Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06141434 |
| Other study ID # |
22-1840 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 1, 2022 |
| Est. completion date |
November 30, 2032 |
Study information
| Verified date |
November 2023 |
| Source |
University of Colorado, Denver |
| Contact |
JANET K SNELL-BERGEON, PhD, MPH |
| Phone |
7208917122 |
| Email |
Janet.Snell-Bergeon[@]cuanschutz.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This research study is called 'PRenatal and Obstetric Maternal Exposures and ISlet
Autoantibodies in Early Life: The PROMISE Study'. The purpose of this study is to find out
more about how exposures during pregnancy, such as having an infection, diet and growth may
impact later risk of type 1 diabetes (TID) and islet autoimmunity in the child. We are also
interested in finding out more about why having a father or sibling with T1D increases risk
of autoimmunity in the child more than having a mother with T1D.
We are enrolling women who are pregnant and either have T1D or another first degree relative
(father or full sibling) of the baby has T1D. The biological father is also invited to enroll
in study, as it is important to understand how the father's health and genetics may
contribute to the child's risk of developing T1D. The study procedures for the mother, father
and baby are explained below.
Mother: Pregnant women will be asked to complete a visit once per trimester (3 visits) during
pregnancy and one visit up to 12 weeks after delivery. At each visit, mothers will consent to
a blood draw, collection of biological samples and the completion of questionnaires. .
Mothers who have T1D will also be asked to download any diabetes device data they have, such
as continuous glucose monitor or insulin pump data.
Father: The (biological) father will be invited to enroll in a single visit. He will consent
to a blood draw and completion of questionnaires. Fathers with T1D will also be asked to
download any diabetes device data they have, such as continuous glucose monitor or insulin
pump data.
Baby: The baby will have blood collected at birth to determine the genetic risk for T1D.
Families will consent to the completion of questionnaires about growth, health and diet at 6,
12, 18 and 24 months of age and between 5-7 years of age, and to complete blood testing for
islet autoantibodies at 24 months and between 5-7 years of age. For those children with a
high genetic risk score, we will also collect blood for autoantibody testing at 6, 12, and 18
months of age.
Description:
We will assemble a prenatal cohort where the offspring has a first degree relative (FDR) with
T1D (mother, father or full sibling). In order to enroll sufficient participants, we are
conducting a multi-center study at the Barbara Davis Center for Diabetes (BDC) in Aurora, CO
[coordinating center], Mt Sinai Hospital in New York, NY, the Joslin Diabetes Center (JDC) in
Boston, MA, and Ohio State University (OSU) in Columbus, OH. These sites were chosen based on
a history of successful prior collaborations, access to large established populations of
people with T1D (these centers are some of the largest in the United States with respect to
pregnancy care for women with T1D, and also have adult and pediatric clinics), site-specific
connections to obstetric practices, and a history of successful recruitment into study
cohorts. In addition to the four study sites named, we have approached additional potential
sites in order to ensure success with recruitment. We have identified an additional potential
site at the Mayo Clinic College of Medicine under the direction of Yogish Kudva, and this
site is prepared to activate should recruitment in the first year of the grant at the four
sites fall short of expectations. Our goal is to assemble a pregnancy cohort of 800 during
this initial funding period, and to enroll up to an additional 1,200 in phases 2 and 3 (total
N=2,000).
D. Description, Risks and Justification of Procedures and Data Collection Tools:
Screening and Consent Procedures: Participants will be screened, consented (available through
paper and electronic consent process) and will complete questionnaires through an online
database with electronic survey capabilities (REDCap) that is HIPAA compliant and can be
accessed anywhere with internet access. If needed, REDCap access can be provided in the
clinic using a tablet. We have successfully used the REDCap database system for numerous
studies involving survey collection and have used online screening and consenting procedures
extensively in studies of adults with T1D (including pregnant women) during the Covid-19
pandemic. Study staff will be available to review the consent form with potential
participants over the phone, using a HIPAA-compliant video platform such as Zoom, or in
person, depending on the circumstances. Screening questions will include the history of T1D
in the pregnant woman or father/sibling of the fetus, maternal age, and obstetric history for
the pregnant woman, including current pregnancy dates (last menstrual period date, expected
date of delivery).
Visit and Specimen Collection Schedule: Study visits and specimen collection (Table 2) will
be scheduled at one of the study sites, at one time point for fathers and at four time points
for mothers: first trimester (8-<14 weeks), second trimester (14-<28 weeks), third trimester
(28+ weeks), and up to 12 weeks postpartum. Medical records will be obtained using medical
record release forms for the pregnancy, delivery and post-partum visits, and for the infants'
birth records. All study sites have access to electronic health records (EHR) that will allow
investigators to obtain medical records for prenatal care and delivery for study participants
who deliver within their hospital network, and all sites have protocols in place and
experience obtaining records from outside facilities using medical record release forms. At
the BDC coordinating center, we have previously collected medical records for pregnancy,
delivery and infant birth records and have abstracted these data into REDCap databases. We
will follow our established procedures for abstraction of obstetric and newborn records for
this study. Maternal and fetal outcomes of women included in this study that are reported to
BDC providers will be obtained by manual chart review of EHR charts. Maternal and fetal
hospitalizations at any hospital system utilizing EPIC and for whom patients authorize
sharing of records can be viewed through EPICS's interoperable sharing tool called Care
Everywhere. Manual review of records will be used to obtain specific outcome measures.
All records will be collected and abstracted at the Barbara Davis Center, to maintain quality
control standards and to streamline training and oversight of staff.
Pregnancy Visits: Pregnant women who are eligible for the study will be enrolled in the first
trimester (before 14 weeks gestation), if at all possible, but after 8 weeks gestation to
reduce the possibility of early pregnancy loss following enrollment. Fathers will be enrolled
at the same time and will be asked to complete their study visit (including a blood sample of
up to 33 ml or 2 1/4 tablespoons of blood) at the same time as the woman's first pregnancy
visit, if at all possible. Women who are already in the second trimester (up to 24 weeks)
when approached about the study will be enrolled and will complete second and third trimester
visits and the post-partum visit. Routine pregnancy visit data, including weight and blood
pressure will be collected in the clinic or from the medical record. Routine pregnancy visit
data, including weight and blood pressure, routine laboratory tests (including HbA1c for
women with T1D, lipids, etc) will be collected from the clinic or from the medical record.
Study visit timing and procedures are shown in Table 3 below.
Specimen Collection: Samples will be collected at each study visit at the participating
clinic location. External centers will ship all samples to the BDC for storage. Sample
collection will be standardized in our Manual of Operations to ensure consistent collection
at all sites. Further, sample collection, timing and types have been carefully designed to be
similar to the collection completed in existing cohorts, in particular the ENDIA study, to
allow for comparison of results across studies. However, timing of trimester-based and
post-partum visits are determined by standard of care in our clinics and may not align
exactly with the ENDIA study. For example, women typically complete a post-partum visit at
4-6 weeks in our clinical centers, and so we will schedule our post-partum data and sample
collection at the same time, to minimize participant burden. In the ENDIA study, mothers
underwent a post-partum visit at 3 months.
A sample of up to 33 ml or 2 ¼ tablespoons of blood will be obtained by phlebotomy. Plasma
will be collected in EDTA tubes, kept on ice and separated by centrifugation. Serum will be
collected in serum separator tubes with gel and separated by centrifugation after being
allowed to clot. Serum and plasma will be aliquotted into 2ml cryovials and stored at - 80°
C. Buffy coats will be stored at each visit for future DNA and methylation studies. Blood RNA
samples will be collected using Tempus™ tubes, which allow for stabilization and isolation of
total RNA from whole blood for gene expression analysis. These samples can be stored for up
to five days at room temperature, and then frozen at 4°C. Optional vaginal swabs will be
self-collected by participants using a CultureSwab transport system. Optional stool samples
will be self-collected by participants using a commercially available stool collection kit
such as the OMNIgene_GUT.
