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1. A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2.

Author

Paules, Catharine, Wang, Jing, Tomashek, Kay, Bonnett, Tyler, Singh, Kanal, Marconi, Vincent, Davey, Richard, Lye, David, Dodd, Lori, Yang, Otto, Benson, Constance, Deye, Gregory, Doernberg, Sarah, Hynes, Noreen, Grossberg, Robert, Wolfe, Cameron, Nayak, Seema, Short, William, Voell, Jocelyn, Potter, Gail, and Rapaka, Rekha

Subjects
Adult, Humans, Antiviral Agents, Azetidines, COVID-19, COVID-19 Drug Treatment, Immunologic Factors, Purines, Pyrazoles, SARS-CoV-2, Sulfonamides, Treatment Outcome, Double-Blind Method
Abstract

BACKGROUND: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib. OBJECTIVE: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile. DESIGN: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579). SETTING: Sixty-seven trial sites in 8 countries. PARTICIPANTS: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants). INTERVENTION: Baricitinib+remdesivir versus placebo+remdesivir. MEASUREMENTS: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories. RESULTS: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile. LIMITATION: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants. CONCLUSION: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Published
2024

2. Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial

Author

Potter, Gail E, Bonnett, Tyler, Rubenstein, Kevin, Lindholm, David A, Rapaka, Rekha R, Doernberg, Sarah B, Lye, David C, Mularski, Richard A, Hynes, Noreen A, Kline, Susan, Paules, Catharine I, Wolfe, Cameron R, Frank, Maria G, Rouphael, Nadine G, Deye, Gregory A, Sweeney, Daniel A, Colombo, Rhonda E, Davey, Richard T, Mehta, Aneesh K, Whitaker, Jennifer A, Castro, Jose G, Amin, Alpesh N, Colombo, Christopher J, Levine, Corri B, Jain, Mamta K, Maves, Ryan C, Marconi, Vincent C, Grossberg, Robert, Hozayen, Sameh, Burgess, Timothy H, Atmar, Robert L, Ganesan, Anuradha, Gomez, Carlos A, Benson, Constance A, de Castilla, Diego Lopez, Ahuja, Neera, George, Sarah L, Nayak, Seema U, Cohen, Stuart H, Lalani, Tahaniyat, Short, William R, Erdmann, Nathaniel, Tomashek, Kay M, and Tebas, Pablo

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Clinical Research, Rehabilitation, Complementary and Integrative Health, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Adult, Humans, Antiviral Agents, Clinical Trials, Phase III as Topic, Dexamethasone, Double-Blind Method, Randomized Controlled Trials as Topic, Treatment Outcome, COVID-19 Drug Treatment, Medical and Health Sciences, General & Internal Medicine, Clinical sciences
Abstract

BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

Published
2022

3. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

Author

Wolfe, Cameron R, Tomashek, Kay M, Patterson, Thomas F, Gomez, Carlos A, Marconi, Vincent C, Jain, Mamta K, Yang, Otto O, Paules, Catharine I, Palacios, Guillermo M Ruiz, Grossberg, Robert, Harkins, Michelle S, Mularski, Richard A, Erdmann, Nathaniel, Sandkovsky, Uriel, Almasri, Eyad, Pineda, Justino Regalado, Dretler, Alexandra W, de Castilla, Diego Lopez, Branche, Angela R, Park, Pauline K, Mehta, Aneesh K, Short, William R, McLellan, Susan LF, Kline, Susan, Iovine, Nicole M, El Sahly, Hana M, Doernberg, Sarah B, Oh, Myoung-Don, Huprikar, Nikhil, Hohmann, Elizabeth, Kelley, Colleen F, Holodniy, Mark, Kim, Eu Suk, Sweeney, Daniel A, Finberg, Robert W, Grimes, Kevin A, Maves, Ryan C, Ko, Emily R, Engemann, John J, Taylor, Barbara S, Ponce, Philip O, Larson, LuAnn, Melendez, Dante Paolo, Seibert, Allan M, Rouphael, Nadine G, Strebe, Joslyn, Clark, Jesse L, Julian, Kathleen G, de Leon, Alfredo Ponce, Cardoso, Anabela, de Bono, Stephanie, Atmar, Robert L, Ganesan, Anuradha, Ferreira, Jennifer L, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori E, Beigel, John H, Kalil, Andre C, and ACTT-4 Study Group

Subjects
ACTT-4 Study Group, Humans, Oxygen, Sulfonamides, Azetidines, Pyrazoles, Purines, Dexamethasone, Treatment Outcome, Double-Blind Method, Adolescent, Adult, Middle Aged, Female, Male, SARS-CoV-2, COVID-19 Drug Treatment, Clinical Trials and Supportive Activities, Lung, Clinical Research, Prevention, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Published
2022

4. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial

Author

Kalil, Andre C, Mehta, Aneesh K, Patterson, Thomas F, Erdmann, Nathaniel, Gomez, Carlos A, Jain, Mamta K, Wolfe, Cameron R, Ruiz-Palacios, Guillermo M, Kline, Susan, Pineda, Justino Regalado, Luetkemeyer, Anne F, Harkins, Michelle S, Jackson, Patrick EH, Iovine, Nicole M, Tapson, Victor F, Oh, Myoung-don, Whitaker, Jennifer A, Mularski, Richard A, Paules, Catharine I, Ince, Dilek, Takasaki, Jin, Sweeney, Daniel A, Sandkovsky, Uriel, Wyles, David L, Hohmann, Elizabeth, Grimes, Kevin A, Grossberg, Robert, Laguio-Vila, Maryrose, Lambert, Allison A, de Castilla, Diego Lopez, Kim, EuSuk, Larson, LuAnn, Wan, Claire R, Traenkner, Jessica J, Ponce, Philip O, Patterson, Jan E, Goepfert, Paul A, Sofarelli, Theresa A, Mocherla, Satish, Ko, Emily R, de Leon, Alfredo Ponce, Doernberg, Sarah B, Atmar, Robert L, Maves, Ryan C, Dangond, Fernando, Ferreira, Jennifer, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori, Tomashek, Kay M, Beigel, John H, members, ACTT-3 study group, Hewlett, Angela, Taylor, Barbara S, Bowling, Jason E, Serrano, Ruth C, Rouphael, Nadine G, Wiley, Zanthia, Phadke, Varun K, Certain, Laura, Imlay, Hannah N, Engemann, John J, Walter, Emmanuel B, Meisner, Jessica, Rajme, Sandra, Billings, Joanne, Kim, Hyun, Martinez-Orozco, Jose A, Felix, Nora Bautista, Elmor, Sammy T, Bristow, Laurel R, Mertz, Gregory, Sosa, Nestor, Bell, Taison D, West, Miranda J, Elie-Turenne, Marie-Carmelle, Grein, Jonathan, Sutterwala, Fayyaz, Choe, Pyoeng Gyun, Kang, Chang Kyung, Sahly, Hana M El, Rhie, Kevin S, Hussein, Rezhan H, Winokur, Patricia L, Mikami, Ayako, Saito, Sho, Benson, Constance A, McConnell, Kimberly, Berhe, Mezgebe, Dishner, Emma, Frank, Maria G, Sarcone, Ellen, Crouch, Pierre-Cedric B, Jang, Hannah, and Jilg, Nikolaus

Subjects
Rehabilitation, Clinical Trials and Supportive Activities, Lung, Clinical Research, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Adenosine Monophosphate, Adult, Aged, Alanine, Antiviral Agents, Double-Blind Method, Female, Humans, Interferon beta-1a, Japan, Male, Mexico, Middle Aged, Oxygen, Oxygen Saturation, Republic of Korea, SARS-CoV-2, Singapore, Treatment Outcome, United States, COVID-19 Drug Treatment, ACTT-3 study group members, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract

BackgroundFunctional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.MethodsWe did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.FindingsBetween Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.InterpretationInterferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.FundingThe National Institute of Allergy and Infectious Diseases (USA).

Published
2021

5. SARS-CoV-2 seroprevalence in vaccine-naïve participants from the Democratic Republic of Congo, Guinea, Liberia, and Mali

Author

Akpa, Esther, Bah, Fatoumata Binta, Barash, Yi-Chi, Beavogui, Abdoul Habib, Biampata, Jean-Luc, Bonnett, Tyler, Brown, Shawn, Burkey, Alissa, Camara, Daouda, Camara, Sekou, Cline-Cole, Elfrida, Coulibaly, Mamadou D, Coulibaly, Nadie, Dewar, Robin, Diallo, Mountaga, Diarra, Samba, Doumbia, Seydou, Eyler, Allison, Fouth Tchos, Karine, Francis, Alyson, Grue, Louis, Highbarger, Helene, Highbarger, Jeroen, Ibanda, Augustin Mbala, Kallon, Kadé, Kindombe, Esaie Luzolu, Kingebeni, Placide Mbala, Kolié, Cece Francis, Lallemand, Perrine, Lim, Caeul, Lokilo, Emmanuel, Lumembe, Raphael, McCormack, Ashley Louise, McNay, Laura, Mukendi, Gael, Mukendi, Thierry, Muyembe, Jean Jacques, Newell, Kevin, Njoh, Wissedi, Pankwa, Isaac Balmayel, Pukuta, Elisabeth, Riziki, Yogolelo, Rupert, Adam, Samake, Seydou, Sandrus, Jennifer, Sangare, Adama, Smolskis, Mary, Souto Adeva, Gema, Stevens, Randy, Tangara, Cheick Oumar, Tounkara, Moctar, Trumbull-Kennedy, Meghan, Tshomba, Antoine, Wague, Mamadou, Weyers, Shera, Worthington, Chris, Laverdure, Sylvain, Kazadi, Donatien, Kone, Kadidia, Callier, Viviane, Dabitao, Djeneba, Dennis, Dehkontee, Haidara, Mory Cherif, Hunsberger, Sally, Mbaya, Olivier Tshiani, Ridzon, Renee, Sereti, Irini, and Shaw-Saliba, Katy

