Clinical trial NCT03541174: A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its Safety
Official title: Multi-center, Blinded, Randomized, Parallel-group, Phase 3 Study With Aprocitentan in Subjects With Resistant Hypertension (RHT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Resistant Hypertension
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Janssen Biotech, Inc.
First posted: 2018-05-30
Enrollment: 730
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Study with multiple periods and parts.

Once eligibility is confirmed during screening and the run-in period, the individuals entered the randomized treatment period consisting of 3 parts: Part 1: double-blind (DB), randomized to aprocitentan 12.5 mg, aprocitentan 25 mg or placebo; Part 2 single-blind (SB) aprocitentan 25 mg; Part 3: double-blind withdrawal (DB-WD) re-randomized to aprocitentan 25 mg or placebo.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to show the blood pressure lowering effect of aprocitentan, a new drug, when added to other anti-hypertensive drugs of patients with difficult to control (resistant) high blood pressure (hypertension), and to show that blood pressure reduction is kept for long period of time.

Detailed description: Participation in the study will be up to 68 weeks.

The study has 4 periods:

1. Screening period
2. Placebo run-in period
3. Randomized treatment period
4. Safety follow-up period

The screening period lasts between 4 and 12 weeks. It starts at the screening visit with the signing of the informed consent form (ICF) and ends the day before the participant enters the run-in period.

At least 4 weeks before the start of the run-in period, the background antihypertensive medication (except beta-blockers) of participants with a diagnosis of true resistant hypertension and having a mean trough sitting systolic blood pressure of equal to or greater than 140 mmHg measured by automated AOBPM will be standardized by switching to a fixed combination of a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan) and a diuretic (hydrochlorothiazide).

In case a beta-blocker is used as one of the background antihypertensive medications or for any other indication, this can be kept, with the provision that it has been initiated and the dose kept stable for at least 4 weeks prior to the screening visit and the dose kept stable until the end-of-treatment.

Following the screening period this study has a run-in period of 4 weeks. During this period, placebo will be administered in order to exclude potential placebo responders.

Following the run-in period eligible participants will enter the randomized treatment period. This period lasts for 48 weeks. It starts at randomization (i.e., Day 1 of the double-blind part) and ends at the end-of-treatment visit (i.e., at the end of the double-blind withdrawal part).

The randomized treatment period consists of 3 parts: Part 1 is double-blind, randomized, parallel-group and placebo-controlled and lasts 4 weeks. Part 2 is single-blind and single-arm and lasts for 32 weeks. Part 3 is a double-blind withdrawal, randomized, parallel-group and placebo-controlled and lasts for 12 weeks.

End-of treatment is at Week 48 (i.e., end of the double-blind withdrawal part). The safety follow-up starts on the day after the last dose of study treatment and ends 30 to 33 days after the last dose of study treatment.

Eligibility criteria: Inclusion Criteria:

Screening period:

* Signed and dated informed consent form (ICF) prior to any study-mandated procedure;
* Male and female participants; 18 years (or year of country specific majority) or older;
* Historical documentation in the participant's medical records on uncontrolled blood pressure despite at least 3 background antihypertensive medications within 1 year before screening visit;
* Treated with at least 3 antihypertensive therapies of different pharmacological classes for at least 4 weeks before the screening visit (Visit 1);
* Mean Sitting Systolic Blood Pressure (SiSBP) greater or equal to 140 mmHg measured by Automated Office Blood Pressure Measurement (AOBPM);
* Women of childbearing potential are eligible only if the following applies:

  * Negative pregnancy test at screening and at baseline (i.e., before randomization);
  * Agreement to undertake pregnancy tests during the study and up to 30 days after randomized study treatment discontinuation;
  * Agreement to use methods of birth control from Screening up to at least 30 days after randomized study treatment discontinuation.

Run-in period (RI):

* Switched to the standardized background antihypertensive therapy at least 4 weeks before the first RI visit;
* Mean trough SiSBP greater than or equal to140 mmHg as measured by AOBPM.

