Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05322655 |
| Other study ID # |
202004606 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 15, 2021 |
| Est. completion date |
March 13, 2024 |
Study information
| Verified date |
April 2024 |
| Source |
University of Iowa |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The objective of the PATHOME study is to (1) develop statistical and computational methods
for examining a complex disease system of interactions between and amongst children, animals,
the environment, and enteric pathogens and (2) build a virtual laboratory for predicting
which social and environmental developmental improvements best prevents multi-pathogen
transmission to infants in urbanizing areas of high disease burden countries. Investigators
will characterize how social and environmental development of urban neighborhoods in disease
endemic settings modifies the "enteric pathome", i.e. the microbial communities of viral,
bacterial, and protozoan pathogens transmitted by human and animal feces in the environment
to infants. They will measure the impact of societal development on pathogen transmission to
infants by applying a One Health ecosystem-based approach to characterizing interactions
between enteric pathome agents in the environment and their transmission via interactions
between infants, caregivers (CGs), animals, and environmental materials across domestic and
public spaces and climate conditions. Data-validated statistical and computational models can
quantify pathogen-specific attributable risk of infection through multiple pathways, and the
extent that these risks are due to pathogen interactions with each other and the environment.
The overall study hypothesis is that joint modeling of enteric pathome agents across urban
households and neighborhoods representing transitional improvements in societal development
will show that development leads to lower pathogen-specific detection frequencies, and thus
evolution of the pathome from complex to simple microbial community structures. By studying
spatial scale, developed and underdeveloped neighborhoods, specific transmission pathways,
and seasonality in this process, the conditions that lead to the greatest declines in enteric
disease incidence can be identified. This virtual laboratory will be built upon extensive
data collection in two different Kenyan cities, including household and neighborhood economic
indicators, clinical, zoonotic, and environmental microbiology, behavioral observation,
geotracking of humans and domestic animals, climate conditions, population density, and
infant anthropometry. This initial virtual lab will provide an evidence-based tool for
predicting effective urban interventions to control fecally-transmitted disease in cities
globally undergoing epidemiological transitions in infectious disease.
Description:
STUDY OBJECTIVES
The overall hypothesis of the PATHOME Study is that joint modeling of enteric pathome agents
across households and neighborhoods that represent contrasts in urban societal development
will show that development leads to pathome evolution from complex to simple community
structures, and thus lower detection frequencies for individual pathogen taxa. The study aims
to (1) develop spatiotemporal and trajectory statistical models to understand the complex
exposure risks for infants from the enteric pathome; (2) collect environmental, behavioral,
spatial, economic, and microbial data to characterize the enteric pathome along pathways for
disease diffusion and the intersection of humans and animals with these pathways; and (3)
develop and validate agent-based models (ABMs) for predicting which social and environmental
urban developmental interventions (e.g. animal penning, building latrines or drains, concrete
floors) best prevent multipathogen transmission to infants in high disease burden countries
using established Kenyan study sites as a model.
To fulfill the modeling and computational aims, comprehensive, interlinked data is needed
that does not currently exist. For example, there is little data on child health and exposure
to enteric pathogens in middle class populations in cities undergoing epidemiological
transitions from infectious to non-communicable disease burden for contrasting against the
more abundant data from children in low-income urban areas. Spatial data on where children
may be exposed and for how long is a complete gap. Therefore, investigators will implement an
empirical data collection study in two different cities in Kenya that collects a broad
variety of socioeconomic, behavioral, spatial, child health, zoonotic vector health,
environmental contamination, behavioral, and climate data in neighborhoods representing high
and low infectious disease transmission potential. This protocol specifically describes the
study design that will be applied to collect, summarize, and report infant health and
exposure data by study group prior to further model development. The objective of the
epidemiological study is to evaluate by city (Nairobi, Kisumu) and neighborhood socioeconomic
development level (low versus middle income):
1. Differences in prevalence of enteric pathogen detection in infant feces, diarrhea and
other health symptoms, stunting and wasting, mid-upper arm circumference, and preterm
birth status
2. Differences in exposure behaviors, environmental contamination, and enteric pathogen
detection in feces of domestic animals that could expose infants to enteric pathogens
METHODS
Study Design. The PATHOME study is four-group prospective 14 day cohort study. Groups include
a low-income and middle income neighborhood each in the cities of Kisumu and Nairobi.