Published
2024
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6. Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials

Author

Hermine, Olivier, Mariette, Xavier, Ravaud, Philippe, Bureau, Serge, Dougados, Maxime, Resche-Rigon, Matthieu, Tharaux, Pierre-Louis, Tibi, Annick, Azoulay, Elie, Cadranel, Jacques, Emmerich, Joseph, Fartoukh, Muriel, Guidet, Bertrand, Humbert, Marc, Lacombe, Karine, Mahevas, Matthieu, Pene, Frédéric, Porcher, Raphaël, Pourchet-Martinez, Valerie, Schlemmer, Frédéric, Yazdanpanah, Yazdan, Baron, Gabriel, Perrodeau, Elodie, Vanhoye, Damien, Kedzia, Cécile, Demerville, Lauren, Gysembergh-Houal, Anne, Bourgoin, Alexandre, Raked, Nabil, Mameri, Lakhdar, Montlahuc, Claire, Biard, Lucie, Alary, St.phanie, Hamiria, Samir, Bariz, Thinhinane, Semri, Hala, Hai, Dhiaa Meriem, Benafla, Moustafa, Belloul, Mohamed, Vauboin, Pernelle, Flamand, Saskia, Pacheco, Claire, Walter-Petrich, Anouk, Stan, Emilia, Benarab, Souad, Nyanou, Corine, Charreteur, Robin, Dupre, Céline, Cardet, Kévin, Lehmann, Blandine, Baghli, Kamyl, Madelaine, Claire, D'Ortenzio, Eric, Puéchal, Oriane, Semaille, Caroline, Savale, Laurent, Harrois, Anatole, Figueiredo, Samy, Duranteau, Jacques, Anguel, Nadia, Pavot, Arthur, Monnet, Xavier, Richard, Christian, Teboul, Jean-Louis, Durand, Philippe, Tissieres, Pierre, Jevnikar, Mitja, Montani, David, Pavy, Stephan, Nocturne, Gaétane, Bitoun, Samuel, Noel, Nicolas, Lambotte, Olivier, Escaut, Lelia, Jauréguiberry, Stephane, Baudry, Elodie, Verny, Christiane, Lefevre, Edouard, Zaidan, Mohamad, Molinari, Domitille, Leprun, Gaël, Fourreau, Alain, Cylly, Laurent, Grimaldi, Lamiae, Virlouvet, Myriam, Meftali, Ramdane, Fabre, Soléne, Licois, Marion, Mamoune, Asmaa, Boudali, Yacine, Le Tiec, Clotilde, Verstuyft, Céline, Roques, Anne-Marie, Georgin-Lavialle, Sophie, Senet, Patricia, Pialoux, Gilles, Soria, Angele, Parrot, Antoine, François, Helene, Rozensztajn, Nathalie, Blin, Emmanuelle, Choinier, Pascaline, Camuset, Juliette, Rech, Jean-Simon, Canellas, Antony, Rolland-Debord, Camille, Lemarié, Nadege, Belaube, Nicolas, Nadal, Marine, Siguier, Martin, Petit-Hoang, Camille, Chas, Julie, Drouet, Elodie, Lemoine, Matthieu, Phibel, Audrey, Aunay, Lucie, Bertrand, Eliane, Ravato, Sylviane, Vayssettes, Marie, Adda, Anne, Wilpotte, Celine, Thibaut, Pélagie, Fillon, Julie, Debrix, Isabelle, Fellahi, Soraya, Bastard, Jean-Philippe, Lefévre, Guillaume, Gottenberg, Jacques-Eric, Hansmann, Yves, Blanc, Frédéric, Ohlmann-Caillard, Sophie, Castelain, Vincent, Chatelus, Emmanuel, Chatron, Eva, Collange, Olivier, Danion, François, De Blay, Frédéric, Diemunsch, Pierre, Diemunsch, Sophie, Felten, Renaud, Goichot, Bernard, Greigert, Valentin, Guffroy, Aurelien, Heger, Bob, Kaeuffer, Charlotte, Kassegne, Loic, Korganow, Anne Sophie, Le Borgne, Pierrick, Lefebvre, Nicolas, Mertes, Paul-Michel, Noll, Eric, Oberlin, Mathieu, Poindron, Vincent, Pottecher, Julien, Ruch, Yvon, Weill, François, Meyer, Nicolas, Andres, Emmanuel, Demonsant, Eric, Tayebi, Hakim, Nisand, Gabriel, Brin, Stéphane, Sublon, Cédric, Becker, Guillaume, Hutt, Anne, Martin, Tristan, Bayer, Sophie, Metzger, Catherine, Mekinian, Arsene, Abisror, Noémie, Adedjouma, Amir, Bollens, Diane, Bonneton, Marion, Bourcicaux, Nathalie, Bourrier, Anne, Thibault Chiarabiani, Maria Chauchard, Chopin, Doroth.e, Cohen, Jonathan, Devred, Ines, Donadille, Bruno, Fain, Olivier, Hariri, Geoffrey, Jachiet, Vincent, Ingliz, Patrick, Garnier, Marc, Gatfosse, Marc, Ghrenassia, Etienne, Gobert, Delphine, Krause le Garrec, Jessica, Landman, Cecilia, Lavillegrand, Jean Remy, Lefebvre, Benedicte, Mahevas, Thibault, Mazerand, Sandie, Meynard, Jean Luc, Morgand, Marjolaine, Ouaz.ne, Zineb, Pacanowski, Jerome, Riviere, S.bastien, Seksik, Philippe, Sokol, Harry, Soliman, Heithem, Valin, Nadia, Urbina, Thomas, McAvoy, Chloé, Miranda, Maria Pereira, Aratus, Gladys, Berard, Laurence, Simon, Tabassome, Nguyen, Anne Daguenel, Girault, Elise, Mayala-Kanda, Cl.mentine, Antignac, Marie, Leplay, Céline, Arlet, Jean-Benoit, Diehl, Jean-Luc, Bellenfant, Florence, Blanchard, Anne, Buffet, Alexandre, Cholley, Bernard, Fayol, Antoine, Flamarion, Edouard, Godier, Anne, Gorget, Thomas, Hamada, Sophie-Rym, Hauw-Berlemont, Caroline, Hulot, Jean-Sébastien, Lebeaux, David, Livrozet, Marine, Michon, Adrien, Neuschwander, Arthur, Pennet, Marie-Aude, Planquette, Benjamin, Ranque, Brigitte, Sanchez, Olivier, Volle, Geoffroy, Briois, Sandrine, Cornic, Mathias, Elisee, Virginie, Denis, Jesuthasan, Djadi-Prat, Juliette, Jouany, Pauline, Junquera, Ramon, Henriques, Mickael, Kebir, Amina, Lehir, Isabelle, Meunier, Jeanne, Patin, Florence, Paquet, Val.rie, Tréhan, Anne, Vigna, Véronique, Sabatier, Brigitte, Bergerot, Damien, Jouve, Charléne, Knosp, Camille, Lenoir, Olivia, Mahtal, Nassim, Resmini, Léa, Lescure, Xavier, Ghosn, Jade, Bachelard, Antoine, Rachline, Anne, Isernia, Valentina, Bao-chau, Phung, Vallois, Dorothée, Sautereau, Aurelie, Neukrich, Catherine, Dossier, Antoine, Borie, Raphaël, Crestani, Bruno, Ducrocq, Gregory, Steg, Philippe Gabriel, Dieude, Philippe, Papo, Thomas, Marcault, Estelle, Chaudhry, Marhaba, Da Silveira, Charléne, Metois, Annabelle, Mahenni, Ismahan, Meziani, Meriam, Nilusmas, Cyndie, Le Gac, Sylvie, Ndiaye, Awa, Louni, Fran.oise, Chansombat, Malikhone, Julia, Zelie, Chalal, Solaya, Chalal, Lynda, Kramer, Laura, Le Grand, Jeniffer, Ouifiya, Kafif, Piquard, Valentine, Tubiana, Sarah, Nguyen, Yann, Honsel, Vasco, Weiss, Emmanuel, Codorniu, Anais, Zarrouk, Virginie, de Lastours, Victoire, Uzzan, Matthieu, Gamany, Naura, Claveirole, Agathe, Navid, Alexandre, Fouque, Tiffanie, Cohen, Yonathan, Lupo, Maya, Gilles, Constance, Rahli, Roza, Louis, Zeina, Boutboul, David, Galicier, Lionel, Amara, Yaël, Archer, Gabrielle, Benattia, Amira, Bergeron, Anne, Bondeelle, Louise, de Castro, Nathalie, Clément, Melissa, Darmon, Michaël, Denis, Blandine, Dupin, Clairelyne, Feredj, Elsa, Feyeux, Delphine, Joseph, Adrien, Lenglin, Etienne, Le Guen, Pierre, Liégeon, Geoffroy, Lorillon, Gwenaël, Mabrouki, Asma, Mariotte, Eric, Martin de Frémont, Grégoire, Mirouse, Adrien, Molina, Jean-Michel, Peffault de Latour, Régis, Oksenhendler, Eric, Saussereau, Julien, Tazi, Abdellatif, Tudesq, Jean-Jacques, Zafrani, Lara, Brindele, Isabelle, Bugnet, Emmanuelle, Lebras, Karine