Randomization period:

* Stable dose of the standardized background antihypertensive therapy for at least 1 week before the end of the RI period;
* Mean trough SiSBP greater than or equal to 140 mmHg measured by AOBPM.

Exclusion Criteria:

* Apparent/pseudo Resistant Hypertension (RHT) due to white coat effect, medical inertia, poor therapeutic adherence, or secondary causes of hypertension (except sleep apnea);
* Confirmed severe hypertension (grade 3) defined as SiSBP greater than or equal to 180 mmHg and/or Sitting Diastolic Blood Pressure (SiDBP) greater than or equal to 110 mmHg as measured by AOBPM at two different timepoints;
* Pregnant or lactating participants;
* Clinically significant unstable cardiac disease at screening or in the past in the opinion of the investigator (exclusion of participants with significant or potential unstable cardiac disease);
* Severe renal insufficiency;
* Any known factor, disease or clinically relevant medical or surgical conditions that, in the opinion of the investigator, might put the participant at risk, interfere with treatment compliance, study conduct or interpretation of the results.
* Treatment with any medication which may affect blood pressure (BP) and/or treatment with high dose of loop diuretics (i.e., furosemide greater than 80 mg/day, or equivalent dosage of other loop diuretics).

Primary outcomes:
measure: Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement
timeFrame: Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1)
Secondary outcomes:
measure: Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Unattended Automated Office Blood Pressure Measurement
timeFrame: Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40
measure: Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement
timeFrame: Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1)
measure: Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Pre-dose Day 1 (Part 1 double-blind randomized baseline) and Week 4 (End of double-blind randomized part 1)
measure: Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure
timeFrame: Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40
measure: Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring
timeFrame: From Week 36 (Part 3 double-blind-withdrawal baseline) and Week 40
Other outcomes:
Locations:
city: Alexander City
country: United States
facility: Advanced Cardiovascular, LLC
state: Alabama
city: Inglewood
country: United States
facility: Chrishard Medical Group
state: California
city: Lincoln
country: United States
facility: Clinical Trials Research
state: California
city: Los Angeles
country: United States
facility: Academic Medical Research Institute Inc
state: California
city: Northridge
country: United States
facility: Amicis Research Center
state: California
city: San Dimas
country: United States
facility: California Kidney Specialists
state: California
city: Brandon
country: United States
facility: Bay Area Cardiology Associates, P.A.
state: Florida
city: Daytona Beach
country: United States
facility: Century Clinical Research, Inc
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Lake Worth
country: United States
facility: Canvas Clinical Research, LLC
state: Florida
city: Saint Augustine
country: United States
facility: East Coast Institute for Research
state: Florida
city: The Villages
country: United States
facility: Premier Medical Associates
state: Florida
city: Springfield
country: United States
facility: SIU School of Medicine Center for Clinical Research
state: Illinois
city: Indianapolis
country: United States
facility: Midwest Institute for Clinical Research
state: Indiana
city: Munster
country: United States
facility: Cardiovascular Research of Northwest Indiana, L.L.C.
state: Indiana
city: Richmond
country: United States
facility: Reid Physician Associates
state: Indiana
city: Bossier City
country: United States
facility: Grace Research, LLC
state: Louisiana
city: Hyattsville
country: United States
facility: MedStar Health Research Institute
state: Maryland
city: Kansas City
country: United States
facility: Clinical Research Consultants, LLC
state: Missouri
city: Eatontown
country: United States
facility: Hypertension and Nephrology Association PA
state: New Jersey
city: Albuquerque
country: United States
facility: Renal Medicine Associates
state: New Mexico
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Laurelton
country: United States
facility: Scott Research Inc
state: New York
city: Westfield
country: United States
facility: Great Lakes Medical Research LLC
state: New York
city: Charlotte
country: United States
facility: Metrolina Internal Medicine/Internal Medicine Research
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Greenville
country: United States
facility: Physician's East Endocrinology
state: North Carolina
city: Morehead City
country: United States
facility: Carteret Medical Group
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center - Neurological Institute
state: Ohio
city: Eugene
country: United States
facility: Willamette Valley Clinical Studies
state: Oregon
city: Columbia
country: United States
facility: TLM Medical Services LLC
state: South Carolina
city: Greer
country: United States
facility: DeGarmo Institute of Medical Research
state: South Carolina
city: Germantown
country: United States
facility: Stern Cardiovascular Foundation, Inc
state: Tennessee
city: Memphis
country: United States
facility: LifeDOC Research PLLC
state: Tennessee
city: Amarillo
country: United States
facility: Amarillo Heart Clinical Research Institute, Inc.
state: Texas
city: Pearland
country: United States
facility: LinQ Research, LLC
state: Texas
city: Webster
country: United States
facility: Mercury Clinical Research
state: Texas
city: Saint George
country: United States
facility: St. George Kidney Care LLC dba Southern Utah Kidney and Hypertension Center
state: Utah
city: Burke
country: United States
facility: Burke Internal Medicine & Research
state: Virginia
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: Wauwatosa
country: United States
facility: Milwaukee Nephrologists, SC
state: Wisconsin
city: Gosford
country: Australia
facility: Renal Research
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital Department of Renal Medicine
state: New South Wales
city: Melbourne
country: Australia
facility: Baker Heart and Diabetes Institute
state: Victoria
city: Melbourne
country: Australia
facility: Hypertension & Kidney Disease / Huma Neurotransmitter Laboratory
state: Victoria
city: Bentley
country: Australia
facility: Curtin University, Faculty of Health Sciences, School of Public Health
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital Unit - The University of Western Australia
state: Western Australia
city: Brussels
country: Belgium
facility: Hospital Erasme - Cardiology department
city: Brussels
country: Belgium
facility: Clinique Universitaires de Saint Luc, Departement cardio-vasculaires intensives
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent Cardiologie
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire du Sart-Tilman
city: Hamilton
country: Canada
facility: Manna Research Inc (North Burlington)
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre - Victoria Hospital
state: Ontario
city: Toronto
country: Canada
facility: Canadian Phase Onward Inc.
state: Ontario
city: Toronto
country: Canada
facility: Stephen S. Chow Medicine Professional Corporation
state: Ontario
city: Waterloo
country: Canada
facility: Clinical Research Solutions Inc.
state: Ontario
city: Baotou
country: China
facility: The First Affiliated Hospital of Baotou Medical College of Inner Mongolia
city: Changsha
country: China
facility: The Third Xiangya Hospital of Central South University
city: Guangzhou
country: China
facility: Guangdong General Hospital
city: Hangzhou
country: China
facility: Zhejiang Province People's Hospital
city: Sanya
country: China
facility: Hainan NO.3 Provincial people's Hospital
city: Shanghai
country: China
facility: Ruijin Hospital Shanghai Jiaotong University School of Medicine
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
city: Brno
country: Czechia
facility: FN U Sv.Anny Brno, kardiologická klinika
city: Prague
country: Czechia
facility: Interni oddeleni, Nefrologie
city: Praha 2
country: Czechia
facility: Všeobecní fakultní nemocnice Praha
city: Praha 4
country: Czechia
facility: Thomayerova nemocnice
city: Přerov
country: Czechia
facility: Kardio Václavík s.r.o
city: Oulu
country: Finland
facility: University of Oulu, Medical Research Center
city: Tampere
country: Finland
facility: TAYS RDI center (Tampere University Hospital,Specialist Internal Medicine, Rare Diseases)
city: Turku
country: Finland
facility: Turku University Central Hospital - Turun yliopistollinen keskussairaala Sisätautien klinikka
city: Grenoble cedex 9
country: France
facility: CHU Grenoble - Alpes
city: Lyon
country: France
