng/kg/minute, and 21 subjects received placebo. Allrandomized patients were included in the intention-to-treat dataset. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion dis-continued for possible safety reasons, with subsequentdiscontinuation of this dose group. Owing to the smallsample size and short duration of infusion in this group,efficacy analyses were not possible. A Consolidated Stan-dards of Reporting Trials diagram of the study is shownin Fig. 1.There were essentially no differences between sele-pressin- and placebo-treated patients in baseline charac-teristics, apart from a lower baseline norepinephrinedose in the 1.25 ng/kg/minute than in the 2.5 ng/kg/mi-nute and placebo groups (Table 1). The most commonunderlying organ dysfunctions were gastrointestinal,metabolic and nutritional, respiratory, and renal(Table 1). The primary infection was predominantly ab-dominal (40%) or pulmonary (31%).MAPs during the 7-day assessment period were simi-lar between groups at approximately 70 mmHg initiallyand increasing over 2 days to approximately 80–85 mmHg (Additional file 1: Figure S1).Effect of selepressin on norepinephrine requirement andduration of septic shockThe mean total selepressin infused doses were 6.1 and8.7 μg/kg infused over 3.6 and 3.2 days in the 1.25 and2.5 ng/kg/minute dose groups, respectively. The swiftFig. 1 Consolidated Standards of Reporting Trials (CONSORT) diagram of patient flow through the studyRussell et al. Critical Care  (2017) 21:213 Page 4 of 10onset of action of selepressin was illustrated by the highproportion of patients receiving 2.5 ng/kg/minute sele-pressin who early on maintained MAP >60 mmHg with-out norepinephrine (about 50% at 12 h and 70% at 24 h)(Fig. 2). In contrast, in the placebo and 1.25 ng/kg/mi-nute selepressin groups, no patient was free of norepin-ephrine at 12 h and ≤20% were free of norepinephrine at24 h (p < 0.01). However, over time, the differences de-creased as more patients recovered also in the lattergroups.The 7-day baseline adjusted mean cumulative doses ofopen-label norepinephrine were 761, 659, and 249 μg/kgfor the placebo, 1.25 ng/kg/minute, and 2.5 ng/kg/mi-nute groups, respectively (p < 0.001 for 2.5 ng/kg/minutevs. placebo groups) (Fig. 3a). Furthermore, thenorepinephrine mean infusion rate was initially reducedmore rapidly in the selepressin 2.5 ng/kg/minute groupthan in the placebo group; at 24 h, the infusion rateswere 0.04 vs. 0.18 μg/kg/minute (p < 0.005) (Fig. 3b).As expected, there were no differences between treat-ment groups in the proportions of patients who main-tained MAP >60 mmHg regardless of norepinephrine,meaning that the patients were generally treated equally(Additional file 1: Table S4). Selepressin at 2.5 ng/kg/mi-nute appeared to result in a faster recovery from shock(off vasopressors, including selepressin) than 1.25 ng/kg/minute and placebo, but without statistical significance(58% vs. 29%, p = 0.11, at 48 h) (Additional file 1: FiguresS2 and S3). There was no significant difference betweengroups in 28-day mortality rates (placebo 4 [21%] of 19,Table 1 Demographic and baseline characteristics of patients with septic shockSelepressin1.25 ng/kg/minute (n = 10)Selepressin2.5 ng/kg/minute (n = 19)Selepressin3.75 ng/kg/minute (n = 2)Placebo(n = 21)DemographicsSexFemale/male, n (%) 7 (70%)/3 (30%) 9 (47%)/10 (53%) 1 (50%)/1 (50%) 6 (29%)/15 (71%)Age, years, mean (SD; median) 59.3 (19.6–62.5) 57.1 (15.4–59) 69 (12.7–69) 63.2 (18–66)Weight, kg, mean (SD; median) 64.8 (14.3–63) 87.6 (28.6–85) 77.5 (17.7–78) 75.1 (15.3–75)Total SOFA score, mean (SD; median) 9.3 (2.2–9.5) 11.2 (3.7–11) 12 (0: 12) 10.4 (3.5–11)Lactate, mEq/L, mean (SD) 2.5 (1.5) 3.0 (2.9) 7.5 (8.1) 2.5 (1.4)Mean arterial pressure, mmHg, mean(SD; median)66 (13–63) 74 (9–70) 69 (15–69) 74 (13–69)Heart rate, beats/minute, mean(SD; median)90 (17–94) 97 (20–91) 110 (6–110) 90 (20–93)Norepinephrine, μg/kg/minute,mean (SD)0.18 (0.09) 0.28 (0.26) 0.39 (0.20) 0.34 (0.35)PaO2/FiO2, mean (SD; median) 231 (108–200) 257 (133–233) 221 (24–221) 246 (129–198)Primary infection typeBacterial, n (%) 7 (70%) 14 (74%) 2 (100%) 15 (71%)Unknown, n (%) 3 (30%) 5 (26%) 5 (24%)Other, n (%) 1 (5%)Primary infection locationUrinary tract, n (%) 1 (10%) 2 (11%) 1 (5%)Lung, n (%) 1 (10%) 6 (32%) 1 (50%) 8 (38%)Abdomen, n (%) 4 (40%) 8 (42%) 9 (43%)Unknown, n (%) 2 (20%) 1 (5%)Other, n (%) 2 (20%) 3 (16%) 1 (50%) 2 (10%)Main concomitant diseasesGastrointestinal, n (%) 8 (80%) 14 (74%) 1 (50%) 20 (95%)Metabolic, n (%) 6 60%) 16 (84%) 2 100%) 18 (86%)Respiratory, n (%) 7 (70%) 12 (63%) 2 100%) 14 (67%)Renal, n (%) 5 (50%) 11 (58%) 1 (50%) 16 (76%)Subjects on mechanical ventilation 4 (40%) 11 (58%) 0 15 (71%)PaO2/FiO2 Ratio of partial pressure arterial oxygen and fraction of inspired oxygen, SOFA Sequential Organ Failure AssessmentRussell et al. Critical Care  (2017) 21:213 Page 5 of 10selepressin 1.25 ng/kg/minute 5 [50%] of 10, selepressin2.5 ng/kg/minute 1 [5%] of 19).Effect of selepressin on mechanical ventilation, fluidbalance, and other morbidityThe proportion of days alive and free of ventilation wasgreater in the selepressin 2.5 ng/kg/minute group thanin the placebo group (54% vs. 23%, p < 0.02) over the 7-day treatment period. There was no difference betweenthe 1.25 ng/kg/minute (31%) and placebo groups (Add-itional file 1: Figure S4).Selepressin at 2.5 ng/kg/minute decreased the cumula-tive net fluid balance over the treatment period com-pared with the 1.25 ng/kg/minute and placebo groups(from about 9 L to 6.5 L, p = 0.1) (Fig. 4), and comparedwith placebo, the difference was significant (p < 0.05)from day 5 (94 h) onward. The differences in fluid bal-ance appeared to be due to fluid input rather than tourine output because there were no differences betweengroups in urine output (Additional file 1: Figure S5).There were no significant differences between groupsin length of stay in the ICU or hospital up to 28 days; inplasma CRP, TNF-α, IL-6, IL-10, or IL-1ra levels; or inany other secondary morbidity endpoint.PharmacokineticsThe mean steady-state concentrations of selepressin(0.50 and 0.99 ng/ml) were proportional to the initial in-fusion rates of 1.25 and 2.5 μg/kg/minute, with a time tosteady-state concentration of approximately 7 h. Themodeled mean total systemic clearance values were 10.0and 13.1 L/h, respectively, increasing with body weightand being higher in men than in women. The terminalhalf-life was approximately 2.5 h in both dose groups,Time after start of treatment, hours12 24 48 96 168)%(stneitapfonoitroporP020406080100Placebo Selepressin 1.25 ng/kg/minSelepressin 2.5 ng/kg/minFig. 2 Proportion of patients maintaining a mean arterial pressure>60 mmHg without any open-label norepinephrine support at theindicated time points. The difference between 2.5 ng/kg/minute andplacebo was statistically significant (p < 0.01) at 24 h. Results aremeans, with bars indicating SDTime, hours0 24 48 72 96 120 144 168gk/gµ,enirhpeniperonevitalumucnaeM02004006008001000PlaceboSelepressin 1.25 ng/kg/minSelepressin 2.5 ng/kg/minATime, hours0 24 48 72 96 120 144 168nim/gk/gµ,etarnoisufninaeM0. 1.25 ng/kg/minSelepressin 2.5 ng/kg/minBPla     21      20        20       20       20       20       20                  20                   20                   20                  191.25  10       10       10        10       10       10       10                  10                    9                     8                    82.5    19       19       19        19       19       19       19                  19                   19                   19                  19Pla     21     20        20       20       20       20       20                  20                   20                   20                  191.25  10      10       10        10       10       10       10                  10                    9                     8                    82.5    19      19       19        19       19       19       19                  19                   19                   19                  19Fig. 3 Mean cumulative amount (a) and infusion rate (b) of open-labelnorepinephrine over time in septic shock patients. Selepressinand placebo were infused at a constant rate as indicated, whereasnorepinephrine was weaned as fast as possible