A Study to Investigate Long-term Safety and Tolerability of Itepekimab in Participants With COPD
- Conditions
- Chronic Obstructive Pulmonary Disease
- Interventions
- Drug: Placebo
- Registration Number
- NCT06208306
- Lead Sponsor
- Sanofi
- Brief Summary
This is a parallel, double blind, Phase 3, 2-arm study that is designed to provide additional safety information, assess the durability of treatment response, and provide additional PK and immunogenicity assessments.
The primary purpose of this study is to evaluate safety and tolerability of both itepekimab SC Q2W or itepekimab SC Q4W in participants with COPD having completed the treatment period of the clinical studies EFC16750 or EFC16819. A secondary purpose of this study is to provide efficacy outcomes beyond the treatment period of the parent trials EFC16750 and EFC16819.
Study details include:
* The study duration will be up to 72 weeks
* The treatment duration will be up to 52 weeks
* A follow-up period of 20 weeks will be conducted
* The number of on-site visits will be 7 and the number of phone contacts will be 5
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 700
- Patients with COPD who completed the treatment period in a previous itepekimab COPD Phase 3 clinical study (ie, EFC16750 or EFC16819) and for which an end-of-treatment (EOT) visit occurred no later than 3 days before the enrolment visit of this study.
- Diagnosis of a malignancy during parent study, except a squamous or basal cell carcinoma of the skin
- Any opportunistic infection during the parent study, such as tuberculosis (TB) or other infections whose nature or course may suggest an immunocompromised status
- Anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment during the parent study
- Any situation that led to a permanent premature IMP discontinuation in parent trials
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Itepekimab Q2W Itepekimab (SAR440340) Subcutaneous (SC) administration of Itepekimab every 2 weeks (Q2W) for up to 52 weeks Itepekimab Q4W Itepekimab (SAR440340) SC administration of Itepekimab every 4 weeks (Q4W) for up to 52 weeks, with alternating SC administration of matching placebo at the 2-week interval between active IMP Itepekimab Q4W Placebo SC administration of Itepekimab every 4 weeks (Q4W) for up to 52 weeks, with alternating SC administration of matching placebo at the 2-week interval between active IMP
- Primary Outcome Measures
Name Time Method Incidence of treatment-emergent AEs, AESIs, SAEs, and AEs leading to permanent treatment discontinuation Baseline up to Week 72 All AEs (serious or nonserious) will be collected from the signing of the informed consent form (ICF) until the end of study visit
- Secondary Outcome Measures
Name Time Method Time to first moderate-to-severe AECOPD Baseline up to Week 52 Time to first severe AECOPD Baseline up to Week 52 Change from baseline of the parent studies (EFC16750, EFC16819): Pre-BD and post-BD FEV1 Baseline of the parent studies (EFC16750,EFC16819) up to Week 52 FEV1 is force expiratory volume in 1 second
Functional itepekimab concentrations in serum Baseline up to Week 52 Incidence of treatmentemergent (TE) anti-drug antibody responses Baseline up to Week 72 Annualized rate of moderatetosevere acute exacerbation of COPD (AECOPD) Baseline up to Week 52 Annualized rate of severe AECOPD Baseline up to Week 52 Change from baseline of the parent studies (EFC16750, EFC16819): SGRQ total score and domain scores Baseline of the parent studies (EFC16750,EFC16819) up to Week 52 The St. George's Respiratory Questionnaire (SGRQ) is a 50-item questionnaire designed to measure and quantify health status in adult participants with chronic airflow limitation.
Change from baseline of the parent studies (EFC16750, EFC16819): EQ-5D-5L single index score Baseline of the parent studies (EFC16750,EFC16819) up to Week 52 The European Quality of Life 5 Dimensions 5 Level Version (EQ 5D 5L) is a standardized health-related quality-of-life (HRQoL) questionnaire which consists of a descriptive system and the EuroQol visual analog scale (EQ-VAS).
Change from Week 0 for CASA-Q Baseline up to Week 52 The cough and sputum assessment questionnaire (CASA-Q) was developed for use in COPD and chronic (non-obstructive) bronchitis patients.