Age-eligible infant participants and their caregivers living in the catchment area of a
participating Community Health Volunteer will be identified through random selection of a
surveillance database, maintained by monthly updates from CHVs on age-eligible infants living
in their catchment area. With an enrollment sample size of 248 infants and their caregivers,
this equates to 124 participants in Nairobi (62 low-income, 62 middle-income) and the same in
Kisumu. To ensure balance in age representation, selection of infants from the database for
enrollment in the study will be performed by identification of an even number of infants
across age groups of 0 to 3, 4 to 6, 7 to 9, and 10-12 month ages. After informed consent is
completed, the study team will schedule a time to begin data collection. Enrollment will be
conditional on procurement of an enrollment infant feces specimen. After enrollment, the team
will follow up with infants and caregivers for fourteen days to complete data collection as
described below. To limit bias from seasonal effects in observed enteric disease outcomes,
enrollment in each city will span 12 consecutive months, implemented in Nairobi first (Nov 21
- Nov 22) followed by Kisumu (Jan 23 - Dec 23). Investigators will recruit three households a
week, with a one week break in enrollment every fifth week when public domain contamination
assessments will be conducted. This five week cycle will be repeated systematically up to 11
times or until sample size requirements are met.
Data Collection Timeline
On the day of enrollment (Day 1), the infant caregiver will be asked to respond to a 45
minute survey on her socioeconomic conditions, hygiene practices, and infant health. Then she
will be given a 14 day pictorial diary and asked to mark any days in the next two weeks when
the child experiences symptoms of diarrhea. Finally, she will be given a pack of diapers
sized by the infant's weight, and asked to use them on the infant for the next week, saving
any diapers containing infant feces. The team will schedule a time to return the next day to
retrieve the diaper with feces and conduct the next exposure assessment phase of data
collection.
On Day 2, enumerators return midday and spend about five hours with caregivers and the
infants. First, enumerators collect the diaper with an infant stool sample, deemed to be the
enrollment or pre-exposure feces specimen. Then, enumerators place a geotracking anklet on
infants and confirm comfortable fit. Geotrackers are also placed on two domestic animals
belonging to the household (separate IACUC approval for animal subjects research). Second,
Otherwise they will collect the diaper with stool during observation. Third, they will
provide the caregiver a new sterile infant toy, such as teething ring or rattle, to give to
the infant for play. Fourth, enumerators will begin a five hour period of structured
observation of the infant, noting any persons or things that the infant interacts with, and
all places where the infant spends time. At the end of the visit, enumerators will collect a
handrinse of the primary caregiver and a soil sample, and will ask the caregiver to continue
to use the diapers to collect infant stool. Finally, a time will be scheduled to return the
next day to collect the geotracking device, any stool samples, and the toy, and to perform
another five hour observation. The stool and environmental samples will be transported to the
lab for processing for microbial assays. The geotrackers remain as placed overnight, although
if the caregiver chooses to remove it from the infant for sleeping, she is asked to place the
device next to but out of reach of the infant and then replace the device when the infant
wakes.
On Day 3, enumerators return early in the morning, retrieve a second feces specimen and
perform a second five-hour block of structured observation. At the end of observation, they
retrieve the geotracker from the infant (and domestic animals) and confirm the diarrhea
calendar is up to date. The infant toy is retrieved and placed in a sterile bag on ice packs
in a cooler for transport to the lab with the feces specimen for microbial testing. A new
replacement toy for the caregiver's permanent keeping is provided. The infant's height and
weight are recorded. Before departure, enumerators will remind caregivers to continue
collecting infant feces and schedule another visit in about 48 hours to retrieve a third
feces sample.
On Day 5, enumerators return to retrieve the third diaper with feces, check the diarrhea
calendar for completion, and encourage the caregiver to continue using diapers to collect
infant stool.
On Day 8, enumerators return to retrieve the fourth diaper with feces and check the diarrhea
calendar for completion.
On Day 14, enumerators return to retrieve the fifth diaper with feces and the 14 day diarrhea
calendar.
Data Collection Methods
1. Surveys. A pre-tested survey of 76 questions will document household wealth, income, and
infrastructure development indicators, demographics of residents, maternal education and
occupation, domestic animal ownership and management practices, types of caregivers,
caregiving behaviors, infant breastfeeding and supplemental feeding diet, vaccination,
and recent disease symptoms and corresponding health care utilization including
antibiotic use for participating infant and other household residents.
2. Collection and analysis of infant and zoonotic feces samples. Up to 1,240 infant feces
samples (248 infants * five sequential feces specimens) and 496 animal feces samples
(248 households * 2 animal feces per household) will be collected during the study.
Diapers are used to collect infant feces samples to protect the feces from contamination
by soil (e.g. scooped from ground) or potties that may be in use by multiple children.
Animal feces will be collected into steril WhirlPak bags from their location, using
caution to collect feces from the center of the pile to avod contamination by soil. A 1
gram portion will be vortexed with an equal amount of Cary blair preservation media and
stored in an ultralow freezer at the African Population and Health Research Center for
future isolation of pathogens. In a biosafety cabinet, a 300 mg portion of each infant
or animal feces specimen will be scooped from the diaper into a Zymo Shield preservation
container with ceramic beads for cell lysis. Tubes will be vortexed for two minutes and
then frozen in an ultralow freezer. DNA and RNA will be extracted in parallel using the
Zymobiomics Miniprep kit and stored in an ultralow freezer until use. An extrinsic
negative control will be exposed to the biosafety cabinet environment each day of stool
processing to monitor for potential background contamination problems that could
influence results. DNA and RNA will be analyzed on a TaqMan Array card containing
primers and probes for an array of enteric pathogens, including but not limited to
Norovirus GI and GII, adenovirus 40/41, SARS-Cov2, Rotavirus, Salmonella enterica,
Shigella spp., Campylobacter jejuni/coli, Listeria monocytogenes, Clostridium difficile,
enterotoxigenic Escherichia coli (ETEC) LT/ST, enteropathogenic Escherichia coli (EPEC),
enteroaggregative Escherichia coli (EAEC), and Shiga-like toxin-producing E. coli (STEC)
stx1/stx2 including E. coli O157. The qRT-PCR cycle threshold will be used to determine
feces positive or negative status.
3. Collection and analysis of environmental samples. Soil (992 household, 160
neighborhood), hands (248), toys (~372), and surface water (80) will be sterilely
collected and transported on ice packs in coolers to the APHRC laboratory. Quantitative
data on microbial contamination will be obtained by measuring three ten-fold seral
dilutions of each sample volume into buffered peptone water for overnight pre-enrichment
at 37-41C. A portion of this primary enrichment will be transferred into selective
secondary enrichment media for the isolation of Salmonella and Shigella spp., Listeria
monocytogenes, Campylobacter jejuni, and Escherichia coli. Selective media will undergo
five hours incubation at 37 to 41C, except for Campylobacter media, followed by plating
of aliquots onto differential and selective media. Incubation of C. jejuni/coli will
occur in anaerobic chambers. Identity of each type of presumptive enteric bacteria
phenotype will be verified by polymerase chain reaction assays for gene indicators of
pathogen-specific identity of isolated colonies. Colonies will also be preserved as
glycerol stocks for future re-isolation and analysis. Concentration of presumptive
microbial species will be determined using the Most Probable Number method and detection
patterns across the three volumes of environmental sample tested. Results will be
reported as count of validated bacterial pathogen per gram/milliliter/hands/toy.
4. Collection and analysis of behavioral data. Quantitative behavioral data on infant
interactions with caregivers, other humans, domestic animals, and environmental fomites
in the household and neighborhood domains will be measured by structured observation
using a pre-tested tablet-based tool. Individual behaviors will be summarized as mean or
median frequency per hour.
5. Collection and analysis of geotracking data. Where infants can be exposed to
environmental fomites and other humans, and how long they spend in public and private
domains will be measured by placing a wearable, lightweight geotracker on their ankle or
waist for a 24 hour period, according to a pre-tested protocol. The geotracker includes
both gps and mobile data capabilities, which uploads date, time, and location to a
server at five minute intervals. This data will be summarized in terms of types of
locations where exposure can occur, duration of time by location, and in anonymized maps
showing trajectories of travel.
6. Collection and analysis of 14-day diarrhea. Caregivers will mark days when their infant
has diarrhea on a 14-day pictorial calendar. This will be summarized as overall
proportion of infants experiencing diarrhea in a 14 day period, as well as number of
consecutive days of symptoms.
7. Collection and analysis of anthropometry data. Infant weight will be measured by
subtracting the difference between caregiver plus infant weight and caregiver weight
alone per a digital scale. Infant length will be measured using length boards per
standard WHO guidelines.
PARTICIPANT ENROLLMENT AND SAFETY
Participant Enrollment. Eligible infants will be identified and recruited through quarterly
surveillance reports by Community Health Volunteers (CHV), who are employees of the Kenyan
Ministry of Health (MOH) in Kenya, on age and location of infants living in their demographic
surveillance area. This area typically corresponds to one village within the neighborhood.