while still keeping thetarget treatment mean arterial pressure ≥65 mmHg. Numbers atthe bottom of the figure indicate number of patients at each time point.Bars indicate SD. Pl Placebo, 1.25 1.25 ng/kg/minute, 2.5 2.5 ng/kg/minuteTime, hours0 24 48 72 96 120 144 168L,ecnalabdiulfevitalumuC0246810 Placebo1.25 ng/kg/min2.5 ng/kg/minPla     21      20        20       20       20       20       20                  20                   20                   20                  191.25  10       10       10        10       10       10       10                  10                    9                     8                    82.5    19       19       19        19       19       19       19                  19                   19                   19                  19Fig. 4 Mean cumulative net fluid balance over 7 days from start ofselepressin/placebo treatment. Selepressin and placebo were infusedat a constant rate as indicated. Numbers at the bottom of the figureindicate number of patients at each time point. Bars indicate SD. PlPlacebo, 1.25 1.25 ng/kg/minute, 2.5 2.5 ng/kg/minuteRussell et al. Critical Care  (2017) 21:213 Page 6 of 10with an initial distribution/elimination phase half-life ofapproximately 10 minutes. The distribution volume atsteady state was 18–31 L, indicating extravascular distri-bution (Additional file 1: Table S5).SafetySelepressin was well tolerated, with no difference be-tween selepressin dose groups and placebo in termsof treatment-emergent adverse events. The high-dosegroup was stopped after two patients because of po-tential adverse events in the second patient. The mostfrequent adverse events were atrial fibrillation, brady-cardia, and hypertension (six subjects on seven occa-sions), equally distributed across treatment groups.The severe treatment-emergent adverse events weregenerally single observations attributable to theunderlying disease (Additional file 1: Table S6). Ninetreatment-emergent adverse events (in eight subjects)were regarded by the investigator to be related totreatment; one, four, and four treatment-emergent ad-verse events were regarded as mild, moderate, and se-vere, respectively (Table 2). Four of the adverse drugreactions in three patients were judged as serious:myocarditis and peripheral ischemia (one patient inthe 2.5 ng/kg/minute group), myocardial ischemia(3.75 ng/kg/minute group), and atrial fibrillation (pla-cebo group). There were no deaths related to ische-mic event(s) attributable to selepressin.There were no regional or global signs of hypoper-fusion, as suggested by similar decreases of lactatelevels (Additional file 1: Figure S5) and serum creatin-ine (Additional file 1: Figure S6), with no significantdifferences between study groups during the treat-ment period.DiscussionIn this phase IIa trial in patients in septic shock, the se-lective V1A agonist selepressin was shown to be an ef-fective vasopressor because infusion of 2.5 ng/kg/minutemaintained an adequate MAP, increased the proportionof patients weaned off norepinephrine during the first24 h, and decreased the mean cumulative dose of nor-epinephrine, thus demonstrating rapid onset and sus-tained activity. Moreover, 2.5 ng/kg/minute selepressincould possibly mitigate lung dysfunction because it wasassociated with a higher proportion of days alive andfree of ventilation over 7 days than placebo. It is wellknown that long duration of mechanical ventilation in-creases the risk of nosocomial pneumonia, neuromuscu-lar weakness, and death. Also, although not statisticallysignificant, twice as many patients were out of shockwithin 48 h with selepressin 2.5 ng/kg/minute comparedwith placebo, suggesting potential clinical benefit. Thus,selepressin appears to shorten duration of shock and thetime with mechanical ventilation and may be expectedto potentially improve the overall treatment outcome.Increased vascular leakage due to increased endothelialpermeability in septic shock results in edema and organdysfunction, and increased positive net fluid balance isdirectly associated with long duration of mechanicalventilation [12] and increased mortality in sepsis andseptic shock [13–15]. An indirect marker of vascular lea-kage—cumulative fluid balance over 7 days—was lowerwith selepressin 2.5 ng/kg/minute than with placebo, aresult that is consistent with animal models of septicshock [8–11]. In a prospective randomized study in anovine Pseudomonas aeruginosa pneumonia model ofseptic shock of selepressin vs. Vasopressin, researchersfound that selepressin blocked vascular leak better thanvasopressin did and that the decreased vascular leakageTable 2 Treatment-emergent adverse drug reactions that were possibly or probably related to treatmentSelepressin 1.25 ng/kg/minute(n = 10)Selepressin 2.5 ng/kg/minute(n = 19)Selepressin 3.75 ng/kg/minute(n = 2)Placebo(n = 21)No. of subjects (%), events No. of subjects (%), events No. of subjects (%), events No. of subjects (%), eventsCardiac disorderAtrial fibrillation 1 (5), 1Cyanosis 1 (5), 1Myocardial ischemia 1 (50), 1Myocarditis 1 (5), 1Metabolism and nutritional disordersHyperlactatemia 1 (5), 1Skin and subcutaneous tissue disordersMacular rash 1 (5), 1Vascular disordersHypertension 2 (11), 2Peripheral ischemia 1 (5), 1Russell et al. Critical Care  (2017) 21:213 Page 7 of 10was reversed by adding the V2 agonist ddAVP to sele-pressin [9]. Taken together, these results suggest that se-lective vasopressin V1A agonism may protect againstincreased vascular leakage in septic shock.The V1A-selective activity of selepressin may also haveother advantages compared with nonselective vasopres-sin agonists in septic shock. Terlipressin is more of aV1A receptor agonist than vasopressin, but it is also aV1B and V2 receptor agonist, whereas selepressin is ahighly selective V1A receptor agonist. In contrast tovasopressin and terlipressin, selepressin does not activatethe vasopressin V2 receptors that are mediating anti-diuretic effects [16], release of von Willebrand factor[16, 17], and vasodilation by stimulation of nitric oxideproduction [18, 19], all of which might be harmful dur-ing septic shock due to exacerbation of oliguria, procoa-gulation, and vasodilation.Selepressin at 1.25 ng/kg/minute had only very limitedpressor effects, suggesting that 2.5 ng/kg/minute was re-quired for an effective discontinuation of norepinephrineinfusion. There was no difference between selepressindose groups and placebo in terms of treatment-emergent adverse events. However, the highest-dosegroup was stopped after two patients because of adverseevents in one of the patients that were regarded to bepossibly related to selepressin. Because selepressin3.75 ng/kg/minute was discontinued following only twopatients with short infusion times, it was not possible toassess the safety and efficacy of this dose. However,3.75 ng/kg/minute and higher infusion rates did notraise any safety concerns in a separate uncontrolled,multicenter, open-label trial in which all 30 patients re-ceived selepressin at infusion rates of 3.75 ng/kg/minuteand higher (Ferring Pharmaceuticals A/S, unpublisheddata). Further assessment of the safety and efficacy of sele-pressin (at infusion rates of 1.7–7.5 ng/kg/minute) vs. pla-cebo is currently ongoing in the phase IIb/III SelepressinEvaluation Programme for Sepsis-Induced Shock -Adaptive Clinical Trial (SEPSIS-ACT; clinicaltrials.gov/ct2/show/NCT02508649?term = selepressin&rank = 1).Selepressin clearance was about 30% lower in septicshock patients than in healthy subjects. Because pep-tides similar in size are eliminated predominantly bypeptidase degradation and excretion in the kidney,the decreased clearance in septic shock may be ex-plained by reduced renal function. Accordingly, theterminal half-life of selepressin was longer in septicshock patients (2.5 h) than in healthy subjects (1.5 h)(Ferring Pharmaceuticals, unpublished data). The lon-ger half-life of selepressin than of norepinephrinewould potentially limit rapid adjustment of theselepressin-induced vasopressor support, especiallyafter steady state has been established. However, theselepressin initial distribution/elimination phase half-life was short (10 minutes), enabling rapid selepressindose adjustment during the early phase. Weaning ofvasopressor support is generally not rapid; there wereno indications that the terminal half-life caused un-due vasopressor-related events. In comparison withvasopressin (short half-life) and terlipressin (long half-life)[20, 21], selepressin’s half-life is intermediate [22, 23].Infusion of selepressin at 2.5 ng/kg/minute appearedsafe and was well tolerated, as shown by the similarfrequency of treatment-emergent adverse events inthe selepressin at 2.5 ng/kg/minute and placebogroups. The treatment-emergent adverse events re-lated to selepressin could generally be attributed tovasoconstriction and were similar in the selepressinand placebo groups, as were occurrence of severe andserious adverse events. There were no differences be-tween groups in indirect markers of regional or globalsigns of hypoperfusion (lactate and serum creatininelevels). The pooled mortality of the selepressin groupswas 20%, very similar to the 21% placebo group mor-tality rate and consistent with mortality rates in re-cent trials in septic shock [24]. The small sample sizeand the wide variability in clinical presentations andoutcomes of septic shock prevented any conclusionson mortality, but none of the deaths was regarded asrelated to selepressin.This was the first trial in patients, and the overallgoal of the trial was to determine whether and towhat degree selepressin could decrease the dose ofnorepinephrine in septic patients requiring vasopres-sor support. Reducing the dose of norepinephri-ne—so-called “de-catecholaminization” [25]—could initself be advantageous because it could decrease theadverse effects of norepinephrine, including excessiveprearteriolar vasoconstriction (compared with vaso-pressin [26] and possibly selepressin) and tachyar-rhythmias; it could have beneficial effects on fluidbalance and vascular leak [8, 9]; and it could possiblyhave more adverse effects on immunity [27] thanselepressin’s selective V1A agonism.It remains to be determined whether rapid and fullsubstitution of norepinephrine with selepressin is su-perior to cotreatment with norepinephrine and sele-pressin. That will be assessed in the ongoing phaseIIb/III SEPSIS-ACT trial. The combination of vaso-pressin and norepinephrine possesses synergistic ef-fects, and the two different modes of action togethermay be superior to aiming to reach target MAP fullywith either strategy alone. However, the potential add-itional benefits of selepressin compared with vaso-pressin, such as reduction of capillary leakage andlack of V2-mediated antidiuresis and procoagulationactivity, may justify earlier use and fuller substitutionof norepinephrine with selepressin.Russell et al. Critical Care  (2017) 21:213 Page 8 of 10Strengths and weaknesses of this trialStrengths of this trial include the randomized, concealed,placebo-controlled design; generalizability (multicenterin Europe and North America); precision of the co-primary endpoints; the inclusion of patients with rela-tively early septic shock; the novel selective V1A agonistselepressin; and administration of a tight protocol incritically ill septic shock patients. Limitations of this trialinclude the small sample size due to the early stage inselepressin’s clinical development in a limited number ofcenters (that may limit the overall impact), but they weresuitable for initial assessment of selepressin in humanseptic shock. The fluid input was not controlled, and wedo not have information about the different solutionsused (crystalloids, colloids, blood products), whichmight, at least in part, have influenced the amount of in-fused fluids, a potential limitation in interpreting thefluid balance. Although the addition of selepressinallowed sparing of norepinephrine and some wouldargue that one is simply substituting one vasopressor(selepressin) for another (norepinephrine), the beneficialeffects on ventilation and fluid balance suggest add-itional nonvasopressor benefits of selepressin vs. nor-epinephrine. The pharmacodynamic effects ofselepressin should be interpreted with caution owing tothe small sample size of this phase IIa trial. We did notmeasure cardiac output, so we cannot comment on