Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Elvitegravir Versus Raltegravir

NCT00708162 | Completed Phase 3 Results DMC

• 2 other identifiers: GS-US-183-01452007-004225-26
• Study Type: interventional
• Target: 724
• Locations: 14 countries
• Sites: 180

Brief Summary

The purpose of this study is to compare the safety, tolerability and efficacy of a regimen containing once-daily elvitegravir (EVG) versus twice-daily raltegravir (RAL) added to a background regimen (1 fully-active ritonavir (RTV)-boosted protease inhibitor (PI) plus 1 or 2 additional antiretroviral (ARV) agents) in HIV-1 infected, ARV treatment-experienced adults who have documented resistance, or at least six months experience prior to screening with two or more different classes of ARV agents. Participants will be randomized in a 1:1 ratio to receive EVG plus background regimen (Elvitegravir group), or raltegravir plus background regimen (Raltegravir group). Due to known drug interactions, participants in the Elvitegravir group receiving RTV-boosted atazanavir (ATV) or RTV-boosted lopinavir (LPV) as part of their background regimen will receive elvitegravir at a lower dose (85 mg).

Conditions

HIV Infection

Keywords

HIV; HIV I; Treatment Experienced

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48

  The percentage of participants achieving and maintaining confirmed HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the FDA-defined Time to Loss of Virologic Response (TLOVR) algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

  Week 48

Secondary Outcomes (17)

• Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96

  Week 96

• Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48

  Week 48

• Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96

  Week 96

• Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)

  Week 48

• Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)

  Week 96

Study Arms (2)

Elvitegravir

EXPERIMENTAL

EVG 85 mg or 150 mg + RAL placebo + background regimen in the Randomized Phase, followed by EVG 85 mg or 150 mg + background regimen in the Open-Label Phase. Participants receiving lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) as part of their background regimen will receive EVG 85 mg; all other participants will receive EVG 150 mg.

Drug: Elvitegravir; Drug: RAL placebo; Drug: Background regimen

Raltegravir

ACTIVE COMPARATOR

RAL 800 mg (400 mg twice daily) + EVG placebo + background regimen in the Randomized Phase, followed by EVG 85 mg or 150 mg + background regimen in the Open-Label Phase. Participants receiving LPV/r or ATV/r as part of their background regimen in the Open-Label Phase will receive EVG 85 mg; all other participants will receive EVG 150 mg.

Drug: Raltegravir; Drug: EVG placebo; Drug: Background regimen

Interventions

Elvitegravir DRUG

Elvitegravir (EVG) tablet administered orally once daily with food

Also known as: Vitekta®, GS-9137

Elvitegravir

Raltegravir DRUG

Raltegravir tablet administered orally twice daily according to prescribing information

Also known as: Isentress®

Raltegravir

EVG placebo DRUG

Placebo to match elvitegravir administered orally once daily

Raltegravir

RAL placebo DRUG

RAL placebo administered orally twice daily.

Elvitegravir

Background regimen DRUG

Background Regimen (administered according to prescribing information) contains 1 fully-active ritonavir-boosted protease inhibitor (PI/r) plus 1 or 2 additional agents. The ritonavir-boosted PIs include either ATV, darunavir, fosamprenavir, LPV (Kaletra®), or tipranavir; the additional agents include abacavir (ABC), Combivir® (lamivudine (LAM)/zidovudine (ZDV) coformulated), didanosine, emtricitabine (FTC), enfuvirtide, Epzicom® (ABC/LAM coformulated), etravirine, LAM, maraviroc, tenofovir disoproxil fumarate (TDF), Truvada®, (FTC/TDF coformulated), and/or ZDV.

