Expanded Noninvasive Genomic Medical Assessment: The Enigma Study

A Clinical Study to Evaluate the Relative Clinical Sensitivity, Specificity, and Performance of the a Laboratory Developed Test as a Screening Test for Fetal Chromosomal Aneuploidy, Infectious and Other Diseases, and RhD Genotyping in the General Population of Pregnant Women

In January 2007, the American Congress of Obstetricians and Gynecologists (ACOG) revised its guidelines that now recommend physicians are ethically obligated to fully inform all pregnant women that screening for fetal chromosomal abnormalities including biochemical screening tests and invasive procedures such as CVS or amniocentesis is available, regardless of age. Further, it is entirely up to the patient to decide whether or not she wishes to be screened for fetal chromosomal abnormalities without judgment from the physician.

Noninvasive laboratory-developed tests (LDTs) that detect an abnormal amount of maternal and fetal DNA in an expectant mother's blood sample (known as circulating cell-free DNA) are now available. These LDTs have not been cleared or approved by the U.S. Food and Drug Administration (FDA). Although LDTs to date have not been subject to U.S. FDA regulation, certification of the laboratory is required under the Clinical Laboratory Improvement Amendments (CLIA) to ensure the quality and validity of the test.

To sample collection study will obtain whole blood specimens from pregnant subjects to be used for development of prenatal assays to assist in the screening for fetal genetic abnormalities, infectious and other diseases, and blood group typing through detection of circulating cell-free DNA extracted from maternal plasma.

Study Overview

• Status: Completed
• Conditions: Down Syndrome; Aneuploidy; DiGeorge Syndrome; Turner Syndrome; Klinefelter Syndrome; Chromosome Deletion; Edwards Syndrome; Patau Syndrome
• Intervention / Treatment: Other: Blood sampling for Laboratory Developed Test (LDT) analysis

Detailed Description

Eligible subjects will provide written informed consent after which basic demographic and clinical data will be collected.

Study procedures involve the collection of 50 mL of whole blood at one or more monthly clinic visits (≥25 days apart) from pregnant women (18 to 54 yrs of age) carrying a single fetus of 8 to 22 weeks of gestational age inclusive.

• Study Type: Observational
• Enrollment (Actual): 760

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Valley Perinatal
  • Louisiana
    • Eunice, Louisiana, United States, 70535
      • Heinen Obstectrics & Gynecology
  • New York
    • Brooklyn, New York, United States, 11220
      • Newlife Wellness OBGYN
  • North Carolina
    • Mooresville, North Carolina, United States, 28117
      • Lakeshore Women's Specialists
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Cincinnati Obgyn
    • Norwalk, Ohio, United States, 44857
      • James D. Kasten, M.D., Inc.
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Regional Obstetrical Consultants
  • Texas
    • Webster, Texas, United States, 77598
      • Texas Maternal-Fetal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 54 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

All pregnant women undergoing standard maternal serum screening for fetal aneuploidy will be considered for enrollment as well as those with a priori risk factors for fetal aneuploidy.

Description

Inclusion Criteria:

• Subject is willing to provide informed consent and comply with study procedures
• Pregnant female, 18 to 54 years of age carrying a singleton fetus of 8 to 22 weeks gestational age
• Willing to provide a study blood sample in accordance with the protocol
• Willing to allow access to her medical records to collect pregnancy outcome information
• Willing to provide consent for release of fetal karyotype if an invasive procedure (CVS or amniocentesis) is performed during the pregnancy
• Subject is known to be at risk for one or more of the following:
• fetal gene and chromosome abnormalities (e.g., T21, T18, T13, microdeletion syndromes, sex chromosome abnormalities)
• congenital fetal infection (e.g. toxoplasmosis, syphilis, HIV, rubella, CMV, HSV)
• irregular blood group antigens (subject or father of the baby)
• other condition amenable to noninvasive prenatal testing such as a single gene disorder (e.g., CF, sickle cell, Fragile X)

Exclusion Criteria:

• No fetal heart activity detected
• Mother or father have known chromosomal abnormalities (including known balanced translocations)
• Women with active or history of malignancy

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Aneuploidy Arm; Includes pregnant women at high risk for fetal chromosome aneuploidy for serum screening	Other: Blood sampling for Laboratory Developed Test (LDT) analysis; Each enrolled subject, either in the first or second trimester, will donate up to 50 mL (just over 3 tablespoons) of whole blood for development of the LDT
TORCH Arm; Infectious disease arm: Toxoplasmosis, other viruses, rubella, cytomegalovirus, and herpes simplex virus (TORCH). Includes pregnant women at low-risk for fetal aneuploidy that may be at increased risk for fetal infection for serum screening	Other: Blood sampling for Laboratory Developed Test (LDT) analysis; Each enrolled subject, either in the first or second trimester, will donate up to 50 mL (just over 3 tablespoons) of whole blood for development of the LDT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Point estimates and 95% CIs for sensitivity, specificity, PPV, and NPV versus birth outcome (trisomy or Unaffected/non-trisomy) for the LDT in the population of pregnancies at mixed-risk for chromosomal abnormalities	Primary Objective	about 3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
To estimate the false positive rate of the LDT versus birth outcome (trisomy or Unaffected/ non-trisomy) in a low-risk sub-population of pregnant women undergoing serum biochemical screening for fetal aneuploidy.	about 3 years

Collaborators and Investigators

• Sponsor: Progenity, Inc.
• Investigators: Study Director: Peter Stiegler, PhD, Head of clinical affairs

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: May 26, 2016
• First Submitted That Met QC Criteria: May 31, 2016
• First Posted (Estimate): June 1, 2016

Study Record Updates

• Last Update Posted (Actual): August 21, 2019
• Last Update Submitted That Met QC Criteria: August 19, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Down syndrome; Aneuploidy; Patau syndrome; Edwards syndrome; Klinefelter syndrome; DiGeorge syndrome; Chromosome Deletion
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Lymphatic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Disease; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Parathyroid Diseases; Intellectual Disability; Heart Defects, Congenital; Cardiovascular Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Chromosome Disorders; Sex Chromosome Disorders; Chromosome Aberrations; Sex Chromosome Disorders of Sex Development; 22q11 Deletion Syndrome; Lymphatic Abnormalities; Hypoparathyroidism; Monosomy; Hypogonadism; Gonadal Dysgenesis; Syndrome; Down Syndrome; Aneuploidy; Turner Syndrome; Trisomy 13 Syndrome; Trisomy 18 Syndrome; DiGeorge Syndrome; Chromosome Deletion; Klinefelter Syndrome
• Other Study ID Numbers: PRO-102-ENIGMA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided