Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06207487 |
| Other study ID # |
3527/23 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 15, 2024 |
| Est. completion date |
December 30, 2024 |
Study information
| Verified date |
January 2024 |
| Source |
AC Camargo Cancer Center |
| Contact |
Anna P Romero de Oliveira, physician |
| Phone |
5511982317986 |
| Email |
anna.oliveira[@]accamargo.org.br |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Rationale. Cancer patients are more likely to develop herpes zoster (HZ) and its
complications. An acute episode of HZ implies in postponement of current cancer treatments,
hospitalization, high risk of development of postherpetic neuralgia and high costs for paying
sources. A better understanding of disease incidence, hospitalization, development of
postherpetic neuralgia, and costs generated for funding sources may increase awareness of the
impact of vaccination on oncology population.
Objectives. Obtain HZ incidence and percentage of hospitalization in study population
according to cancer type, topography, and stage. Estimate hospital costs arising from
hospitalizations for different paying sources: National Public Health System (SUS - Unified
Health System), health operators and private source (patient).
Methods. We propose a retrospective descriptive study of HZ episodes occurred in oncological
population attended at AC Camargo Cancer Center between 2019 September and 2022 August.
Description:
Rationale
Cancer patients are more likely to develop herpes zoster (HZ) 1, as well as reactivation
after first episode, complications such as skin infection, postherpetic neuralgia, vision
loss (ophthalmic involvement) and severe forms of disease (disseminated, encephalitis). Other
relevant implications to be mentioned: 1) an acute episode of HZ implies in postponement2 of
current cancer treatments, which can impact the chances of cure/control of cancer; 2)
compared to general population there is greater need for hospitalization3; 3) postherpetic
neuralgia can be a big detractor of quality of life and performance status4. Besides that,
episodes of HZ in oncologic population generate high costs for paying sources to treat acute
episodes and its sequelae5. Treatment of HZ is based on antiviral agents and analgesics for
postherpetic neuralgia. For prevention of an episode there are two types of vaccines: 1) live
attenuated herpes zoster vaccine is available in Brazil for use in private network since
2008, but oncological population (immunocompromised) or those under 60 years of age are not
eligible; 2) In August 2021 a HZ recombinant vaccine6,7 was approved by ANVISA for
immunocompromised patients over 18 years old; this vaccine has been available at private
vaccination clinics since June 2022. A better understanding of disease incidence,
hospitalization, development of postherpetic neuralgia, and costs generated for funding
sources may increase awareness of the impact of vaccination on oncology population.
Objectives
Primary goals
To estimate HZ prevalence in study population according to cancer type, topography, and
stage.
To estimate percentage of hospitalization in study population.
To estimate hospital costs arising from hospitalizations for different paying sources:
National Public Health System (SUS - Unified Health System), health operators and private
source (patient);
Secondary goals
Describe temporal correlation between occurrence of HZ episode and oncological therapy in
progress (chemotherapy, radiotherapy, immunotherapy, surgery in the last 90 days) to stablish
a timeline of occurrence of HZ during oncological journey;
2.2.2. Estimate the occurrence of neuropathic pain in this population;
2.2.3. Estimate the impact of the episode in delaying cancer treatment;
2.2.4. Estimate the prevalence of recurrence within one year of the initial episode.
3. Methods
3.1. Study design
We propose a retrospective descriptive study of HZ episodes occurred in oncological
population attended at AC Camargo Cancer Center between 2019 September and 2022 August. AC
Camargo Cancer Center is a private hospital, located in the city of São Paulo - Brazil,
specialized in cancer treatment, which annually performs around 23,000 attendances. Hospital
costs in 2022 were funded approximately 85% by health insurers, 10% by National Health
Service (SUS) and 5% on private basis. Inclusion of patients will be carried out in two ways:
1) search in electronic medical records of attendances occurred between 2019 september and
2022 august in which HZ ICD - 10 (Table1) (International Statistical Classification of
Diseases and Related Health Problems) has been included among diagnoses; 2) through internal
records from hospital infection control sector of patients who remained in contact and/or
aerosol precaution, in this period, under the hypothesis of HZ. After initial selection, a
detailed search for mentions of HZ diagnosis in medical evolutions will be carried out to
confirm inclusion. Diagnosis of HZ is clinical and is based on a painful, polymorphic, acute
cutaneous lesions composed of macules, papules, vesicles and crusts at different stages of
development, affecting delimited dermatomes or disseminated (when it affects two or more
dermatomes).
