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Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes (CHARMED)

Primary Purpose

Congenital Heart Disease, Viremia, Virus Diseases

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Stool and Blood Specimen Collection

Follow-up Medical Record Review

About this trial

This is an interventional screening trial for Congenital Heart Disease

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleAccepts Healthy Volunteers

Exclusion Criteria - All Cohorts

Women under the age of 18 or older than 45.
Prediabetes defined as an HbA1C between 5.7% and 6.5% or current diagnosis of pancreatic diabetes or gestational diabetes (GDM).
Body Mass Index greater than or equal to 35 or less than or equal to 18.
Women unable to give informed consent and/or considered a prisoner.
Use of any of the following drugs within the last 6 months:

5a.Systemic antibiotics, antifungals, antivirals or antiparasitics (intravenous, intramuscular, or oral); 5b.Cytokines; 5c. Immunomodulators or immunosuppressive cytotoxic agents; 5d. Large doses of commercial probiotics consumed (greater than or equal to 108 cfu or organisms per day) - includes tablets, capsules, lozenges, chewing gum or powders in which probiotic is a primary component. Ordinary dietary components such as fermented beverages/milks, yogurts, foods do not apply.

6. A positive test for HIV, HBV or HCV or any confirmed or suspected condition/state of immunosuppression or immunodeficiency.

7. History of autoimmune disorders other than T1D or treated thyroid disease.

8. Major surgery of the GI tract, except for cholecystectomy and appendectomy, in the past five years.

9. Any major bowel resection at any time.

10. History of active uncontrolled gastrointestinal disorders or diseases including: 10a. Inflammatory bowel disease (IBD) including ulcerative colitis (mild-moderate-severe), 10b. Crohn's disease (mild-moderate-severe), or indeterminate colitis; 10c. Irritable bowel syndrome (IBS) (moderate-severe); 10d. Persistent, infectious gastroenteritis, colitis or gastritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated).

11. Acute disease at the time of enrollment (defer sampling until subject recovers). Acute disease is defined as the presence of a moderate or severe illness with or without fever.

12. Use of assisted reproductive technology (ART)including but not limited to In vitro Fertilization (IVF), Gamete intrafallopian transfer (GIFT) and Zygote intrafallopian transfer (ZIFT).

13. Any other condition which, in the opinion of the investigators, renders the patient unfit for study participation and procedures.

Sites / Locations

Barnes Jewish HospitalRecruiting
St Louis Childrens HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Placebo Comparator

Active Comparator

Arm Label

Healthy Non Pregnant Women (HNPW)

Diabetic Non Pregnant Women (DNPW)

Healthy Pregnant Women (HPW)

Diabetic Pregnant Women (DPW)

Arm Description

HNPW are healthy women and not pregnant

DNPW are diabetic and not pregnant

HNPW are healthy women and currently pregnant

DNPW are diabetic and currently pregnant

Outcomes

Primary Outcome Measures

Prevalence of EVB Viremia

Determine the prevalence of EVB among women with or without diabetes. For this aim, the investigators will use PCR analysis of stool and blood to detect EVB and ELISA (IgM and IgG) of blood to detect anti-EVB antibodies in samples collected from pregnant and non-pregnant women (with or without diabetes) at multiple time points. The investigators will also sequence the PCR amplicons and carry out antibody neutralization assays of IgM/IgG positive samples to identify the specific EVB. The non-pregnant cohort will consist of 225 women with diabetes (and 225 without) sampled at 3-month intervals over 1 years. The pregnant cohort will consist of 450 women with diabetes (and 450 without) with sampling at 1st, 2nd and 3rd trimesters.

Cardiotropic Virus Detection

Determine the burden of other pathogenic human viruses in pregnant women with diabetes. Beyond EVB, other viruses could (and likely do) cause CHD. Further, while PCR is quite sensitive for detection of nucleic acid sequences of interest, its results are primer dependent. Therefore, in this aim, the investigators will perform a comprehensive virome analysis (the viral component of the microbiome) using metagenomic shotgun sequencing with ViroCap enrichment, a method developed by a co-PI of this proposal, on 1st trimester stool samples from a subset (~4-500) of women (both EVB positive and negative) enrolled in Aim 1. The investigators will complement this data with VirScan® (version 3) analysis of blood collected from the same women at 1st and 2nd/3rd trimester. VirScan® is a revolutionary new technique for comprehensive profiling of sera for antibodies against ~400 species and strains of pathogenic human viruses.

