Immune Modulators for Treating COVID-19
- Conditions
- Covid19
- Interventions
- Registration Number
- NCT04593940
- Lead Sponsor
- Daniel Benjamin
- Brief Summary
ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics, including remdesivir (provided). The SoC may change during the course of the study based on other research findings. Comparisons of the agents among themselves is not a research objective.
The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients both in and out of the ICU are included in the study population.
- Detailed Description
ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone.
The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned.
The CVC arm of the study was closed to enrollment on 3-Sep-2021.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1971
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Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19.
-
Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
-
Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
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Male or non-pregnant female adults ≥18 years of age at time of enrollment.
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Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen.
-
Ongoing illness of any duration, and at least one of the following:
- Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
- Blood oxygen saturation (SpO2) ≤94% on room air, OR
- Requiring supplemental oxygen, OR
- Requiring mechanical ventilation or ECMO.
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Women of childbearing potential must agree to either abstinence or use of at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60.
-
Agrees to not to participate in another interventional trial for the treatment of COVID-19 through Day 60.
Exception 1: Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C). Exception 2: Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up.
Exception 3: If participant is already participating in a COVID-19 vaccine trial but develops COVID-19 disease that requires hospitalization, participant is eligible for this study, assuming all other inclusion/exclusion criteria are met.
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ALT or AST >10 times the upper limit of normal.
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Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration).
Exception: Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been stable without renal replacement therapy for ≥1 month and they are not current candidates for renal replacement therapy. These participants will not receive remdesivir.
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Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L).
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Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L)
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Pregnancy or breast feeding.
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Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
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Known allergy to any study medication.
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Received cytotoxic or biologictargeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, or T-cell or B-cell targeted therapies ([e.g., rituximab), tyrosine kinase], JAK inhibitors [including baricitinib,], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening., whichever is longer. Steroid dependency, defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month within 2 weeks of screening, is exclusionary. Note Exception 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines. Note Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also allowed.
Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment is also allowed.
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BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if. Participants are also excluded if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
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Based on medical history and concomitant therapies that would suggest infection,Known or suspected serious, active bacterial, fungal, or viral (infection (excepting SARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with the latter defined as a CD4 count <200 or an unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
Note: Broad-spectrum empiric antibiotic usage does not exclude participation.
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Have received any live vaccine (that is,or live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any vaccine for COVID-19.
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Severe hepatic impairment (defined as liver cirrhosis Child stage C).
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CurrentKnown severe heart failure (New York Heart Association [NYHA] III-IV).) or new-onset left-systolic or global cardiac dysfunction in the setting of COVID-19.
Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is permitted.
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In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard of Care + cenicriviroc or matching placebo (closed to enrollment as of 3-Sep-2021) cenicriviroc (closed to enrollment as of 3-Sep-2021) cenicriviroc \[tablet, Day 1/Loading Dose: 450 mg (300mg morning and 150mg evening) Day 2 - 29/Maintenance Dose: 300 mg (150 mg BID) through Day 29\]. or matching placebo Standard of Care + infliximab or matching placebo Infliximab infliximab (single dose IV 5mg/kg given on day 1) or matching placebo Standard of Care + cenicriviroc or matching placebo (closed to enrollment as of 3-Sep-2021) Remdesivir cenicriviroc \[tablet, Day 1/Loading Dose: 450 mg (300mg morning and 150mg evening) Day 2 - 29/Maintenance Dose: 300 mg (150 mg BID) through Day 29\]. or matching placebo Standard of Care + infliximab or matching placebo Remdesivir infliximab (single dose IV 5mg/kg given on day 1) or matching placebo Standard of Care + abatacept or matching placebo Abatacept abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo Standard of Care + abatacept or matching placebo Remdesivir abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo
- Primary Outcome Measures
Name Time Method Number of Participants Who Had Recovered by Day 28 Days 1-28 Time to recovery by day 28. The number of participants who have recovered by day 28.
- Secondary Outcome Measures
Name Time Method Number of Participants With Clinical Status for Day 14 Using an 8 Point Ordinal Scale Day 14 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) To determine a participant's clinical status using the ordinal scale their clinical status was collected at Day 15 assessing day 14.
The scale used in this study is as follows (from worst to best):
1. Death;
2. Hospitalized, on invasive mechanical ventilation or ECMO;
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
4. Hospitalized, requiring supplemental oxygen;
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise);
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.
