NCT03211039: NSIGHT2

Perinatal Precision Medicine

Status unknown NA Results posted Last updated 1 March 2024

What this trial tests

NA trial testing Genomic sequencing and molecular diagnostic results, if any. in Genetic Diseases in 213 participants. Status unknown.

Timeline

29 June 2017

Primary endpoint
9 October 2018

30 July 2024

Quick facts

Lead sponsor	Rady Pediatric Genomics & Systems Medicine Institute
Phase	NA
Status	Status unknown
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	single
Primary purpose	diagnostic
Enrollment	213
Start date	29 June 2017
Primary completion	9 October 2018
Estimated completion	30 July 2024
Sites	1 location across United States

Drugs / interventions tested

• Genomic sequencing and molecular diagnostic results, if any.

Conditions studied

• Genetic Diseases — all drugs for Genetic Diseases →
• Genetic Syndrome — all drugs for Genetic Syndrome →
• Mendelian Disorders — all drugs for Mendelian Disorders →

Sponsor

Rady Pediatric Genomics & Systems Medicine Institute

Who can join

Under 4 Months, any sex, with Genetic Diseases or Genetic Syndrome. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Subject's Main Provider's Perceived Clinical Utility of Genomic Sequencing Primary · Within one week of the return of results

Perceived utility/benefit of sequencing based on "Clinician Assessment" questionnaire completed by patient's providers. Question: Was the test clinically useful? Response was measured on a 5-point Likert scale (very useful=5, useful=4, neutral=3, not very useful=2, not useful at all=1.

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	66
Diagnostic Rapid Whole Exome Sequencing	66
Ultra-rapid Diagnostic Whole Genome Sequencing	24

Test Results Led to Change in Patient Management Primary · Within 1 week of return of results

Test results led to Change in clinical management (select all that apply): * Surgical intervention added * Surgical intervention removed * Surgical intervention changed * Medication added * Medication removed * Medication changed * Diet changed * New specialty service sought * Prior specialty service no longer required * New imaging sought * Prior imaging cancelled * New test ordered * Prior testing cancelled * Screening for additional comorbidities added * Screening for additional comorbidities removed * Palliative care initiated * Palliative care withdrawn * Other: (text box for written des

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	23
Diagnostic Rapid Whole Exome Sequencing	19
Ultra-rapid Diagnostic Whole Genome Sequencing	15

Test Led to Changes in Management That Altered Patient Outcome Primary · 1 year

Primary physician perception of change in outcome

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	9
Diagnostic Rapid Whole Exome Sequencing	17
Ultra-rapid Diagnostic Whole Genome Sequencing	6

Diagnostic Proportion for Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES) Secondary · Within approximately 30 days of enrollment

WGS and WES are two clinical diagnostic test modalities. Results of testing were placed in the electronic medical record. Results either provided a molecular diagnosis that explained the patient's condition or did not. The diagnostic proportion is the number of patients who received a molecular diagnosis by the test modality divided by the total number of patients who were tested by that modality.

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	18
Diagnostic Rapid Whole Exome Sequencing	19
Ultra-rapid Diagnostic Whole Genome Sequencing	11

Result Within 7 Days of Sample Receipt Secondary · Within 7 days of sample receipt

Time to result.

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	10
Diagnostic Rapid Whole Exome Sequencing	4
Ultra-rapid Diagnostic Whole Genome Sequencing	17

Parental Perceived Usefulness of Test Secondary · Within one week of the return of results and approximately one year after enrollment

Parental perception that test was useful

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	54
Diagnostic Rapid Whole Exome Sequencing	55
Ultra-rapid Diagnostic Whole Genome Sequencing	15

Parental Perception of Test Benefit for Their Infant Secondary · Within one week of the return of results and approximately one year after enrollment

Parental perception that the test benefitted their infant

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	58
Diagnostic Rapid Whole Exome Sequencing	50
Ultra-rapid Diagnostic Whole Genome Sequencing	13

Parental Decisional Regret With Sequencing Secondary · Within one week of the return of results and approximately one year after enrollment

Markers of harm in genetic diagnosis as evidenced by Brehaut's Decisional Regret scale. Scale 0-100. Higher scores indicate higher regret.