Celli, Chabert, Julien, Djaghout, Lamia, Fauvaux, Catherine, Jegu, Anne Lise, Kozakiewicz, Ewa, Meunier, Martine, Tremorin, Marie-Thérèse, Davoine, Claire, Madelaine, Isabelle, Caillat-Zucman, Sophie, Delaugerre, Constance, Morin, Florence, Sène, Damien, Burlacu, Ruxandra, Chousterman, Benjamin, Mégarbanne, Bruno, Richette, Pascal, Riveline, Jean-Pierre, Frazier, Aline, Vicaut, Eric, Berton, Laure, Hadjam, Tassadit, Vazquez-Ibarra, Miguel Alejandro, Jourdaine, Clément, Tran, Olivia, Jouis, Véronique, Jacob, Aude, Smati, Julie, Renaud, Stéphane, Pernin, Claire, Suarez, Lydia, Semerano, Luca, Abad, Sébastien, nainous, Ruben B., Bonnet, Nicolas, Comparon, Celine, Cohen, Yves, Cordel, Hugues, Dhote, Robin, Dournon, Nathalie, Duchemann, Boris, Ebstein, Nathan, Gille, Thomas, Giroux-Leprieur, Benedicte, Goupil de Bouille, Jeanne, Nunes, Hilario, Oziel, Johanna, Roulot, Dominique, Sese, Lucile, ClaireTantet, Uzunhan, Yurdagul, Bloch-Queyrat, Coralie, Levy, Vincent, Messani, Fadhila, Rahaoui, Mohammed, Petit, Myléne, Brahmi, Sabrina, Rathoin, Vanessa, Rigal, Marthe, Costedoat-Chalumeau, Nathalie, Luong, Liem Binh, Hamou, Zakaria Ait, Benghanem, Sarah, Blanche, Philippe, Carlier, Nicolas, Chaigne, Benjamin, Gauzit, Remy, Joumaa, Hassan, Jozwiak, Mathieu, Lachétre, Marie, Lafoeste, Hélène, Launay, Odie, Legendre, Paul, Marey, Jonathan, Morbieu, Caroline, Palmieri, Lola-Jade, Szwebel, Tali-Anne, Abdoul, Hendy, Bruneau, Alexandra, Beclin-Clabaux, Audrey, Larrieu, Charly, Montanari, Pierre, Dufour, Eric, Clarke, Ada, Le Bourlout, Catherine, Marin, Nathalie, Menage, Nathalie, Saleh-Mghir, Samira, Cisse, Mamadou Salif, Cheref, Kahina, Guerin, Corinne, Zerbit, Jérémie, Michel, Marc, Gallien, Sébastien, Crickx, Etienne, Le Vavasseur, Benjamin, Kempf, Emmanuelle, Jaffal, Karim, Vindrios, William, Oniszczuk, Julie, Guillaud, Constance, Lim, Pascal, Fois, Elena, Melica, Giovanna, Matignon, Marie, Jalabert, Maud, Lelièvre, Jean-Daniel, Schmitz, David, Bourhis, Marion, Belazouz, Sylia, Languille, Laetitia, Boucle, Caroline, Cita, Nelly, Didier, Agnés, Froura, Fahem, Ledudal, Katia, Sadaoui, Thiziri, Thiemele, Alaki, Le Febvre De Bailly, Delphine, Verlinde, Muriel Carvhalo, Mayaux, Julien, Cacoub, Patrice, Saadoun, David, Vautier, Mathieu, Bugaut, Héléne, Benveniste, Olivier, Allenbach, Yves, Leroux, Gaëlle, Rigolet, Aude, Guillaume-Jugnot, Perrine, Domont, Fanny, Desbois, Anne Claire, Comarmond, Chloé, Champtiaux, Nicolas, Toquet, Segolene, Ghembaza, Amine, Vieira, Matheus, Maalouf, Georgina, Boleto, Goncalo, Ferfar, Yasmina, Corvol, Jean-Christophe, Louapre, C.line, Sambin, Sara, Mariani, Louise-Laure, Karachi, Carine, Tubach, Florence, Estellat, Candice, Gimeno, Linda, Martin, Karine, Bah, Aicha, Keo, Vixra, Ouamri, Sabrine, Messaoudi, Yasmine, Yelles, Nessima, Faye, Pierre, Cavelot, Sebastien, Larcheveque, Cecile, Annonay, Laurence, Benhida, Jaouad, Zahrate-Ghoul, Aida, Hammal, Soumeya, Belilita, Ridha, Charbonnier, Fanny, Aguilar, Claire, Alby-Laurent, Fanny, Burger, Carole, Campos-Vega, Clara, Chavarot, Nathalie, Fournier, Benjamin, Rouzaud, Claire, Vimpére, Damien, Elie, Caroline, Bakouboula, Prissile, Choupeaux, Laure, Granville, Sophie, Issorat, Elodie, Broissand, Christine, Alyanakian, Marie-Alexandra, Geri, Guillaume, Derridj, Nawal, Sguiouar, Naima, Meddah, Hakim, Djadel, Mourad, Chambrin-Lauvray, Héléne, Duclos-vallée, Jean-Charles, Saliba, Faouzi, Sacleux, Sophie-Caroline, Kounis, Ilias, Tamazirt, Sonia, Rudant, Eric, Michot, Jean-Marie, Stoclin, Annabelle, Colomba, Emeline, Pommeret, Fanny, Willekens, Christophe, Da Silva, Rosa, Dejean, Valérie, Mekid, Yasmina, Ben-Mabrouk, Ines, Netzer, Florence, Pradon, Caroline, Drouard, Laurence, Camara-Clayette, Valérie, Morel, Alexandre, Garcia, Gilles, Mohebbi, Abolfazl, Berbour, Férial, Dehais, Mélanie, Pouliquen, Anne-Lise, Klasen, Alison, Soyez-Herkert, Loren, London, Jonathan, Keroumi, Younes, Guillot, Emmanuelle, Grailles, Guillaume, El amine, Younes, Defrancq, Fanny, Fodil, Hanane, Bouras, Chaouki, Dautel, Dominique, Gambier, Nicolas, Dieye, Thierno, Bienvenu, Boris, Lancon, Victor, Lecomte, Laurence, Beziriganyan, Kristina, Asselate, Belkacem, Allanic, Laure, Kiouris, Elena, Legros, Marie-Héléne, Lemagner, Christine, Martel, Pascal, Provitolo, Vincent, Ackermann, Félix, Le Marchand, Mathilde, Chan Hew Wai, Aurélie, Fremont, Dimitri, Coupez, Elisabeth, Adda, Mireille, Duée, Frédéric, Bernard, Lise, Gros, Antoine, Henry, Estelle, Courtin, Claire, Pattyn, Anne, Guinot, Pierre-Grégoire, Bardou, Marc, Maurer, Agnes, Jambon, Julie, Cransac, Amélie, Pernot, Corinne, Mourvillier, Bruno, Marquis, Eric, Benoit, Philippe, Roux, Damien, Gernez, Coralie, Yelnik, Cécile, Poissy, Julien, Nizard, Mandy, Denies, Fanette, Gros, Helene, Mourad, Jean-Jacques, Sacco, Emmanuelle, Renet, Sophie, Ader, F., Yazdanpanah, Y., Mentre, F., Peiffer-Smadja, N., Lescure, F.X., Poissy, J., Bouadma, L., Timsit, J.F., Lina, B., Morfin-Sherpa, F., Bouscambert, M., Gaymard, A., Peytavin, G., Abel, L., Guedj, J., Andrejak, C., Burdet, C., Laouenan, C., Belhadi, D., Dupont, A., Alfaiate, T., Basli, B., Chair, A., Laribi, S., Level, J., Schneider, M., Tellier, M.C., Dechanet, A., Costagliola, D., Terrier, B., Ohana, M., Couffin-Cadiergues, S., Esperou, H., Delmas, C., Saillard, J., Fougerou, C., Moinot, L., Wittkop, L., Cagnot, C., Le Mestre, S., Lebrasseur-Longuet, D., Petrov-Sanchez, V., Diallo, A., Mercier, N., Icard, V., Leveau, B., Tubiana, S., Hamze, B., Gelley, A., Noret, M., D’Ortenzio, E., Puechal, O., Semaille, C., Welte, T., Paiva, J.A., Halanova, M., Kieny, M.P., Balssa, E., Birkle, C., Gibowski, S., Landry, E., Le Goff, A., Moachon, L., Moins, C., Wadouachi, L., Paul, C., Levier, A., Bougon, D., Djossou, F., Epelboin, L., Dellamonica, J., Marquette, C.H., Robert, C., Gibot, S., Senneville, E., Jean-Michel, V., Zerbib, Y., Chirouze, C., Boyer, A., Cazanave, C., Gruson, D., Malvy, D., Andreu, P., Quenot, J.P., Terzi, N., Faure, K., Chabartier, C., Le Moing, V., Klouche, K., Ferry, T., F, Valour, Gaborit, B., Canet, E., Le Turnier, P., Boutoille, D., Bani-Sadr, F., Benezit, F., Revest, M., Cameli, C., Caro, A., Um Tegue, MJ Ngo, Le