A Study on Cytomegalovirus (CMV) Infection Outcomes Among Solid Organ Transplant (SOT) Participants in Europe and Canada

Study Overview
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Brief Summary
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The main aim of the study is to assess the clinical outcomes of current CMV management across different regions of the world (Europe [EU] and Canada [CAN]). Data will be collected retrospectively from medical charts. No study medicines will be provided to participants in this study.

Detailed Description
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This study consists of two cohorts: Cohort 1 (resistant, refractory or intolerant to anti-CMV agents) includes participants who had an SOT after January 1, 2016. Cohort 2 (pre-emptive treatment for CMV viremia) includes participants who had an SOT after January 1, 2019. Participants who meet the criteria for both cohorts will be evaluated in each cohort separately (i.e., Cohort 1 and Cohort 2 are not mutually exclusive, and participants will be analyzed in both cohorts using unique index dates with respect to the cohort-specific eligibility criteria). Participant follow-up in the medical record must be available for at least one year from the CMV index date or death, whichever occurs first. The start date of data collection corresponds to the end of participant follow up. For Cohort 1, it is expected that follow-up data will be available for up to 7 years (for those participants with an index date in 2016 and followed through 2022). For Cohort 2, it is expected that follow-up data will be available for up to 4 years (for those participants with an index date in 2019 and followed through 2022).

Official Title
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A Multinational, Non-Interventional, Retrospective Study on CMV Infection Outcomes, Treatment Patterns and Healthcare Utilization Study (OTUS) Among Solid Organ Transplant (SOT) Recipients in Europe and Canada (OTUS SOT Extension in the EUCAN Countries: Austria, Belgium, Canada, Greece, Israel, Italy, Netherlands, Poland and Sweden)

Conditions
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Cytomegalovirus (CMV)

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (Cohort 1) Resistant / Refractory or Intolerant: Aged greater than or equal to (>=) 18 years at the time of the SOT. Received an SOT after January 1, 2016. Diagnosed with asymptomatic or symptomatic CMV infection any time after the SOT date. Required >=1 anti-CMV agent to manage CMV infection and were subsequently considered: resistant to currently available anti-CMV agent; OR refractory to currently available anti-CMV agent; OR intolerant to currently available anti-CMV agent. Follow-up information is available for at least 12 months from the index date (that is, date when the participant was first considered resistant, refractory or intolerant to anti-CMV agent) or death, whichever occurs first. Provided written informed consent prior to the initiation of any study procedures (unless waiver was granted by the Institutional Ethical Committee [IEC]). (Cohort 2) Pre-emptive treatment for CMV viremia: Aged >=18 years at the time of the SOT. Received an SOT after January 1, 2019. Diagnosed with CMV viremia any time after the SOT date and received pre-emptive anti-CMV agent. Follow-up information is available for at least 12 months from the index date (that is, date when the participant was first preemptively treated with an anti-CMV agent) or death, whichever occurs first. Provided written informed consent prior to the initiation of any study procedures (unless waiver was granted by the IEC). Exclusion Criteria: (Cohorts 1 and 2) Diagnosed as being positive for human immunodeficiency virus before the SOT. Unable to demonstrate a minimum of 12 months of follow-up from the index date (example, incomplete information on dates showing follow-up time). Participation in a clinical trial related to CMV treatment during the study period .