Change from baseline of the parent studies (EFC16750, EFC16819): EQ-VAS Baseline of the parent studies (EFC16750,EFC16819) up to Week 52 The EuroQol visual analog scale (EQ VAS) records the participant's self-rated health on a vertical VAS.
Trial Locations
- Locations (223)
Investigational Site Number : 8260004
🇬🇧Portsmouth, Hampshire, United Kingdom
Investigational Site Number : 1560019
🇨🇳Pingxiang, China
Investigational Site Number : 1560020
🇨🇳Shanghai, China
Investigational Site Number : 1560006
🇨🇳Shanghai, China
Investigational Site Number : 6420002
🇷🇴Cluj Napoca, Romania
Investigational Site Number : 7030002
🇸🇰Humenné, Slovakia
Investigational Site Number : 7240007
🇪🇸Madrid, Spain
Investigational Site Number : 7240001
🇪🇸Málaga, Spain
Investigational Site Number : 7240004
🇪🇸Palma, Spain
Investigational Site Number : 7240012
🇪🇸Zaragoza, Spain
Investigational Site Number : 1580005
🇨🇳Kaohsiung City, Taiwan
Investigational Site Number : 1580006
🇨🇳Taichung, Taiwan
Investigational Site Number : 1000018
🇧🇬Ruse, Bulgaria
Investigational Site Number : 7920001
🇹🇷Istanbul, Turkey
Investigational Site Number : 7920006
🇹🇷Kirikkale, Turkey
Investigational Site Number : 8260003
🇬🇧Bradford, United Kingdom
Investigational Site Number : 8260014
🇬🇧Hounslow, United Kingdom
Investigational Site Number : 8260005
🇬🇧Liverpool, United Kingdom
Investigational Site Number : 8260010
🇬🇧London, United Kingdom
Investigational Site Number : 8260008
🇬🇧Milton Keynes, United Kingdom
Chandler Clinical Research Trials- Site Number : 8401034
🇺🇸Chandler, Arizona, United States
Noble Clinical Research Site Number : 8401182
🇺🇸Tucson, Arizona, United States
Tucson Clinical Research Institute- Site Number : 8401431
🇺🇸Tucson, Arizona, United States
IMAX Clinical Trials- Site Number : 8401419
🇺🇸La Palma, California, United States
Antelope Valley Clinical Trials Site Number : 8401003
🇺🇸Lancaster, California, United States
Downtown L.A. Research Center- Site Number : 8401027
🇺🇸Los Angeles, California, United States
Allianz Research Institute CO Site Number : 8402061
🇺🇸Aurora, Colorado, United States
Alpine Clinical Research Center - Boulder - 47th Street- Site Number : 8401180
🇺🇸Boulder, Colorado, United States
Helix Biomedics- Site Number : 8402049
🇺🇸Boynton Beach, Florida, United States
Beautiful Minds Clinical Research Center Site Number : 8401201
🇺🇸Cutler Bay, Florida, United States
Omega Research Consultants - Debary - North Charles Richard Beall Boulevard- Site Number : 8402031
🇺🇸DeBary, Florida, United States
Science Connections, LLC Site Number : 8402045
🇺🇸Doral, Florida, United States
Direct Helpers Research Center- Site Number : 8402065
🇺🇸Hialeah, Florida, United States
Premier Medical Associates Site Number : 8401388
🇺🇸Lady Lake, Florida, United States
Advanced Pulmonary Research Institute Site Number : 8402018
🇺🇸Loxahatchee Groves, Florida, United States
Deluxe Health Center Site Number : 8401188
🇺🇸Miami Lakes, Florida, United States
Finlay Medical Research- Site Number : 8402007
🇺🇸Miami, Florida, United States
Elite Clinical Research - Miami- Site Number : 8402009
🇺🇸Miami, Florida, United States
DL Research Solutions- Site Number : 8401033
🇺🇸Miami, Florida, United States
My Community Research Center Site Number : 8402060
🇺🇸Miami, Florida, United States