Questionnaire Collection: Participants will be asked to complete questionnaires online using
the REDCap database program for each visit, to reduce the time needed to complete the in
person appointments for study participants completing visits at the clinics, and to
streamline data collection/entry procedures and reduce data entry errors. Questionnaires will
include dietary intake using a validated food frequency questionnaire43, tobacco and alcohol
using validated questionnaires44,45, and we will collect screening questionnaires addressing
general [Patient Health Questionnaire-8]46 and perinatal [Edinburgh Postnatal Depression
Scale]47 depression. Women who screen positive (a PHQ8 score of 14 or higher, or an Edinburgh
Postnatal Depression score of 10 or higher) on either of these questionnaires will be
referred to their regular provider for further evaluation.
Among mothers and fathers with T1D, assessments of the T1D distress scale (T1-DDS), diabetes
self-management and hypoglycemia fear will be assessed using validated instruments. Fathers
with T1D will complete the questionnaires at a single visit, whereas mothers with T1D will be
asked to complete these questionnaires at each study visit (once per trimester, and
post-partum). Diabetes care records, including HbA1cs and other laboratory tests (lipids,
urinary albumin to creatinine ratio, serum creatinine), retinopathy exams and examination
records will be requested for the year prior to enrollment for determination of complications
and glycemic control.
Pregnancy history and outcomes: We will collect data on maternal and fetal outcomes of the
pregnancy with medical records; we will obtain gestational age at delivery, infant birth
weight, delivery complications, and maternal and fetal outcomes by obtaining records for each
hospital admission for labor and delivery. As a backup for these hospital records and in case
we are unable to access medical records (such as if a woman moves outside of our electronic
health record area and we can't obtain records using a medical record release), we will
collect the same data using a survey we developed for one of our previous pregnancy studies.
It inquires about delivery date, gestational age, infant birth weight and length, living
status of the infant, infant sex, preterm labor, type of delivery, 16 specific pregnancy
complications, 15 specific labor complications, 5 specific neonatal complications, and
admission to the neonatal intensive care unit (NICU). Breastfeeding practices will be
collected at the post-partum visit. We will also collect data through a medical chart review
for health information prior to pregnancy for women with T1D (blood pressure, kidney
function, retinopathy, height and weight). We will verify gestational dating by obtaining
records of ultrasounds performed for dating.
Glycemic factors among women with T1D: HbA1c and glucose values (CGM and glucose meter
downloads), current insulin dosing and insulin delivery method are collected during routine
pregnancy visits and will be collected from the medical record. We will also access data
downloaded from CGM devices (for those women who use a CGM regularly) during routine
pregnancy visits to evaluate indices of glycemic variability such as time spent in pertinent
glucose ranges (time in range: 63-140 mg/dL [pregnancy] and 70-180 mg/dL [post-partum],
hypoglycemia: <63 mg/dL [pregnancy] and <70 mg/dL [post-partum], and hyperglycemia: >140
mg/dL [pregnancy] and >180 mg/dL [post-partum]50, coefficient of variation, and SD).
Cord blood and stool collection: Collection of cord blood up to 20 ml will be prioritized,
since it is an ideal sample for examining the DNA methylation in the infant at birth and
before exposure to the outside environment, including breastfeeding or bottle feeding,
exposure to microbes and other environmental factors, as a contrast to later samples obtained
during early life. Collecting cord blood has been accomplished in our prior studies through
agreements with screening hospitals, and through the use of cord blood collection kits sent
to the mother for obtaining and mailing back the samples. Given that women will be giving
birth at any number of hospitals nationally in this cohort, we will plan to send/give cord
blood collection kits to the pregnant mothers with detailed instructions for collection and
return of the samples, using our established protocol. In the case that cord blood collection
isn't possible, we will include a kit for collecting a heel stick sample of up to 1ml of
blood as soon as possible after birth (preferably within a week of delivery). We also plan to
give women stool kits for collection of a stool/meconium sample soon after delivery.
Screening for High Risk Genotypes among the Offspring: Newborns will be screened for genetic
risk for T1D at birth using dried blood spot collections obtained within the first week of
life. Samples will be sent to the laboratory of Dr. William Hagopian for determination of the
genetic risk score 2 (GRS2), a panel of 67 single nucleotide polymorphisms (SNPs) that has
been shown to discriminate risk for T1D, especially for early-onset T1D (AUC 0.96)1.
