Maribavir for Treatment of Resistant or Refractory CMV Infections in Transplant Recipients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire
ClinicalTrials.gov Identifier:
NCT01611974
First received: June 1, 2012
Last updated: November 13, 2015
Last verified: December 2014
  Purpose
This study will assess safety, antiviral activity, and pharmacokinetics of different doses of maribavir administered orally for up to 24 weeks for treatment of CMV infections that are resistant or refractory to treatment with ganciclovir/valganciclovir or foscarnet in recipients of stem cell or solid organ transplants.

Condition Intervention Phase
Cytomegalovirus Infections
Drug: Maribavir
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized Study to Assess the Safety and Anti-cytomegalovirus (CMV) Activity of Different Doses of Maribavir for Treatment of CMV Infections That Are Resistant or Refractory to Treatment With Ganciclovir/Valganciclovir or Foscarnet in Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Number of Participants With Confirmed Undetectable Plasma Cytomegalovirus (CMV) Within 6 Weeks [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    Blood samples were collected at the study sites, processed to plasma aliquots, and sent to the central laboratory for quantitative CMV DNA polymerase chain reaction (PCR) testing. Plasma samples were assayed for CMV concentration using a qualified PCR method. This method was linear over 200-100,000 viral copies/mL with a lower limit of quantification (LLOQ) of 200 copies/mL. Results below LLOQ were considered undetectable. Confirmed undetectable plasma CMV DNA within 6 weeks was defined as 2 consecutive post-baseline, on-treatment undetectable results separated by >/= 5 days (assessed by the central laboratory). Samples were collected on Days 1 and 8, weekly during Weeks 2-6, and once in Weeks 8, 10, 12, 16, 20, 24 (treatment) and Weeks 1, 4, 8, 12 (follow-up). Permissible assessment windows were: Days 8-15 +/- 1 day; Weeks 3-4 +/- 2 days; Weeks 5-6 +/- 3 days; Weeks 8-12 +/- 4 days; Weeks 16-24 +/- 7 days (treatment) and Weeks 1-4 +/- 2 days; Weeks 8-12 +/- 4 days (follow-up).

  • Number of Participants With a Treatment Emergent Adverse Event (TEAE). [ Time Frame: 25 weeks ] [ Designated as safety issue: No ]
    Treatment-emergent adverse events are those events that occurred on or after study drug administration through 7 days after the last dose of study drug, or are events that occurred prior to study drug administration and recurred with increased severity after taking study drug through 7 days after the last dose of study drug.


Secondary Outcome Measures:
  • Number of Participants With CMV Recurrence [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
    Blood samples were collected at the study sites, processed to plasma aliquots, and sent to the central laboratory for quantitative CMV DNA polymerase chain reaction (PCR) testing. Plasma samples were assayed for CMV concentration using a qualified PCR method. CMV recurrence was defined as achievement of undetectable plasma CMV DNA at any time after Day 1 in at least 2 consecutive samples separated by at least 5 days, followed by detectable plasma CMV DNA in at least 2 consecutive samples separated by at least 5 days (assessed by the central laboratory). For the analyses of CMV recurrence, the first of 2 consecutive confirmed undetectable plasma CMV DNA results had to be on-treatment. CMV DNA PCR values of ≥200 copies/mL were considered detectable. Participants assessed for recurrence (n= 29, 27, 30) are the subset of the ITT-S who had at least 2 consecutive undetectable plasma CMV DNA results separated by at least 5 days, including early withdrawn qualified subjects.

  • Time to First Confirmed Undetectable Plasma CMV DNA Within 6 Weeks and at Any Time During The Study [ Time Frame: 6 weeks after start of treatment, within 36 weeks of start of treatment ] [ Designated as safety issue: No ]
    Blood samples were collected at the study sites, processed to plasma aliquots, and sent to the central laboratory for quantitative CMV DNA polymerase chain reaction (PCR) testing. Plasma samples were assayed for CMV concentration using a qualified PCR method. The time to event was defined as the time from first dose of study drug to first undetectable plasma CMV DNA within 6 weeks and at any time during the study, defined as the date of the first of at least 2 consecutive post-baseline, on-treatment undetectable results (<200 copies/mL) separated by at least 5 days; as assessed by the central laboratory. The median values are Kaplan-Meier estimates.

  • Time to CMV Recurrence [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
    Blood samples were collected at the study sites, processed to plasma aliquots, and sent to the central laboratory for quantitative CMV DNA polymerase chain reaction (PCR) testing. Plasma samples were assayed for CMV concentration using a qualified PCR method. The time to event was defined as the time of the first of at least 2 consecutive samples, separated by at least 5 days, with detectable plasma CMV DNA after achievement of undetectable plasma CMV DNA in at least 2 consecutive samples, separated by at least 5 days, at any time after Day 1; as assessed by the central laboratory. Participants assessed for recurrence (n= 29, 27, 30) are the subset of the ITT-S who had at least 2 consecutive undetectable plasma CMV DNA results separated by at least 5 days, including early withdrawn qualified subjects. The median values are Kaplan-Meier estimates.

  • Maximum Concentration (Cmax) of Maribavir [ Time Frame: pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit ] [ Designated as safety issue: No ]
    For the subset of participants who had pharmacokinetic (PK) profiling performed, non-compartmental PK analyses were used to determine Cmax, time to Cmax (tmax), time of last non-zero concentration (tlast), area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration (AUClast), and half-life (t½). Values below the LLOQ post-baseline were replaced with a value of 0 ug/mL. Values below the LLOQ at baseline were replaced with zero as it was assumed that subjects had no levels of maribavir at baseline. At the designated timepoints, the PK sample was obtained 2-4 hours after the dose of study drug; for subjects who were inpatients, a pre-dose PK sample also was collected. These samples were not required at Day 8 and Week 4 for subjects who had PK profiles performed on those days.

  • Time to Maximum Concentration (Tmax) of Maribavir [ Time Frame: pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit ] [ Designated as safety issue: No ]
    For the subset of participants who had pharmacokinetic (PK) profiling performed, non-compartmental PK analyses were used to determine Cmax, time to Cmax (tmax), time of last non-zero concentration (tlast), area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration (AUClast), and half-life (t½). Values below the LLOQ post-baseline were replaced with a value of 0 ug/mL. Values below the LLOQ at baseline were replaced with zero as it was assumed that subjects had no levels of maribavir at baseline. At the designated timepoints, the PK sample was obtained 2-4 hours after the dose of study drug; for subjects who were inpatients, a pre-dose PK sample also was collected. These samples were not required at Day 8 and Week 4 for subjects who had PK profiles performed on those days.

  • Time of Last Non-Zero Concentration (Tlast) of Maribavir [ Time Frame: pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit ] [ Designated as safety issue: No ]
    For the subset of participants who had pharmacokinetic (PK) profiling performed, non-compartmental PK analyses were used to determine Cmax, time to Cmax (tmax), time of last non-zero concentration (tlast), area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration (AUClast), and half-life (t½). Values below the LLOQ post-baseline were replaced with a value of 0 ug/mL. Values below the LLOQ at baseline were replaced with zero as it was assumed that subjects had no levels of maribavir at baseline. At the designated timepoints, the PK sample was obtained 2-4 hours after the dose of study drug; for subjects who were inpatients, a pre-dose PK sample also was collected. These samples were not required at Day 8 and Week 4 for subjects who had PK profiles performed on those days.