Phoenix Medical Research - Miami - 24th Street- Site Number : 8402019
🇺🇸Miami, Florida, United States
Research Institute of South Florida- Site Number : 8401006
🇺🇸Miami, Florida, United States
Reed Medical Research Site Number : 8401032
🇺🇸Miami, Florida, United States
High Quality Research Site Number : 8401406
🇺🇸Miami, Florida, United States
Renstar Medical Research - Ocala - Northeast 1st Avenue- Site Number : 8402015
🇺🇸Ocala, Florida, United States
Heuer M.D. Research- Site Number : 8402016
🇺🇸Orlando, Florida, United States
Florida Institute for Clinical Research Site Number : 8401013
🇺🇸Orlando, Florida, United States
Oviedo Medical Research Site Number : 8402026
🇺🇸Oviedo, Florida, United States
Innovation Medical Research Center - Palmetto Bay- Site Number : 8402067
🇺🇸Palmetto Bay, Florida, United States
Pines Care Research Center- Site Number : 8402056
🇺🇸Pembroke Pines, Florida, United States
Tellabio International Research Services Site Number : 8401411
🇺🇸Pembroke Pines, Florida, United States
Clinical Research of West Florida - Tampa - North Howard Avenue- Site Number : 8402008
🇺🇸Tampa, Florida, United States
Appalachian Clinical Research Site Number : 8400024
🇺🇸Calhoun, Georgia, United States
Private Practice - Dr. David Kavtaradze- Site Number : 8401029
🇺🇸Cordele, Georgia, United States
Alpha Clinical Research Group - Dunwoody- Site Number : 8401190
🇺🇸Dunwoody, Georgia, United States
Covenant Pulmonary Critical Care Site Number : 8401183
🇺🇸East Point, Georgia, United States
OSF Saint Fracis Medical Center- Site Number : 8402024
🇺🇸Peoria, Illinois, United States
Benchmark Research - Covington- Site Number : 8401193
🇺🇸Covington, Louisiana, United States
Care Access - Shreveport- Site Number : 8402047
🇺🇸Shreveport, Louisiana, United States
Private Practice - Dr. Paul Shapero- Site Number : 8401016
🇺🇸Bangor, Maine, United States
Care Access - Boston- Site Number : 8402276
🇺🇸Boston, Massachusetts, United States
Revive Research Institute - Lathrup Village- Site Number : 8402186
🇺🇸Lathrup Village, Michigan, United States
Pulmonary and Medicine Associates- Site Number : 8401403
🇺🇸Warren, Michigan, United States
Hannibal Regional Healthcare System-HRMG-Hannibal Site Number : 8401383
🇺🇸Hannibal, Missouri, United States
Midwest Chest Consultants- Site Number : 8401002
🇺🇸Saint Charles, Missouri, United States
Washington University- Site Number : 8402035
🇺🇸Saint Louis, Missouri, United States
Henderson Clinical Trials Site Number : 8401365
🇺🇸Henderson, Nevada, United States
VA Western New York Healthcare System Site Number : 8402050
🇺🇸Buffalo, New York, United States
Schenectady Pulmonary and Critical Care Associates - Schenectady Main Office- Site Number : 8402029
🇺🇸Schenectady, New York, United States
East Carolina University- Site Number : 8401022
🇺🇸Greenville, North Carolina, United States
Advanced Respiratory and Sleep Medicine - Huntersville- Site Number : 8400022
🇺🇸Huntersville, North Carolina, United States
OK Clinical Research- Site Number : 8402001
🇺🇸Edmond, Oklahoma, United States
Clinical Research Associates of Central PA - Dubois- Site Number : 8401023
🇺🇸DuBois, Pennsylvania, United States
Allegheny General Hospital- Site Number : 8402058
🇺🇸Pittsburgh, Pennsylvania, United States
MedTrial- Site Number : 8402048
🇺🇸Columbia, South Carolina, United States
