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Efficacy and Safety Study of Maribavir Compared to Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant Recipients

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ClinicalTrials.gov Identifier: NCT02927067
Recruitment Status : Recruiting
First Posted : October 6, 2016
Last Update Posted : March 11, 2019
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
The purpose of this study is to compare the efficacy of maribavir to valganciclovir for the treatment of cytomegalovirus (CMV) infection in asymptomatic hematopoietic stem cell transplant (HSCT) recipients.

Condition or disease Intervention/treatment Phase
Cytomegalovirus (CMV) Drug: Maribavir Drug: Valganciclovir Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled Study to Assess the Efficacy and Safety of Maribavir Compared to Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant Recipients
Actual Study Start Date : April 14, 2017
Estimated Primary Completion Date : August 13, 2021
Estimated Study Completion Date : August 13, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Maribavir/ Placebo
Participants will receive 400 milligrams (mg) of maribavir (2*200 mg tablets) twice daily (BID) orally along with a placebo matched to valganciclovir for 8 weeks.
Drug: Maribavir
Participants will receive 400 mg of maribavir BID orally.

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

Active Comparator: Valganciclovir/ Placebo
Participants will receive 900 mg of valganciclovir (2*450 mg tablets) BID orally along with a placebo matched to maribavir for 8 weeks. Valganciclovir dose may be adjusted to 450 mg BID or 450 mg QD during the study for renal function impairment or neutropenia.
Drug: Valganciclovir
Participants will receive valganciclovir tablets orally.

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




Primary Outcome Measures :
  1. Proportion of Participants With Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at the End of Study Week 8, Regardless of Whether Study Assigned Treatment was Completed [ Time Frame: Week 8 ]
    Confirmed CMV viremia clearance is defined as plasma CMV DNA concentrations less than lower limit of quantification (LLOQ; i.e. <137 International units per milliliter [IU/mL]), when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive post baseline samples separated by at least 5 days. The participant must have received exclusively study-assigned treatment.


Secondary Outcome Measures :
  1. Proportion of Participants Who Maintained Confirmed CMV Viremia Clearance Achieved at the End of Study Week 8 Through Study Week 16, Regardless of Whether Study Assigned Treatment was Completed [ Time Frame: Week 8 through Week 16 ]
    Confirmed CMV viremia clearance is defined as plasma CMV DNA concentrations <LLOQ (<137 IU/mL), when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive post baseline samples separated by at least 5 days. It will be measured from plasma CMV DNA by quantitative PCR assay. The participant must have received exclusively study-assigned treatment.

  2. Proportion of Participants Who Achieve Confirmed CMV Viremia Clearance After 8 Weeks of Receiving Study-assigned Treatment [ Time Frame: Week 8 ]
    Confirmed CMV viremia clearance is defined as plasma CMV DNA concentrations <LLOQ (<137 IU/mL), when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive post baseline samples separated by at least 5 days. It will be measured from plasma CMV DNA by quantitative PCR assay.

  3. Proportion of Participants Who Maintained Confirmed CMV Viremia Clearance After Completion of 8 Weeks of Receiving Study-Assigned Treatment Through Study Weeks 12, 16 and 20 [ Time Frame: Week 8 through Weeks 12, 16 and 20 ]
    Confirmed CMV viremia clearance is defined as plasma CMV DNA concentrations <LLOQ (<137 IU/mL), when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive post baseline samples separated by at least 5 days. It will be measured from plasma CMV DNA by quantitative PCR assay.

  4. Proportion of Participants Who Maintained Confirmed CMV Viremia Clearance After Completion of 8 Weeks of Receiving Study-Assigned Treatment Through Study Weeks 12, 16 and 20 Regardless of Whether Study Assigned Treatment was Completed [ Time Frame: Week 8 through Weeks 12, 16 and 20 ]
    Confirmed CMV viremia clearance is defined as plasma CMV DNA concentrations <LLOQ (<137 IU/mL), when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive post baseline samples separated by at least 5 days. It will be measured from plasma CMV DNA by quantitative PCR assay.

  5. Proportion of Participants With Confirmed Recurrence of Viremia While on Study Treatment and Off Treatment [ Time Frame: Baseline up to Week 20 ]
    Recurrence of CMV viremia is defined as plasma CMV DNA concentration greater than or equal to (>=) LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive plasma samples at least 5 days apart, after being unquantifiable (<LLOQ) for at least 5 days in 2 consecutive samples during the first 8 weeks of the study, during the 12 weeks of the followup study phase, and at any time during the study.

  6. Incidence of Grade 3 or 4 Neutropenia [ Time Frame: Baseline up to Week 8 ]
    Grade 3 and grade 4 neutropenia are defined as absolute neutophil count (ANC) < 1000 per cubic millimeter (/mm^3) and ANC < 500/mm^3 respectively.

  7. Number of Participants With Treatment-Emergent Adverse Events [ Time Frame: Baseline up to Week 20 ]
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE that has a start date on or after the first dose of study treatment, or that has a start date before the date of first dose of study treatment but increases in severity after the first dose of study treatment, will be considered a treatment-emergent AE (TEAE).

  8. Predose Concentration (Cmin) of Maribavir [ Time Frame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1 ]
    Cmin of Maribavir will be assessed.

  9. Area Under the Concentration-Time Curve Over the 12-Hour Dosing Interval at Steady State AUC(0-tau) of Maribavir [ Time Frame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1 ]
    AUC(0-tau) of Maribavir will be assessed.

  10. Maximum Observed Plasma Concentration (Cmax) of Maribavir [ Time Frame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1 ]
    Cmax of Maribavir will be assessed.

  11. Time When Maximum Concentration is Observed (Tmax) of Maribavir [ Time Frame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1 ]
    Tmax of Maribavir will be assessed.

  12. Apparent Oral Clearance (CL/F) of Maribavir [ Time Frame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1 ]
    CL/F of Maribavir will be assessed.

  13. Apparent Volume of Distribution (Vz/F) of Maribavir [ Time Frame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1 ]
    Vz/F of Maribavir will be assessed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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 x 10^9/L].
    2. Platelet count >= 25,000/mm^3 [25 x 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 cidofovir) 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 x ULN at screening (except for documented Gilbert's syndrome), as analyzed by local or central lab.
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02927067


Contacts
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Contact: Shire Contact 866-842-5335 ClinicalTransparency@shire.com

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Sponsors and Collaborators
Shire
Investigators
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Study Director: Study Director Shire

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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT02927067     History of Changes
Other Study ID Numbers: SHP620-302
2015-004726-34 ( EudraCT Number )
First Posted: October 6, 2016    Key Record Dates
Last Update Posted: March 11, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection
Valganciclovir
Maribavir
Antiviral Agents
Anti-Infective Agents