High-risk human leukocyte antigen (HLA) genotypes are strongly associated with IA and T1D
risk, but use of the GRS2 has demonstrated to be nearly twice as efficient as only screening
for high-risk HLA genotype. The use of this risk score has been proposed as a more efficient
method of newborn screening, allowing for closer monitoring of the children at highest risk
for developing IA and T1D, especially early in childhood. All visits and procedures for the
offspring are shown in Table 4.
Based on data from the TEDDY study, a GRS2 conferring risk equivalent to the 90th percentile
in the general population identified 23% of TEDDY participants with an FDR as high risk,
compared to 10% of the general population. Given that TEDDY participants with an FDR were
selected based on their high risk HLA genotype, we estimate that the percentage identified as
high risk based on GRS2 score in this proposed prenatal cohort (where all FDRs will be
enrolled regardless of HLA risk) will be slightly lower than the percentage observed in
TEDDY. Therefore, we have estimated that ~20% of the FDR offspring in the proposed pregnancy
cohort will be identified as high risk and will be followed more closely than those at
low-risk.
Children with the highest risk on the GRS2 (e.g., risk higher than the equivalent of 90% of
general population risk scores) will have blood collected for IA screening and genetic marker
storage every six months through 2 years of age and then between 5-6 years.
Children with a low risk GRS2 will have blood collected for IA screening at 2 years and
between 5-6 years of age. HLA genotyping and IA testing will be done at the Clinical
Immunology Lab at the BDC (NIH/NIDDK designated North American Autoantibody/HLA Core) as
previously reported40. Other blood samples will be retained for case-control studies of DNA
methylation, Virscan and future metabolomic/proteomic markers..
Infant growth and health: Infant growth data will be obtained by self-report from parents
through REDCap surveys, and through medical records requests for pediatric records.
Immunization records will be obtained. Every 6 months until the age of 2 years, clinical
measurements (including collection of up to 20 ml or just over a tablespoon blood), illnesses
and infant/child feeding practices will be collected from the high risk group at the clinic
visit; this data will be collected by a REDCap questionnaire for the low risk group.
Islet Autoantibody Assessments: The main outcome measure of the overall study (all phases)
will be persistent positivity for islet autoantibodies (IA) in the child. Serum samples will
be obtained for measurement of four islet autoantibodies in high genetic risk offspring at 6,
12, 18, 24 months, and at 5-6 years. The low genetic risk offspring will be tested at 24
months and 5-6 years of age. Samples will be collected, processed and sent from the external
sites to the BDC for measurement of IAs. Serum will be stored at -70°C until assayed. The
more frequent monitoring for IA among high risk offspring is needed because IA can appear as
early as in the first year of life and T1D is more commonly being diagnosed at younger ages.
Therefore, we plan to monitor both IA and evolution of dysglycemia (stage 2 T1D), as
described below.
IA assays will be conducted on coded samples for IAA, GADA, IA-2A and ZnT8A in the Barbara
Davis Center Core Autoantibody Laboratory, under the direction of Liping Yu, MD. This
laboratory is CLIA certified, and CAP accredited and has been designated as an NIH/NIDDK
North American Autoantibody/HLA Core Laboratory. For the past several decades, the Barbara
Davis Center Autoantibody laboratory has served a number of major T1D clinical trials,
including the TEDDY study, TrialNet, DPT-1, T1DGC, ITN and others. The assays for GAD65 and
IA-2 have been harmonized recently in collaboration with the NIH/NIDDK Diabetes Autoantibody
Harmonizing Committee using a standard assay protocol with a common antibody unit expressed
as DK units/ml (NIDDK units). This made it possible for autoantibody test results to be
comparable among all of the ongoing national/international trials between different
laboratories worldwide. BDC's Autoantibody/HLA Core Facility is one of three international
laboratories helping to accomplish these harmonized assay protocols. All positive samples and
5% of negative samples will undergo blinded duplicate testing. IA will be defined as
positivity for at least one of the four islet autoantibodies on ≥2 consecutive visits, or a
single positive test followed by diagnosis of T1D. Children with an initial positive
autoantibody test will be asked to return for a confirmation test as soon as possible after
the initial test.
