A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]

The overall purpose of the study is to determine whether either of the Improved Response Polymorphisms (IRPs) individually predicts a differential DrotAA treatment effect in patients with severe sepsis and high risk of death. This will be an international, multicenter, "prospective-retrospective", nonrandomized, controlled, outcome-blinded, genotype-blinded, matched-patients study. No prospective enrollment or treatment of patients will occur under this protocol. Retrospectively collected clinical data and DNA samples will be analyzed for existing cohorts of patients with severe sepsis who were previously treated with DrotAA (treatment group) or not (control group) as part of their standard care in an ICU.

Start Date01 Oct 2011

Sponsor / Collaborator

Sirius Genomics, Inc.

NL-OMON35983

/ CompletedNot ApplicableIIT

Effect of Intravenous Administration of Recombinant Human Activated Protein C on Local Inflammation and Coagulation after Bronchial Instillation of House Dust Mite Allergen and Lipopolysaccharide in Asthma Patients - ACHILLES study

Start Date28 Sep 2011

Sponsor / Collaborator-

100 Clinical Results associated with Drotrecogin alfa (activated)

100 Translational Medicine associated with Drotrecogin alfa (activated)

100 Patents (Medical) associated with Drotrecogin alfa (activated)

1,002

Literatures (Medical) associated with Drotrecogin alfa (activated)

01 Oct 2024·Seminars in Thrombosis and Hemostasis

Heparins May Not Be the Optimal Anticoagulants for Sepsis and Sepsis-Associated Disseminated Intravascular Coagulation

Review

Author: Helms, Julie ; Levy, Jerrold H. ; Totoki, Takaaki ; Iba, Toshiaki

AbstractHistorically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.