Tulzo, Y., Laviolle, B., Laine, F., Thiery, G., Meziani, F., Hansmann, Y., Oulehri, W., Tacquard, C., Vardon-Bounes, F., Riu-Poulenc, B., Murris-Espin, M., Bernard, L., Garot, D., Hinschberger, O., Martinot, M., Bruel, C., Pilmis, B., Bouchaud, O., Loubet, P., Roger, C., Monnet, X., Figueiredo, S., Godard, V., Mira, J.P., Lachatre, M., Kerneis, S., Aboab, J., Sayre, N., Crockett, F., Lebeaux, D., Buffet, A., Diehl, J.L., Fayol, A., Hulot, J.S., Livrozet, M., Dessap, A Mekontso, Ficko, C., Stefan, F., Le Pavec, J., Mayaux, J., Ait-Oufella, H., Molina, J.M., Pialoux, G., Fartoukh, M., Textoris, J., Brossard, M., Essat, A., Netzer, E., Riault, Y., Ghislain, M., Beniguel, L., Genin, M., Gouichiche, L., Betard, C., Belkhir, L., Altdorfer, A., Centro, V Fraipont, Braz, S., Ribeiro, JM Ferreira, Alburqueque, R Roncon, Berna, M., Alexandre, M., Lamprecht, B., Egle, A., Greil, R., Joannidis, M., Patterson, Thomas F., Ponce, Philip O., Taylor, Barbara S., Patterson, Jan E., Bowling, Jason E., Javeri, Heta, Kalil, Andre C., Larson, LuAnn, Hewlett, Angela, Mehta, Aneesh K., Rouphael, Nadine G., Saklawi, Youssef, Scanlon, Nicholas, Traenkner, Jessica J., Trible, Ronald P., Jr., Walter, Emmanuel B., Ivey, Noel, Holland, Thomas L., Ruiz-Palacios, Guillermo M., Ponce de León, Alfredo, Rajme, Sandra, Hsieh, Lanny, Amin, Alpesh N., Watanabe, Miki, Lee, Helen S., Kline, Susan, Billings, Joanne, Noren, Brooke, Kim, Hyun, Bold, Tyler D., Tapson, Victor, Grein, Jonathan, Sutterwala, Fayyaz, Iovine, Nicole, Beattie, Lars K., Wakeman, Rebecca Murray, Shaw, Matthew, Jain, Mamta K., Mocherla, Satish, Meisner, Jessica, Luque, Amneris, Sweeney, Daniel A., Benson, Constance A., Ali, Farhana, Atmar, Robert L., El Sahly, Hana M., Whitaker, Jennifer, Falsey, Ann R., Branche, Angela R., Rozario, Cheryl, Pineda, Justino Regalado, Martinez-Orozco, José Arturo, Lye, David Chien, Ong, Sean WX., Chia, Po Ying, Young, Barnaby E., Sandkovsky, Uriel, Berhe, Mezgebe, Haley, Clinton, Dishner, Emma, Cantos, Valeria D., Kelley, Colleen F., Rebolledo Esteinou, Paulina A., Kandiah, Sheetal, Doernberg, Sarah B., Crouch, Pierre-Cedric B., Jang, Hannah, Luetkemeyer, Anne F., Dwyer, Jay, Cohen, Stuart H., Thompson, George R., 3rd, Nguyen, Hien H., Finberg, Robert W., Wang, Jennifer P., Perez-Velazquez, Juan, Wessolossky, Mireya, Jackson, Patrick E.H., Bell, Taison D., West, Miranda J., Taiwo, Babafemi, Krueger, Karen, Perez, Johnny, Pearson, Triniece, Paules, Catharine I., Julian, Kathleen G., Ahmad, Danish, Hajduczok, Alexander G., Arguinchona, Henry, Arguinchona, Christa, Erdmann, Nathaniel, Goepfert, Paul, Ahuja, Neera, Frank, Maria G., Wyles, David, Young, Heather, Oh, Myoung-don, Park, Wan Beom, Kang, Chang Kyung, Marconi, Vincent, Moanna, Abeer, Cribbs, Sushma, Harrison, Telisha, Kim, Eu Suk, Jung, Jongtak, Song, Kyoung-Ho, Kim, Hong Bin, Tan, Seow Yen, Shafi, Humaira, Chien, Jaime, Fong, Raymond KC., Murray, Daniel D., Lundgren, Jens, Nielsen, Henrik, Jensen, Tomas, Zingman, Barry S., Grossberg, Robert, Riska, Paul F., Yang, Otto O., Ahn, Jenny, Arias, Rubi, Rapaka, Rekha R., Hauser, Naomi, Campbell, James D., Short, William R., Tebas, Pablo, Baron, Jillian T., McLellan, Susan L.F., Blanton, Lucas S., Seashore, Justin B., Creech, C. Buddy, Rice, Todd W., Walker, Shannon, Thomsen, Isaac P., Lopez de Castilla, Diego, Van Winkle, Jason W., Riedo, Francis X., Pada, Surinder Kaur, Wang, Alvin DY., Lin, Li, Harkins, Michelle, Mertz, Gregory, Sosa, Nestor, Ann Chai, Louis Yi, Tambyah, Paul Anantharajah, Tham, Sai Meng, Archuleta, Sophia, Yan, Gabriel, Lindholm, David A., Markelz, Ana Elizabeth, Mende, Katrin, Mularski, Richard, Hohmann, Elizabeth, Torres-Soto, Mariam, Jilg, Nikolaus, Maves, Ryan C., Utz, Gregory C., George, Sarah L., Hoft, Daniel F., Brien, James D., Paredes, Roger, Mateu, Lourdes, Loste, Cora, Kumar, Princy, Thornton, Sarah, Mohanraj, Sharmila, Hynes, Noreen A., Sauer, Lauren M., Colombo, Christopher J., Schofield, Christina, Colombo, Rhonda E., Chambers, Susan E., Novak, Richard M., Wendrow, Andrea, Gupta, Samir K., Lee, Tida, Lalani, Tahaniyat, Holodniy, Mark, Chary, Aarthi, Huprikar, Nikhil, Ganesan, Anuradha, Ohmagari, Norio, Mikami, Ayako, Price, D. Ashley, Duncan, Christopher J.A., Dierberg, Kerry, Neumann, Henry J., Taylor, Stephanie N., Lacour, Alisha, Masri, Najy, Swiatlo, Edwin, Widmer, Kyle, Neaton, James D., Bessesen, Mary, Stephens, David S., Burgess, Timothy H., Uyeki, Timothy M., Walker, Robert, Marks, G. Lynn, Osinusi, Anu, Cao, Huyen, Cardoso, Anabela, de Bono, Stephanie, Schlichting, Douglas E., Chung, Kevin K., Ferreira, Jennifer L., Green, Michelle, Makowski, Mat, Wierzbicki, Michael R., Conrad, Tom M., El-Khorazaty, Jill Ann, Hill, Heather, Bonnett, Tyler, Gettinger, Nikki, Engel, Theresa, Lewis, Teri, Wang, Jing, Beigel, John H., Tomashek, Kay M., Ghazaryan, Varduhi, Beresnev, Tatiana, Nayak, Seema, Dodd, Lori E., Dempsey, Walla, Nomicos, Effie, Lee, Marina, Pikaart-Tautges, Rhonda, Elsafy, Mohamed, Jurao, Robert, Koo, Hyung, Proschan, Michael, Yokum, Tammy, Arega, Janice, Florese, Ruth, Voell, Jocelyn D., Davey, Richard, Serrano, Ruth C., Wiley, Zanthia, Phadke, Varun K., Goepfert, Paul A., Gomez, Carlos A., Sofarelli, Theresa A., Certain, Laura, Imlay, Hannah N., Wolfe, Cameron R., Ko, Emily R., Engemann, John J., Felix, Nora Bautista, Wan, Claire R., Elmor, Sammy T., Bristow, Laurel R., Harkins, Michelle S., Iovine, Nicole M., Elie-Turenne, Marie-Carmelle, Tapson, Victor F., Choe, Pyoeng Gyun, Mularski, Richard A., Rhie, Kevin S., Hussein, Rezhan H., Ince, Dilek, Winokur, Patricia L., Takasaki, Jin, Saito, Sho, McConnell, Kimberly, Wyles, David L., Sarcone, Ellen, Grimes, Kevin A., Perez, Katherine, Janak, Charles, Whitaker, Jennifer A., Rebolledo, Paulina A., Gharbin, John, Lambert, Allison A., Zea, Diego F., Bainbridge, Emma, Hostler, David C., Hostler, Jordanna M., Shahan, Brian T., Ling, Evelyn, Go, Minjoung, Hubbard, Fleesie A., Chakrabarty, Melony, Laguio-Vila, Maryrose, Walsh, Edward E., Guirgis, Faheem, Marconi, Vincent C., Madar, Christian, Borgetti, Scott A., Levine, Corri, Nock, Joy, Candiotti, Keith, Rozman, Julia, Dangond, Fernando, Hyvert, Yann, Seitzinger, Andrea, Cross, Kaitlyn, Pettibone, Stephanie, Nayak, Seema U., Deye, Gregory A., Siempos, Ilias I., Belhadi, Drifa, Veiga, Viviane Cordeiro, Cavalcanti, Alexandre Biasi, Branch-Elliman, Westyn, Papoutsi, Eleni, Gkirgkiris, Konstantinos, Xixi, Nikoleta A., and Kotanidou, Anastasia