Selected cases will be submitted to following data collection:
3.1.1. Demographic data;
3.1.2 Type of cancer (hematological or solid tumor - solid tumor topography such as: central
nervous system, skin, head and neck, chest/lung, breast, gastrointestinal tract, urinary
tract, sarcomas, bone tumors) and stage (TNM Staging System)8;
3.1.3. Ongoing oncological therapy modality - chemotherapy, radiotherapy, immunotherapy and
surgery performed up to one year before hospital admission; in case of hematologic
malignancies, if patient underwent bone marrow transplantation; individuals not receiving any
oncological therapy modality will be classified as treatment naïve or palliative care.
Individuals submitted to more than one treatment modality will be grouped according to the
combinations found.
3.1.4. Severity of HZ episode (local disease or disseminated, eye or central nervous system
involvement);
3.1.5. Medical fees and fixed hospital costs related to attendance in emergency ward and
hospitalization; ambulatory costs will not be included;
3.1.6. Medical records related to schedule of oncological therapies (chemotherapy,
radiotherapy, immunotherapy and surgery) and records of changes or postponements of treatment
after an acute episode of HZ - to avoid bias, will only be included for this analysis cases
in which HZ is the only complication reported in the period;
3.1.7. Records of persistent neuropathic pain three months after initial HZ episode;
3.1.8. Records of HZ recurrence after one year.
3.2. Study population
Adult cancer population (solid tumor or hematologic malignancies) from Ac Camargo Cancer
Center, São Paulo - Brazil.
3.2.1. Inclusion criteria.
Patients aged 18 years and older
Admission at AC Camargo Cancer Center between 2019 september and 2022 august at emergency
department and/or inpatient ward, including intensive care unit
Acute episode of Herpes Zoster or recurrence (see item 5.1. for ICD-10 codes).
Acute episode of HZ is clinically defined as painful, polymorphic, acute cutaneous lesions
composed of macules, papules, vesicles and crusts at different stages of development,
affecting delimited dermatomes or disseminated (when it affects two or more dermatomes).
Recurrence of HZ is defined as any occurrence of HZ that happens after the initial episode.
Active cancer is defined as: diagnosis of local, regionally advanced or metastatic cancer;
treatment naïve, receiving oncological therapies or palliative care in the last year.
Exclusion criteria.
Age under 18 years
Absence of evidence of oncological disease: cases classified as complete remission or without
evidence of oncological disease (not receiving any kind of oncological treatment for at least
one year)
3.2.3. Sampling
It is estimated that 150 individuals will be included in the study through convenience
sampling through all available chart reviews.
Study endpoints
3.3.1. Primary endpoint: profile the occurrence of HZ in oncological population treated in a
Brazilian cancer center.
3.3.2. Secondary endpoints: estimate hospital costs of HZ; estimate impact in changing or
delaying treatment planning in cancer patients.
3.4. Data collection.
Data will be collected from Tasy Philips electronic medical record. Data analysis will be
performed using data exported to IBM SPSS Statistics version 28 software.
3.5. Analysis.
3.5.1. Costs analysis
For patients hospitalized will be calculated average and mean revenue per patient/per day. We
choose to use "per day" to decrease the impact of patients that have longer length of
stay. For patients not hospitalized (emergency room attendances) we will use average and mean
revenue per patient. Costs will be presented in American dollars.
3.5.2. Statistical analysis.
The point prevalence is calculated as follows:
Formula:
Point Prevalence= total number of HZ cases in time period/ total number of all patients in
time period (per year). The total number of patients will be the "catchment
population" or oncology patients attending the hospital each year
In terms of temporal correlation or incidence, the calculation of time will consider dates
related to the oncological therapy scheme (chemotherapy, radiotherapy, immunotherapy, and
surgery), dates of records of alterations or postponements of treatment after an acute
episode of HZ, dates of records of persistent neuropathic pain three months after the initial
episode of HZ, and dates of HZ recurrence records after one year.
To avoid bias of incidence all individuals diagnosed with HZ in the period will be included
(according to inclusion criteria) independent of stage (severe or mild disease) of
oncological disease.
We will use instrumental variables to control for confounding such as cancer type and stage,
tumor topography. An instrumental variable is a factor that is associated with the exposure
of interest (often a determinant of the exposure of interest), so that if we categorize the
study population by different levels of the instrumental variable, these categories will have
different levels of exposure of interest. However, an important condition is that the
instrumental variable is not directly associated with the outcome or indirectly associated
with the outcome by variables other than the exposure of interest. If these requirements are
met and the risk of the study outcome varying between groups with different levels of the
instrumental variable, then this variation can only be explained by difference in exposure
levels of interest between groups or by chance. As the instrumental variable is unrelated to
the outcome, except for exposure, even unknown confounding is removed.
For continuous numerical variables, we will calculate measures of central tendency, that is,
means (standard deviation) or medians (range and range interquartile).
