- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01611974
Maribavir for Treatment of Resistant or Refractory CMV Infections in Transplant Recipients
May 12, 2021 updated by: Shire
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
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.
Study Overview
Study Type
Interventional
Enrollment (Actual)
120
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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California
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Los Angeles, California, United States, 90095
- UCLA Medical Center
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Stanford, California, United States, 94305
- Stanford University Medical Center
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Colorado
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Denver, Colorado, United States, 80045
- University of Colorado
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Connecticut
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New Haven, Connecticut, United States, 06520
- Yale University
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Florida
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Gainesville, Florida, United States, 32610
- University of Florida
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Tampa, Florida, United States, 33614
- Tampa General Hospital
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Georgia
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Atlanta, Georgia, United States, 30322
- Emory University
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Illinois
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Chicago, Illinois, United States, 60637
- University of Chicago
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Chicago, Illinois, United States, 60611
- Northwestern University Medical Center
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Louisiana
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New Orleans, Louisiana, United States, 70121
- Ochsner Clinic Foundation
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Maryland
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Baltimore, Maryland, United States, 21205
- Johns Hopkins Hospital
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Massachusetts
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Boston, Massachusetts, United States, 02115
- Brigham and Women's Hospital
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Worcester, Massachusetts, United States, 01655
- University of Massachusetts
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Michigan
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Ann Arbor, Michigan, United States, 48109
- University of Michigan
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Detroit, Michigan, United States, 48202
- Henry Ford Health Care System
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Minnesota
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Minneapolis, Minnesota, United States, 55454
- University of Minnesota Medical Center
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Nebraska
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Omaha, Nebraska, United States, 68198
- University of Nebraska
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New York
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New York, New York, United States, 10032
- Columbia University
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New York, New York, United States, 10065
- Memorial Sloan-Kettering Cancer Center
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North Carolina
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Durham, North Carolina, United States, 30322
- Duke University Medical Center
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest Medical Center
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Ohio
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic Foundation
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Columbus, Ohio, United States, 43205
- Nationwide Children's Hospital
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania
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Philadelphia, Pennsylvania, United States, 19141
- Albert Einstein Medical Center
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Pittsburgh, Pennsylvania, United States, 15213
- University of Pittsburg
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South Carolina
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Charleston, South Carolina, United States, 29425
- Medical University of South Carolina
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Tennessee
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Nashville, Tennessee, United States, 37212
- Vanderbilt Medical Center
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Texas
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San Antonio, Texas, United States, 78229
- Methodist Healthcare System
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Utah
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Salt Lake City, Utah, United States, 84132
- University of Utah
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Washington
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Seattle, Washington, United States, 98109
- University of Washington
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Seattle, Washington, United States, 98195
- Fred Hutchinson Cancer Research Center
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
10 years and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria
- Be ≥12 years of age.
- Weigh ≥ 40 kg.
- Be a recipient of stem cell or solid organ transplantation.
- Have documented CMV infection in blood or plasma, with a screening value of ≥1,000 DNA copies/mL.
- 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.
- If female, be either postmenopausal, surgically sterile, or have a negative pregnancy test prior to randomization.
- Be able to swallow tablets.
- 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).
- 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
- Be receiving any other anti-CMV agent(s).
- Have a current CMV infection that is considered resistant or refractory due to inadequate adherence to prior oral anti-CMV treatment.
- Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the time of enrollment.
- Have severe hepatic impairment.
- Require mechanical ventilation or vasopressors for hemodynamic support at the time of enrollment.
- Have expected survival less than 6 weeks.
- Be pregnant or breastfeeding.
- Other clinically significant medical or surgical condition.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Maribavir 400 mg twice daily
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Tablet for oral administration
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Experimental: Maribavir 800 mg twice daily
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Tablet for oral administration
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Experimental: Maribavir 1200 mg twice daily
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Tablet for oral administration
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Confirmed Undetectable Plasma Cytomegalovirus (CMV) Within 6 Weeks
Time Frame: 6 weeks
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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).
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6 weeks
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Number of Participants With a Treatment Emergent Adverse Event (TEAE).
Time Frame: 25 weeks
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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.
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25 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With CMV Recurrence
Time Frame: 36 weeks
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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.
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36 weeks
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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
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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.
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6 weeks after start of treatment, within 36 weeks of start of treatment
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Time to CMV Recurrence
Time Frame: 36 weeks
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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.
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36 weeks
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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
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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.
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pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit
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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
|
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.
|
pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit
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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
|
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.
|
pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit
|
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
|
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.
|
pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit
|
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
|
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.
|
pre-dose and 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 8 and the Week 4 visit
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Chou S, Song K, Wu J, Bo T, Crumpacker C. Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection. J Infect Dis. 2022 Sep 4;226(4):576-584. doi: 10.1093/infdis/jiaa462.
- Papanicolaou GA, Silveira FP, Langston AA, Pereira MR, Avery RK, Uknis M, Wijatyk A, Wu J, Boeckh M, Marty FM, Villano S. Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study. Clin Infect Dis. 2019 Apr 8;68(8):1255-1264. doi: 10.1093/cid/ciy706.
- Schubert A, Ehlert K, Schuler-Luettmann S, Gentner E, Mertens T, Michel D. Fast selection of maribavir resistant cytomegalovirus in a bone marrow transplant recipient. BMC Infect Dis. 2013 Jul 19;13:330. doi: 10.1186/1471-2334-13-330.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
July 17, 2012
Primary Completion (Actual)
December 5, 2014
Study Completion (Actual)
December 5, 2014
Study Registration Dates
First Submitted
June 1, 2012
First Submitted That Met QC Criteria
June 1, 2012
First Posted (Estimate)
June 5, 2012
Study Record Updates
Last Update Posted (Actual)
June 2, 2021
Last Update Submitted That Met QC Criteria
May 12, 2021
Last Verified
May 1, 2021
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1263-202
- SHP620-202 (Other Identifier: Shire Development LLC)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Yes
IPD Plan Description
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5).
These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
IPD Sharing Access Criteria
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/.
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.
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
- Informed Consent Form (ICF)
- Clinical Study Report (CSR)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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