Per their standard practice, they will approach all households with pregnant women or young
children to ensure they receive health information and have support to access health care.
When CHVs identify such households, they register them in a list provided to the Community
Health Extension Worker, a formal nurse assigned to provide health care to a broader
catchment. The African Population Health and Research Center (APHRC) will work with CHVs in
the selected neighborhoods of Kisumu and Nairobi to monitor these records monthly and update
information about age-eligible children. This is necessary because migration within, and
in/out of these neighborhoods is common.
The APHRC research team will create two separate lists for the low income and middle income
neighborhoods of a city, and randomly select 6 children from each list each month, equal to
one to two infants per age group (0-3 months, 4-6 months, 7-9 months, 10-12 months). CHVs and
the APHRC team will then approach households with caregivers of eligible children to verify
their age via national identity card and to determine if they are interested in
participating. The adult subject/primary caregiver will be informed about study activities,
including an enrollment survey, household environmental sampling, geotracking of infants, and
the use of structured observation of their interactions with the infant. The team will return
the next day to obtain consent from a child's primary caregiver to participate in the study
by reading forms to the caregiver in English, or in Swahili if they are not fluent in
English, in the presence of their CHV as a witness. Consent forms will be signed by the
caregiver with signature or thumb print and by their CHV witness. A copy of the consent form
will be provided for the caregiver's permanent records. If consent is provided, a return
visit will be scheduled to conduct the enrollment survey, structured observation, and
sampling. If consent is not provided, the team will select a new potential infant of same age
from the list.
Participant Safety. The primary risks associated with participation in the study are infant
discomfort during wearing of the geotracker or during measurement of length. In order to
mitigate the risks for infant discomfort during geotracking or anthropometry, clear Standard
Operation Procedures (SOPs) and oversight mechansims will be followed to ensure the
consistent use of good technique and the right of study participants to end geotracking or
anthropometry data collection without penalty. Specifically for geotracking, the protocol
involves a caregiver-led process for choosing where and how to place the tracker on the
infant, and clear instruction to remove the device if the infant shows signs of distress
related to wearing it. Caregivers are asked that if the device is removed, to place it on
themselves or nearby but out of reach of the infant.
Caregivers may feel uncomfortable in answering some sensitive questions about their hygiene
practices during data collection, or may be concerned about social perceptions or conflict
associated with others knowing they are participating in a research study. Loss of privacy
may lead to social or family conflict. This, however, presents a minimal risk to subjects.
The SARS-CoV-2 pandemic may continue for months or years over the course of this study, and
subjects may feel concerned about study staff transmitting the virus to their family. The
privacy of subjects will be protected by (1) always collecting data in a private location
where no other adults or older children are present that could overhear subject responses,
(2) safely managing and storing all paper and electronic forms containing their information
by collecting data on password protected tablets and limiting access to identifiable data to
a limited number of qualified individuals, (3) destroying all forms with individual
identifying information after five years' time, (4) training all staff in ethical practices
for human subjects research and making the consequences for violating those practices clear,
and (5) informing the subject that they are free to leave the study at any time, or to refuse
to answer questions that make them uncomfortable.
Diarrheal disease may occur in infants during the enrollment period. In the event that a CHV
or team member visits the home and observes the child in distress, or that caregivers report
by phone or personal communication that the child is in distress, they will be instructed to
refer caregivers to local health care centers and to report the adverse event to the clinical
research team at APHRC and the University of Iowa. Distress may include diarrhea, severe
malnutrition, or other symptoms. The goal will be to ensure that CHVs continue to provide
standard care. The clinical research staff will then follow-up with caregivers in a timely
fashion to offer further medical council. All observed or reported child illnesses will be
documented by the APHRC team and discussed with the entire team during bimonthly conference
calls.
In the event an adverse event is observed that appears to be linked to the study, rather than
random illness, the APHRC team will immediately notify APHRC PI, who will notify the APHRC
IRB committee and Study Director Kelly K. Baker. The subject's enrollment in the study will
be terminated with their referral to an appropriate clinical provider for long-term
monitoring. PI Baker will immediately notify the University of Iowa IRB committee and seek
further advice on appropriate response. Stool specimens will be collected using diapers
provided to the mother for wearing by the child. No rectal swabs will be performed and no
medical treatment will be rendered. No other biological specimens will be collected.