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1: Resistant, Refractory, or Intolerant (RRI) to Anti-CMV Treatment<br>Participants who had an SOT after January 1, 2016 and must have developed post-transplant CMV infection and were subsequently characterized as RRI to currently available anti-CMV treatment at least 12 months before enrollment in the study will be observed in this retrospective study for 24 months. | |
| Cohort 2: Pre-emptive CMV Treatment<br>Participants who had an SOT after January 1, 2019, and who were preemptively treated for CMV at least 12 months before enrollment in the study will be observed in this retrospective study for 24 months. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from Solid Organ Transplant (SOT) Until Start Date of the Symptomatic or Asymptomatic Index Episode | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Symptomatic episode is an episode wherein there is Tissue invasive/end organ disease or CMV syndrome at any time, and asymptomatic when there is no such observation. | From SOT up to start date of the index episode (Up to 7 years 3 months) | 
| Percentage of Participants who are Asymptomatic and Symptomatic at the Index and Recurrent Episodes | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Recurrent episodes is defined as new CMV infection in a participant with previous evidence of CMV infection. Symptomatic episode is an episode wherein there is Tissue invasive/end organ disease or CMV syndrome at any time, and asymptomatic when there is no such observation. | Up to 7 years 3 months | 
| Percentage of Participants With CMV Viremia Clearance as Defined by Site Investigator at the Index Episode and for Recurrent Episodes | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Recurrent episodes is defined as new CMV infection in a participant with previous evidence of CMV infection. CMV viremia clearance is defined as when an active CMV viremia can be considered cleared from the participant, as determined by the site investigator. | Up to 7 years 3 months | 
| Time From Start of Index Episode to CMV Viremia Clearance as Defined by Site Investigator | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. CMV viremia clearance is defined as when an active CMV viremia can be considered cleared from the participant, as determined by the site investigator. | From start of index episode to CMV viremia clearance (Up to 7 years 3 months) | 
| Percentage of Participants With CMV Viremia Clearance as Defined by Site Investigator at Week 8 After Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). CMV viremia clearance is defined as when an active CMV viremia can be considered cleared from the participant, as determined by the site investigator. The assessment will be based on Kaplan-Meier estimate. | At Week 8 after index date | 
| Percentage of Participants With CMV Viremia Clearance as Defined by Site Investigator at Week 20 After Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). CMV viremia clearance is defined as when an active CMV viremia can be considered cleared from the participant, as determined by the site investigator. The assessment will be based on Kaplan-Meier estimate. | At Week 20 after index date | 
| Percentage of Participants With CMV Viremia Clearance as Defined by Site Investigator at 1-year After Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). CMV viremia clearance is defined as when an active CMV viremia can be considered cleared from the participant, as determined by the site investigator. The assessment will be based on Kaplan-Meier estimate. Non-detectable CMV is defined as highest minimum detectable level of CMV assays across all sites. | At 1-year after index date | 
| Percentage of Participants With Non-detectable CMV During the Index Episode Prior to and After the Index Date | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) OR pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). The assessment will be based on Kaplan-Meier estimate. | Up to 7 years 3 months | 
| Percentage of Participants With Evidence of Non-detectable CMV at Week 8 After Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). Non-detectable CMV is defined as highest minimum detectable level of CMV assays across all transplant sites. The assessment will be based on Kaplan-Meier estimate. | At Week 8 after index date | 
| Percentage of Participants With Evidence of Non-detectable CMV at Week 20 After Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). Non-detectable CMV is defined as highest minimum detectable level of CMV assays across all transplant sites. The assessment will be based on Kaplan-Meier estimate. | At Week 20 after index date | 
| Percentage of Participants With Evidence of Non-detectable CMV at 1-year After Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date). Non-detectable CMV is defined as highest minimum detectable level of CMV assays across all transplant sites. | At 1-year after index date | 
| Time From Treatment Initiation to CMV Viremia Clearance as Defined by Site Investigator at the Index Episode | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. CMV viremia clearance is defined as when an active CMV viremia can be considered cleared from the participant, as determined by the site investigator. | From Treatment Initiation to CMV Viremia Clearance (Up to 7 years 3 months) | 