01 May 2024·The Lancet Respiratory Medicine

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

Article

Author: Colin, Gwenhael ; Laurent Martin-, Lefevre ; Pierre François, DEQUIN ; Siami, Shidasp ; Stephan, EHRMANN ; Hamid, Merdji ; Roland, AMATHIEU ; Yen-Lan, NGUYEN ; Chimot, Loïc ; Luc, Desmedt ; Brun-Buisson, Christian ; Celine, Gonzalez ; Emmanuelle, MERCIER ; Frederic, PENE ; Leroy, Olivier ; Benali, Mohamed Ali ; Alexandra, Monnier ; Julien, Charpentier ; Denis, GAROT ; Heming, Nicholas ; Remi, Bruyere ; Thierry, BOULAIN ; Gregoire, Muller ; Mohamed, ALI BEN ALI ; Gauthier, Blonz ; Marc, Amouretti ; Aihem, Yehia ; Nicolas, Chudeau ; Xavier, FORCEVILLE ; Bounab, Rania ; Annick, LEGRAS ; Loic, CHIMOT ; Jean-Baptiste, Roudaut ; Tristan, MORICHAU-BEAUCHANT ; Philippe, Vignon ; François, BARBIER ; Matthieu, Henry ; Sandrine, Wiramus ; Dominique, Vivier ; Laura, Federici ; Philippe, CHAMPIN ; Anne-Laure, FEDOU ; Hassene, Rahmani ; Sarah, Benghanem ; Laetitia, BODET-CONTENTIN ; Yonatan, Perez ; Megarbane, Bruno ; Combes, Alain ; Karim, ASEHNOUNE ; Guillaume, GERI ; Jean François, Timsit ; Stephan, Ehrmann ; Julien, Textoris ; Antoine, GALY ; Patrick, Lafforgue ; Schwebel, Carole ; Xavier, Tchenio ; Jean Daniel, CHICHE ; Michel, WOLFF ; Dargent, Auguste ; Slama, Michel ; Julien, Vaidie ; Bellissant, Eric ; Sophie, Tollec ; David, Orlikowski ; Marjorie, Saint-Martin ; Brian, Emonet ; Michel, Djibre ; Patrice, Tirot ; Djillali, Annane ; Dhonneur, Gilles ; Anne-Laure, Fedou ; Maité, GARROUSTE ORGEAS ; Paris, Meng ; Patrice, TALEC ; Adrien, BOUGLE ; Franck, PETITPAS ; Bruno, MEGARBANE ; Denis, Garot ; Mickael, Landais ; Noemie, Zucman ; Jean-Pierre, QUENOT ; Alain, CARIOU ; Thomas, Daix ; Raphaël, CINOTTI ; Louis-Marie, Dumont ; Marie, Labruyere ; Aurélie, JORET ; Armelle, Mathonnet ; Benoit, MISSET ; Emmanuelle, Begot ; Pierre-Yves, Olivier ; Clément, BRUN ; Hissem, Tarik ; Nicolas, Pichon ; Jean Paul, MIRA ; Jean, REIGNIER ; François, Bruno ; Djillali, ANNANE ; Francis, Schneider ; Alexandre, Elabbadi ; Alain, Combes ; Aihem, YEHIA ; Pierre, Lahillaire ; Forceville, Xavier ; Jean François, ARNOULD ; Alia, MEGHENEM ; Maxime, Virginie ; Gilles, D'HONNEUR ; Samia, Touati ; Marlene, Morisseau ; Asehnoune, Karim ; Adrien, Robine ; Olivier, LEROY ; Bruno, FRANCOIS ; Charlotte, Salmon-Gandonniere ; Jean-François, LORIFERNE ; Charlotte, SALMONGANDONNIERE ; Claire, ARA SOMOHANO ; Fabrice, DAVIAUD ; Julien, Maizel ; Arnaud, Desachy ; Julien, Lorber ; Antoine, Galy ; Anne, Bretagnol ; Catherine, CHAPELLAS ; Laetitia, Bodet-Contentin ; Youenn, Jouan ; Yannick, MONSEAU ; Virginie, Maxime ; Jonathan, Messika ; Gilles, CAPELLIER ; Emmanuelle, ROUVE ; Charlene, Le Moal ; Rania, Bounab ; Eric, Boulet ; Annick, Legras ; Benoît, RAGONNET ; Carole, SCHWEBEL ; Marine, Jacquier ; Grégoire, MULLER ; Sophie, Jacquier ; David, Luis ; Julie, Mankikian ; Remi, Bernardon ; Lila, Bouadma ; Jean-Baptiste, Lascarrou ; Claire, Mancia ; Charpentier, Claire ; Bertrand, SOUWEINE ; Caroline, Pouplet ; Guillaume, Gilbert ; Mélanie, SAINT-LEGER ; Pierre, Moine ; Walid, Darwiche ; Loriferne, Jean-François ; Jean Christophe, Callahan ; Maud, Fiancette ; Thierry, Boulain ; Marine, Goudelin ; Christian, BRUN-BUISSON ; Nicolas, Sedillot ; François, ANTONINI ; Eric, LEVESQUE ; Cedric, Darreau ; Gwenhaël, COLIN ; Jean-Claude, LACHERADE ; Baudin, François ; Jean-Claude, Lacherade ; Christine, LEBERT ; Antoine, Guillon ; Christine, Lebert ; Konstantinos, Bachoumas ; Dalila, Benzekri Lefevre ; Andrea, Polito ; Constantin, Jean Michel ; Fabrice, COOK ; Marc, Clavel ; Fouad, Fadel ; Claire, LHOMMET ; Petitpas, Frank ; Jean-Baptiste, LASCARROU ; Bruno, Mourvillier ; Marine, DEMESMAY ; Emmanuelle, BEGOT ; Dalila, Benzekri ; Laure, Stiel ; Michel, SLAMA ; Youenn, JOUAN ; Julie, MANKIKIAN ; Claude Denis, Martin ; Annane, Djillali ; Isabelle, Vinatier ; Clémence, MINET ; Isabelle, Runge ; Raphael, Clere-Jehl ; Maxime, LUGOSI ; Renault, Alain ; Mai-Anh, Nai ; Quenot, Jean-Pierre ; Guillaume, CARTEAUX ; Yves, Poncelin ; Timsit, Jean-Francois ; Julie, Helms ; Jean Christophe, Navellou ; Arthur, Bailly ; François, Philippart ; Frederic, Jacobs ; Shidasp, SIAMI ; Constance, Vuillard ; Julien, BOHE ; Bruno, Evrard ; Mohammed, Lassi ; Boulain, Thierry ; Cook, Fabrice ; Ania, Nieszkowska ; Ronan, Le FLOCH ; Francois, Barbier ; Jean, CHASTRE ; Pierre Henri, DESSALLES ; Antoine, ROQUILLY ; Moine, Pierre ; Claire, CHARPENTIER ; Dominique, DEMEURE dit LATTE ; Kuperminc, Emmanuelle ; Damien, Roux ; Marion, ANTONA ; Mercier, Emmanuelle ; Pascal, Andreu ; Laurent, MARTIN-LEFEVRE ; Muriel-Sarah, Fartoukh ; Marie-Ange, Azais ; Leone, Marc ; Romain, DUMONT ; Tarek, Sharshar ; Bernard, Clair ; Olivier, LOUTREL ; Bohé, Julien ; Dominique, PERROTIN ; Jean, Kuba ; Matthieu, HENRY-LAGARRIGUE ; Misset, Benoît ; Francois, BAUDIN ; Emmanuelle, Mercier ; Sandrine, BEDON-CARTE ; Jean-Michel, CONSTANTIN ; François, BRIVET ; Clara, Vigneron ; Ali, Ait-Hssain ; Nicolas, DE PROST ; Benoit, Derrien ; Souweine, Bertrand ; Cariou, Alain ; Pierre-Joachim, MAHE ; Dominique, Prat ; Emmanuelle, Rouve ; Keyvan, RAZAZI ; Capellier, Gilles ; Remy, Marnai ; Antoine, Studer ; Vincent, Willems

BACKGROUNDGlucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.METHODSAPROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209).FINDINGSOf 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction).INTERPRETATIONIn a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup.FUNDINGProgramme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

01 Nov 2023·The Lancet Respiratory Medicine

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials

Article

Author: Zhuo, Hanjing ; Kangelaris, Kirsten N ; Walley, Keith R ; Wu, Nelson ; Gomez, Antonio D ; Langelier, Charles R ; Willmore, Andrew ; Churpek, Matthew M ; He, June ; Delucchi, Kevin L ; Chambers, Julia ; Matthay, Michael A ; Ware, Lorraine B ; Mick, Eran ; Neyton, Lucile ; Liu, Kathleen D ; Wickersham, Nancy ; Leligdowicz, Aleksandra ; Calfee, Carolyn S ; Hendrickson, Carolyn M ; Jauregui, Alejandra ; Sarma, Aartik ; Jones, Chayse ; Abbott, Jason ; Russell, James A ; Kerchberger, V Eric ; Sinha, Pratik

BACKGROUNDIn sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials.METHODSWe used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect.FINDINGSA two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72).INTERPRETATIONMolecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis.FUNDINGUS National Institutes of Health.

100 Deals associated with Drotrecogin alfa (activated)

External Link

KEGG	Wiki	ATC	Drug Bank
D03918	Drotrecogin alfa (activated)	B01AD10	DB00055

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Organ Failure	Discovery	Norway	Eli Lilly Nederland BV	22 Aug 2002
Multiple Organ Failure	Discovery	European Union	Eli Lilly Nederland BV	22 Aug 2002
Multiple Organ Failure	Discovery	Iceland	Eli Lilly Nederland BV	22 Aug 2002
Multiple Organ Failure	Discovery	Liechtenstein	Eli Lilly Nederland BV	22 Aug 2002
Sepsis	Discovery	United States	Eli Lilly & Co.	21 Nov 2001

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ARVO2014	Not Applicable	Central retinal vein occlusion - ischemic	10	Intravitreal Activated Protein C Injection	(ncozkdsdqk) = No adverse events, including endophthalmitis, clinically evident inflammation, increased intraocular pressure, retinal tears, or retinal detachments, have developed in any patient. Iris neovascularization occurred in 3 patients, which was successfully treated with laser photocoagulation or trabeculectomy. lpqfkwbnjt (wesnwmwffv )	Positive	01 Apr 2014
NCT00604214 (PROWESS-SHOCK, CTgov)	Phase 3	Shock, Septic	1,696	Drotrecogin alfa (activated) (Drotrecogin Alfa (Activated))	zfxzensqrf(cikyqooctx) = lgogxuvfjp rnumoapkvc (ofbfprjlhg, svzyyjwjnf - fryxfbqbcb) View more	-	18 Sep 2012
				Placebo (Placebo)	zfxzensqrf(cikyqooctx) = ttwpzwkwdo rnumoapkvc (ofbfprjlhg, wipdgsodqk - ewjeesaosr) View more
NCT00604214 (Pubmed \| Br Dent J \| N Engl J Med) Manual	Phase 3	Shock, Septic	1,697	Drotrecogin alfa	rvglybwvvk(qpgddeyift) = olpvqbkfud xaycmcniej (hcoeyhcfnt ) View more	Negative	31 May 2012
				Placebo	rvglybwvvk(qpgddeyift) = cbrijtlump xaycmcniej (hcoeyhcfnt ) View more
NCT00191724 (CTgov)	Phase 2	Pulmonary Embolism	47	Drotrecogin Alfa (Activated) - 6 (Drotrecogin Alfa (Activated) - 6)	(yjjfyrtclm) = vvexyfnvyp kjcwjeidqa (yrdmnjkley, vvjndsvpsf - axccbyygas) View more	-	17 Jun 2009
				Drotrecogin Alfa (Activated) - 12 (Drotrecogin Alfa (Activated) - 12)	(yjjfyrtclm) = zgxuffsrrt kjcwjeidqa (yrdmnjkley, kegplftcyh - hmvtwzlasc) View more
ARVO2004	Not Applicable	Hemorrhage	-	Recombinant Human Activated Protein C (RH-APC)	(jduvxhbzuc) = We describe a patient who survived sepsis and disseminated intravascular coagulation, but developed bilateral vitreous hemorrhages and a hemorrhagic retinal detachment while being treated with RH-APC avjdpwustr (zauoywcuaz )	Negative	01 May 2004
				Placebo

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