We will use the Kolmogorov-Smirnov test and the Shapiro-Wilk test to test the normality of
continuous variables. Student's t test or ANOVA will be used to compare means between 2
or more groups. For variables that do not meet the requirements of a normal distribution, we
will use the Mann-Whitney test for two groups and the Kuskal-Wallis test for three or more
groups. For categorical variables, when comparing each group, the percentage or risk will be
evaluated using the chi-square or Fisher's exact test. We will use instrumental variables
to control for confusion. An instrumental variable is a factor that is associated with the
exposure of interest (often a determinant of the exposure of interest), so that if we
categorize the study population by different levels of the instrumental variable, these
categories will have different levels of the exposure of interest. . However, an important
condition is that the instrumental variable is not directly associated with the outcome or
indirectly associated with the outcome through variables other than the exposure of interest.
If these requirements are met and the risk of the study outcome varying between groups with
different levels of the instrumental variable, then this variation can only be explained by
difference in exposure levels of interest between groups or by chance. As the instrumental
variable is unrelated to the outcome, except for exposure, even unknown confounding is
removed.
Univariate and Multivariate Logistic Regression will also be performed to calculate the
association and estimate risk-OR, with its respective confidence interval-CI/95%. P values
will be considered significant when <0.05. We will select the variables for the regression
models after
- Careful analysis of the categories - 2x2 contingency table - without reset cells.
- Quantitative independent variable, will be categorized, with cutoff point from the
literature.
- Chi-square test - p<0.20 - UNIVARIATE - increasing input order of p-value, for
Multivariate Regression.
3.5 Study Conduct, Management and Ethics
The diagnosis of Herpes Zoster can be established, in most patients, based on history and
classic dermatomal appearance of the rash (painful, polymorphic, acute cutaneous lesions
composed of macules, papules, vesicles and crusts at different stages of development,
affecting delimited dermatomes or disseminated (when it affects two or more dermatomes).
Varicella-zoster DNA PCR tools can be used for confirmation in patients with atypical
clinical presentations; of all clinical specimens, the yield of the first vesicular lesions
is the greatest. If vesicular fluid cannot be obtained, other acceptable alternatives include
lesion scrapings, scabs, tissue biopsy, saliva, cerebrospinal fluid (CSF), and blood. In
Brazil, molecular methods are not widely available. At Ac Camargo, this diagnostic tool is
available at a high added cost (not covered by health insurers), and is not routinely used,
only as an exception, when the clinical aspect is not typical and there is diagnostic doubt9.
In Ac Camargo Cancer Center (research Center) the information is electronic. The PI will lead
this study's data extraction and management. Anonymized aggregated HZ patient data will
be extracted from the medical chart databases following the study timeframe. The data
integrity will be maintained throughout the data extraction process by placing a quality
assurance process to avoid missing data. This study will comply with all applicable laws
regarding participant privacy and the guiding principles of the Declaration of Helsinki. No
direct subject contact or primary collection of individual human subject data will occur.
Study results will be in tabular form, and aggregate analyses that omit subject
identification; therefore, informed consent are not required. Any publications and reports
will not include subject identifiers. The study will be submitted to the ICE/IRB review and
approval and will be submitted to Plataforma Brasil, the national and unified base of records
of research involving human beings for the entire Research Ethics Committees system, which
articulates different primary sources of information on research involving human beings in
Brazil.
3.6. Limitations
Cancer patients usually have many clinical intercurrences, which may make it difficult to
attribute the delay in oncology schedule to HZ episode. Deficits in register of ICD in
medical records may limit inclusion of subjects.
Data Dissemination
We intend to disseminate the results of the study to the scientific community by publishing
the study in searchable, peer-reviewed scientific literature within 12 months from the
completion of the analysis. We intend to disseminate the results in congresses such as the
Brazilian Congress of Infectology, as well as in international congresses, as the European
Society of Clinical Microbiology and Infectious Diseases (ESCMID) and IDWEEK Annual World
Congress.
4. External Collaborators, Experts and Institutions
Contributing External Authors:
Rosa Nascimento Marcusso - statistics professional; will contribute with statistical
analysis.
Contributing Authors from A.C. Camargo Cancer Center
Karen Cristina Migotto - Pharmacist; will contribute to data collection and preparation of
manuscript.
Ivan Leonardo Avelino Franca E Silva - infectious diseases physician; will contribute to the
preparation of the manuscript.
Natalia Martinez Martos - Costs Specialist; will contribute with costs analysis.
Tables
Table 1. ICD - 10 included codes
B02
Zoster [herpes zoster]
B02.0
Zoster encephalitis
B02.1
Zoster meningitis
B02.2
Zoster, other, with CNS involvement
B02.3
Zoster eye disease
B02.7
Disseminated Zoster
B02.8
Zoster, with other complications
B02.9
Zoster, uncomplicated
G53.0
Postzoster neuralgia
International Statistical Classification of Diseases and Related Health Problems 10th
revision
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