Published
2024
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7. Endpoints for randomized controlled clinical trials for COVID-19 treatments

Author

Dodd, Lori E, Follmann, Dean, Wang, Jing, Koenig, Franz, Korn, Lisa L, Schoergenhofer, Christian, Proschan, Michael, Hunsberger, Sally, Bonnett, Tyler, Makowski, Mat, Belhadi, Drifa, Wang, Yeming, Cao, Bin, Mentre, France, and Jaki, Thomas

Subjects
Statistics - Methodology, Quantitative Biology - Populations and Evolution, Quantitative Biology - Quantitative Methods
Abstract

Introduction: Endpoint choice for randomized controlled trials of treatments for COVID-19 is complex. A new disease brings many uncertainties, but trials must start rapidly. COVID-19 is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks and can end in death. While improvement in mortality would provide unquestionable evidence about clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly in relating to the uncertainty about the time-course of COVID-19. Outcomes measured at fixed time-points may risk missing the time of clinical benefit. An endpoint such as time-to-improvement (or recovery), avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" vs "not recovered." Methods: We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials. Results: Power for fixed-time point methods depends heavily on the time selected for evaluation. Time-to-improvement (or recovery) analyses do not specify a time-point. Time-to-event approaches have reasonable statistical power, even when compared to a fixed time-point method evaluated at the optimal time. Discussion: Time-to-event analyses methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.

Published
2020

8. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Author

Kalil, Andre C, Patterson, Thomas F, Mehta, Aneesh K, Tomashek, Kay M, Wolfe, Cameron R, Ghazaryan, Varduhi, Marconi, Vincent C, Ruiz-Palacios, Guillermo M, Hsieh, Lanny, Kline, Susan, Tapson, Victor, Iovine, Nicole M, Jain, Mamta K, Sweeney, Daniel A, El Sahly, Hana M, Branche, Angela R, Regalado Pineda, Justino, Lye, David C, Sandkovsky, Uriel, Luetkemeyer, Anne F, Cohen, Stuart H, Finberg, Robert W, Jackson, Patrick EH, Taiwo, Babafemi, Paules, Catharine I, Arguinchona, Henry, Erdmann, Nathaniel, Ahuja, Neera, Frank, Maria, Oh, Myoung-Don, Kim, Eu-Suk, Tan, Seow Y, Mularski, Richard A, Nielsen, Henrik, Ponce, Philip O, Taylor, Barbara S, Larson, LuAnn, Rouphael, Nadine G, Saklawi, Youssef, Cantos, Valeria D, Ko, Emily R, Engemann, John J, Amin, Alpesh N, Watanabe, Miki, Billings, Joanne, Elie, Marie-Carmelle, Davey, Richard T, Burgess, Timothy H, Ferreira, Jennifer, Green, Michelle, Makowski, Mat, Cardoso, Anabela, de Bono, Stephanie, Bonnett, Tyler, Proschan, Michael, Deye, Gregory A, Dempsey, Walla, Nayak, Seema U, Dodd, Lori E, and Beigel, John H

Subjects
Rehabilitation, Clinical Trials and Supportive Activities, Lung, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Adenosine Monophosphate, Adult, Aged, Alanine, Antiviral Agents, Azetidines, COVID-19, Double-Blind Method, Drug Therapy, Combination, Female, Hospital Mortality, Hospitalization, Humans, Janus Kinase Inhibitors, Male, Middle Aged, Oxygen Inhalation Therapy, Purines, Pyrazoles, Respiration, Artificial, Sulfonamides, Treatment Outcome, COVID-19 Drug Treatment, ACTT-2 Study Group Members, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundSevere coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.MethodsWe conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.ResultsA total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).ConclusionsBaricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

Published
2021

9. Remdesivir for the Treatment of Covid-19 — Final Report

Author

Beigel, John H, Tomashek, Kay M, Dodd, Lori E, Mehta, Aneesh K, Zingman, Barry S, Kalil, Andre C, Hohmann, Elizabeth, Chu, Helen Y, Luetkemeyer, Annie, Kline, Susan, Lopez de Castilla, Diego, Finberg, Robert W, Dierberg, Kerry, Tapson, Victor, Hsieh, Lanny, Patterson, Thomas F, Paredes, Roger, Sweeney, Daniel A, Short, William R, Touloumi, Giota, Lye, David Chien, Ohmagari, Norio, Oh, Myoung-Don, Ruiz-Palacios, Guillermo M, Benfield, Thomas, Fätkenheuer, Gerd, Kortepeter, Mark G, Atmar, Robert L, Creech, C Buddy, Lundgren, Jens, Babiker, Abdel G, Pett, Sarah, Neaton, James D, Burgess, Timothy H, Bonnett, Tyler, Green, Michelle, Makowski, Mat, Osinusi, Anu, Nayak, Seema, and Lane, H Clifford

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Clinical Trials and Supportive Activities, Clinical Research, Rehabilitation, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Adenosine Monophosphate, Administration, Intravenous, Adult, Aged, Alanine, Antiviral Agents, Betacoronavirus, COVID-19, Coronavirus Infections, Double-Blind Method, Extracorporeal Membrane Oxygenation, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Oxygen Inhalation Therapy, Pandemics, Pneumonia, Viral, Respiration, Artificial, SARS-CoV-2, Time Factors, Young Adult, COVID-19 Drug Treatment, ACTT-1 Study Group Members, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundAlthough several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.MethodsWe conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.ResultsA total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P

Published
2020

10. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials

Author

Amstutz, Alain, Speich, Benjamin, Mentré, France, Rueegg, Corina Silvia, Belhadi, Drifa, Assoumou, Lambert, Burdet, Charles, Murthy, Srinivas, Dodd, Lori Elizabeth, Wang, Yeming, Tikkinen, Kari A O, Ader, Florence, Hites, Maya, Bouscambert, Maude, Trabaud, Mary Anne, Fralick, Mike, Lee, Todd C, Pinto, Ruxandra, Barratt-Due, Andreas, Lund-Johansen, Fridtjof, Müller, Fredrik, Nevalainen, Olli P O, Cao, Bin, Bonnett, Tyler, Griessbach, Alexandra, Taji Heravi, Ala, Schönenberger, Christof, Janiaud, Perrine, Werlen, Laura, Aghlmandi, Soheila, Schandelmaier, Stefan, Yazdanpanah, Yazdan, Costagliola, Dominique, Olsen, Inge Christoffer, and Briel, Matthias

Published
2023
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11. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