sele-pressin vs. norepinephrine effects on this parameter. Ofnote, vasopressin and norepinephrine had similareffects—no decrease in cardiac output in VASST [28].Interaction of vasopressin and corticosteroids has beenreported elsewhere, but owing to the small sample size,it was not possible to assess the potential interaction ofcorticosteroids and selepressin in this trial.ConclusionsThe novel selective vasopressin V1A receptor agonist sele-pressin at an infusion rate of 2.5 ng/kg/minute rapidly re-placed norepinephrine while maintaining target MAP andmay have improved fluid balance and shortened the timeof mechanical ventilation. Further studies of selepressin’smechanism of action and additional larger randomizedcontrolled trials to investigate its efficacy are needed andongoing to assess its ability to improve the treatment out-come of patients in septic shock.Additional fileAdditional file 1: Table S1. Exclusion criteria. Table S2. Study drugdiscontinuation criteria. Table S3. Study drug weaning protocol. Table S4.Proportion of patients maintaining MAP >60 mmHg. Table S5.Pharmacokinetic parameters of selepressin in septic shock patients.Table S6. Summary of treatment emergent severe adverse events bysystem organ class and preferred term. Figure S1. Mean arterialpressure over time. Figure S2. Proportion of patients out of shockduring the first 72 h of treatment with selepressin or placebo. Figure S3.Kaplan-Mayer estimation of time to septic shock resolution. Figure S4.Proportion of days alive and off ventilator during the 7-day period from startof selepressin/placebo treatment. Figure S5. Mean cumulative urine outputover time in septic shock patients. Figure S6. Mean lactate over timein septic shock patients. Figure S7. Mean creatinine over time inseptic shock patients. (DOCX 138 kb)AcknowledgementsThe authors thank the patients and their families, doctors, nurses, and otherswho participated in this study. Participating study site investigators(alphabetically by country) were as follows:Belgium: F. Foret, B. Dinant; P. F. Laterre, Brussels; H. Spapen, Brussels; J.-L.Vincent, BrusselsCanada: J. A. Russell, Vancouver, BCDenmark: M. H. Bestle, Hillerød, P. Carl, Hvidovre, A. Perner, Copenhagen; F.Pott, CopenhagenUnited States: V. Bandi, Houston, TX; P. Dellinger, Camden, NJ; G. Fulda,Newark, NJ; A. Manasia, New York, NY; V. Ohaju, Duluth, MN; M. Schreiber,Portland, OR; M. Tidswell, Springfield, MAFundingFerring Pharmaceuticals A/S supported this work.Availability of data and materialsAll data generated or analyzed during the present study are included in thispublished article and its supplementary information files.Authors’ contributionsJAR, JLV, ALK, HO, AB, and LG conceived of and designed the study. JAR,ALK, HO, AB, and LG analyzed and interpreted data. JAR, ALK, HO, and LGdrafted or revised the manuscript. All authors read and approved the finalmanuscript.Ethics approval and consent to participateThe study protocol and informed consent documents were approved by theindependent ethics committees or research ethics boards of all participatinginstitutions, and written informed consent was obtained from all patients,their next of kin, or another surrogate decision maker, as appropriate prior toenrollment. The study was also approved by the competent regulatoryauthorities of each country participating in the trial.Consent for publicationInformed written consent was received for publication of the manuscriptand figures.Competing interestsJAR reports patents owned by the University of British Columbia (UBC) thatare related to PCSK9 inhibitor(s) and sepsis and related to the use ofvasopressin in septic shock. JAR is an inventor on these patents. JAR is afounder, director, and shareholder in Cyon Therapeutics Inc. (developing asepsis therapy). JAR has share options in Leading BioSciences Inc. JAR is ashareholder in Molecular You Corp. JAR reports receiving consulting feesfrom Cubist Pharmaceuticals (now owned by Merck; formerly was TriusPharmaceuticals; developing antibiotics), Leading BioSciences Inc.