  • Area Under The Plasma Concentration Versus Time Curve From The Time of Dosing to The Last Measurable Concentration (AUClast) of Maribavir [ Time Frame: pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit ] [ Designated as safety issue: No ]
    For the subset of participants who had pharmacokinetic (PK) profiling performed, non-compartmental PK analyses were used to determine Cmax, time to Cmax (tmax), time of last non-zero concentration (tlast), area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration (AUClast), and half-life (t½). Values below the LLOQ post-baseline were replaced with a value of 0 ug/mL. Values below the LLOQ at baseline were replaced with zero as it was assumed that subjects had no levels of maribavir at baseline. At the designated timepoints, the PK sample was obtained 2-4 hours after the dose of study drug; for subjects who were inpatients, a pre-dose PK sample also was collected. These samples were not required at Day 8 and Week 4 for subjects who had PK profiles performed on those days.

  • Half-Life (T½) of Maribavir [ Time Frame: pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit ] [ Designated as safety issue: No ]
    For the subset of participants who had pharmacokinetic (PK) profiling performed, non-compartmental PK analyses were used to determine Cmax, time to Cmax (tmax), time of last non-zero concentration (tlast), area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration (AUClast), and half-life (t½). Values below the LLOQ post-baseline were replaced with a value of 0 ug/mL. Values below the LLOQ at baseline were replaced with zero as it was assumed that subjects had no levels of maribavir at baseline. At the designated timepoints, the PK sample was obtained 2-4 hours after the dose of study drug; for subjects who were inpatients, a pre-dose PK sample also was collected. These samples were not required at Day 8 and Week 4 for subjects who had PK profiles performed on those days.


Enrollment: 120
Study Start Date: July 2012
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Maribavir 400 mg twice daily Drug: Maribavir
Tablet for oral administration
Experimental: Maribavir 800 mg twice daily Drug: Maribavir
Tablet for oral administration
Experimental: Maribavir 1200 mg twice daily Drug: Maribavir
Tablet for oral administration

  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Be ≥12 years of age.
  2. Weigh ≥ 40 kg.
  3. Be a recipient of stem cell or solid organ transplantation.
  4. Have documented CMV infection in blood or plasma, with a screening value of ≥1,000 DNA copies/mL.
  5. Have a current CMV infection that is resistant (known CMV genetic mutations) or refractory (clinical failure to respond) to treatment with ganciclovir/valganciclovir and/or foscarnet.
  6. If female, be either postmenopausal, surgically sterile, or have a negative pregnancy test prior to randomization.
  7. Be able to swallow tablets.
  8. If adult, provide written informed consent. If child (age <18 years), have a parent/legal guardian who is willing and able to provide written informed consent (with assent from the child when appropriate).
  9. Be assessed by the investigator to determine whether prophylaxis for non-CMV herpesvirus infections (e.g., herpes simplex virus [HSV type 1 and type 2] and varicella zoster virus [VZV]) is appropriate according to institutional guidelines or standard practices, keeping in mind that maribavir is not active in vitro against these viruses.

Exclusion Criteria

  1. Be receiving any other anti-CMV agent(s).
  2. Have a current CMV infection that is considered resistant or refractory due to inadequate adherence to prior oral anti-CMV treatment.
  3. Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the time of enrollment.
  4. Have severe hepatic impairment.
  5. Require mechanical ventilation or vasopressors for hemodynamic support at the time of enrollment.
  6. Have expected survival less than 6 weeks.
  7. Be pregnant or breastfeeding.
  8. Other clinically significant medical or surgical condition.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01611974

  Show 32 Study Locations
Sponsors and Collaborators
Shire
Investigators
Study Director: Stephen A. Villano, M.D. ViroPharma Incorporated
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01611974     History of Changes
Other Study ID Numbers: 1263-202  SHP620-202 
Study First Received: June 1, 2012
Results First Received: November 13, 2015
Last Updated: November 13, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Shire:
CMV
cytomegalovirus
resistant
refractory
transplant
treatment

Additional relevant MeSH terms:
Infection
Communicable Diseases
Cytomegalovirus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases

ClinicalTrials.gov processed this record on August 25, 2016