Author

Wahid, Lana, Walter, Emmanuel B., Belur, Akhila G., Dreyer, Grace, Patterson, Jan E., Bowling, Jason E., Dixon, Danielle O., Hewlett, Angela, Odrobina, Robert, Pupaibool, Jakrapun, Mocherla, Satish, Lazarte, Suzana, Cayabyab, Meilani, Hussein, Rezhan H., Golamari, Reshma R., Krill, Kaleigh L., Rajme, Sandra, Riska, Paul F., Zingman, Barry S., Mertz, Gregory, Sosa, Nestor, Goepfert, Paul A., Berhe, Mezgebe, Dishner, Emma, Fayed, Mohamed, Hubel, Kinsley, Martinez-Orozco, José Arturo, Bautista Felix, Nora, Elmor, Sammy T., Bechnak, Amer Ryan, Saklawi, Youssef, Van Winkle, Jason W., Zea, Diego F., Laguio-Vila, Maryrose, Walsh, Edward E., Falsey, Ann R., Carvajal, Karen, Hyzy, Robert C., Hanna, Sinan, Olbrich, Norman, Traenkner, Jessica J., Kraft, Colleen S., Tebas, Pablo, Baron, Jillian T, Levine, Corri, Nock, Joy, Billings, Joanne, Kim, Hyun, Elie-Turenne, Marie-Carmelle, Whitaker, Jennifer A., Luetkemeyer, Anne F., Dwyer, Jay, Bainbridge, Emma, Gyun Choe, Pyoeng, Kyung Kang, Chang, Jilg, Nikolaus, Cantos, Valeria D, Bhamidipati, Divya R., Nithin Gopalsamy, Srinivasa, Chary, Aarthi, Jung, Jongtak, Song, Kyoung-Ho, Kim, Hong Bin, Benson, Constance A., McConnell, Kimberly, Wang, Jennifer P., Wessolossky, Mireya, Perez, Katherine, Eubank, Taryn A, Berjohn, Catherine, Utz, Gregory C., Jackson, Patrick E.H., Bell, Taison D., Haughey, Heather M., Moanna, Abeer, Cribbs, Sushma, Harrison, Telisha, Colombo, Christopher J., Schofield, Christina, Colombo, Rhonda E., Tapson, Victor F., Grein, Jonathan, Sutterwala, Fayyaz, Ince, Dilek, Winokur, Patricia L., Fung, Monica, Jang, Hannah, Wyles, David, Frank, Maria G., Sarcone, Ellen, Neumann, Henry, Viswanathan, Anand, Hochman, Sarah, Mulligan, Mark, Eckhardt, Benjamin, Carmody, Ellie, Ahuja, Neera, Nadeau, Kari, Svec, David, Macaraeg, Jeffrey C., Morrow, Lee, Quimby, Dave, Bessesen, Mary, Nicholson, Lindsay, Adams, Jill, Kumar, Princy, Lambert, Allison A., Arguinchona, Henry, Alicic, Radica Z., Saito, Sho, Ohmagari, Norio, Mikami, Ayako, Chien Lye, David, Hong Lee, Tau, Ying Chia, Po, Hsieh, Lanny, Amin, Alpesh N., Watanabe, Miki, Candiotti, Keith A., Castro, Jose G., Antor, Maria A., Lee, Tida, Lalani, Tahaniyat, Novak, Richard M., Wendrow, Andrea, Borgetti, Scott A., George, Sarah L., Hoft, Daniel F., Brien, James D., Cohen, Stuart H., Thompson, George R., 3rd, Chakrabarty, Melony, Guirgis, Faheem, Davey, Richard T., Voell, Jocelyn, Strich, Jeffrey R., Lindholm, David A., Mende, Katrin, Wellington, Trevor R., Rapaka, Rekha R., Husson, Jennifer S., Levine, Andrea R., Yen Tan, Seow, Shafi, Humaira, Chien, Jaime M F, Hostler, David C., Hostler, Jordanna M., Shahan, Brian T., Adams, David H., Osinusi, Anu, Cao, Huyen, Burgess, Timothy H., Rozman, Julia, Chung, Kevin K., Nieuwoudt, Christina, El-Khorazaty, Jill A., Hill, Heather, Pettibone, Stephanie, Gettinger, Nikki, Engel, Theresa, Lewis, Teri, Wang, Jing, Deye, Gregory A., Nomicos, Effie, Pikaart-Tautges, Rhonda, Elsafy, Mohamed, Jurao, Robert, Koo, Hyung, Proschan, Michael, Yokum, Tammy, Arega, Janice, Florese, Ruth, Wolfe, Cameron R, Tomashek, Kay M, Patterson, Thomas F, Gomez, Carlos A, Marconi, Vincent C, Jain, Mamta K, Yang, Otto O, Paules, Catharine I, Palacios, Guillermo M Ruiz, Grossberg, Robert, Harkins, Michelle S, Mularski, Richard A, Erdmann, Nathaniel, Sandkovsky, Uriel, Almasri, Eyad, Pineda, Justino Regalado, Dretler, Alexandra W, de Castilla, Diego Lopez, Branche, Angela R, Park, Pauline K, Mehta, Aneesh K, Short, William R, McLellan, Susan L F, Kline, Susan, Iovine, Nicole M, El Sahly, Hana M, Doernberg, Sarah B, Oh, Myoung-don, Huprikar, Nikhil, Hohmann, Elizabeth, Kelley, Colleen F, Holodniy, Mark, Kim, Eu Suk, Sweeney, Daniel A, Finberg, Robert W, Grimes, Kevin A, Maves, Ryan C, Ko, Emily R, Engemann, John J, Taylor, Barbara S, Ponce, Philip O, Larson, LuAnn, Melendez, Dante Paolo, Seibert, Allan M, Rouphael, Nadine G, Strebe, Joslyn, Clark, Jesse L, Julian, Kathleen G, de Leon, Alfredo Ponce, Cardoso, Anabela, de Bono, Stephanie, Atmar, Robert L, Ganesan, Anuradha, Ferreira, Jennifer L, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori E, Beigel, John H, and Kalil, Andre C

Published
2022
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12. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-blind, randomised, placebo-controlled, phase 3 trial

Author

Hewlett, Angela, Taylor, Barbara S, Bowling, Jason E, Serrano, Ruth C, Rouphael, Nadine G, Wiley, Zanthia, Phadke, Varun K, Certain, Laura, Imlay, Hannah N, Engemann, John J, Walter, Emmanuel B, Meisner, Jessica, Rajme, Sandra, Billings, Joanne, Kim, Hyun, Martinez-Orozco, Jose A, Bautista Felix, Nora, Elmor, Sammy T, Bristow, Laurel R, Mertz, Gregory, Sosa, Nestor, Bell, Taison D, West, Miranda J, Elie-Turenne, Marie-Carmelle, Grein, Jonathan, Sutterwala, Fayyaz, Gyun Choe, Pyoeng, Kyung Kang, Chang, El Sahly, Hana M, Rhie, Kevin S, Hussein, Rezhan H, Winokur, Patricia L, Mikami, Ayako, Saito, Sho, Benson, Constance A, McConnell, Kimberly, Berhe, Mezgebe, Dishner, Emma, Frank, Maria G, Sarcone, Ellen, Crouch, Pierre-Cedric B, Jang, Hannah, Jilg, Nikolaus, Perez, Katherine, Janak, Charles, Cantos, Valeria D, Rebolledo, Paulina A, Gharbin, John, Zingman, Barry S, Riska, Paul F, Falsey, Ann R, Walsh, Edward E, Branche, Angela R, Arguinchona, Henry, Arguinchona, Christa, Van Winkle, Jason W, Zea, Diego F, Jung, Jongtak, Song, Kyoung-Ho, Kim, Hong Bin, Dwyer, Jay, Bainbridge, Emma, Hostler, David C, Hostler, Jordanna M, Shahan, Brian T, Hsieh, Lanny, Amin, Alpesh N, Watanabe, Miki, Short, William R, Tebas, Pablo, Baron, Jillian T, Ahuja, Neera, Ling, Evelyn, Go, Minjoung, Yang, Otto O, Ahn, Jenny, Arias, Rubi, Rapaka, Rekha R, Hubbard, Fleesie A, Campbell, James D, Cohen, Stuart H, Thompson, George R, 3rd, Chakrabarty, Melony, Taylor, Stephanie N, Masri, Najy, Lacour, Alisha, Lee, Tida, Lalani, Tahaniyat, Lindholm, David A, Markelz, Ana Elizabeth, Mende, Katrin, Colombo, Christopher J, Schofield, Christina, Colombo, Rhonda E, Guirgis, Faheem, Holodniy, Mark, Chary, Aarthi, Bessesen, Mary, Hynes, Noreen A, Sauer, Lauren M, Marconi, Vincent C, Moanna, Abeer, Harrison, Telisha, Lye, David C, Ong, Sean W X, Ying Chia, Po, Huprikar, Nikhil, Ganesan, Anuradha, Madar, Christian, Novak, Richard M, Wendrow, Andrea, Borgetti, Scott A, George, Sarah L, Hoft, Daniel F, Brien, James D, McLellan, Susan L F, Levine, Corri, Nock, Joy, Yen Tan, Seow, Shafi, Humaira, Chien, Jaime M F, Candiotti, Keith, Finberg, Robert W, Wang, Jennifer P, Wessolossky, Mireya, Utz, Gregory C, Chambers, Susan E, Stephens, David S, Burgess, Timothy H, Rozman, Julia, Hyvert, Yann, Seitzinger, Andrea, Osinusi, Anu, Cao, Huyen, Chung, Kevin K, Conrad, Tom M, Cross, Kaitlyn, El-Khorazaty, Jill A, Hill, Heather, Pettibone, Stephanie, Wierzbicki, Michael R, Gettinger, Nikki, Engel, Theresa, Lewis, Teri, Wang, Jing, Deye, Gregory A, Nomicos, Effie, Pikaart-Tautges, Rhonda, Elsafy, Mohamed, Jurao, Robert, Koo, Hyung, Proschan, Michael, Davey, Richard, Yokum, Tammy, Arega, Janice, Florese, Ruth, Kalil, Andre C, Mehta, Aneesh K, Patterson, Thomas F, Erdmann, Nathaniel, Gomez, Carlos A, Jain, Mamta K, Wolfe, Cameron R, Ruiz-Palacios, Guillermo M, Kline, Susan, Regalado Pineda, Justino, Luetkemeyer, Anne F, Harkins, Michelle S, Jackson, Patrick E H, Iovine, Nicole M, Tapson, Victor F, Oh, Myoung-don, Whitaker, Jennifer A, Mularski, Richard A, Paules, Catharine I, Ince, Dilek, Takasaki, Jin, Sweeney, Daniel A, Sandkovsky, Uriel, Wyles, David L, Hohmann, Elizabeth, Grimes, Kevin A, Grossberg, Robert, Laguio-Vila, Maryrose, Lambert, Allison A, Lopez de Castilla, Diego, Kim, EuSuk, Larson, LuAnn, Wan, Claire R, Traenkner, Jessica J, Ponce, Philip O, Patterson, Jan E, Goepfert, Paul A, Sofarelli, Theresa A, Mocherla, Satish, Ko, Emily R, Ponce de Leon, Alfredo, Doernberg, Sarah B, Atmar, Robert L, Maves, Ryan C, Dangond, Fernando, Ferreira, Jennifer, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori, Tomashek, Kay M, and Beigel, John H

Published
2021
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14. Discussion on the meeting on ‘Signs and sizes: understanding and replicating statistical findings’

Author

Hutton, Jane L., Diggle, Peter J., Bird, Sheila M., Hennig, Christian, Longford, Nick, Mathur, Maya B., VanderWeele, Tyler J., Ioannidis, John P. A., Chai, Christine P., Dowe, David L., Ferguson, John, Fitz-Simon, Nicola, Friede, Tim, Röver, Christian, Grieve, A. P., Kumar, Kuldeep, Ly, Alexander, Mansmann, Ulrich, Mateu, Jorge, Matthews, Robert A. J., Neuenschwander, Beat, Zwahlen, Marcel, Pericchi, Luis, Roes, Kit C. B., Senn, Stephen, Wagenmakers, Eric-Jan, Rice, Kenneth, Krakauer, Chloe, Bonnett, Tyler, and Held, Leonhard

Published
2020

15. A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2.

Author

Paules, Catharine I., Wang, Jing, Tomashek, Kay M., Bonnett, Tyler, Singh, Kanal, Marconi, Vincent C., Davey Jr., Richard T., Lye, David C., Dodd, Lori E., Yang, Otto O., Benson, Constance A., Deye, Gregory A., Doernberg, Sarah B., Hynes, Noreen A., Grossberg, Robert, Wolfe, Cameron R., Nayak, Seema U., Short, William R., Voell, Jocelyn, and Potter, Gail E.