| Time From Treatment Initiation Until Evidence of Non-detectable CMV at the Index Episode | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Non-detectable CMV is defined as highest minimum detectable level of CMV assays across all sites. | Time from treatment initiation until evidence of non-detectable CMV (Up to 7 years 3 months) | 
| Time from Start of Index Episode to First Symptomatic CMV Diagnosis | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Symptomatic CMV is defined CMV-related tissue invasive disease or CMV syndrome. | From start of index episode to first symptomatic CMV diagnosis (Up to 7 years 3 months) | 
| Time From Stop Date of the Index Episode to First Recurrent Asymptomatic and Symptomatic CMV Viremia | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Recurrent episodes is defined as new CMV infection in a participant with previous evidence of CMV infection. | From stop date of the index episode to first recurrent asymptomatic and symptomatic CMV viremia (Up to 7 years 3 months) | 
| Percentage of Participants With Anti-CMV Treatment-related Myelosuppression and Nephrotoxicity | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Percentage of participants with anti-CMV treatment-related myelosuppression each type and nephrotoxicity overall and during the index episode will be reported. | Up to 7 years 3 months | 
| Percentage of Participants With Organ Rejection From SOT | Organ rejection will include overall and by type (acute, chronic or both for T-cell and anti-body mediated). | Up to 7 years 3 months | 
| Percentage of Participants With Graft Loss From SOT and the Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Graft loss is defined as lack of a functioning graft attributable to infection, immunological response in the organ recipient, recurrent disease, or recurrent underlying disease as described in the physician notes. | Up to 7 years 3 months | 
| Percentage of Participants who Died due to any Cause From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date, Percentage of participants who died due to any cause from sot and from the index date will be reported. | Up to 7 years 3 months | 
| Percentage of Participants who Died due to CMV Infection From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Percentage of participants who died due to CMV infection from SOT and the index date will be reported. | Up to 7 years 3 months | 
| Number of Genetic Mutations Conferring Anti-CMV Resistance From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Genetic mutation includes UL27, UL54, UL56, UL97, other, unknown mutation. Number of genetic mutations conferring anti-CMV resistance from SOT and at index date will be reported. | Up to 7 years 3 months | 
| Percentage of Participants With a Genetic Mutation Conferring Anti-CMV Resistance From SOT at the Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Genetic mutation includes UL27, UL54, UL56, UL97, other, unknown mutation. Percentage of participants with genetic mutations conferring anti-CMV resistance from SOT at index date will be reported. | Up to 7 years 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Anti-CMV Primary or Secondary Prophylaxis and Preemptive Treatment | Primary Prophylaxis is defined as when the start date of the anti-CMV prophylaxis was prior to start date of first CMV episode. Secondary Prophylaxis is defined as when the start date of the anti-CMV prophylaxis was on/ after the end date of the previous CMV episode and before the start date of the subsequent CMV episode, or if the start date of the anti-CMV was after the last CMV episode. Preemptive treatment is defined as anti-CMV treatment was initiated preemptively when the plasma CMV DNA concentration necessitated therapy based on the risk profile of the participant per clinical judgement. Percentage of participants with anti-CMV primary or secondary prophylaxis and preemptive treatment overall, at index episode and for recurrent episodes will be reported. | Up to 7 years 3 months | 
| Number of Anti-CMV Therapies Used for Primary or Secondary Prophylaxis and Preemptive Treatment | Primary Prophylaxis is defined as when the start date of the anti-CMV prophylaxis was prior to start date of first CMV episode. Secondary Prophylaxis is defined as when the start date of the anti-CMV prophylaxis was on/ after the end date of the previous CMV episode and before the start date of the subsequent CMV episode, or if the start date of the anti-CMV was after the last CMV episode. Preemptive treatment is defined as anti-CMV treatment was initiated preemptively when the plasma CMV DNA concentration necessitated therapy based on the risk profile of the participant per clinical judgement. Number of anti-CMV therapies used for primary or secondary prophylaxis and preemptive treatment will be reported. | Up to 7 years 3 months | 
| Duration of Anti-CMV Prophylaxis Therapy | Duration of anti-CMV prophylaxis therapy will be reported. | Up to 7 years 3 months | 
| Percentage of Participants With Mono-therapy and Dual-therapy of Anti-CMV Agents of Interest During CMV Episodes | Monotherapy of anti-CMV agents of interest includes specifically ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir and maribavir, and dual therapy, namely ganciclovir and foscarnet, valganciclovir and foscarnet, cidofovir and valganciclovir, cidofovir and valganciclovir, others which includes acyclovir, valacyclovir, immunoglobulin G (IgG), etc. CMV episode is generally characterized by elevated CMV viremia levels resulting in anti-CMV treatment. Percentage of participants with mono-therapy and dual-therapy of anti-CMV agents of interest during CMV episodes will be reported. | Up to 7 years 3 months | 
