A Study of Maribavir Compared to Valganciclovir to Treat Cytomegalovirus Infections in People Who Have Received Stem Cell Transplants

NCT ID: NCT02927067

Last Updated: 2023-03-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 553 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-14
• Study Completion Date: 2022-07-01

Brief Summary

This study is about treatment options for cytomegalovirus infections in people who have received stem cell transplants. The main aim of the study is to check if the cytomegalovirus infection can no longer be detected after treatment with marivabir or valganciclovir.

Participants will take 2 tablets of marivabir or valganciclovir and 2 tablets of placebo twice a day for 8 weeks. A placebo will look like marivabir or valganciclovir but will not have any medicine in it.

After treatment, each participant will be followed up for up to 12 weeks.

Participants will visit their study clinic up to 18 times during the study.

Conditions

Cytomegalovirus (CMV)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Valganciclovir 900 mg BID

Participants received 900 milligrams (mg) of valganciclovir along with a placebo matched to maribavir, twice daily (BID) orally for 8 weeks. Valganciclovir dose was allowed to be adjusted to 450 mg BID or 450 mg QD based on renal function impairment assessed at baseline or development of neutropenia during the study.

Group Type: ACTIVE_COMPARATOR

Valganciclovir

Intervention Type: DRUG

Participants will receive valganciclovir tablets orally.

Placebo

Intervention Type: OTHER

Participants will receive placebo tablets matched to either maribavir or valganciclovir.

Maribavir 400 mg BID

Participants received 400 mg of maribavir along with a placebo matched to valganciclovir, BID orally for 8 weeks.

Group Type: EXPERIMENTAL

Maribavir

Intervention Type: DRUG

Participants will receive 400 mg of maribavir BID orally.

Placebo

Intervention Type: OTHER

Participants will receive placebo tablets matched to either maribavir or valganciclovir.

Interventions

Maribavir

Participants will receive 400 mg of maribavir BID orally.

Intervention Type: DRUG

Valganciclovir

Participants will receive valganciclovir tablets orally.

Intervention Type: DRUG

Placebo

Participants will receive placebo tablets matched to either maribavir or valganciclovir.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Be able to provide written, personally signed, and dated informed consent to participate in the study before completing any study-related procedures. As applicable, a parent/both parents or legally authorized representative (LAR) must provide signature of informed consent and there must be documentation of assent by the participants before completing any study-related procedures. During the COVID-19 public health emergency, informed consent from a potential or current trial participant may, if permitted by local laws and regulations, be obtained via electronic informed consent (eIC) capabilities or an electronic face-to-face consent interview when these individuals are unable to travel to the site (FDA COVID-19 Guidance, 27 January 2021, Q11).
• Be greater than or equal to (>=) 16 years of age at the time of consent.
• Be a recipient of hematopoietic stem cell transplant.
• Have a documented asymptomatic CMV infection, with a screening value of CMV DNA >=1365 International Units per millilitre (IU/mL) to less than or equal to (<=) 273000 IU/mL in whole blood or >=455 IU/mL to <=91000 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. Both samples should be taken within 14 days prior to randomization with second sample obtained within 5 days prior to randomization. Same laboratory and same sample type (whole blood or plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection that does not present with tissue invasive CMV disease, as assessed by the investigator. Participants with CMV DNA less than (<) 910 and >=455 IU/mL in plasma or <2730 and >=1365 IU/mL in whole blood will also need to meet at least 1 of the following criteria for high-risk CMV infection to be eligible:

1. Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 1 of the following 3 HLA-gene loci: HLA-A, -B or -DR,

2. Haploidentical donor

3. Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA -gene loci: HLA-A, -B, -C and -DRB1,

4. Use of umbilical cord blood as stem cell source,

5. Use of ex vivo T-cell-depleted grafts,

6. Grade 2 or greater graft-versus-host-disease (GVHD), requiring the use of systemic corticosteroids (defined as the use of >=1 milligram per kilogram per day (mg/kg/day) of prednisone or equivalent dose of another corticosteroid).

• Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or reactivation, which in the investigator's opinion requires treatment.
• Per investigator's judgment, be eligible for treatment with valganciclovir.
• Have all of the following results as part of screening laboratory assessments (results from either the central laboratory or a local laboratory can be used for qualification):

1. Absolute neutrophil count to >=1000 per cubic millimeter (/mm^3) [1.0*10^9/L].

2. Platelet count >=25,000/mm^3 [25*10^9/L].

3. Hemoglobin >=8 grams per deciliter (g/dL).

4. Estimated creatinine clearance >=30 milliliters per minute (mL/min).

• Have a negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test at screening, if a female of child bearing potential. Urine pregnancy tests may be done per institutional requirements; however they are not sufficient for eligibility determination. Sexually active females of child bearing potential must agree to comply with any applicable contraceptive requirements of the protocol. If male, must agree to use an acceptable method of birth control, as defined in the protocol, during the study treatment administration period and for 90 days afterward the last dose of study treatment.
• Be able to swallow tablets.
• Have life expectancy of >=8 weeks.
• Weigh >=40 kilograms (kg).
• Be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol.

Exclusion Criteria

• Have CMV tissue invasive disease as assessed by the investigator at the time of screening and randomization at Visit 2/Day 0.
• Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, foscarnet, or cidofovir based on documented evidence.
• Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a participants who had at least one previously documented episode of CMV infection post-transplant, and who has had at least 2 weeks of undetectable CMV DNA between the episodes during active surveillance, based on same local laboratory and same sample type). The Participants must also have been off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection may be considered continuation of the prior infection.
• Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus [HSV] co-infection requiring use of any of these agents after the randomization) or would need a co-administration with maribavir for CMV infection.
• Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated.

Note: Participants who may be receiving leflunomide must discontinue the use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Participants receiving letermovir must discontinue use 3 days prior to first dose of study treatment. Participants receiving artesunate must discontinue the use prior to the first dose of study treatment.

• Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet or letermovir) for the current CMV infection for longer than 72 hours.
• Have known hypersensitivity to the active substance or to an excipient of the study treatments.
• Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the first dose of study treatment that would preclude administration of oral medication.
• Require mechanical ventilation or vasopressors for hemodynamic support at the time of randomization.
• Be female and pregnant or nursing.
• Have previously completed, discontinued, or have been withdrawn from this study.
• Have received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or CMV vaccine at any time.
• Have received any unapproved agent or device within 30 days before initiation of study treatment.
• Have any clinically significant medical or surgical condition that, in the investigator's opinion, could interfere with interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the participant.
• Have previously received maribavir.
• Have serum aspartate aminotransferase (AST) greater than (>) 5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase (ALT) >5 times ULN at screening, or total bilirubin >= 3.0*ULN at screening (except for documented Gilbert's syndrome), as analyzed by local or central laboratory.
• Have known (previously documented) positive results for human immunodeficiency virus (HIV). Participants must have a confirmed negative HIV test result within 3 months of study entry or, if unavailable, be tested by a local laboratory during the screening period.
• Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the investigator. Participants who experience relapse or progression of their underlying malignancy (for which HSCT was performed), as determined by the investigator, are not to be enrolled.
• Be undergoing treatment for acute or chronic hepatitis C

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda Development Center Americas, Inc.

INDUSTRY

Sponsor Role: collaborator

Shire

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Shire

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

UCLA Medical Center

Los Angeles, California, United States

Stanford University

Stanford, California, United States

Colorado Blood Cancer Institute - PPDS

Denver, Colorado, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Emory University

Atlanta, Georgia, United States

University of Chicago

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

University of Maryland School of Medicine

Baltimore, Maryland, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Brigham and Womens Hospital

Boston, Massachusetts, United States

UMass Memorial Medical Center

Worcester, Massachusetts, United States

Harper University Hospital

Detroit, Michigan, United States

Henry Ford Health System

Detroit, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic - PIN

Rochester, Minnesota, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Joan and sandford I. Weill Medical College of Cornell University Clinic

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

TriStar Centennial Medical Center

Nashville, Tennessee, United States

Saint Davids South Austin Medical Center

Austin, Texas, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Texas Transplant Institute

San Antonio, Texas, United States

VA Puget Sound Health Care System - NAVREF - PPDS

Seattle, Washington, United States

The Medical College of Wisconsin, Inc.

