Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05072132 |
| Other study ID # |
IRB20-1058 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 16, 2021 |
| Est. completion date |
May 31, 2023 |
Study information
| Verified date |
May 2024 |
| Source |
University of Chicago |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In recent years, returning genetic results to research participants has become a topic of
debate, with a growing consensus that researchers should offer to return incidental findings
and research results to participants. Currently, the research and debates surrounding return
of results (ROR) have primarily taken place in high-income countries. Less attention has been
paid to ROR in lower-resource countries. However, research participants in these settings may
have additional threats, barriers, and/or competing interests that reduce the benefit or
relevance of receiving genetic results.
Arsenic is a toxic metal. Exposure to arsenic increases a person's risk for cancer,
especially in the lung, kidney, bladder and skin. Many people in Bangladesh are exposed to
elevated environmental levels of arsenic through naturally contaminated drinking water.
People who metabolize arsenic (remove it from their body) slower compared to people who
metabolize arsenic more efficiently are at higher risk for arsenic toxicities (e.g. cancer).
The investigators have designed a study in which they plan to enroll individuals who have had
consistently high urine As levels (≥200 µg/g creatinine) based on 15-20 years of follow-up
data. The treatment and control groups will be selected based on genotype (i.e. inefficient
and efficient As metabolizers, respectively), allowing for the selection of the groups to be
quasi-random (based on inherited genotypes). A standard informational intervention will be
provided to both the treatment and controls groups, reminding them of the effects of As
exposure and strategies to reduce their exposure.
The research question is whether the treatment group will, have a larger decrease in urine
arsenic levels compared to the control group, indicating that the ROR intervention caused a
change in water-seeking behavior leading to lower arsenic exposure.
Description:
Abstract: In recent years, returning genetic results to research participants has become a
topic of debate, with a growing consensus that researchers should offer to return incidental
findings and research results to participants. The research and debates surrounding return of
results (ROR) have primarily taken place in high-income countries. Less attention has been
paid to ROR in lower-resource countries. The investigators propose to examine the impact of
ROR on behavioral changes related to arsenic exposure reduction within The Health Effects of
Arsenic Longitudinal Study (HEALS) cohort (IRB18-1331). This cohort study is located in
Araihazar, Bangladesh, a rural area of Bangladesh with substantial exposure to arsenic
through naturally contaminated drinking water from local wells. In this cohort, the
investigators have participant data on inherited genetic variation known to impact arsenic
metabolism efficiency and risk for arsenic toxicities. These genetic data allow us to
identify participants who are inefficient (vs. efficient) arsenic metabolizers. The
investigators previously surveyed 200 HEALS participants regarding their attitudes towards
receiving information about their genetic susceptibility to arsenic toxicity, and 100% of the
participants indicated they wanted to receive this information. The investigators are
proposing a study in which they enroll adults who have had consistently high urine arsenic
levels (≥200 µg/g creatinine) based on 15-20 years of follow-up data. The 2 intervention
groups (n=200) will be selected based on genotype (i.e. inefficient and efficient arsenic
metabolizers, respectively), allowing for the selection of the groups to be quasi-random
(based on inherited genotypes). The control group (n=100), will be selected at random within
the HEALS participants who have had consistently high urine arsenic levels. The intervention
will consist of three arms: 2 intervention groups (n=200) and 1 control group (n=100). The
intervention arm will consist of two groups; intervention 1 and intervention 2. Participants
in intervention 1 group will be selected based on being inefficient arsenic metabolizers,
while participants in intervention 2 group will be selected based on being efficient arsenic
metabolizers. The control group will consist of a random sample of HEALS participants. A
standard informational intervention will be provided to both the intervention and controls
groups, reminding them of the effects of arsenic exposure and strategies to reduce their
exposure. The intervention groups will additionally be offered information on their arsenic
metabolism efficiency (i.e., their genetic results indicating they are inefficient/efficient
metabolizers and at increased/decreased risk for arsenic toxicities). Six months after the
intervention, the urine arsenic levels of all groups will be measured. The investigators
hypothesize that the intervention 1 group (inefficient arsenic metabolizers) will have a
larger decrease in urine arsenic levels compared to the control group. The
investigatorshypothesize that the intervention 2 group will have urine arsenic levels that
differ from intervention 1 group
Specific Aims:
Aim 1. To enroll arsenic-exposed individuals to an intervention study to assess the impact of
returning information on genetic susceptibility on arsenic exposure levels. To achieve this
aim, The investigators will first recruit HEALS participants (residing in Araihazar,
Bangladesh) with consistently high arsenic exposure (based on >15 years of exposure data).
Using genetic information to perform quasi-randomization, the investigators will then assign
low-efficiency metabolizers to the intervention 1 arm and high-efficiency metabolizers to the
intervention 2 arm(return of genetic results + exposure reduction information) and the
control arm (exposure reduction information only).
Aim 2. To assess the impact of the ROR intervention on arsenic exposure levels, the
investigators will collect urine samples 6 months after the intervention and compare the
arsenic levels to arsenic levels assessed in urine at baseline. The investigators will test
the association between the intervention arms and the change in arsenic levels between
baseline and follow-up.
Background Returning genetic results to research participants has become a topic of debate in
recent years due in part to increasing availability of whole-genome genotyping and sequencing
data and an improved understanding of genetic causes of disease. Whole genome sequencing data
can contain information relevant to the health care of a research participant, although not
necessarily relevant to the research questions; this has been termed "incidental findings."
There is a growing consensus that researchers should offer to return such incidental findings
to research participants. Groups such as the American College of Medical Genetics (ACMG) have
provide recommendations regarding which genes and variants should be considered "medically
relevant and offered to participants as part of the incidental findings. There is also a
trend among researchers and funders to make research participants' genetic data freely
available to them should participants want to access to it. These types of data could be
specific research results (i.e., the specific genetic variants[s] under study in meeting a
research project's aims) or genome-wide measures of genetic variation (potentially
communicated as polygenic estimates of risk for specific disease or as an interpretation of
participants' genetic ancestry). It has been suggested that providing participants their
genetic results is one way by which researchers can demonstrate respect for participants and
enhance participants' engagement in research.
Study overview This study's primary goals are to test the feasibility and benefits of
returning genetic results to a population in a rural and low resource setting. To accomplish
the specific aims, the investigators will use data from the HEALS cohort from which they have
previously obtained information regarding arsenic exposure as well as genomic information
from Bangladeshi adults (age 18-70). Participants within this cohort will be eligible for
this intervention study if they have had consistently high urine arsenic levels throughout
the follow-up period (15-20 years of information). The information and knowledge gained from
this study is critical for advancing understanding the potential benefits of returning
genetic results within a low resource setting.
The investigators will collaborate with UChicago Research Bangladesh (URB) to enroll
individuals from the HEALS cohort in Araihazar, Bangaldesh. URB will identify HEALS
participants who have had consistently high urine arsenic levels (≥200 µg/g creatinine) based
on 15-20 years of follow-up data. Intervention1 and intervention 2 groups will be selected
based on genotype (i.e. inefficient and efficient arsenic metabolizers, respectively),
allowing for the selection of the groups to be quasi-random (based on inherited genotypes).
The control group will be selected randomly from HEALS participants. At initial contact (Time
1), URB filed staff in Araihazar will obtain urine samples from all participants. A standard
informational intervention will be provided to intervention and controls groups, reminding
them of the effects of arsenic exposure and strategies to reduce their exposure. The
intervention groups will additionally be offered information on metabolism efficiency (i.e.,
their genetic results). Six months after the onset of the intervention (Time 2), the urine
arsenic levels of both intervention and control groups will be measured again.
Duration The length of the data collection period for each participant will be 6 months. The
initialization of the study will be Time 1, at which the first urine sample will be obtained,
6 months later (Time 2) the URB researchers will follow-up with the participants to obtain
the last urine sample for this study. Given that data collection will be staggered across
participants, collection of all urine samples is expected to take 1 year. Measurement of
arsenic in those samples will take 6 months, and downstream analyses of data will take
another 6 months. So the investigators expect ~2 years for this study once data collection
has begun.