| Number of Individual and Dual-therapy of Anti-CMV Agents Used During CMV Episodes | CMV episode is generally characterized by elevated CMV viremia levels resulting in anti-CMV treatment. Number of individual and dual-therapy of anti-CMV agents used during CMV episodes will be reported. | Up to 7 years 3 months | 
| Number With Individual and Dual Therapy of Anti-CMV Agents Used by Line of Treatment Overall and During the Index Episodes | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. Number of individual and dual therapy of anti-CMV agents used by line of treatment overall and during the index episodes will be reported. | Up to 7 years 3 months | 
| Duration of Anti-CMV Therapy During CMV Episodes | CMV episode is generally characterized by elevated CMV viremia levels resulting in anti-CMV treatment. Duration of anti-CMV therapy during CMV episodes will be reported. | Up to 7 years 3 months | 
| Number of Participants With Distribution of Switches of Anti-CMV Agents at the Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Number of participants with distribution of switches of anti-CMV agents at the index date will be reported. | Up to 7 years 3 months | 
| Percentage of Participants Administered With First, Second, Third and Fourth Line of Anti-CMV Treatments From SOT | Percentage of participants administered with first, second, third and fourth line of anti-CMV treatments from SOT will be reported. | Up to 7 years 3 months | 
| Time From SOT to Administration of First-line Anti-CMV Agents of Interest and Between First-line Through the Fourth Line of Treatment | Anti-CMV agents of interest includes specifically ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir and maribavir, ganciclovir and foscarnet, valganciclovir and foscarnet, cidofovir and valganciclovir, cidofovir and valganciclovir, others which includes acyclovir, valacyclovir, immunoglobulin G (IgG), etc. | Up to 7 years 3 months | 
| Number of Participants Based on Reasons for Anti-CMV Dose Changes or Discontinuation for Anti-CMV Agents of Interest | Recurrent episodes is defined as new CMV infection in a participant with previous evidence of CMV infection. Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. CMV episode is generally characterized by elevated CMV viremia levels resulting in anti-CMV treatment. Number of participants based on reasons for anti-CMV dose changes or discontinuation for anti-CMV agents of interest overall during CMV episodes, the index episode and for recurrent episodes will be reported. | Up to 7 years 3 months | 
| Number of Participants With Anti-CMV Agent Administered When Diagnosed With Myelosuppression and Nephrotoxicity | Index episode is first CMV episode in which the participant is considered RRI to anti-CMV treatment or had CMV viremia and received pre-emptive treatment, without becoming RRI during that episode. CMV episode is generally characterized by elevated CMV viremia levels resulting in anti-CMV treatment. | Up to 7 years 3 months | 
| Number of Participants Using Immunosuppressant From SOT | Number of participants using immunosuppressant from SOT will be reported. | Up to 7 years 3 months | 
| Number of Participants With CMV-related Outpatient Clinic Visits From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Number of participants with CMV-related outpatient clinic visits from SOT and index date will be reported. | From SOT and index date up to 7 years 3 months | 
| Number of Participants Based on Selected Procedures Performed at Outpatient Clinical Visits From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Selected procedures include preemptive monitoring, diagnostic imaging, treatment infusion, toxicities from anti-CMV agents. | From SOT and index date up to 7 years 3 months | 
| Number of Participants Based on CMV-related Hospitalizations and Emergency Department Visits From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Number of participants based on CMV-related hospitalizations and emergency department visits from SOT and index date will be reported. | From SOT and index date up to 7 years 3 months | 
| Number of Participants Categorized Based on Reasons for CMV-related Hospitalization | Primary reason for hospitalization will include treatment infusions, CMV progression. Number of participants categorized based on reasons for CMV-related hospitalization will be reported. | Up to 7 years 3 months | 
| Number of Participants Based on Selected Procedures Performed at Hospitalizations and Emergency Department Visits From SOT and Index Date | Index date is the date when participant was considered resistant, refractory or intolerant to anti-CMV treatment for the first time after transplant (RRI CMV index date) or pre-emptive treatment for the first time after transplant following CMV viremia (CMV preemptive treatment index date. Selected procedures will include diagnostic imaging, treatment infusion, toxicities from anti-CMV agents. | From SOT and index date up to 7 years 3 months | 
| Length of Hospital Stay for CMV-related Hospitalizations and Hospital Acquired CMV Viremia | Length of hospital stay in days for CMV-related hospitalizations and hospital acquired CMV viremia will be reported. | Up to 7 years 3 months | 
| Duration of Stay in Critical Care and Non-critical Care | Duration in days of stay in critical care and non-critical care will be reported. | Up to 7 years 3 months |