Subjects
COVID-19, COVID-19 treatment, BARICITINIB, SARS-CoV-2, PLATELET count
Abstract

This post hoc analysis of the randomized, double-blind, placebo-controlled trial ACTT-2 (Adaptive COVID-19 Treatment Trial-2) sought to determine whether any patient characteristics are associated with treatment benefit from the immunomodulator baricitinib among hospitalized patients with COVID-19 who fall into the "high-risk" quartile. Visual Abstract. A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2 This post hoc analysis of the randomized, double-blind, placebo-controlled trial ACTT-2 (Adaptive COVID-19 Treatment Trial-2) sought to determine whether any patient characteristics are associated with treatment benefit from the immunomodulator baricitinib among hospitalized patients with COVID-19 who fall into the "high-risk" quartile. Background: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib. Objective: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile. Design: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579) Setting: Sixty-seven trial sites in 8 countries. Participants: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants). Intervention: Baricitinib+remdesivir versus placebo+remdesivir. Measurements: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories. Results: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile. Limitation: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants. Conclusion: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19. Primary Funding Source: National Institute of Allergy and Infectious Diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Counting Monkeypox Lesions in Patient Photographs: Limits of Agreement of Manual Counts and Artificial Intelligence

Author

McNeil, Andrew J., primary, House, David W., additional, Mbala-Kingebeni, Placide, additional, Mbaya, Olivier Tshiani, additional, Dodd, Lori E., additional, Cowen, Edward W., additional, Nussenblatt, Véronique, additional, Bonnett, Tyler, additional, Chen, Ziche, additional, Saknite, Inga, additional, Dawant, Benoit M., additional, and Tkaczyk, Eric R., additional

Published
2023
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17. Design of an observational multi-country cohort study to assess immunogenicity of multiple vaccine platforms (InVITE)

Author

Sereti, Irini, primary, Shaw-Saliba, Kathryn, additional, Dodd, Lori E., additional, Dewar, Robin L., additional, Laverdure, Sylvain, additional, Brown, Shawn, additional, Mbaya, Olivier Tshiani, additional, Muyembe Tamfum, Jean Jacques, additional, Mblala-Kingebeni, Placide, additional, Sow, Ydrissa, additional, Akpa, Esther, additional, Haidara, Mory Cherif, additional, Fouth Tchos, Karine, additional, Beavogui, Abdoul Habib, additional, Neal, Aaron, additional, Arlinda, Dona, additional, Lokida, Dewi, additional, Grue, Louis, additional, Smolskis, Mary, additional, McNay, Laura A., additional, Gayedyu-Dennis, Dehkontee, additional, Ruiz-Palacios, Guillermo M., additional, Montenegro-Liendo, Abelardo, additional, Tounkara, Moctar, additional, Samake, Seydou, additional, Jargalsaikhan, Ganbolor, additional, Zulkhuu, Delgersaikhan, additional, Weyers, Shera, additional, Bonnett, Tyler, additional, Potter, Gail E., additional, Stevens, Randy, additional, Rupert, Adam, additional, Aboulhab, Jamila, additional, Biampata, Jean-Luc, additional, Delamo, Alexandre, additional, Camara, Bienvenu Salim, additional, Kosasih Indonesia, Herman, additional, Karyana, Muhammad, additional, Duworko, James T., additional, Regalado-Pineda, Justino, additional, Guerra-de-Blas, Paola del Carmen, additional, Doumbia, Seydou, additional, Dabitao, Djeneba, additional, Dashdorj, Naranjargal, additional, Dashdorj, Naranbaatar, additional, Newell, Kevin, additional, Francis, Alyson, additional, Rubenstein, Kevin, additional, Bera, Victoria, additional, Gulati, Iman, additional, Sardana, Ratna, additional, Millard, Monica, additional, Ridzon, Renee, additional, and Hunsberger, Sally, additional

Published
2022
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18. Unraveling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2

Author

Fintzi, Jonathan, primary, Bonnett, Tyler, additional, Tebas, Pablo, additional, Marconi, Vincent C, additional, Levine, Corri B, additional, El Sahly, Hana M, additional, McLellan, Susan L F, additional, Benson, Constance A, additional, Rostad, Christina A, additional, Ganesan, Anuradha, additional, Huprikar, Nikhil, additional, Frank, Maria G, additional, Mularski, Richard A, additional, Atmar, Robert L, additional, Park, Pauline K, additional, Short, William R, additional, Beigel, John H, additional, Mehta, Aneesh K, additional, and Sweeney, Daniel A, additional

Published
2022
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19. Effects of Remdesivir in Hospitalized Patients with COVID-19: Systematic Review and Individual Patient Data Meta-Analysis of Randomized Clinical Trials

Author

Amstutz, Alain, primary, Speich, Benjamin, additional, Mentré, France, additional, Rueegg, Corina Silvia, additional, Belhadi, Drifa, additional, Assoumou, Lambert, additional, Burdet, Charles, additional, Murthy, Srinivas, additional, Dodd, Lori Elizabeth, additional, Wang, Yeming, additional, Tikkinen, Kari, additional, Ader, Florence, additional, Hites, Maya, additional, Bouscambert-Duchamp, Maude, additional, Trabaud, Mary-Anne, additional, Fralick, Mike, additional, Lee, Todd Campbell, additional, Pinto, Ruxandra, additional, Barratt-Due, Andreas, additional, Lund-Johansen, Fridtjof, additional, Müller, Fredrik, additional, Nevalainen, Olli, additional, Cao, Bin, additional, Bonnett, Tyler, additional, Griessbach, Alexandra, additional, Taji Heravi, Ala, additional, Schönenberger, Christof, additional, Janiaud, Perrine, additional, Werlen, Laura, additional, Aghlmandi, Soheila, additional, Schandelmaier, Stefan, additional, Yazdanpanah, Yazdan, additional, Costagliola, Dominique, additional, Olsen, Inge Christoffer, additional, and Briel, Matthias, additional

Published
2022
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20. How do I… facilitate a rapid response to a public health emergency requiring plasma collection with a public–private partnership?

Author

Miller, Maureen J., primary, Skrzekut, Adam, additional, Kracalik, Ian, additional, Jones, Jefferson M., additional, Lofy, Kathryn H., additional, Konkle, Barbara A., additional, Haley, N. Rebecca, additional, Duvenhage, Michael, additional, Bonnett, Tyler, additional, Holbrook, Michael, additional, Higgs, Elizabeth, additional, Basavaraju, Sridhar V., additional, and Paranjape, Suman, additional

Published
2021
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21. Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization

Author

Fintzi, Jonathan, primary, Bonnett, Tyler, additional, Sweeney, Daniel A, additional, Huprikar, Nikhil A, additional, Ganesan, Anuradha, additional, Frank, Maria G, additional, McLellan, Susan L F, additional, Dodd, Lori E, additional, Tebas, Pablo, additional, and Mehta, Aneesh K, additional

Published
2021
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22. Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization.

Author

Fintzi, Jonathan, Bonnett, Tyler, Sweeney, Daniel A, Huprikar, Nikhil A, Ganesan, Anuradha, Frank, Maria G, McLellan, Susan L F, Dodd, Lori E, Tebas, Pablo, and Mehta, Aneesh K

Subjects
*DISEASE progression, *DRUG efficacy, *COVID-19, *CONFIDENCE intervals, *ANTIVIRAL agents, *DISEASE incidence, *MEDICAL care use, *SEVERITY of illness index, *ARTIFICIAL respiration, *CRITICAL care medicine, *DESCRIPTIVE statistics, *SECONDARY analysis, *EVALUATION
Abstract

Background The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death. Methods We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1. We developed competing risks models that estimate the effect of remdesivir therapy on cumulative incidence of clinical improvement and deterioration, and multistate models that utilize the entirety of each patient's clinical course to characterize the effect of remdesivir on progression along the 4 pathways above. Results Based on a competing risks analysis, remdesivir reduced clinical deterioration (hazard ratio [HR], 0.73; 95% confidence interval [CI]:.59–.91) and increased clinical improvement (HR, 1.22; 95% CI: 1.08, 1.39) relative to baseline. Our multistate models indicate that remdesivir inhibits worsening to ordinal scores of greater clinical severity among patients on room air or low-flow oxygen (HR, 0.74; 95% CI:.57–.94) and among patients receiving mechanical ventilation or high-flow oxygen/noninvasive positive-pressure ventilation (HR, 0.73; 95% CI:.53–1.00) at baseline. We also find that remdesivir reduces expected intensive care respiratory therapy utilization among patients not mechanically ventilated at baseline. Conclusions Remdesivir speeds time to recovery by preventing worsening to clinical states that would extend the course of hospitalization and increase intensive respiratory support, thereby reducing the overall demand for hospital care. [ABSTRACT FROM AUTHOR]

Published
2022
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23. Endpoints for randomized controlled clinical trials for COVID-19 treatments

