A Study of Cytomegalovirus Disease Epidemiology in Pediatric and Adult Liver Transplant Recipients in China
Conditions: Cytomegalovirus (CMV) Infections Among Children and Adult Liver Transplantation Patients in China
Sponsor: Lin Zhong

Study Protocol and Statistical Analysis 
Plan
A Study of Cytomegalovirus Disease Epidemiology in Pediatric 
and Adult Liver Transplant Recipients in China
June 12, 2023
NCT Number: NCT05958186
Document Date: June 12, 2023

Contents
1
Study Protocol
1
1.1
Background and Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2
Study Objectives
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2.1
Primary Objective
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2.2
Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.3
Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.4
Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.4.1
Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.4.2
Exclusion Criteria
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.5
Study Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.6
Outcome Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.6.1
Primary Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.6.2
Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.7
Ethical Considerations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2
Statistical Analysis Plan
2
2.1
Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.1.1
Full Analysis Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.1.2
Per-Protocol Set
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2
Sample Size Calculation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
2.3
Statistical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
2.3.1
Primary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
2.3.2
Secondary Analyses
. . . . . . . . . . . . . . . . . . . . . . . . . . .
3
2.3.3
Handling of Missing Data
. . . . . . . . . . . . . . . . . . . . . . . .
3
2.4
Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
2.5
Software . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
2.6
Significance Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3

1
Study Protocol
1.1
Background and Rationale
Cytomegalovirus (CMV) remains one of the most common and clinically significant infections
following solid organ transplantation, particularly liver transplantation. In China, the epidemi-
ology of CMV disease in liver transplant recipients is not well characterized, especially in
pediatric populations. This study aims to fill this knowledge gap by providing comprehensive
data on CMV disease incidence, risk factors, and outcomes in both pediatric and adult liver
transplant recipients across multiple Chinese transplant centers.
1.2
Study Objectives
1.2.1
Primary Objective
To determine the incidence of CMV disease within the first year post-transplantation in pedi-
atric and adult liver transplant recipients.
1.2.2
Secondary Objectives
1. To identify risk factors for CMV disease development
2. To compare outcomes between patients who develop CMV disease and those who do not
3. To evaluate the impact of different CMV prevention strategies on CMV disease incidence
4. To assess economic burden associated with CMV disease management
1.3
Study Design
Prospective, multicenter, observational cohort study with 12-month follow-up period.
1.4
Study Population
1.4.1
Inclusion Criteria
• Pediatric (ages 0-17 years) or adult (ages 18 years) patients
• Recipients of primary liver transplantation
• Willing and able to provide informed consent (or parental consent for minors)
• Planned follow-up at participating center for at least 12 months
1.4.2
Exclusion Criteria
• Multi-organ transplant recipients
• HIV-positive patients
• Re-transplantation cases
• Expected survival less than 72 hours post-transplantation
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1.5
Study Procedures
1. Baseline data collection: Demographic information, transplant characteristics, CMV
serostatus of donor and recipient
2. Regular follow-up visits at months 1, 3, 6, 9, and 12 post-transplantation
3. CMV DNA monitoring by PCR at each visit and when clinically indicated
4. Documentation of CMV disease episodes, treatment, and outcomes of data on immuno-
suppression regimens and other infections
1.6
Outcome Measures
1.6.1
Primary Endpoint
Incidence of CMV disease (syndrome or end-organ disease) within 12 months post-transplantation.
1.6.2
Secondary Endpoints
• Time to first CMV disease episode
• CMV disease recurrence rate
• Graft function and rejection episodes
• Patient survival
• Healthcare resource utilization
1.7
Ethical Considerations
The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical
Practice guidelines. The protocol has been approved by the institutional review boards of all
participating centers. Written informed consent will be obtained from all participants or their
legal representatives.
2
Statistical Analysis Plan
2.1
Analysis Populations
2.1.1
Full Analysis Set
All enrolled patients who meet eligibility criteria and have at least one post-baseline assess-
ment.
2.1.2
Per-Protocol Set
Patients who complete the study without major protocol deviations.
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2.2
Sample Size Calculation
Assuming a CMV disease incidence of 25% in the overall population, with 80% power and
5% significance level, a sample size of 800 patients (600 adults and 200 children) will allow
detection of a 10% difference in CMV incidence between key subgroups.
2.3
Statistical Methods
2.3.1
Primary Analysis
The incidence of CMV disease will be calculated as the proportion of patients developing CMV
disease within 12 months post-transplantation, with 95% confidence intervals. Kaplan-Meier
analysis will be used to estimate time-to-event curves.
2.3.2
Secondary Analyses
• Risk factor analysis using multivariable Cox proportional hazards regression
• Comparison of outcomes between groups using chi-square tests, t-tests, or non-parametric
tests as appropriate
• Subgroup analyses by age group (pediatric vs. adult), CMV serostatus, and immunosup-
pression regimen
• Economic analysis using generalized linear models for cost data
2.3.3
Handling of Missing Data
Multiple imputation will be used for handling missing data for key variables. Sensitivity anal-
yses will be performed to assess the impact of missing data.
2.4
Interim Analysis
No formal interim analysis for efficacy is planned. A safety interim analysis will be conducted
after enrollment of 400 patients to assess serious adverse events.
2.5
Software
All statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc., Cary, NC)
and R version 4.0 or higher.
2.6
Significance Level
A two-sided alpha level of 0.05 will be used for all statistical tests, with adjustments for multiple
comparisons where appropriate.
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