facility: Hôpital de la Croix-Rousse - Rhône
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou- Centre d' Investigation Clinique
city: Toulon
country: France
facility: Centre Hospitalier Intercommunal Toulon La Seyne sur Mer
city: Berlin
country: Germany
facility: Jewish Hospital Berlin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Klinik für Nephrologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen Klinische Forschungsstation (CRC)
city: Homburg/Saar
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Leipzig
country: Germany
facility: Herzzentrum Leipzig Universitätsklinik für Kardiologie
city: Nürnberg
country: Germany
facility: Universitätsklinikum Nürnberg Süd
city: Athens
country: Greece
facility: General Hospital of Athens, Ippokrateio
city: Athens
country: Greece
facility: General Hospital of Athens Georgios Gennimatas
city: Athens
country: Greece
facility: Asklepeion General Hospital
city: Nea Ionia
country: Greece
facility: General Hospital Konstantopouleio-Patision
city: Balatonfüred
country: Hungary
facility: DRC Gyógyszervizsgáló Központ Kft.
city: Budapest
country: Hungary
facility: Gottsegen György Országos Kardiológiai Intézet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem - Klinikai Központ
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatókórház
city: Afula
country: Israel
facility: Haemek Medical Center
city: Ashkelon
country: Israel
facility: Barzilai Medical Center, Cardiovascular Institute
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Tel HaShomer
country: Israel
facility: Sheba Medical Center
city: Brescia
country: Italy
facility: University Brescia Department Clinical and Experimental Science
city: Monza
country: Italy
facility: Ospedale San Gerardo, Clinica Medica
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana - Department Clinical and Experimental Medicine
city: Roma
country: Italy
facility: Azienda Ospedaliera S. Andrea di Roma - Division of Cardiology and of Cardiothoracic and Vascular Science Department -
city: Torino
country: Italy
facility: SCU Medicina Interna e Centro Ipertensione arteriosa. Dipartimento di Scienze Mediche Università di Torino, Aou Citta' Salute E Scienza Torino
city: Kaunas
country: Lithuania
facility: JSC "InMedica"
city: Klaipeda
country: Lithuania
facility: Clinic of Cardiology and Rehabilitation
city: Amsterdam
country: Netherlands
facility: Academic Medical Center Amsterdam
city: Geleen
country: Netherlands
facility: Zuyderland Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center, Dept. of Medicine
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne Centrum Kardiologii
city: Katowice
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny im. Andrzeja Mielęckiego Śląskiego Uniwersytetu Medycznego w Katowicach
city: Kraków
country: Poland
facility: Diamond Clinic
city: Lodz
country: Poland
facility: SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Łodzi
city: Lublin
country: Poland
facility: KO-MED. CentraKliniczne Sp. Z o.o. Ośrodek Badań Klinicznych w Lublinie II
city: Lublin
country: Poland
facility: ETG Lublin
city: Olsztyn
country: Poland
facility: Etyka Ośrodek Badań Klinicznych
city: Puławy
country: Poland
facility: KO-MED. Centra Kliniczne Sp. Z o.o. Ośrodek Badań Klinicznych w Puławach
city: Skierniewice
country: Poland
facility: ETG Skierniewice
city: Warszawa
country: Poland
facility: Medycyna Kliniczna
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie
city: Warszawa
country: Poland
facility: ETG Warszawa
city: Warszawa
country: Poland
facility: Klinika Wad Wrodzonych Serca Instytut Kardiologii im. Kardynala Wyszynskiego
city: Zamość
country: Poland
facility: Samodzielny Publiczny Szpital Wojewódzki im. Papieża Jana Pawła II w Zamościu
city: Zgierz
country: Poland
facility: ETG Zgierz
city: Arkhangelsk
country: Russian Federation
facility: State Budgetary Healthcare Institution of Arkhangelsk Region "First City Clinical Hospital n.a. E.E. Volosevich"
city: Kazan
country: Russian Federation
facility: Federal State Autonomous Institution of Higher Education "Kazan (Volga Region) Federal University"
city: Kemerovo
country: Russian Federation
facility: Federal State Budget Scientific Institution "Scientific Research Institute for Complex Issues of Cardiovascular Diseases"
city: Krasnodar
country: Russian Federation
facility: Scientific Research Institute - Regional Clinical Hospital №1
city: Moscow
country: Russian Federation
facility: National Medical Research Center for Preventive Medicine