Location Collection of biospecimens and questionnaire data will take place in Araihazar,
Bangladesh. The URB has local offices in this area. Arsenic measurement will occur at the
University of Illinois in Chicago. Data analyses will occur at the University of Chicago.
Methodology:
Study population and participant selection: All participants will be recruited from the
Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh, a study that
has >20,000 participants. HEALS is a prospective study of health outcomes associated with
arsenic exposure through drinking water in a cohort of adults in Araihazar, Bangladesh, a
rural area east of the capital city, Dhaka. Trained study physician conducted in-person
interviews, clinical evaluations (including ascertainment of skin lesions), and urine
collection at baseline and follow-up visits (every 2 years). Blood samples were also
collected from the participants at baseline.
Type and number of experimental subjects: For this present study, Uchicago Research
Bangladesh (URB) study staff will work to identify patients who meet the inclusion and
exclusion criteria from the established HEALS cohort study during which the URB staff will
obtain informed consent. The inclusion criteria for the study are HEALS cohort members (age
18-70) who have had consistently high urine arsenic levels (≥ 200 µg/g creatinine) based on
15-20 years of follow-up data and participants who have genetic information regarding the
AS3MT variant that classifies them as being an inefficient or efficient arsenic metabolizer.
The exclusion criteria for this study would be HEALS members who are missing baseline urine
samples as well as those who are missing the latest follow-up urine samples. There will be a
total of 300 subjects enrolled,100 for the intervention 1 group, 100 for the intervention 2
group and 100 for the control group. The investigators will collect urine samples from each
participant to assess current levels of arsenic exposure. Urine samples will be shipped to
the University of Chicago. Information regarding each HEALS participant's well usage will be
updated at baseline.
Genetic information and Classification of slow vs. Fast metabolizers: Once consumed,
inorganic arsenic is converted to mono- and di-methylated (DMA) forms. DMA, expressed as a
percentage of urinary arsenic, is a measure of arsenic metabolism efficiency (AME). Common
variation in the 10q24.32 region, containing the arsenic methyltransferase (AS3MT) gene, is
associated with AME. Additionally, a genetic variant in the formiminotransferse
cyclodeaminase (FTCD) gene is associated with AME. FTCD is critical for catabolism of
histidine, a process that generates one-carbon units that can enter the one-carbon/folate
cycle, which provides methyl groups for arsenic metabolism. In the HEALS cohort, these
genetic variants in FTCD and AS3MT together explain ~10% of the variation in DMA% and have
clear effects on risk for arsenic toxicity (i.e. arsenic-induced skin lesions). These
inherited genetic variants will be used in the present study to classify participants as
efficient or inefficient arsenic metabolizers.
Intervention (receiving information on arsenic): In this study, intervention and control
groups will receive a standard informational intervention which will remind them of the
effects of arsenic exposure and potential strategies that can be implemented to reduce their
exposure. In addition, the intervention groups will receive information regarding their
genetic results that informs them of their arsenic metabolism efficiency. The intervention
groups will receive this information through a factsheet appropriate for a lay audience. The
factsheet will contain information regarding arsenic metabolism and its role in removing
arsenic from the body. The factsheet will describe how there is variability among individuals
with respect to the efficiency with which arsenic is removed from the body, due to inherited
differences in genes that affect arsenic metabolism. The factsheet will connect metabolism
speed with toxicity risk. In other words, slower metabolizers remove arsenic slower from the
body compared to others while fast metabolizers remove arsenic faster from the body compared
to others. This leads to increased risk for arsenic toxicities, normal arsenic metabolizer
remove arsenic from the body at an average rate, and fast arsenic metabolizers remove arsenic
from the body faster than most other people, which leads to decreased toxicity risk. Lastly,
the factsheet will inform the participants in the intervention groups that they have been
identified as a slow/fast metabolizer of arsenic based on their genes. This information will
be given to participants by URB staff, with a study physician available during the study
visit who would be able to address additional questions and concerns from the participant.