Milwaukee, Wisconsin, United States

Westmead Hospital

Westmead, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

Medizinische Universitat Wien (Medical University of Vienna)

Vienna, Vienna, Austria

Elisabethinen Hospital Linz

Linz, , Austria

UZ Antwerpen

Edegem, Antwerpen, Belgium

Institute Jules Bordet

Brussels, Brussels Capital, Belgium

Cliniques Universitaires Saint-Luc

Brussels, Brussels Capital, Belgium

Universitair Ziekenhuis Brussel - PIN

Jette, Brussels Capital, Belgium

University Hospital Gent

Ghent, Oost-Vlaanderen, Belgium

UZ Leuven

Leuven, Vlaams Brabant, Belgium

AZ Sint-Jan AV

Bruges, West-Vlaanderen, Belgium

CHU de Liège

Liège, , Belgium

Vancouver General Hospital

Vancouver, British Columbia, Canada

Queen Elizabeth II Health Sciences Center

Halifax, Nova Scotia, Canada

Hamilton Health Sciences Corporation

Hamilton, Ontario, Canada

Peking University First Hospital

Beijing, Beijing Municipality, China

Peking University People's Hospital

Beijing, Beijing Municipality, China

Nanfang Hospital Southern Medical University

Guangzhou, Guangdong, China

The First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, China

Xiangya Hospital Central South University

Changsha, , China

Guangzhou First People's Hospital

Guangzhou, , China

The First Affiliated Hospital, College of Medicine, Zhejiang University

Hangzhou Zhejiang, , China

Henan Cancer Hospital

Zhengzhou, , China

University Hospital Center Zagreb

Zagreb, , Croatia

Fakultni nemocnice v Motole

Prague, Praha, Hlavní Mesto, Czechia

Ustav hematologie a krevni transfuze

Prague, , Czechia

Institut de Cancérologie Strasbourg Europe

Strasbourg, Bas-Rhin, France

Hopital de Hautepierre

Strasbourg, Bas-Rhin, France

CHU de Bordeaux

Pessac, Gironde, France

Hôpital Universitaire Dupuytren

Limoges, Haute-Vienne, France

CHU de GRENOBLE

Grenoble, Isère, France

Hôtel Dieu

Nantes, Loire-Atlantique, France

CHU Angers

Angers, Maine-et-Loire, France

Hopital Henri Mondor

Créteil, Val-de-Marne, France

Hopital Jean Minjoz

Besnçon, , France

Institut Paoli Calmettes

Nice, , France

Hôpital Saint Antoine

Paris, , France

Hôpital Saint Louis

Paris, , France

EDOG - Institut Claudius Regaud - PPDS

Toulouse, , France

Universitätsklinikum Münster

Münster, North Rhine-Westphalia, Germany

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, Rhineland-Palatinate, Germany

Universität des Saarlandes

Homburg, Saarland, Germany

Universitatsklinikum Leipzig

Leipzig, Saxony, Germany

Universitätsklinikum Augsburg

Augsburg, , Germany

Helios Klinikum Berlin-Buch

Berlin, , Germany

Martin Luther Universitat Halle Wittenberg

Halle, , Germany

Universitätsklinikum Hamburg Eppendorf

Hamburg, , Germany

Universitätsklinik Rostock

Rostock, , Germany

Robert Bosch Krankenhaus

Stuttgart, , Germany

Universitätsklinikum Tübingen

Tübingen, , Germany

Attikon University General Hospital

Athens, Attica, Greece

Georgios Papanikolaou General Hospital of Thessaloniki

Thessaloniki, , Greece

Del-pesti Centrumkorhaz- Orszagos Hematologiai és Infektologiai Intezet

Budapest, , Hungary

Sheba Medical Center - PPDS

Ramat Gan, Central District, Israel

Hadassah Medical Center - PPDS

Jerusalem, Jerusalem, Israel

Rambam Medical Center - PPDS

Haifa, , Israel

Tel Aviv Sourasky Medical Center PPDS

Tel Aviv, , Israel

Ospedale Dell'Angelo

Brescia, Lombardy, Italy

Ospedale Infantile Regina Margherita - INCIPIT - PIN

Turin, Piedmont, Italy

Azienda Ospedaliera Universitaria Integrata Di Verona

Verona, Veneto, Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, , Italy

Fondazione Policlinico Universitario A Gemelli

Roma, , Italy

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Torino, , Italy

Auckland City Hospital

Grafton, Auckland, New Zealand

Canterbury Health Laboratories

Christchurch, South Island, New Zealand

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu

Wroclaw, Lower Silesian Voivodeship, Poland

MTZ Clinical Research Sp z o o - PRATIA - PPDS

Warsaw, Masovian Voivodeship, Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, , Poland