Elvitegravir; Raltegravir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening
• Documented resistance or at least six months experience prior to screening with two or more different classes of antiretroviral agents
• Stable antiretroviral regimen for at least 30 days prior to screening: however, participants may discontinue the antiretroviral regimen after screening and remain off therapy until baseline at the discretion of the investigator
• Eligible to receive one of the fully-active ritonavir-boosted-PIs, and an allowed second agent
• Normal ECG
• Adequate renal function (estimated glomerular filtration rate according to the Cockcroft-Gault formula ≥ 60 mL/min)
• Hepatic transaminases ≤ 5 × upper limit of normal
• Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin
• Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm\^3; platelets ≥ 50,000/mm\^3; hemoglobin ≥ 8.5 g/dL)
• Serum amylase \< 1.5 × the upper limit of the normal range
• Negative serum pregnancy test (females of childbearing potential only)
• Males and females of childbearing potential must agree to use highly effective contraception methods
• Age ≥ 18 years
• Life expectancy ≥ 1 year
• Ability to understand and sign a written informed consent form

You may not qualify if:

• New AIDS-defining condition diagnosed within the 30 days prior to screening
• Prior treatment with any HIV-1 integrase inhibitor
• Participants experiencing ascites
• Participants experiencing encephalopathy
• Females who are breastfeeding
• Positive serum pregnancy test at any time during the study (female of childbearing potential)
• Participants receiving ongoing therapy with any disallowed medication
• Current alcohol or substance use judged by the investigator to potentially interfere with study compliance
• Malignancy other than cutaneous Kaposi's sarcoma or basal cell carcinoma
• Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline
• Participation in any other clinical trial (except for the etravirine or maraviroc expanded access program), without prior approval from sponsor
• Any other clinical condition or prior therapy that would make participants unsuitable for the study
• Known hypersensitivity to study drug, metabolites or formulation excipients

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (180)

Southwest Center for HIV/AIDS

Phoenix, Arizona, 85006, United States

Location

Health for Life Clinic, PLLC

Little Rock, Arkansas, 72207, United States

Location

Pacific Oaks Medical Group

Beverly Hills, California, 90211, United States

Location

AIDS Healthcare Foundation-Research Center

Beverly Hills, California, 90804, United States

Location

Center for Special Immunology

Fountain Valley, California, 92708, United States

Location

The Living Hope Foundation

Long Beach, California, 90813, United States

Location

Kaiser Permanente

Los Angeles, California, 90027, United States

Location

Jeffrey Goodman Special Care Clinic

Los Angeles, California, 90028, United States

Location

University of Southern California, AIDS Clinical Trials Unit

Los Angeles, California, 90033, United States

Location

Peter J. Ruane, MD, Inc.

Los Angeles, California, 90036, United States

Location

Tony Mills, MD Internal Medicine

Los Angeles, California, 90069, United States

Location

Orange Coast Medical Group

Newport Beach, California, 92663, United States

Location

Alameda County Medical Center

Oakland, California, 94602, United States

Location

East Bay AIDS Center

Oakland, California, 94609, United States

Location

Kaiser Permanente

Sacramento, California, 95825, United States

Location

David J. Shamblaw, MD Inc.

San Diego, California, 92103, United States

Location

Metropolis Medical

San Francisco, California, 94115, United States

Location

San Francisco VA Medical Center/UCSF

San Francisco, California, 94121, United States

Location

Connecticut Health Care Group

Glastonbury, Connecticut, 06033, United States

Location

Circle Medical LLC

Norwalk, Connecticut, 06851, United States

Location

The Stamford Hospital - Stamford ID

Stamford, Connecticut, 06902, United States

Location

Whitman-Walker Clinic

Washington D.C., District of Columbia, 20009, United States

Location

The George Washington University Medical Center

Washington D.C., District of Columbia, 20037, United States

Location

South Florida Clinical Research

Atlantis, Florida, 33462, United States

Location

Lifeway , Inc.

Fort Lauderdale, Florida, 33308, United States

Location

NorthPoint Medical

Fort Lauderdale, Florida, 33308, United States

Location

Therafirst Medical Centers

Fort Lauderdale, Florida, 33308, United States

Location

Broward Health CCC

Fort Lauderdale, Florida, 33311, United States

Location

Gary Richmond, MD, PA, Inc.

Fort Lauderdale, Florida, 33316, United States

Location

Associates In Infectious Diseases

Ft. Pierce, Florida, 34952, United States

Location

The Kinder Medical Group

Miami, Florida, 33133, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Wohlfeiler, Piperato and Associates, LLC

North Miami Beach, Florida, 33169, United States

Location

Orlando Immunology Center

Orlando, Florida, 32803, United States

Location

Infectious Disease of Central Florida

Orlando, Florida, 32806, United States

Location

Barry M. Rodwick, M. D.