Clinical Research of Rock Hill Site Number : 8401008
🇺🇸Rock Hill, South Carolina, United States
REX Clinical Trials - Beaumont- Site Number : 8401371
🇺🇸Beaumont, Texas, United States
South Texas Medical Research Institute - TTS Research- Site Number : 8402012
🇺🇸Boerne, Texas, United States
ClinRx Research - Carrollton- Site Number : 8401021
🇺🇸Carrollton, Texas, United States
Corsicana Medical Research- Site Number : 8401018
🇺🇸Corsicana, Texas, United States
The Methodist Hospital Research Institute Site Number : 8401194
🇺🇸Houston, Texas, United States
Metroplex Pulmonary and Sleep Center Site Number : 8401015
🇺🇸McKinney, Texas, United States
Clear Lake Specialties Research Center, PLLC Site Number : 8401025
🇺🇸Webster, Texas, United States
Rheumatology & Pulmonary Clinic- Site Number : 8402053
🇺🇸Beckley, West Virginia, United States
Investigational Site Number : 0320012
🇦🇷Berazategui, Buenos Aires, Argentina
Investigational Site Number : 0320013
🇦🇷La Plata, Buenos Aires, Argentina
Investigational Site Number : 0320003
🇦🇷Rosario, Santa Fe, Argentina
Investigational Site Number : 0320007
🇦🇷Rosario, Santa Fe, Argentina
Investigational Site Number : 0320008
🇦🇷Rosario, Santa Fe, Argentina
Investigational Site Number : 0320011
🇦🇷Rosario, Santa Fe, Argentina
Investigational Site Number : 0320010
🇦🇷Buenos Aires, Argentina
Investigational Site Number : 0320005
🇦🇷Buenos Aires, Argentina
Investigational Site Number : 0320002
🇦🇷Buenos Aires, Argentina
Investigational Site Number : 0320006
🇦🇷Buenos Aires, Argentina
Investigational Site Number : 0320009
🇦🇷Buenos Aires, Argentina
Investigational Site Number : 0320004
🇦🇷Mendoza, Argentina
Serviços Especializados em Reumatologia- Site Number : 0760020
🇧🇷Salvador, Bahia, Brazil
Centro De Cardiologia Clinica E Pesquisa- Site Number : 0760018
🇧🇷Brasília, Distrito Federal, Brazil
Centro de Diagnostico e Pesquisa da Osteoporose do Espirito Santo- Site Number : 0760009
🇧🇷Vitoria, Espírito Santo, Brazil
Santa Casa de Misericordia de Belo Horizonte- Site Number : 0760014
🇧🇷Belo Horizonte, Minas Gerais, Brazil
Centro de Estudos em Terapias Inovadoras- Site Number : 0760012
🇧🇷Curitiba, Paraná, Brazil
Irmandade da Santa Casa de Misericórdia de Porto Alegre- Site Number : 0760001
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Instituto Ceos Site Number : 0760021
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital São Lucas da PUCRS - Porto Alegre - Avenida Ipiranga- Site Number : 0760007
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
WM Pesquisas Clínicas em Doenças Respiratórias- Site Number : 0760006
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Universidade Estadual Paulista - Faculdade de Medicina de Botucatu- Site Number : 0760005
🇧🇷Botucatu, São Paulo, Brazil
Hospital e Maternidade Celso Pierro - PUC-Campinas- Site Number : 0760010
🇧🇷Campinas, São Paulo, Brazil
Centro Multidisciplinar de Estudos Clínicos- Site Number : 0760015
🇧🇷São Bernardo Do Campo, São Paulo, Brazil
Núcleo de Pesquisa Clínica da Rede São Camilo- Site Number : 0760013
🇧🇷São Paulo, Brazil
Investigational Site Number : 1000004
🇧🇬Gabrovo, Bulgaria
Investigational Site Number : 1000007
🇧🇬Haskovo, Bulgaria
Investigational Site Number : 1000010
🇧🇬Ruse, Bulgaria
Investigational Site Number : 1000016