7. Not hospitalized, limitation on activities and/or requiring home oxygen
8. Not hospitalized,Mortality Through 14 Days Day 1-14 mortality at day 14
Duration (Days) Alive and Free of Supplemental Oxygen Day 1 to day 28 Days alive and free of supplemental oxygen
Mean Change in the 8-point Ordinal Scale From Day 0 to Day 7 Day 0 to day 7 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities=best)
Duration (Days) Alive and Out of the Hospital Through day 28 Days alive and out of the hospital
Number of Patients With SAEs Through Day 28 Day 28 Cumulative Incidence of SAEs through day 28
Number of Patients With Adverse Events Leading to Dose Modification Day 1-28 Number of patients with adverse events (serious and non serious) leading to dose modification
Mortality Through 28 Days Day 1-28 mortality at day 28
Mean Change in the 8-point Ordinal Scale From Day 0 to Day 28 Day 0 to day 28 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)
Number of Patients With New Supplemental Oxygen Use Day 1-day 28 Number of patients with new supplemental oxygen use
Number of Participants With Clinical Status for Day 28 Using an 8 Point Ordinal Scale Day 28 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) To determine a participant's clinical status using the ordinal scale their clinical status was collected at Day 29 assessing day 28.
The scale used in this study is as follows (from worst to best):
1. Death;
2. Hospitalized, on invasive mechanical ventilation or ECMO;
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
4. Hospitalized, requiring supplemental oxygen;
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise);
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.
7. Not hospitalized, limitation on activities and/or requiring home oxygen
8. Not hospitalized,Number of Participants Who Met a One Point Improvement in Two Categories From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale Day 1- day 28 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best). Number of people who met a two category improvement.
The scale used in this study is as follows (from worst to best):
1. Death;
2. Hospitalized, on invasive mechanical ventilation or ECMO;
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
4. Hospitalized, requiring supplemental oxygen;
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise);
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.
7. Not hospitalized, limitation on activities and/or requiring home oxygen
8. Not hospitalized, no limitations on activities.Mean Change in the 8-point Ordinal Scale From Day 0 to Day 2 Day 0 to day 2 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best)
Number of Participants Who Met a One Point Improvement in One Category From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale Day 1-day 28 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best). Number of people who met a 1 point improvement.
The scale used in this study is as follows (from worst to best):
1. Death;
2. Hospitalized, on invasive mechanical ventilation or ECMO;
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
4. Hospitalized, requiring supplemental oxygen;
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise);
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.
7. Not hospitalized, limitation on activities and/or requiring home oxygen
8. Not hospitalized, no limitations on activities.Mean Change in the 8-point Ordinal Scale From Day 0 to Day 4 Day 0 to day 4 8 point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)
Number of Patients With New Mechanical Ventilation or ECMO Use Day 1 to day 28 Number of patients with new mechanical ventilation or ECMO use
Number of Patients With Grade 3 and 4 Adverse Events Day 28 Cumulative incidence of adverse events of grade 3 and 4
Mean Change in the 8-point Ordinal Scale From Day 0 to Day 10 Day 0 to day 10 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)
Mean Change in the 8-point Ordinal Scale From Day 0 to Day 14 Day 0 to day 14 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)
Mean Change in the 8-point Ordinal Scale From Day 0 to Day 21 Day 0 to day 21 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)
Duration (Days) Alive and Free of Non-invasive Ventilation/ High Flow Oxygen Day 1 to day 28 Days alive and free of non-invasive ventilation/ high flow oxygen
Number of Patients With New Non-invasive Ventilation/High Flow Oxygen Use Day 1-day 28 Number of patients with new non-invasive ventilation/high flow oxygen use
Duration (Days) Alive and Free of Invasive Mechanical Ventilation or ECMO Day 1 to day 28 Days alive and free of invasive mechanical ventilation or ECMO
Trial Locations
- Locations (91)
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
University of Arkansas Medical Sciences
🇺🇸Little Rock, Arkansas, United States
Johns Hopkins Medical Center
🇺🇸Baltimore, Maryland, United States
Avera McKennan Hospital
🇺🇸Sioux Falls, South Dakota, United States