Monitoring for dysglycemia: Families will be educated on the signs and symptoms of T1D and
will be instructed to contact study staff to report any concerns or questions about potential
signs and/or symptoms in their children. Families of children who develop IA will be provided
access to the ASK study team, assuming funding for this study is still active, for enrollment
into the ASK follow-up study for education, monitoring and support including educational
materials to explain risk factors associated with islet autoantibody status, repeat testing
of autoantibodies and HbA1c every three to six months to monitor for progression, provided
with a free glucometer, strips, and training. A continuous glucose monitor may be provided
free of charge every 3- 6 months. In addition, the ASK the Experts national monitoring
program, also funded by Helmsley Charitable Trust, will be available to those families who
have local providers or pediatric endocrinologists that can work in tandem with the ASK the
Experts team at the Barbara Davis Center for education, monitoring and support. If the
ASK/ASK the Experts studies are no longer funded, the same education and support will be
provided through this study protocols, including measurement of HbA1c every three to six
months and free glucometer, glucose strips and training.
Viral exposure assessments: Exposure to viruses will be assessed longitudinally in mothers
and offspring using the Virscan assay. For the initial three year study period analysis,
serum samples from visits during each trimester of pregnancy and post-partum as well as those
collected at 6 months of life among selected high risk infants (as described in the data
analysis plan) will be tested on the Virscan pan-viral serological surveillance tool. This
platform is based on phage immunoprecipitation sequencing (PhIP-seq) technology that uses a
bacteriophase library containing proteome-wide peptides from human-pathogenic viruses. The
Virscan library contains peptides representing most known pathogenic, human viruses (~400
species and strains) as well as other antigens listed in the National Institute of Allergy
and Infectious Diseases Immune Epitope Database (www.iedb.org). The goal of the longer-term
study once all phases are complete and a sufficient number of offspring have developed IA is
to perform a case-control study of viral exposure in mothers and offspring among those who
have developed IA versus age and HLA-matched control offspring who have not developed IA.
To perform the serological screening, serum samples are mixed with the library allowing
antibodies to bind with pathogen specific epitopes displayed on the phage surface. The
bacteriophage-antibody complexes are then immunoprecipitated and the phage DNA region
encoding the artificially expressed peptide antigens to which an antibody was bound are
sequenced by NGS to reveal the repertoire of anti-viral antibodies in a given serum sample.
Data analysis to detect antibodies against a wide-range of pathogens relies on statistical
assessment (p values) of relative enrichment of pathogen-specific peptides in serum
specimens. The resulting data are therefore qualitative in nature and are not directly
comparable to antibody titers that can be obtained from conventional, singleplex serological
methods.
Epigenetic and gene expression studies: DNA methylation will be measured in maternal
peripheral whole blood and gene expression (RNA) measured in whole blood RNA samples
collected during pregnancy and post-partum, and in offspring whole blood and RNA samples
collected in early life prior to the development of IA. Measurements of DNA methylation and
gene expression will be compared in the initial three year study period in cord blood from
offspring of mothers with T1D (n=86) compared to offspring who have a father with T1D but a
mother without diabetes (N=86) in a case-control design matched for maternal age and HLA
risk. The goal of the longer-term analysis once all phases are complete is to examine
epigenetic changes and gene expression in a case-control study design, selecting IA cases
from among infants who are persistently IA positive, and among controls matched on age and
HLA risk. Methylation quantification will be performed using the Infinium
HumanMethylation450K Beadchip ("450 K") and the Infinium MethylationEPIC Beadchip ("EPIC") as
previously described41. The University of Colorado Anschutz Medical Campus houses a
state-of-the-art facility and has launched an RNA Bioscience Initiative
(https://medschool.cuanschutz.edu/rbi) with the goal to provide a 'fluid pipeline from basic
to clinical RNA research at the Anschutz Medical Campus" through combining RNA testing and
informatics resources.