Group	Value	95% CI
Diagnostic Rapid Whole Genome Sequencing	5	0 – 60
Diagnostic Rapid Whole Exome Sequencing	0	0 – 100
Ultra-rapid Diagnostic Whole Genome Sequencing	15	0 – 30

Adverse events — posted to ClinicalTrials.gov

Time frame: 1 year for parental perception of harm; 28 days for mortality. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Diagnostic Rapid Whole Genome Sequencing

Serious: 0/94 (0%)

Deaths: 0/94

Diagnostic Rapid Whole Exome Sequencing

Serious: 0/95 (0%)

Deaths: 3/95

Ultra-rapid Diagnostic Whole Genome Sequencing

Serious: 0/24 (0%)

Deaths: 5/24

Other adverse events (1 terms — click to expand)

Reaction	System	Diagnostic Rapid Whole Gen…	Diagnostic Rapid Whole Exo…	Ultra-rapid Diagnostic Who…
Parental perception that test was harmful to infant	Social circumstances	—	—	—

Data from ClinicalTrials.gov NCT03211039 adverse events section.

Sponsor's own description

This study will seek to determine if rapid genomic sequencing improves outcomes for acutely ill infants. The investigator will enroll up to 1,000 acutely ill infants in a prospective, randomized, blinded study to either rapid Whole Genome Sequencing (WGS) or rapid Whole Exome Sequencing (WES, which is 2% of the genome and \~4-fold less expensive). 213 infants were actually enrolled. Outcomes will be measured both by objective clinical measures and family perceptions (patient/family centered outcomes). Primary analysis of WGS or WES will be in infants alone. Secondary analysis, in infants who do not receive a diagnosis, will be of families - ideally trios (mother, father, and affected infant), which is \~2-fold more expensive. Trios will be analyzed within the same randomization arm (WGS or WES). This study is designed to quantify which acutely ill infants benefit from rapid genomic sequencing, by how much they benefit, how they benefit, which rapid genomic sequencing method is superior, and the cost effectiveness of such testing.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants.
   Kingsmore SF, Cakici JA, Clark MM, Gaughran M, et al · · 2019 · cited 279× · PMID 31564432 · DOI 10.1016/j.ajhg.2019.08.009
2. Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation.
   Clark MM, Hildreth A, Batalov S, Ding Y, et al · · 2019 · cited 195× · PMID 31019026 · DOI 10.1126/scitranslmed.aat6177
3. The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.
   Petrikin JE, Cakici JA, Clark MM, Willig LK, et al · · 2018 · cited 180× · PMID 29449963 · DOI 10.1038/s41525-018-0045-8
4. An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm.
   Dimmock DP, Clark MM, Gaughran M, Cakici JA, et al · · 2020 · cited 147× · PMID 33157007 · DOI 10.1016/j.ajhg.2020.10.003
5. Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.
   De La Vega FM, Chowdhury S, Moore B, Frise E, et al · · 2021 · cited 89× · PMID 34645491 · DOI 10.1186/s13073-021-00965-0
6. A Prospective Study of Parental Perceptions of Rapid Whole-Genome and -Exome Sequencing among Seriously Ill Infants.
   Cakici JA, Dimmock DP, Caylor SA, Gaughran M, et al · · 2020 · cited 80× · PMID 33157008 · DOI 10.1016/j.ajhg.2020.10.004
7. Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing.
   Owen MJ, Wright MS, Batalov S, Kwon Y, et al · · 2023 · cited 40× · PMID 36757698 · DOI 10.1001/jamanetworkopen.2022.54069
8. Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing.
   Kingsmore SF, Henderson A, Owen MJ, Clark MM, et al · · 2020 · cited 35× · PMID 33154820 · DOI 10.1038/s41525-020-00155-8