Author

Dodd, Lori E, primary, Follmann, Dean, additional, Wang, Jing, additional, Koenig, Franz, additional, Korn, Lisa L, additional, Schoergenhofer, Christian, additional, Proschan, Michael, additional, Hunsberger, Sally, additional, Bonnett, Tyler, additional, Makowski, Mat, additional, Belhadi, Drifa, additional, Wang, Yeming, additional, Cao, Bin, additional, Mentre, France, additional, and Jaki, Thomas, additional

Published
2020
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24. EndpointManuscript_revision_SUPPLEMENTARY_MATERIAL – Supplemental material for Endpoints for randomized controlled clinical trials for COVID-19 treatments

Author

Dodd, Lori E, Follmann, Dean, Wang, Jing, Koenig, Franz, Korn, Lisa L, Schoergenhofer, Christian, Proschan, Michael, Hunsberger, Sally, Bonnett, Tyler, Makowski, Mat, Drifa Belhadi, Yeming Wang, Cao, Bin, Mentre, France, and Jaki, Thomas

Subjects
FOS: Clinical medicine, 160807 Sociological Methodology and Research Methods, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, FOS: Sociology
Abstract

Supplemental material, EndpointManuscript_revision_SUPPLEMENTARY_MATERIAL for Endpoints for randomized controlled clinical trials for COVID-19 treatments by Lori E Dodd, Dean Follmann, Jing Wang, Franz Koenig, Lisa L Korn, Christian Schoergenhofer, Michael Proschan, Sally Hunsberger, Tyler Bonnett, Mat Makowski, Drifa Belhadi, Yeming Wang, Bin Cao, France Mentre and Thomas Jaki in Clinical Trials

Published
2020
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25. Remdesivir for the Treatment of Covid-19-Final Report

Author

Beigel, John H., Tomashek, Kay M., Dodd, Lori E., Mehta, Aneesh K., Zingman, Barry S., Kalil, Andre C., Hohmann, Elizabeth, Chu, Helen Y., Luetkemeyer, Annie, Kline, Susan, de Castilla, Diego Lopez, Finberg, Robert W., Dierberg, Kerry, Tapson, Victor, Hsieh, Lanny, Patterson, Thomas F., Paredes, Roger, Sweeney, Daniel A., Short, William R., Touloumi, Giota, Lye, David Chien, Ohmagari, Norio, Oh, Myoung-don, Ruiz-Palacios, Guillermo M., Benfield, Thomas, Faetkenheuer, Gerd, Kortepeter, Mark G., Atmar, Robert L., Creech, C. Buddy, Lundgren, Jens, Babiker, Abdel G., Pett, Sarah, Neaton, James D., Burgess, Timothy H., Bonnett, Tyler, Green, Michelle, Makowski, Mat, Osinusi, Anu, Nayak, Seema, Lane, H. Clifford, Beigel, John H., Tomashek, Kay M., Dodd, Lori E., Mehta, Aneesh K., Zingman, Barry S., Kalil, Andre C., Hohmann, Elizabeth, Chu, Helen Y., Luetkemeyer, Annie, Kline, Susan, de Castilla, Diego Lopez, Finberg, Robert W., Dierberg, Kerry, Tapson, Victor, Hsieh, Lanny, Patterson, Thomas F., Paredes, Roger, Sweeney, Daniel A., Short, William R., Touloumi, Giota, Lye, David Chien, Ohmagari, Norio, Oh, Myoung-don, Ruiz-Palacios, Guillermo M., Benfield, Thomas, Faetkenheuer, Gerd, Kortepeter, Mark G., Atmar, Robert L., Creech, C. Buddy, Lundgren, Jens, Babiker, Abdel G., Pett, Sarah, Neaton, James D., Burgess, Timothy H., Bonnett, Tyler, Green, Michelle, Makowski, Mat, Osinusi, Anu, Nayak, Seema, and Lane, H. Clifford

Abstract

BackgroundAlthough several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. MethodsWe conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. ResultsA total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). ConclusionsOur data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Aller

Published
2020

31. Examining the bias-efficiency tradeoff from incorporation of nonconcurrent controls in platform trials: A simulation study example from the adaptive COVID-19 treatment trial.

Author

Bonnett T, Potter GE, and Dodd LE

Abstract

Background: Platform trials typically feature a shared control arm and multiple experimental treatment arms. Staggered entry and exit of arms splits the control group into two cohorts: those randomized during the same period in which the experimental arm was open (concurrent controls) and those randomized outside that period (nonconcurrent controls). Combining these control groups may offer increased statistical power but can lead to bias if analyses do not account for time trends in the response variable. Proposed methods of adjustment for time may increase type I error rates when time trends impact arms unequally or when large, sudden changes to the response rate occur. However, there has been limited exploration of the degree of type I error inflation one can plausibly expect in real-world scenarios., Methods: We use data from the Adaptive COVID-19 Treatment Trial (ACTT) to mimic a realistic platform trial with a remdesivir control arm. We compare four strategies for estimating the effect of interferon beta-1a (the ACTT-3 experimental arm) relative to remdesivir (data from ACTT-1, ACTT-2, and ACTT-3) on recovery and death by day 29: utilizing concurrent controls only (the prespecified analysis), pooling all remdesivir arm data without adjustment (the "unadjusted-pooled" analysis), adjusting for time as a categorical variable, and a Bayesian hierarchical model implementation which adjusts for time trends using smoothing techniques (the "Bayesian time machine"). We compare type I error rates and relative efficiency of each method in simulation settings based on observed ACTT remdesivir arm data., Results: The unadjusted-pooled approach provided substantially different estimates of the effect of interferon beta-1a relative to remdesivir compared with the concurrent-only and model-based approaches, indicating that changes in recovery and death rates over time were not ignorable across different stages of ACTT. The model-based approaches rely on an assumption of constant treatment effects for each arm in the platform relative to control; error rates more than doubled in settings where this was not satisfied. Relative efficiency of the model-based approaches compared with the concurrent-only analysis was moderate., Conclusions: In simulation settings where key model assumptions were not met, potential efficiency gains from incorporation of nonconcurrent controls were outweighed by the risk of substantial type I error rate inflation. This leads us to advise against these strategies for primary analyses in confirmatory clinical trials, aligning with current FDA guidance advising against comparisons to nonconcurrent controls in COVID-19 settings. The model-based adjustment methods may be useful in other settings, but we recommend performing the concurrent-only analysis as a reference for assessing the degree to which nonconcurrent controls drive results., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2025
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32. Correction: Design of an observational multi-country cohort study to assess immunogenicity of multiple vaccine platforms (InVITE).

Author

Sereti I, Shaw-Saliba K, Dodd LE, Dewar RL, Laverdure S, Brown S, Mbaya OT, Muyembe Tamfum JJ, Mblala-Kingebeni P, Sow Y, Akpa E, Haidara MC, Tchos KF, Beavogui AH, Neal A, Arlinda D, Lokida D, Grue L, Smolskis M, McNay LA, Gayedyu-Dennis D, Ruiz-Palacios GM, Montenegro-Liendo A, Tounkara M, Samake S, Jargalsaikhan G, Zulkhuu D, Weyers S, Bonnett T, Potter GE, Stevens R, Rupert A, Aboulhab J, Biampata JL, Delamou A, Camara BS, Indonesia HK, Karyana M, Duworko JT, Regalado-Pineda J, Guerra-de-Blas PDC, Doumbia S, Dabitao D, Dashdorj N, Dashdorj N, Newell K, Francis A, Rubenstein K, Bera V, Gulati I, Sardana R, Millard M, Ridzon R, and Hunsberger S

Abstract

[This corrects the article DOI: 10.1371/journal.pone.0273914.]., (Copyright: © 2024 Sereti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2024
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33. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

Author

Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, Lusakibanza Manzo M, Nzolo D, Tshomba Oloma A, Ibanda A, Ali R, Coulibaly S, Levine AC, Grais R, Diaz J, Lane HC, Muyembe-Tamfum JJ, Sivahera B, Camara M, Kojan R, Walker R, Dighero-Kemp B, Cao H, Mukumbayi P, Mbala-Kingebeni P, Ahuka S, Albert S, Bonnett T, Crozier I, Duvenhage M, Proffitt C, Teitelbaum M, Moench T, Aboulhab J, Barrett K, Cahill K, Cone K, Eckes R, Hensley L, Herpin B, Higgs E, Ledgerwood J, Pierson J, Smolskis M, Sow Y, Tierney J, Sivapalasingam S, Holman W, Gettinger N, Vallée D, and Nordwall J

Subjects
Adenosine Monophosphate analogs & derivatives, Adolescent, Adult, Alanine adverse effects, Alanine therapeutic use, Antibodies, Monoclonal adverse effects, Antiviral Agents adverse effects, Child, Child, Preschool, Democratic Republic of the Congo epidemiology, Disease Outbreaks, Ebolavirus genetics, Female, Hemorrhagic Fever, Ebola mortality, Humans, Infant, Infant, Newborn, Infusions, Intravenous, Male, RNA, Viral blood, Ribonucleotides adverse effects, Single-Blind Method, Young Adult, Alanine analogs & derivatives, Antibodies, Monoclonal therapeutic use, Antiviral Agents therapeutic use, Hemorrhagic Fever, Ebola drug therapy, Ribonucleotides therapeutic use
Abstract

Background: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial., Methods: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days., Results: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs., Conclusions: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.)., (Copyright © 2019 Massachusetts Medical Society.)

Published
2019
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