Safety Harbor, Florida, 34695, United States

Location

St. Joseph's Comprehensive Research Institute

Tampa, Florida, 33614, United States

Location

Treasure Coast Infectious Disease Consultants

Vero Beach, Florida, 32960, United States

Location

AIDS Research Consortium of Atlanta

Atlanta, Georgia, 30308, United States

Location

The Emory Clinic, Inc., Division of Infectious Diseases

Atlanta, Georgia, 30308, United States

Location

Atlanta ID Group

Atlanta, Georgia, 30309, United States

Location

Infectious Disease Specialists of Atlanta (IDSA)

Decatur, Georgia, 30033, United States

Location

Mercer Univ. School of Medicine

Macon, Georgia, 31201, United States

Location

Chatham County Health Department

Savannah, Georgia, 31401, United States

Location

Hawaii AIDS Clinical Research Program HACRP

Honolulu, Hawaii, 96316, United States

Location

The Ruth M. Rothstein CORE Center

Chicago, Illinois, 60612, United States

Location

Howard Brown Health Center

Chicago, Illinois, 60613, United States

Location

Northstar Medical Center

Chicago, Illinois, 60657, United States

Location

University of Kentucky Healthcare/Bluegrass Care Clinic

Lexington, Kentucky, 40536, United States

Location

University of Maryland, Institute of Human Virology

Baltimore, Maryland, 21201, United States

Location

Community Research Initiative of New England

Boston, Massachusetts, 02215, United States

Location

Be Well Medical Center

Berkley, Michigan, 48072, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Henry Ford Hospital Div of Infectious Disease

Detroit, Michigan, 48202, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Southampton Healthcare, Inc.

St Louis, Missouri, 63139, United States

Location

ID Care

Hillsborough, New Jersey, 08844, United States

Location

Saint Michael's Medical Center

Newark, New Jersey, 07102, United States

Location

University of Medicine and Dentistry of New Jersey; University Hospital Infectious Disease Practice

Newark, New Jersey, 07103, United States

Location

South Jersey Infectious Disease

Somer Point, New Jersey, 08244, United States

Location

Southwest C.A.R.E. Center

Santa Fe, New Mexico, 87505, United States

Location

Albany Medical College

Albany, New York, 12208, United States

Location

STAR Health Care Center

Brooklyn, New York, 11203, United States

Location

Greiger Clinic

Mount Vernon, New York, 10550, United States

Location

Beth Israel Medical Center

New York, New York, 10003, United States

Location

Chelsea Village Medical, PC

New York, New York, 10011, United States

Location

Ricky K. Hsu, MD, PC

New York, New York, 10011, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

AIDS Community HealthCenter

Rochester, New York, 14604, United States

Location

Montefiore Medical Center

The Bronx, New York, 10573, United States

Location

University of North Carolina/ School of Medicine Division of Infectious Diseases/ AIDS Clinical Trials Unit

Chapel Hill, North Carolina, 27514, United States

Location

Carolinas Medical Center

Charlotte, North Carolina, 28207, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Brody School of Medicine at East Carolina University

Greenville, North Carolina, 27834, United States

Location

Rosedale Infectious Diseases

Huntersville, North Carolina, 28078, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Summa Health CARE Center

Akron, Ohio, 44304, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Philadelphia FIGHT

Philadelphia, Pennsylvania, 19107, United States

Location

Thomas Jefferson University Jefferson Alumni Hall

Philadelphia, Pennsylvania, 19107, United States

Location

Central Texas Clinical Research

Austin, Texas, 78705, United States

Location

AIDS Arms/ Peabody Health Center

Dallas, Texas, 75215, United States

Location

Southwest Infectious Disease Clinical Research

Dallas, Texas, 75219, United States

Location

Presbyterian Hospital of Dallas

Dallas, Texas, 75231, United States

Location

North Texas Infectious Disease Consultants

Dallas, Texas, 75246, United States

Location

Tarrant County Infectious Disease Associates

Fort Worth, Texas, 76104, United States

Location

Garcia Family Health Group

Harlingen, Texas, 78550, United States

Location

University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

Gordon E. Crofoot, MD, PA

Houston, Texas, 77098, United States

Location

The Schrader Clinic

Houston, Texas, 77098, United States

Location

Joseph C. Gathe, JR. MD, F.A.C.P.

Houston, Texas, 77478, United States

Location

DCOL Center for Clinical Research

Longview, Texas, 75605, United States

Location

Clinical Alliance for Research & Education - Infectious Diseases, LLC (CARE-ID)

Annandale, Virginia, 22003, United States

Location

EHS Pulmonary and Critical Care

Spokane, Washington, 99204, United States

Location

Royal Prince Alfred Hospital

Camperdown, New South Wales, 2050, Australia

Location

Ground Zero Medical Centre

Darlinghurst, New South Wales, 2010, Australia

Location

Holdsworth House Medical Practice

Darlinghurst, New South Wales, 2010, Australia

Location

St. Vincent's Hospital, Sydney

Darlinghurst, New South Wales, 2010, Australia

Location

St George Hospital

Kogarah, New South Wales, 2217, Australia

Location

Albion Street Centre

Sydney, New South Wales, 2010, Australia

Location

East Sidney Doctors

Sydney, New South Wales, 2010, Australia

Location

Westmead Hospital

Wentworthville, New South Wales, 2145, Australia

Location

Institute of Tropical Medicine

Antwerp, 2000, Belgium

Location

C.H.U. St Pierre

Brussels, 1000, Belgium

Location

Hôpital Erasme

Brussels, 1070, Belgium

Location

CHU de Charleroi-Hopital civil

Charleroi, 6000, Belgium

Location

Centre Hospitalier Universitaire de Liège

Liège, 4000, Belgium

Location

Downtown Infectious Diseases Clinic

Vancouver, British Columbia, V35 4N9, Canada

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3H 1V7, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

CascAids Research

Toronto, Ontario, M4T 3A7, Canada

Location

Canadian Immunodeficiency Research Collaborative (CIRC) Inc.

Toronto, Ontario, M5B 1L6, Canada

Location

University Health Network, Toronto General Hospital

Toronto, Ontario, M5G 2N2, Canada

Location

Clinique medicale l'Actuel

Montreal, Quebec, H2L 4P9, Canada

Location

Immunodeficiency Service, McGill University Health Centre (MUHC)

Montreal, Quebec, H2X 2P4, Canada

Location

University of Manitoba - Health Sciences Centre

Winnipeg, R3A 1R9, Canada

Location

Hopital de Bicentre - Service de medecine Interne et Immunologie

Le Kremlin-Bicêtre, 94270, France

Location

University Hospital of Montpellier - Gui de Chauliac

Montpellier, 34295, France

Location

CHU Nantes

Nantes, 44093, France

Location

C.H.U. de Nice - Hopital de l'Archet 1

Nice, 06202, France

Location

Hopital Saint Louis

Paris, 75010, France

Location

Hopital Saint Antoine - Infectious Desease Department

Paris, 75012, France

Location

Hopital Pitie Salpetriere - Infectious Deseases Department

Paris, 75013, France

Location

APHP Hopital Bichat-Claude Bernard

Paris, 75018, France

Location

Hopital Tenon

Paris, 75020, France

Location

CHU Bordeaux

Pessac, 33604, France

Location

Hopital Purpan - Service of Infectious Diseases

Toulouse, 31059, France

Location

Universitatsklinikum Bonn

Bonn, 53125, Germany

Location

Klinikum der Universitat zu Koln

Cologne, 50937, Germany

Location

Universitatsklinikum Dusseldorf

Düsseldorf, 40225, Germany

Location

Universitatklinikum Essen

Essen, 45122, Germany

Location

Klinikum der J.W. Goethe-Universitat

Frankfurt, 60590, Germany

Location

IFI-Institute

Hamburg, 20099, Germany

Location

Ambulanzzentrum am Universitatsklinikum Hamburg Eppendorf

Hamburg, 20251, Germany

Location

Medizinische Universitatsklinik Kiel

Kiel, 24116, Germany

Location

MUC Research

Munich, 80335, Germany

Location

Ospedali Riuniti Di Bergamo

Bergamo, 24128, Italy

Location

Spedali Civili di Brescia

Brescia, 25137, Italy

Location

Fondazione Centro San Raffaele del Monte Tabor

Milan, 20127, Italy

Location

Ospedale L. Sacco

Milan, 20157, Italy

Location

Ospedale Luigi Sacco

Milan, 20157, Italy

Location

Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani I.R.C.C.S.

