Clinical trial NCT04640168: Adaptive COVID-19 Treatment Trial 4 (ACTT-4)
Official title: A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (ACTT-4)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: ACTT
Adaptive
COVID-19
Efficacy
Multicenter
novel coronavirus
Safety
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2020-11-23
Enrollment: 1010
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 primary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29.

Detailed description: This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. New arms can be introduced according to scientific and public health needs. There will be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms.

ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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.

All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized).

The primary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29. The key secondary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir according to clinical status (8-point ordinal scale) at Day 15.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Eligibility criteria: Inclusion Criteria:

1. Hospitalized with symptoms suggestive of COVID-19.
2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures and understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adult \> / = 18 years of age at time of enrollment.
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva \< / = 14 days prior to randomization.
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or increased oxygen requirement if on chronic oxygen) and requires at the time of randomization low or high flow oxygen devices or use of non-invasive mechanical ventilation (ordinal scale category 5 or 6).
6. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29.
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.

Exclusion Criteria:

1. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation in ACTT was terminated early.
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).
3. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of randomization.
4. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
5. Subjects with a low glomerular filtration rate (eGFR), specifically:

   1. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI, the potential benefit of participation outweighs the potential risk of study participation.
   2. All subjects with an eGFR \<15 mL/min
   3. All subjects on hemodialysis and/or hemofiltration at screening, irrespective of eGFR are excluded.
6. Neutropenia (absolute neutrophil count \<700 cells/microliter, 0.7 x 10\^3/microliter).
7. Lymphopenia (absolute lymphocyte count \<200 cells/microliter, 0.20 x 10\^3/microliter).
8. Received five or more doses of remdesivir including the loading dose, outside of the study as treatment for COVID-19.
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until two weeks after the last study product is given are not excluded).
10. Allergy to any study medication.
11. Received convalescent plasma or intravenous immunoglobulin \[IVIg\] for COVID-19, the current illness for which they are being enrolled.
12. Received any of the following in the two weeks prior to screening as treatment of COVID-19:

    * More than one dose of baricitinib for the treatment of COVID-19;
    * Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, etc.);
    * monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 \[IL-1\], anti-IL-6 \[tocilizumab or sarilumab\], etc.);
    * monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. Note: receipt of anti-SARS-CoV-2 monoclonal antibody (mAb) prior to enrollment (e.g. bamlanivimab) for their current COVID-19 illness is not exclusionary
13. Use of probenecid that cannot be discontinued at study enrollment.
14. Received 6 mg or more of dexamethasone by mouth (po) or Intravenous (IV) (or equivalent for other glucocorticoids) in one day, on more than one day, in the 7 days prior to time of randomization. Note: 6 mg dexamethasone dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 160 mg hydrocortisone.
15. Received \> / = 20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for \> / = 14 consecutive days in the 4 weeks prior to screening.
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 weeks with appropriate therapy (by history only, no screening required).
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive medications that in the opinion of the investigator could constitute a risk when taking baricitinib or dexamethasone.
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations including SARS-CoV-2 vaccine is allowed for all subjects.
19. Had a known Venous thromboembolism (VTE)(deep vein thrombosis \[DVT\] or pulmonary embolism \[PE\]) during the current COVID-19 illness.