Maternal Immune Response

Determine the extent of correlation between EVB and other viruses with CHD. Because CHD cannot typically be diagnosed until 20-24 weeks gestation and the investigators are prospectively enrolling participants at 6-14 weeks, they will not know which participants will develop CHD during the enrolled pregnancies. The investigators anticipate ~40-50 CHD-affected pregnancies. If not done in Aim 2, the investigators will carry out virome (blood and stool) and VirScan® (blood) analysis of 1st trimester samples from these women.

Secondary Outcome Measures

Full Information

NCT ID

NCT04769167

First Posted

February 14, 2021

Last Updated

August 2, 2022

Sponsor

Washington University School of Medicine

1. Study Identification

Unique Protocol Identification Number

NCT04769167

Brief Title

Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes

Acronym

CHARMED

Official Title

Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Recruiting

Study Start Date

February 1, 2021 (Actual)

Primary Completion Date

December 2026 (Anticipated)

Study Completion Date

December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Beyond EV-B, there are clinical observations to implicate other viruses in birth defects, including CHD. Since the Rubella epidemic of 1960s', however, viruses have received little attention and certainly no comprehensive study, especially using next generation sequencing (NGS), has been undertaken in this context. The current pandemic as well as those caused by Zika, influenza, Ebola and Lassa Fever (among many) have shown pregnant women and their baby are at high risk. Therefore, an open-minded approach is warranted when considering the role of maternal viral infections in CHD. Even less is known about maternal immune response, such as antibody production, to these viruses. The investigator's goal is to answer the above gaps in knowledge. The investigators propose to do that using two different approaches; one retrospective (analysis of samples in two existing, large biorepositories) and the other prospective. The investigator's have created a multi-disciplinary team to bring together the needed expertise from individuals who have overlapping and vested interest in this project. The investigator's specific aim is to examine the diversity of the gut virome in non-pregnant and pregnant women with and without diabetes, with special emphasis on known cardiotropic viruses (those with tropism for cardiac tissues). This study is seen by the investigator's as the first step prior to a larger prospective multi-institutional study to specifically assess the linkage between the maternal virome and CHD pathogenesis.

Detailed Description

To determine prevalence in non-pregnant women (i) the investigators will perform PCR analysis of stool and blood from a prospective cohort of 225 women with diabetes (and 225 without) and sequence the amplicons, and (ii) perform ELISA (IgM and IgG) analysis of sera collected concurrently. They will assay IgM/IgG positive samples for neutralizing antibodies. To determine prevalence in pregnant women (i) the investigators will perform PCR analysis of 1st trimester stool and blood from a prospective cohort of 450 women with diabetes (and 450 without diabetes) and sequence the amplicons, and (ii) perform ELISA (IgM and IgG) analysis of sera collected at 1st and 2nd or 3rd trimester. They will assay IgM/IgG positive samples for neutralizing antibodies. The investigators will also perform a comprehensive virome analysis using metagenomic shotgun sequencing with ViroCap enrichment, a method developed by co-PI, on 1st trimester stool samples from a subset (~4-500) of women (both EVB positive and negative) enrolled in Aim 1. The investigators will complement this data with VirScan® analysis of blood collected from the same women at 1st and 2nd/3rd trimester. VirScan® is a revolutionary new technique for comprehensive profiling of sera for antibodies against ~400 species and strains of pathogenic viruses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Congenital Heart Disease, Viremia, Virus Diseases, Enterovirus, Enterovirus Infections, Heart Defects, Congenital, Heart Diseases, Prenatal Infection, Diabetes, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 1, Diabetes Mellitus, Pregnancy in Diabetic, Pregnancy Complications, Prenatal

7. Study Design

Primary Purpose

Screening

Study Phase

Not Applicable

Interventional Study Model

Factorial Assignment

Model Description

All participants will provide the same biologic specimens (stool & blood) during their study arm's designated timeframe. All collected specimens will be analyzed per the study protocol.

Masking

Participant

Masking Description

All participant's will not know whether they had evidence of recent viremia as this analysis is conducted in the future and the diagnosis of enteroviral viremia does not impact clinical treatment.