city: Novosibirsk
country: Russian Federation
facility: State budget healthcare institution of Novosibirsk region "City clinical hospital #34"
city: Novosibirsk
country: Russian Federation
facility: Federal State Budget Scientific Institution "Federal Research Center Institute of Cytology and Genetics of Siberian Department of Russian Academy of Sciences"
city: Saint Petersburg
country: Russian Federation
facility: Federal State Military Educational Institution of Higher Professional Education, Military Medical Academy named for S. M. Kirov of the Ministry of Defense of the Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budget Institution National Medical Research Center n.a. V.A. Almazov of the Ministry of Healthcare of the Russia
city: Saratov
country: Russian Federation
facility: State Healthcare Institution "Regional Clinical Cardiology Dispensary"
city: Saratov
country: Russian Federation
facility: Federal State Budget Educational Institution of Higher Education "Saratov State Medical University n.a. V.I. Razumovskiy" of the Ministry of Healthcare of the Russian Federation
city: Smolensk
country: Russian Federation
facility: State Budgetary Educational Institution of Higher Professional Education Smolensk State Medical Academy
city: St. Petersburg
country: Russian Federation
facility: Federal State Budget Institution "National Medical Research Center n.a. V.A. Almazov" of the Ministry of healthcare of the Russian Federation
city: Tomsk
country: Russian Federation
facility: Federal State Budget Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences"
city: Tyumen
country: Russian Federation
facility: Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Fundació Puigvert
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Granada
country: Spain
facility: Hospital Virgen de las Nieves - Internal Medicine Department
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos - Istituto de Investigacion Sanitaria San Carlos (IdISSC)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio Departamento de Medicina Interna
city: Valencia
country: Spain
facility: Hospital Clínic Universitari de València
city: Valencia
country: Spain
facility: Hypertension Clinic, Internal Medicine, Hospital Clinico, University of Valencia, Valencia
city: Kharkiv
country: Ukraine
facility: State Institution "L.T. Malaya Therapy National Institute of the NAMS of Ukraine"
city: Kharkiv
country: Ukraine
facility: Municipal non-profit enterprise "Clinical Hospital # 8"of Kharkiv City Council
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Hospital # 1
city: Kyiv
country: Ukraine
facility: Kyiv Municipal Clinical Emergency Hospital
city: Kyiv
country: Ukraine
facility: State Institution "National Scientific Center "M.D. Strazhesko Institute of Cardiology" of the National Academy of Medical Sciences of Ukraine"
city: Kyiv
country: Ukraine
facility: State Institution "D.F. Chebotarev Institute of Gerontology, National Academy of Medical Science of Ukraine"
city: Kyiv
country: Ukraine
facility: State Institution "Institute of Gerontology named after D.F. Chebotarev of National Academy of Medical Sciences of Ukraine"
city: Lutsk
country: Ukraine
facility: Volyn Regional Center for Cardiovascular Pathology, Rehabilitation Department
city: Lviv
country: Ukraine
facility: Danylo Halytsky Lviv National Medical University
city: Vinnytsya
country: Ukraine
facility: Communal Non-profit Enterprise "Vinnytsya regional Clinical Hospital named after. N.I. Pirogov Vinnytsia Regional Council"/ National Pirogov Memorial Medical University, Vinnytsya
city: Zhytomyr
country: Ukraine
facility: O.F. Herbachevsky Zhytomyr Regional Clinical Hospital, Cardiology department
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary, Clinical Pharmacology Unit
city: Edinburgh
country: United Kingdom
facility: Clinical Research Centre The University of Edinburgh Centre for Cardiovascular Science
city: London
country: United Kingdom
facility: Queen Mary University of London
Study officials:
affiliation: Idorsia Pharmaceuticals Ltd.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
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citation: Schlaich MP, Bellet M, Weber MA, Danaietash P, Bakris GL, Flack JM, Dreier RF, Sassi-Sayadi M, Haskell LP, Narkiewicz K, Wang JG; PRECISION investigators. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. 2022 Dec 3;400(10367):1927-1937. doi: 10.1016/S0140-6736(22)02034-7. Epub 2022 Nov 7.