Rome, 00149, Italy

Location

Universita La Sapienza Policlinico Umberto I

Rome, 00161, Italy

Location

Universita' Cattolica Del Sacro Cuore

Rome, 00168, Italy

Location

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMYNSZ)

México, D.f., 14000, Mexico

Location

Hospital Regional de Leon Guanajuato

León, Guanajuato, 31320, Mexico

Location

Hospital Civil de Guadalajara

Guadalajara, Jalisco, 44280, Mexico

Location

Hospital Central Morones Prieto

San Luis Potosí City, San Luis Potsi, 78240, Mexico

Location

Erasmus Medisch Centrum

Rotterdam, 3000CA, Netherlands

Location

Hospital Fernando Fonseca

Amadora, 2720-276, Portugal

Location

Hospital Santo Antonio dos Capuchos

Lisbon, 1150-069, Portugal

Location

Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

Hospital Pulido Valente

Lisbon, 1769-001, Portugal

Location

Hospital de Sao Joao

Porto, 42020-451, Portugal

Location

Instituto de Investigacion Cientifica del Sur

Ponce, 00731, Puerto Rico

Location

Clinical Research Puerto Rico, Inc.

San Juan, 00909, Puerto Rico

Location

HOPE Clinical Research

San Juan, 00909, Puerto Rico

Location

VA Caribbean healthcare System

San Juan, 00921, Puerto Rico

Location

University of Puerto Rico, School of Medicine, Proyecto ACTU

San Juan, 00936, Puerto Rico

Location

Hospital General Universitario de Alicante

Alicante, 03010, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Clinic i Provincial de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario Germans Trias i Pujol

Barcelona, 08916, Spain

Location

Hospital Reina Sofia

Córdoba, 14004, Spain

Location

Hospital General Universitario del Elche

Elche, 03203, Spain

Location

Hospital Clinico San Cecilio

Granada, 18014, Spain

Location

Hospital La Princesa

Madrid, 28006, Spain

Location

Hospital General Universitario Gregorio Maranon

Madrid, 28007, Spain

Location

Hospital Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Doce De Octubre

Madrid, 28041, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario de Canarias

Santa Cruz de Tenerife, 38320, Spain

Location

Hospital Virgen del Rocio

Seville, 41013, Spain

Location

Complexo Hospitalario Xeral-Cies (Chuvi) Vigo

Vigo, 36204, Spain

Location

Universitatsspital Zurich

Zurich, CH-8091, Switzerland

Location

RIDU, Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

Location

Imperial College Healthcare NHS Trust, St. Mary's Campus

London, W2 1NY, United Kingdom

Location

Royal Free and University College Medical School

London, WC1E 6JB, United Kingdom

Location

North Manchester General Hospital

Manchester, M8 6RB, United Kingdom

Location

Related Publications (1)

• Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, Zhong L, Margot N, Cheng AK, Chuck SL; Study 145 Team. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis. 2012 Jan;12(1):27-35. doi: 10.1016/S1473-3099(11)70249-3. Epub 2011 Oct 18.

  PMID: 22015077 RESULT

MeSH Terms

Conditions

HIV Infections

Interventions

elvitegravir; Raltegravir Potassium

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

10 participants from a single study site were excluded from Intent-to-Treat (ITT) Analysis Set due to critical and multiple protocol violations (elvitegravir arm: n = 3; raltegravir arm: n = 7).

Results Point of Contact

• Title: Clinical Trial Disclosures
• Organization: Gilead Sciences, Inc.

ClinicalTrialDisclosures@gilead.com

Study Officials

• Javier Szwarcberg, MD, MPH

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 30, 2008
• First Posted: July 2, 2008
• Study Start: July 1, 2008
• Primary Completion: December 1, 2010
• Study Completion: April 1, 2015
• Last Updated: May 30, 2016
• Results First Posted: November 6, 2014

Record last verified: 2016-04

Locations

DE (9); CA (9); ME (4); ES (16); CH (1); PT (5); NL (1); GB (4); PR (5); IT (8); AU (8); BE (5); US (94); FR (11)