First St. Petersburg State Medical University n.a. I.P Pavlov

Saint Petersburg, Sankt-Peterburg, Russia

Regional Oncology Center

Irkutsk, , Russia

Kirov Research Institute of Haematology and Blood Transfusion

Kirov, , Russia

National University Hospital

Singapore, , Singapore

Singapore General Hospital (SGH)

Singapore, , Singapore

Dong-A University Hospital

Busan, , South Korea

Keimyung University Dongsan Hospital

Daegu, , South Korea

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Universitario Marques de Valdecilla

Santander, Cantabria, Spain

Complejo Asistencial Universitario de Salamanca - H. Clinico

Salamanca, Castille and León, Spain

Hospital Universitario Vall d'Hebrón - PPDS

Barcelona, , Spain

ICO l'Hospitalet Hospital Duran i Reynals

Barcelona, , Spain

C.H. Regional Reina Sofia - PPDS

Córdoba, , Spain

Hospital Universitario Virgen de Las Nieves

Granada, , Spain

Hospital Universitario de La Princesa

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

Hospital Universitario Puerta de Hierro - Majadahonda

Madrid, , Spain

Hospital Regional Universitario de Malaga - Hospital General

Málaga, , Spain

Hospital Universitario de Donostia

San Sebastian Gipuzkoa, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, , Spain

Universitätsspital Zürich

Zurich, , Switzerland

Baskent University Medical Faculty Adana Practice and Research Center

Adana, , Turkey (Türkiye)

Ankara University Medica Faculty Hematology Department Clinical Research Area PPDS

Ankara, , Turkey (Türkiye)

Birmingham Heartlands Hospital

West Midlands, Birmingham, United Kingdom

Hammersmith Hospital

London, London, City of, United Kingdom

University College London

London, London, City of, United Kingdom

St George's Hospital

Tooting, London, United Kingdom

Clatterbridge Cancer Centre Liverpool

Liverpool, Merseyside, United Kingdom

The Christie NHS Foundation Trust - PPDS

Manchester, , United Kingdom

Southampton University Hospitals NHS Trust

Southampton, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; China; Croatia; Czechia; France; Germany; Greece; Hungary; Israel; Italy; New Zealand; Poland; Russia; Singapore; South Korea; Spain; Switzerland; Turkey (Türkiye); United Kingdom

References

Chou S, Winston DJ, Avery RK, Cordonnier C, Duarte RF, Haider S, Maertens J, Peggs KS, Solano C, Young JH, Gu J, Pocock G, Papanicolaou GA. Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection. J Infect Dis. 2025 Mar 17;231(3):e470-e477. doi: 10.1093/infdis/jiae469.

Reference Type: DERIVED

PMID: 39302855 (View on PubMed)

Papanicolaou GA, Avery RK, Cordonnier C, Duarte RF, Haider S, Maertens J, Peggs KS, Solano C, Young JH, Fournier M, Murray RA, Wu J, Winston DJ; AURORA Trial Investigators. Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir. Clin Infect Dis. 2024 Mar 20;78(3):562-572. doi: 10.1093/cid/ciad709.

Reference Type: DERIVED

PMID: 38036487 (View on PubMed)

Stewart AG, Kotton CN. What's New: Updates on Cytomegalovirus in Solid Organ Transplantation. Transplantation. 2024 Apr 1;108(4):884-897. doi: 10.1097/TP.0000000000004855. Epub 2023 Oct 30.

Reference Type: DERIVED

PMID: 37899366 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f6b5fd74db2bf003ab46ecf

To obtain more information on the study, click here/on this link

Other Identifiers

2015-004726-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SHP620-302

Identifier Type: -

Identifier Source: org_study_id