Clinical Trial Results:
A Phase 3, Open-Label, Single-Arm Study to Assess the Efficacy, Safety, and Pharmacokinetics of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection in Japanese Recipients of a Hematopoietic Stem Cell Transplant (HSCT) or Solid Organ Transplant (SOT)
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Summary
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EudraCT number |
2022-002374-82 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
27 Jun 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jun 2024
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First version publication date |
23 Jun 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TAK-620-3001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05137717 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Takeda
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Sponsor organisation address |
95 Hayden Avenue, Lexington, United States, MA 02421
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Public contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Jun 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Jun 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of the study is to evaluate the efficacy of maribavir in CMV viremia clearance at the end of Study Week 8 (8 weeks after start of administration) in Japanese HSCT or SOT recipients with CMV infection. Also, to assess the safety and tolerability of maribavir in Japanese transplant recipients with CMV infection.
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Protection of trial subjects |
This study was conducted in accordance with the protocol, the International Council for Harmonisation Guideline for GCP E6 (ICH GCP, 1996; ICH E6 R2, 2016), Title 21 of the US Code of Federal Regulations (US CFR), the European Union Directives (2001/20/EC; 2005/28/EC), and applicable national and local regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Jan 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Japan: 41
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Worldwide total number of subjects |
41
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
34
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 23 sites in Japan from 18 January 2022 to 27 June 2023. | ||||||||||||
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Pre-assignment
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Screening details |
A total of 61 Japanese participants with cytomegalovirus (CMV) infection were screened and enrolled, of which 41 participants received maribavir treatment in this study. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Maribavir | ||||||||||||
Arm description |
Participants received maribavir 400 milligrams (mg), oral tablet, twice a day (BID) for up to 8 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Maribavir
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Investigational medicinal product code |
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Other name |
SHP620, TAK-620
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Maribavir 400 mg, tablets, orally, BID for up to 8 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Maribavir
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Reporting group description |
Participants received maribavir 400 milligrams (mg), oral tablet, twice a day (BID) for up to 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Maribavir
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Reporting group description |
Participants received maribavir 400 milligrams (mg), oral tablet, twice a day (BID) for up to 8 weeks. | ||
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End point title |
Percentage of Participants Who Achieved Confirmed Clearance of Plasma CMV Deoxyribose Nucleic Acid (DNA) at Week 8 [1] | ||||||||
End point description |
The confirmed viremia clearance was defined as a plasma CMV DNA concentration below the lower limit of quantification (LLOQ) (that is [i.e.], less than [<] 34.5 international units per milliliter [IU/mL]) when assessed by the COBAS® 8800/COBAS® CMV Test, in two consecutive post-baseline samples, separated by at least 5 days. To be considered a responder for the primary endpoint, the participant must have received exclusively study-assigned treatment (regardless of whether study-assigned treatment was completed). FAS included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
At Week 8
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [2] | ||||||||||
End point description |
A TEAEs was defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsened in either intensity or frequency following exposure to the investigational product or medicinal product. An SAE was any untoward medical occurrence or effect that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability / incapacity, was a congenital anomaly / birth defect or was medically important due to other reasons than the above mentioned criteria. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants With TEAEs Leading to Treatment Discontinuation with Maribavir [3] | ||||||
End point description |
The number of participants with TEAEs leading to maribavir study treatment discontinuation (including treatment interruption or withdrawal) were reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Vital Signs [4] | ||||||
End point description |
Vital sign assessments included blood pressure, pulse, respiratory rate and body temperature. Any clinically meaningful change in vital signs which were deemed clinically significant by the investigator were reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Abnormalities in Physical Examination Findings [5] | ||||||
End point description |
Physical examination included assessments of the head, eyes, ears, nose, throat, neck, lymph nodes, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Any clinically meaningful change in physical examination which were deemed clinically significant by the investigator were reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Abnormalities in Clinical Laboratory Parameters [6] | ||||||
End point description |
Clinical laboratory parameters included evaluations of hematology, chemistry, urinalysis. Any clinically meaningful change in clinical laboratory parameters which were deemed clinically significant by the investigator were reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Electrocardiograms (ECGs) [7] | ||||||
End point description |
12-lead ECG were evaluated. Any change in ECG assessments which are deemed clinically meaningful by the investigator were reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Events of Immunosuppressant Drug Level Increased in Blood [8] | ||||||
End point description |
Immunosuppressant drug concentration testing was solely for participants who received immunosuppressive therapy with tacrolimus, cyclosporine, or everolimus. The number of participants with an increased level of at least one immunosuppressant drug was reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 8
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants with TEAEs of New Onset of Acute or Chronic Graft-versus-host Disease (GVHD), Graft Rejection, or Graft Loss [9] | ||||||||||
End point description |
New onset of acute or chronic GVHD assessed as TEAEs, and graft rejection, or graft loss assessed were reported. Safety set included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to Week 20
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Percentage of Participants With Recurrence of Confirmed CMV Viremia During Follow-up Period in Participants With Confirmed Viremia Clearance at Week 8 who Required Additional Anti-CMV Treatment | ||||||||
End point description |
Recurrence of confirmed CMV viremia was defined as plasma CMV DNA concentration greater than or equal to (>= 34.5 IU/mL) LLOQ when assessed by the COBAS® 8800/COBAS®CMV Test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. FAS included of all participants who had taken at least 1 dose of study treatment. Here, “number of participants analysed” signifies participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