Investigators will minimize the risk of Covid-19 transmission by regular, rigorous screening
of staff for symptoms prior to their engagement with the community and testing where
warranted, limiting the number of staff closely interacting with participants, requiring
masks and/or face shields and other hygiene PPE during data collection, social distancing of
2 meters during data collection, sterilizing all materials transmitted into and out of the
subject's household, and provision of masks to subjects for surveys if they do not have one
of their own.
CONFIDENTIALITY AND DATA MANAGEMENT
Confidentiality. Data will be handled in a confidential manner to prevent loss of privacy.
All personnel hired for this project will be required to take a five day intensive training
class that includes training in ethical practices for conducting research on human subjects.
Any violation of a subject's confidentiality will result in immediate termination and
potential further consequences. Paper forms collected by field staff will be immediately
submitted to supervisors at the end of each data collection day, and stored in a locked
cabinet in a secure office at the rural office until transport to APHRC. Hardcopy forms will
then be stored for up to five years in a locked cabinet in a locked office at APHRC, after
which they will be destroyed. Electronic files will be stored in an encrypted and password
protected database on a secure server at APHRC and the University of Iowa. Only the primary
investigators and approved members of the research team will have access to information
linked to subject identifiers. Information will be stored in an encrypted (meeting mandated
IT security standards) password-protected database and will contain subject identifiers such
as name, address, date of birth, and medical record numbers. This information is necessary to
maintain contact with the subjects during the full year of the study. Only the primary
investigator and members of the research team that will contact the subjects will have access
to information linked to subject identifiers.
Data Management. Paper/hard copy records (hard copy surveys, questionnaires, case report
forms, pictures, etc.) - A database manager at the APHRC will periodically print out lists of
eligible infants and contact information for recruitment purposes and for follow up
throughout the 14 day period of time subjects are enrolled. This will be retained by APHRC
supervisors until the study is completed, and then destroyed by shredding. Consent forms will
be collected on hardcopy forms and will be stored in locked file cabinets in locked offices
at the APHRC. Similarly, the 14 day diarrhea calendars will be identified only by the random
household ID, but will nonetheless be stored after collection in a locked office at APHRC.
Electronic records (computer files, electronic databases, etc.) - Data will be collected
using mobile technology using ODK software on password protected tablets. These tablets will
be issued by supervisors to enumerators every morning and retrieved each evening. Data from
tablets will be uploaded by APHRC supervisor via the internet or cellular data to a
HIPPA-compliant APHRC shared server, and then deleted from the tablet to prevent accrual of
private information on subjects on a device used in the field. Electronic records with
identifiable information stored on the server will only be accessible to the UI and APHRC
leadership team. PHI must be removed from any data that is used by other individuals and that
is to be stored on personal laptops or computers. Data quality checks will be built into the
data capture software to ensure that no missing information or implausible values are
accepted. Once all the completed interviews on each tablet are validated by the field team
leader and signed off for synchronization, every data collector will transmit the data in
his/her tablet to a central server via internet connection. This will ensure that the data is
not tampered with thereafter and to minimize possibility of data losses in the course of data
collection that may arise from human error or equipment failure or loss. Synchronized data
once in the server will be checked further for any inconsistency by running data quality
scripts daily that generate any error reports for immediate sharing with the field teams for
further review and correction as may be necessary while the field teams are still working in
the study areas where data with the errors have been noted. Upon completion of field data
collection, data will be verified, validated and thoroughly cleaned. All data will be stored
(through Internet linkage) to a secure physically located server with standard operating
procedures for access, security, and data backup.
Security features include remote access that will be through passwords and only from
registered computers. All stored data will be encrypted along with encrypted data transfer
using SSL transport layer encryption to secure the transfer of packets of data uploaded
incrementally to a dedicated mobile dispatch server (MDS).
Biologic samples - When stool samples are collected in households, they will be labeled only
with a randomly selected barcode ID, which will be linked to individual households by
scanning the barcode into a tablet based file linked to the subject's identifying
information. From this point forward, stool samples will retain the random ID through
processing at the APHRC lab to molecular analysis at the UI lab. Lab technicians will be
blinded to subject identity. The final results of stool analysis for each random ID will be
sent by the UI lab to the database manager, who at the final stage will merge them by random
ID into the overall dataset that contains identifiable information. Thus, biological samples
will be identified at all stages except point of collection and point of analysis.
FUNDING The PATHOME study is funded by the United States National Institutes of Health
Fogarty Institute R01TW011795 to University of Iowa, PIs Kelly K. Baker and Daniel Sewell. It
has been approved by human subjects review boards at the University of Iowa, African
Population and Health Research Center, AMREF and NACOSTI.