University of Tennessee Medical Center
🇺🇸Knoxville, Tennessee, United States
West Virginia University
🇺🇸Morgantown, West Virginia, United States
Hospital Interzonal Dr Jose Penna Bahia Blanca
🇦🇷Bahía Blanca, Buenos Aires, Argentina
Hospital Ramos Mejia
🇦🇷Buenos Aires, Argentina
Sanatorio Allende
🇦🇷Córdoba, Argentina
Hospital Central FAP
🇵🇪Lima, Lima/Lima, Peru
Hospital Brasília
🇧🇷Brasília, DF, Brazil
Hospital Felício Rocho
🇧🇷Belo Horizonte, MG, Brazil
Hospital Ernesto Dornelles
🇧🇷Porto Alegre, Rio Grande D Sul /RS, Brazil
Hospital e Maternidade Celso Pierro - PUC Campinas
🇧🇷Campinas, São Paulo/SP, Brazil
Hospital de Clinicas de Porto Alegre HCPA
🇧🇷Porto Alegre, Rio Grande Do Sul / RS, Brazil
Santa Casa de Misericordia de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul/RS, Brazil
Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"
🇲🇽Guadalajara, Guadalajara Jalisco, Mexico
Hospital Regional Lambayeque
🇵🇪Chiclayo, Peru
Hospital Nacional Aezobispo Loayza
🇵🇪Lima, Peru
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
New York University Langone Medical Center
🇺🇸New York, New York, United States
Harlem Hospital Center
🇺🇸New York, New York, United States
Duke University
🇺🇸Durham, North Carolina, United States
University of Rochester Medical Center-Strong Memorial Hospital
🇺🇸Rochester, New York, United States
Reading Hospital Study
🇺🇸Wyomissing, Pennsylvania, United States
University of Kansas
🇺🇸Kansas City, Kansas, United States
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Wake Forest University
🇺🇸Winston-Salem, North Carolina, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Banner University Medical Center
🇺🇸Phoenix, Arizona, United States
UCLA - Ronald Reagan Medical Center
🇺🇸Los Angeles, California, United States
Riverside University
🇺🇸Moreno Valley, California, United States
Scripps Clinical Medical Group
🇺🇸La Jolla, California, United States
UC Irvine Medical Center
🇺🇸Orange, California, United States
Stanford University Medical Center
🇺🇸Palo Alto, California, United States
UCLA Medical Center- Santa Monica
🇺🇸Santa Monica, California, United States
Medstar Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
University of Florida-Jacksonville
🇺🇸Jacksonville, Florida, United States
University of Illinois at Chicago
🇺🇸Chicago, Illinois, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Anne Arundel Medical Center
🇺🇸Annapolis, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
U Mass University Medical Center
🇺🇸Worcester, Massachusetts, United States
MidMichigan Medical Center- Gratiot
🇺🇸Alma, Michigan, United States
U Mass Memorial Medical Center
🇺🇸Worcester, Massachusetts, United States
MidMichigan Medical Center - Midland
🇺🇸Midland, Michigan, United States
University of Missouri Health Care
🇺🇸Columbia, Missouri, United States
Trinitas Hospital
🇺🇸Elizabeth, New Jersey, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Rutgers New Jersey Medical School
🇺🇸New Brunswick, New Jersey, United States
NYU Brooklyn
🇺🇸Brooklyn, New York, United States
University at Buffalo
🇺🇸Buffalo, New York, United States
Jamaica Hospital Medical Center
🇺🇸Jamaica, New York, United States
Flushing Hospital Medical Center
🇺🇸Flushing, New York, United States
NYU Long Island
🇺🇸Long Island City, New York, United States
Weill Cornell Medicine
🇺🇸New York, New York, United States
St Lawrence Health System
🇺🇸Potsdam, New York, United States
Mercy Saint Vincent Medical Center
🇺🇸Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Trinity Mother Frances Hospital
🇺🇸Tyler, Texas, United States
University of Texas Health Science Center - Houston
🇺🇸Houston, Texas, United States
Methodist Health System Clinical Research Institute
🇺🇸Dallas, Texas, United States
University of Texas Health Center at Tyler
🇺🇸Tyler, Texas, United States
Providence Medical Research Center
🇺🇸Spokane, Washington, United States
Gundersen Health System
🇺🇸La Crosse, Wisconsin, United States
Instituto Medico Platense
🇦🇷La Plata, Buenos Aires, Argentina
Sanatorio Ramon Cereijo
🇦🇷Caba, Buenos Aires, Argentina
Clinica Central S.A.
🇦🇷Villa Regina, Rio Negro, Argentina
Hospital Rawson
🇦🇷Cordoba, Argentina
Sanatorio Britanico
🇦🇷Rosario, Argentina
Sanatorio Diagnóstico/ Instituto del Buen Aire
🇦🇷Santa Fe, Argentina
Instituto DOR de Ensino e Pesquisa Hospital Glória D'Or
🇧🇷Rio De Janeiro, Rio De Janeiro / RJ, Brazil
Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
🇲🇽Nuevo León, Monterrey, Mexico
Hospitala Nacional Hipólito Unánue
🇵🇪Lima, Peru
Hospital de Chancay y Servicios Basicos de Salud
🇵🇪Lima, Peru
Clínica Belén SANNA
🇵🇪Piura, Peru
Tulane School of Medicine
🇺🇸New Orleans, Louisiana, United States
University Medical Center New Orleans
🇺🇸New Orleans, Louisiana, United States
Ochsner Medical Center
🇺🇸New Orleans, Louisiana, United States
University of North Carolina - Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Virginia Commonwealth University Medical Center
🇺🇸Richmond, Virginia, United States