From Week 9 up to Week 20
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to First Confirmed CMV Viremia Clearance | ||||||||
End point description |
Time to first confirmed viremia clearance was defined as time from the start date of first dose of study treatment to the date of confirmed viremia clearance (event), or the date of last CMV DNA assessment on study before the initiation of alternative anti-CMV treatment (censored). The time to first confirmed CMV viremia clearance was calculated as date of first confirmed CMV viremia clearance – randomization date + 1). The date of first confirmed CMV viremia clearance was the date of first of two consecutive samples with plasma CMV DNA <LLOQ that meet the criteria of confirmed CMV viremia clearance. FAS included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug up to Week 20
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at Week 8 Through Weeks 12, 16 and 20 | ||||||||||||||||
End point description |
The confirmed viremia clearance was defined as a plasma CMV DNA concentration below the LLOQ (i.e., <34.5 IU/mL) when assessed by the COBAS® 8800/COBAS® CMV Test, in two consecutive post-baseline samples, separated by at least 5 days. Percentage of participants who maintained combined CMV viremia clearance and CMV infection symptom control at Week 8 Through Weeks 12, 16 and 20 were reported. FAS included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
At Week 8 through Weeks 12, 16 and 20
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in Plasma CMV Viremia Load | ||||||||||||||||||||||||||||||||||||||||
End point description |
The change from baseline in plasma CMV viral load, i.e., plasma CMV DNA concentration was assessed and reported. FAS included of all participants who had taken at least 1 dose of study treatment. Here, “number of participants analysed” signifies participants who were evaluable for this endpoint and “n” signifies those participants who were evaluable for the specified timepoints.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 14, 16, 18 and 20
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants With Recurrence of CMV Viremia During Study Treatment and in the Follow-Up Period After the Participants are Discontinued from Study Treatment and While On/Off Study Assigned Treatment | ||||||||||||||||||
End point description |
Recurrence of CMV viremia was defined as plasma CMV DNA concentration >= lower limit of quantification (LLOQ, i.e. >=34.5 IU/mL) when assessed by COBAS® 8800/COBAS® CMV Test in 2 consecutive plasma samples at least 5 days apart, after being unquantifiable (<LLOQ, i.e. <34.5 IU/mL) for at least 5 days in 2 consecutive samples during the first 8 weeks of the study. Study Treatment: The first stipulated 8 weeks treatment. Follow up period: period started after completion of stipulated 8 weeks treatment to Week 20. While on study assigned treatment: period over which participants received actual dosing regardless of stipulated 8 weeks completion (Week 8 or earlier). While off study assigned treatment: period after study treatment, regardless of stipulated 8 weeks completion (Week 8 or earlier up to Week 20). FAS included of all participants who had taken at least 1 dose of study treatment. Here, “number of participants analysed” signifies participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Study treatment: Week 0 to Week 8; Follow-up Period:Week 9 to Week 20; At Any time during study:Week 0 to Week 20; While on study assigned treatment: Week 0 to EOT(Week 8 or earlier); While off study assigned treatment: EOT (Week 8 or earlier) to Week 20
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance at Week 8 to be less than (<) 137 IU/mL | ||||||||
End point description |
The confirmed CMV viremia clearance at Week 8 was defined as plasma CMV DNA concentrations <137 IU/mL, in 2 consecutive post-baseline samples separated by at least 5 days, regardless of whether study treatment was discontinued before the end of the stipulated 8 weeks of therapy. FAS included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
At Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With Any Mutations in the CMV Genes Conferring Resistance to Maribavir | ||||||||
End point description |
Plasma samples were obtained and tested to identify mutations in the viral UL97 and UL54 genes confer resistance to maribavir. Percentage of participants with any mutations in the CMV genes conferring resistance to maribavir was reported. FAS included of all participants who had taken at least 1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug up to Week 20
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| No statistical analyses for this end point | |||||||||
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End point title |
Minimum Observed Plasma Concentration (Cmin) of Maribavir | ||||||||||||||
End point description |
Cmin (pre-dose) of maribavir was assessed. Pharmacokinetic set included of all participants in the safety set who had plasma sample drawn and tested for maribavir concentrations. Here, “number of participants analyzed” signifies participants who were evaluable for this endpoint and “n” signifies those participants who were evaluable for the specified timepoints.
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End point type |
Secondary
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End point timeframe |
At Weeks 1, 4, and 8: Pre-dose
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the first dose of study drug up to Week 20
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Adverse event reporting additional description |
Safety set included of all participants who had taken at least 1 dose of study treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26
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Reporting groups
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Reporting group title |
Maribavir
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Reporting group description |
Participants received maribavir 400 mg, oral tablet, BID for up to 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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28 Oct 2021 |
-Standardized the deadline for reporting SAE to the sponsor/emergency reception center for safety information (ERCSI) to "within 24 hours of first awareness of the event."- Added cidofovir as currently available systemic anti-CMV agents outside Japan.- Deleted a sentence regarding dose proportionality.- Changed the description of concurrent administration with Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inducers, focusing on rifampin and maribavir interaction.- Modified the wording of efficacy endpoints and inclusion criteria for clarity and specificity.- Unified the terminology from "beta-human chorionic gonadotropin (β-hCG)" to "human chorionic gonadotropin (hCG)."- Adjusted secondary objectives and endpoints related to CMV infections and resistance.- Modified HIV testing to be available at both local and central laboratories.- Specified the dose of maribavir per dose.- Updated Table 6 "Common Excluded Treatments and Associated Washout Period" and its footnotes.- Revised descriptions of prohibited concomitant medications and treatments to align with changes in Table 6.- Added "CMV history" as an item to be collected at the Screening Visit.- Revised the description of screen failure and eligibility criteria. - Modified CMV genotyping procedures and frequency.- Clarified the terminology related to CMV recurrence and rebound.- Aligned efficacy endpoints with the protocol of Study SHP620-302.- Changed "exploratory" to "secondary" in describing certain analyses.- Added Baseline safety analyses definition.- Included a list of CMV mutations known to confer resistance to valganciclovir and other anti-CMV agents as Appendix 6. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