Allocation

Non-Randomized

Enrollment

1500 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Healthy Non Pregnant Women (HNPW)

Arm Type

Placebo Comparator

Arm Description

HNPW are healthy women and not pregnant

Arm Title

Diabetic Non Pregnant Women (DNPW)

Arm Type

Active Comparator

Arm Description

DNPW are diabetic and not pregnant

Arm Title

Healthy Pregnant Women (HPW)

Arm Type

Placebo Comparator

Arm Description

HNPW are healthy women and currently pregnant

Arm Title

Diabetic Pregnant Women (DPW)

Arm Type

Active Comparator

Arm Description

DNPW are diabetic and currently pregnant

Intervention Type

Other

Intervention Name(s)

Stool and Blood Specimen Collection

Intervention Description

Stool and Blood specimens will be collected at 3 designated time points

Intervention Type

Other

Intervention Name(s)

Follow-up Medical Record Review

Intervention Description

Participant medical records as well as the medical records of infants during study enrollment will be reviewed up to 3 years from the date of enrollment.

Primary Outcome Measure Information:

Title

Prevalence of EVB Viremia

Description

Time Frame

6 years

Title

Cardiotropic Virus Detection

Description

Time Frame

6 years

Title

Maternal Immune Response

Description

Time Frame

6 years

10. Eligibility

Sex

Female

Gender Based

Yes

Gender Eligibility Description

Women born with a female reproductive system.

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Exclusion Criteria - All Cohorts Women under the age of 18 or older than 45. Prediabetes defined as an HbA1C between 5.7% and 6.5% or current diagnosis of pancreatic diabetes or gestational diabetes (GDM). Body Mass Index greater than or equal to 35 or less than or equal to 18. Women unable to give informed consent and/or considered a prisoner. Use of any of the following drugs within the last 6 months: 5a.Systemic antibiotics, antifungals, antivirals or antiparasitics (intravenous, intramuscular, or oral); 5b.Cytokines; 5c. Immunomodulators or immunosuppressive cytotoxic agents; 5d. Large doses of commercial probiotics consumed (greater than or equal to 108 cfu or organisms per day) - includes tablets, capsules, lozenges, chewing gum or powders in which probiotic is a primary component. Ordinary dietary components such as fermented beverages/milks, yogurts, foods do not apply. 6. A positive test for HIV, HBV or HCV or any confirmed or suspected condition/state of immunosuppression or immunodeficiency. 7. History of autoimmune disorders other than T1D or treated thyroid disease. 8. Major surgery of the GI tract, except for cholecystectomy and appendectomy, in the past five years. 9. Any major bowel resection at any time. 10. History of active uncontrolled gastrointestinal disorders or diseases including: 10a. Inflammatory bowel disease (IBD) including ulcerative colitis (mild-moderate-severe), 10b. Crohn's disease (mild-moderate-severe), or indeterminate colitis; 10c. Irritable bowel syndrome (IBS) (moderate-severe); 10d. Persistent, infectious gastroenteritis, colitis or gastritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated). 11. Acute disease at the time of enrollment (defer sampling until subject recovers). Acute disease is defined as the presence of a moderate or severe illness with or without fever. 12. Use of assisted reproductive technology (ART)including but not limited to In vitro Fertilization (IVF), Gamete intrafallopian transfer (GIFT) and Zygote intrafallopian transfer (ZIFT). 13. Any other condition which, in the opinion of the investigators, renders the patient unfit for study participation and procedures.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Chelsea T Mannie, BSN

Phone

3144542326

mannie@wustl.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pirooz Eghtesady, MD, PhD

Organizational Affiliation

Faculty

Official's Role

Principal Investigator

Facility Information:

Facility Name

Barnes Jewish Hospital

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Chelsea T Mannie, BSN

Phone

314-454-2326

mannie@wustl.edu

First Name & Middle Initial & Last Name & Degree

Pirooz Eghtesady, MD,PhD

Facility Name

St Louis Childrens Hospital

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Chelsea T Mannie, BSN

Phone

314-454-2326

mannie@wustl.edu

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

The IPD collected in this study will be house in the PI's Biospecimen and Data Repository. Plans to make IPD available to other researchers has not been determined.

Learn more about this trial

Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes

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