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1000001
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1000009
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1000017
🇧🇬Stara Zagora, Bulgaria
Investigational Site Number : 1000003
🇧🇬Stara Zagora, Bulgaria
Investigational Site Number : 1000013
🇧🇬Veliko Tarnovo, Bulgaria
Investigational Site Number : 1000006
🇧🇬Vidin, Bulgaria
Investigational Site Number : 1240006
🇨🇦Sherwood Park, Alberta, Canada
Investigational Site Number : 1240021
🇨🇦Ajax, Ontario, Canada
Investigational Site Number : 1240009
🇨🇦Toronto, Ontario, Canada
Investigational Site Number : 1240022
🇨🇦Windsor, Ontario, Canada
Investigational Site Number : 1240018
🇨🇦Windsor, Ontario, Canada
Investigational Site Number : 1240004
🇨🇦Sherbrooke, Quebec, Canada
Investigational Site Number : 1240001
🇨🇦Trois-rivières, Quebec, Canada
Investigational Site Number : 1240002
🇨🇦Victoriaville, Quebec, Canada
Investigational Site Number : 1520008
🇨🇱Valdivia, Los Ríos, Chile
Investigational Site Number : 1520007
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520001
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520003
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520002
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520006
🇨🇱Talca, Maule, Chile
Investigational Site Number : 1520005
🇨🇱Quillota, Valparaíso, Chile
Investigational Site Number : 1560012
🇨🇳Beijing, China
Investigational Site Number : 1560004
🇨🇳Changchun, China
Investigational Site Number : 1560001
🇨🇳Chengdu, China
Investigational Site Number : 1560018
🇨🇳Haikou, China
Investigational Site Number : 1560016
🇨🇳Hefei, China
Investigational Site Number : 1560017
🇨🇳Hohhot, China
Investigational Site Number : 1560002
🇨🇳Jinan, China
Investigational Site Number : 1560014
🇨🇳Nanchang, China
Investigational Site Number : 1560008
🇨🇳Shenyang, China
Investigational Site Number : 1560005
🇨🇳Wuhan, China
Investigational Site Number : 1560011
🇨🇳Xiangtan, China
Investigational Site Number : 1560007
🇨🇳Xuzhou, China
Investigational Site Number : 1560015
🇨🇳Yangzhou, China
Investigational Site Number : 2030003
🇨🇿Havlíčkův Brod, Czechia
Investigational Site Number : 2030001
🇨🇿Jindřichův Hradec, Czechia
Investigational Site Number : 2330001
🇪🇪Tartu, Estonia
Investigational Site Number : 2500001
🇫🇷Lyon, France
Investigational Site Number : 2500004
🇫🇷Reims, France
Investigational Site Number : 2680006
🇬🇪Batumi, Georgia
Investigational Site Number : 2680002
🇬🇪Tbilisi, Georgia
Investigational Site Number : 2680003
🇬🇪Tbilisi, Georgia
Investigational Site Number : 2680001
🇬🇪Tbilisi, Georgia
Investigational Site Number : 2760006
🇩🇪Bendorf, Germany
Investigational Site Number : 2760010
🇩🇪Berlin, Germany
Investigational Site Number : 2760005
🇩🇪Frankfurt, Germany
Investigational Site Number : 2760008
🇩🇪Leipzig, Germany
Investigational Site Number : 2760007
🇩🇪Leipzig, Germany
Investigational Site Number : 2760003
🇩🇪Lübeck, Germany
Investigational Site Number : 2760001
🇩🇪Mainz, Germany
Investigational Site Number : 2760011
🇩🇪Rosenheim, Germany
Investigational Site Number : 3000008
🇬🇷Palaio Faliro, Greece
Investigational Site Number : 3000002
🇬🇷Thessaloniki, Greece
Investigational Site Number : 3480009
🇭🇺Budapest, Hungary
Investigational Site Number : 3480001
🇭🇺Gödöllő, Hungary
Investigational Site Number : 3480004