The control group will not receive the information regarding their genetic results that
informs them of their arsenic metabolism efficiency.
Arsenic Assessment and Urine Sample: Urine samples will be obtained by URB study staff at
Time1 (initial contact) and Time2 (Six months after the onset of the intervention). The
investigators plan to assess arsenic exposure from urine samples from all recruited
participants. Prior studies have demonstrated high correlation between water arsenic levels
and urinary arsenic. Urine arsenic will be measured using Inductively Coupled Plasma Mass
spectrometry (ICPMS) at the CACHET (The Chicago Center for Health and Environment) biomarkers
core facility at UIC (University of Illinois at Chicago).
Questionnaires: All participants will undergo a genetic comprehension questionnaire. Genetic
information presents challenges to all participants within studies, but especially those with
low and marginal genetic literacy. Low genetic comprehension may be a barrier for
participants to understand the utility of the return of genetic results information,
therefore, the investigatorswill measure genetic comprehension through the use of the
questionnaire the Measure of Genetic Susceptibility Knowledge. This questionnaire will be
administered orally to the study participants by the URB staff who will follow structured
protocols. This questionnaire was created by selecting questions from previous questionnaires
that measure genetic knowledge in the general population as well as creating comprehension
questions from a previous questionnaire that used on this population called the Return of
Results (Genetic) Questionnaire from IRB18-1331.
Participants in the intervention arms will also be given a questionnaire to measure any
psychological stress due to receiving ROR. It is important to understand the psychological
consequences for patients receiving genomic tests results in a variety of settings,
therefore, the investigators will measure psychological stress through the use of the
Feelings About genomiC Testing Results (FACToR) questionnaire, that has been designed to
measure the psychological impact of receiving genomic test results in a wide range of
conditions.
Additionally, participants identified the well water used as their primary source of drinking
water at baseline in the HEALS cohort study, the investigators will follow-up on this
question to have the most up to date information.
Potential risks and benefits: There is no more than minimal physical risk to participate in
this study. The investigators are requesting to obtain urine samples and questionnaire data
from all of the participants. While the study is no more than minimal physical risk/harm, the
investigators will have numerous precautions to protect confidentiality.
Additionally, there may be some risk of stigma or stress to individuals in the intervention
arm, who are identified as slow arsenic metabolizers, however, this is offset by the
potential health benefit gained through the knowledge. According to the health belief model,
if genetic risk information changes an individual's perceived susceptibility to arsenic
toxicities, the likelihood to adopt health behaviors may change. Therefore, for the
participants in this specific study who are at higher risk for arsenic toxicities due to
having higher urine arsenic levels throughout the 15-20 years of follow-up data in the HEALS
cohort, obtaining information regarding being a slower arsenic metabolizers may additionally
motivate lifestyle modification if it increases an individual's risk perception, thereby
offsetting the potential risk through this benefit. Furthermore, a subset of 200 participants
in the HEALS study have previously been asked if they would like to receive their genetic
information regarding arsenic metabolism efficiency, 100% of the participants questioned
stated they would want this information.
Monitoring of Safety: This study involves no physical risks. The intervention is
informational in nature, and occurs at a single point in time (i.e., the baseline visit).
Should individuals want to further discuss the genetic information received with a health
care professional, a contact number for a HEALS study physician will be provided to all
participants. Furthermore, all HEALS participants can access free primary health care through
the local HEALS clinic, should participants have any health concerns related the
arsenic-related information received during participation in this study.
Procedure to obtain and record informed consent: For this present study, Uchicago Research
Bangladesh (URB) study staff will work to identify patients who meet the inclusion and
exclusion criteria from the established HEALS cohort study during which the URB staff will
obtain informed consent.
Confidentiality: While the study is no more than minimal physical risk/harm, the
investigators will have numerous precautions to protect confidentiality. The study does not
involve the collection of identifiable information, and the URB study staff will assign a
coded unique study ID to all participant data and samples. The investigators will ensure that
all samples are coded, and all data will be protected, stored, and analyzed on secure
password-protected servers in the Department of Public Health Studies (PHS) at the University
of Chicago.