(developing a sepsis therapeutic), Ferring Pharmaceuticals (manufacturer ofvasopressin and developing selepressin), Grifols (seller of albumin), La JollaPharmaceutical Co. (developing angiotensin II; JAR chairs the data safety andmonitoring board of a trial of angiotensin II), CytoVale Inc. (developing asepsis diagnostic), and Asahi Kasei Pharma America (AKPA; developingrecombinant thrombomodulin). JAR reports having received an investigator-initiated grant from Grifols that is provided to and administered by UBC. HO,ALK, LG, and AB are employees of Ferring Pharmaceuticals A/S. JLV is editor-in-chief of Critical Care. JLV, HS, PC, and PFL declare that they have nocompeting interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Russell et al. Critical Care  (2017) 21:213 Page 9 of 10Author details1Centre for Heart Lung Innovation, Division of Critical Care Medicine, St.Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver,BC V6Z 1Y6, Canada. 2Department of Intensive Care, ULB Erasme UniversityHospital (Université Libre de Bruxelles), Route de Lennik 808, B-1070 Brussels,Belgium. 3Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK-2300Copenhagen, Denmark. 4Dienst Intensieve Geneeskunde, UZ Brussel,Laarbeeklaan 101, B-1090 Brussels, Belgium. 5Anaestesiology Department,Hvidovre Hospital, DK-2650 Hvidovre, Denmark. 6Clinique UniversitaireSt.-Luc, Service des Soins Intensifs, 10 Avenue Hippocrate, B-1200 Brussels,Belgium.Received: 12 March 2017 Accepted: 20 July 2017References1. 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Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, et al.The importance of fluid management in acute lung injury secondary toseptic shock. Chest. 2009;136(1):102–9.16. Ball SG. Vasopressin and disorders of water balance: the physiology andpathophysiology of vasopressin. Ann Clin Biochem. 2007;44(Pt 5):417–31.17. Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects ofdesmopressin (DDAVP). J Thromb Haemost. 2003;1(4):682–9.18. Kaufmann JE, Iezzi M, Vischer UM. Desmopressin (DDAVP) induces NOproduction in human endothelial cells via V2 receptor- and cAMP-mediatedsignaling. J Thromb Haemost. 2003;1(4):821–8.19. O’Connor PM, Cowley Jr AW. Vasopressin-induced nitric oxide production inrat inner medullary collecting duct is dependent on V2 receptor activationof the phosphoinositide pathway. Am J Physiol Renal Physiol. 2007;293(2):F526–32.20. Morelli A, Ertmer C, Pietropaoli P, Westphal M. Terlipressin: a promisingvasoactive agent in hemodynamic support of septic shock. Expert OpinPharmacother. 2009;10(15):2569–75.21. Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Cecchini V, et al.Continuous terlipressin versus vasopressin infusion in septic shock(TERLIVAP): a randomized, controlled pilot study. Crit Care. 2009;13(4):R130.22. Laporte R, Kohan A, Heitzmann J, Wisniewska H, Toy J, La E, et al.Pharmacological characterization of FE 202158, a novel, potent, selective,and short-acting peptidic vasopressin V1a receptor full agonist for thetreatment of vasodilatory hypotension. J Pharmacol Exp Ther. 2011;337(3):786–96.23. Wisniewski K, Galyean R, Tariga H, Alagarsamy S, Croston G, Heitzmann J, etal. New, potent, selective, and short-acting peptidic V1a receptor agonists. JMed Chem. 2011;54(13):4388–98.24. The ProCESS Investigators. A randomized trial of protocol-based care forearly septic shock. N Engl J Med. 2014;370(18):1683–93.25. Asfar P, Russell JA, Tuckermann J, Radermacher P. Selepressin in septic shock: astep toward decatecholaminization? Crit Care Med. 2016;44(1):234–6.26. Edwards RM, Trizna W, Kinter LB. Renal microvascular effects of vasopressinand vasopressin antagonists. Am J Physiol. 1989;256(2 Pt 2):F274–8.27. Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M.Potentially inadvertent immunomodulation: norepinephrine use in sepsis.Am J Respir Crit Care Med. 2016;194(5):550–8.28. Gordon AC, Wang N, Walley KR, Ashby D, Russell JA. The cardiopulmonaryeffects of vasopressin compared with norepinephrine in septic shock. Chest.2012;142(3):593–605.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Russell et al. Critical Care  (2017) 21:213 Page 10 of 10


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