🇭🇺Hajdunanas, Hungary
Investigational Site Number : 3480002
🇭🇺Mosonmagyaróvár, Hungary
Investigational Site Number : 3480003
🇭🇺Püspökladány, Hungary
Investigational Site Number : 3560001
🇮🇳Calicut, India
Investigational Site Number : 3560006
🇮🇳Chandigarh, India
Investigational Site Number : 3560005
🇮🇳Hyderabad, India
Investigational Site Number : 3560009
🇮🇳Jaipur, India
Investigational Site Number : 3560004
🇮🇳Jaipur, India
Investigational Site Number : 3560012
🇮🇳Kanpur, India
Investigational Site Number : 3560010
🇮🇳Nagpur, India
Investigational Site Number : 3560011
🇮🇳Nagpur, India
Investigational Site Number : 3560007
🇮🇳Nagpur, India
Investigational Site Number : 3560003
🇮🇳Nagpur, India
Investigational Site Number : 3560013
🇮🇳Pune, India
Investigational Site Number : 3760008
🇮🇱Haifa, Israel
Investigational Site Number : 3760003
🇮🇱Jerusalem, Israel
Investigational Site Number : 3760002
🇮🇱Jerusalem, Israel
Investigational Site Number : 3760006
🇮🇱Kefar Sava, Israel
Investigational Site Number : 3760001
🇮🇱Petah Tikva, Israel
Investigational Site Number : 3760009
🇮🇱Ramat Gan, Israel
Investigational Site Number : 3760004
🇮🇱Rehovot, Israel
Investigational Site Number : 3760007
🇮🇱Tel Aviv, Israel
Investigational Site Number : 3800001
🇮🇹Ferrara, Italy
Investigational Site Number : 3920008
🇯🇵Nagoya, Aichi, Japan
Investigational Site Number : 3920002
🇯🇵Kurume, Fukuoka, Japan
Investigational Site Number : 3920007
🇯🇵Kure, Hiroshima, Japan
Investigational Site Number : 3920006
🇯🇵Himeji, Hyogo, Japan
Investigational Site Number : 3920009
🇯🇵Yokohama, Kanagawa, Japan
Investigational Site Number : 3920001
🇯🇵Matsusaka, Mie, Japan
Investigational Site Number : 3920005
🇯🇵Kiyose, Tokyo, Japan
Investigational Site Number : 3920003
🇯🇵Fukuoka, Japan
Investigational Site Number : 3920004
🇯🇵Tokyo, Japan
Investigational Site Number : 4100002
🇰🇷Wonju-si, Gangwon-do, Korea, Republic of
Investigational Site Number : 4100001
🇰🇷Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 4400002
🇱🇹Kaunas, Lithuania
Investigational Site Number : 4840007
🇲🇽Durango, Mexico
Investigational Site Number : 5280001
🇳🇱Breda, Netherlands
Investigational Site Number : 5780001
🇳🇴Lørenskog, Norway
Investigational Site Number : 6160001
🇵🇱Bialystok, Podlaskie, Poland
Investigational Site Number : 6160002
🇵🇱Ostrowiec Swietokrzyski, Swietokrzyskie, Poland
Investigational Site Number : 6200006
🇵🇹Porto, Portugal
Investigational Site Number : 7030004
🇸🇰Prešov, Slovakia
Investigational Site Number : 7030003
🇸🇰Spišská Nová Ves, Slovakia
Investigational Site Number : 7100004
🇿🇦Benoni, South Africa
Investigational Site Number : 7100001
🇿🇦Durban, South Africa
Investigational Site Number : 7100006
🇿🇦Durban, South Africa
Investigational Site Number : 7100005
🇿🇦Durban, South Africa
Investigational Site Number : 7240014
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number : 7240006
🇪🇸Sant Boi de Llobregat, Catalunya [Cataluña], Spain
Investigational Site Number : 7240008
🇪🇸Pozuelo de Alarcón, Madrid, Spain
Investigational Site Number : 7240003
🇪🇸Madrid, Spain
Investigational Site Number : 1580003
🇨🇳Taipei City, Taiwan
Investigational Site Number : 7920002
🇹🇷Akdeniz, Turkey
Investigational Site Number : 7920007
🇹🇷Ankara, Turkey
Investigational Site Number : 8260002
🇬🇧Chertsey, Surrey, United Kingdom