Primary outcomes:
measure: The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: Day 1 through Day 29
measure: The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Race
timeFrame: Day 1 through Day 29
measure: The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Ethnicity
timeFrame: Day 1 through Day 29
measure: The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Sex
timeFrame: Day 1 through Day 29
Secondary outcomes:
measure: Change From Baseline in Alanine Aminotransferase (ALT)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Aspartate Aminotransferase (AST)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in C-reactive Protein (CRP)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Creatinine
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in D-dimer Concentration
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Glucose
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Hemoglobin
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Platelets
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Prothrombin International Normalized Ratio (INR)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Total Bilirubin
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in White Blood Cell Count (WBC)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Neutrophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Lymphocytes
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Monocytes
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Basophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Eosinophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs)
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Day 1 through Day 29
measure: Days of Invasive Mechanical Ventilation / Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: Day 1 through Day 29
measure: Days of Non-invasive Ventilation/High Flow Oxygen
timeFrame: Day 1 through Day 29
measure: Duration of Supplemental Oxygen Use
timeFrame: Day 1 through Day 29
measure: Desirability of Outcome Ranking (DOOR) at Day 15
timeFrame: Day 1 through Day 15
measure: Desirability of Outcome Ranking (DOOR) at Day 29
timeFrame: Day 1 through Day 29
measure: Duration of Hospitalization
timeFrame: Day 1 through Day 29
measure: Number of Participants With Discontinuation or Temporary Suspension of Study Product Administration
timeFrame: Day 1 through Day 10
measure: 14-day Participant Mortality
timeFrame: Day 1 through Day 15
measure: 28-day Participant Mortality
timeFrame: Day 1 through Day 29
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 1
timeFrame: Day 1
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 3
timeFrame: Day 3
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 5
timeFrame: Day 5
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 8
timeFrame: Day 8
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 11
timeFrame: Day 11
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15
timeFrame: Day 15
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 22
timeFrame: Day 22
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 29
timeFrame: Day 29
measure: Percentage of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories
timeFrame: Day 15
measure: The Proportion of Participants Not Meeting Criteria for One of the Three Most Severe Ordinal Scale Categories at Any Time.
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of One Category From Baseline Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of Two Categories From Baseline Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to Recovery
timeFrame: Day 1 through Day 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine - Infectious Disease
state: Alabama
city: Fresno
country: United States
facility: UCSF Fresno Center for Medical Education and Research - Clinical Research Center
state: California
city: La Jolla
country: United States
facility: University of California San Diego Health - Jacobs Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center - Westwood Clinic
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center - Infectious Disease
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System - Infectious Diseases
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center - Internal Medicine - Infectious Disease
state: California
city: San Diego
country: United States
facility: Kaiser Permanente San Diego Medical Center
state: California
city: San Diego
country: United States
facility: Naval Medical Center San Diego - Infectious Disease Clinic
state: California
city: San Francisco
country: United States
facility: University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine
state: California
city: Stanford
country: United States
facility: Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
state: California
city: West Hollywood
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Aurora
country: United States
facility: VA Eastern Colorado Health Care System
state: Colorado
city: Denver
country: United States
facility: Denver Health Division of Hospital Medicine - Main Campus
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center - Division of Infectious Diseases
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Health - Jacksonville - Department of Emergency Medicine
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine - Infectious Diseases
state: Florida
city: Decatur
country: United States
facility: Emory Vaccine Center - The Hope Clinic
state: Georgia
city: Decatur
country: United States
facility: Atlanta VA Medical Center - Infectious Diseases Clinic
state: Georgia
city: Honolulu
country: United States
facility: Tripler Army Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Hospital - Infectious Disease
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago College of Medicine - Division of Infectious Diseases
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics - Department of Internal Medicine
state: Iowa
city: New Orleans
country: United States
facility: Tulane University - Section of Pulmonary Diseases, Critical Care, and Environmental Medicine
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital - Medicine - Infectious Diseases
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital - Infectious Diseases
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School - Infectious Diseases and Immunology
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan - Infectious Disease Clinic at Taubman Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University - Center for Vaccine Development
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center - Infectious Diseases
state: Nebraska
city: Omaha
country: United States
facility: CHI Health Creighton University Medical Center - Bergan Mercy - Pulmonary Medicine
state: Nebraska
city: Morristown
country: United States
facility: Atlantic Health System - Morristown Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Clinical and Translational Science Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center - Infectious Diseases
state: New York
city: New York
country: United States
facility: New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center - Vaccine Research Unit
state: New York
city: Durham
country: United States
facility: Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
state: North Carolina
city: Fort Bragg
country: United States
facility: Womack Army Medical Center - Pulmonary and Respiratory Services
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Science Center - Surgery
state: Oklahoma
city: Portland
country: United States
facility: Kaiser Permanente Northwest - Center for Health Research
state: Oregon
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania - Infectious Diseases
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh - Medicine - Infectious Diseases
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch - Division of Infectious Disease
state: Texas
city: Houston
country: United States
facility: Methodist Hospital - Houston
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Molecular Virology and Microbiology
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio - Infectious Diseases
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Infectious Diseases
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia - Acute Care Surgery
state: Virginia
city: Portsmouth
country: United States
facility: Naval Medical Center Portsmouth - Infectious Disease Division
state: Virginia
city: Kirkland
country: United States
facility: EvergreenHealth Infectious Disease Service
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center - Infectious Disease Clinic
state: Washington
city: Tokyo
country: Japan
facility: Tokyo Medical and Dental University - Medical Hospital - Department of Respiratory Medicine
city: Tokyo
country: Japan
facility: National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
city: Bundang-gu Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital - Division of Infectious Diseases
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Jongno-gu
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
city: Mexico City
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
city: Singapore
country: Singapore
facility: National University Health System - Division of Infectious Diseases
city: Singapore
country: Singapore
facility: National University Health System - Alexandra Hospital - Division of Infectious Diseases
city: Singapore
country: Singapore
facility: National Centre for Infectious Diseases
city: Singapore
country: Singapore
facility: Changi General Hospital - Clinical Trials and Research Unit (CTRU)
city: Singapore
country: Singapore
facility: Ng Teng Fong General Hospital - Infectious Disease Service
Study officials:
References:
citation: Wolfe CR, Tomashek KM, Patterson TF, Gomez CA, Marconi VC, Jain MK, Yang OO, Paules CI, Palacios GMR, Grossberg R, Harkins MS, Mularski RA, Erdmann N, Sandkovsky U, Almasri E, Pineda JR, Dretler AW, de Castilla DL, Branche AR, Park PK, Mehta AK, Short WR, McLellan SLF, Kline S, Iovine NM, El Sahly HM, Doernberg SB, Oh MD, Huprikar N, Hohmann E, Kelley CF, Holodniy M, Kim ES, Sweeney DA, Finberg RW, Grimes KA, Maves RC, Ko ER, Engemann JJ, Taylor BS, Ponce PO, Larson L, Melendez DP, Seibert AM, Rouphael NG, Strebe J, Clark JL, Julian KG, de Leon AP, Cardoso A, de Bono S, Atmar RL, Ganesan A, Ferreira JL, Green M, Makowski M, Bonnett T, Beresnev T, Ghazaryan V, Dempsey W, Nayak SU, Dodd LE, Beigel JH, Kalil AC; ACTT-4 Study Group. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022 Sep;10(9):888-899. doi: 10.1016/S2213-2600(22)00088-1. Epub 2022 May 23.
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.