Genetic Testing to Understand and Address Renal Disease Disparities Across the United States

NCT ID: NCT04191824

Last Updated: 2025-04-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 6789 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-10
• Study Completion Date: 2024-05-17

Brief Summary

GUARDD-US is a prospective, multicenter, unblinded, two arm randomized pragmatic clinical trial. Participants will be randomized in a 1:1 ratio to immediate APOL1 gene testing and return of results (ROR) to participant and provider (Intervention arm) versus delayed APOL1 gene testing and ROR to participant and provider (Control arm). The main study will compare outcomes between APOL1 positive participants in the Intervention arm (i.e., early knowledge of APOL1 status) to APOL1 positive participants in the Control arm (i.e., delayed knowledge of APOL1 status). Participants that are APOL1 negative in the Intervention and Control groups will not be included in the main study analyses.

GUARDD-US also includes a substudy to determine the effect of knowledge of genetic test results that predict efficacy of various antihypertensive medications on change in SBP from baseline to 3 months in APOL1 negative individuals at participating sites.

This substudy is listed separately on clinicaltrials.gov as NCT06748040 and Unique Protocol ID - PRO00102997_A

Detailed Description

High-risk variants in the APOL1 gene explain approximately 70% of the excess prevalence of CKD in African Americans (AAs), conferring a 5 times higher risk for hypertensive CKD and a 10 times higher risk for ESRD. A pilot study (GUARDD), showed that returning APOL1 gene test results had a statistically significant improvement in SBP at 3 months when comparing APOL1 positives to APOL1 negatives who received their genetic testing results and when comparing APOL1 positives that received their results early to overall controls who did not receive their results until after the 3 month visit. GUARDD was not however powered to evaluate the effects of having and knowing a positive APOL1 status on outcomes for those with high risk of developing CKD (i.e., comparing outcomes for APOL1 positive patients who know their genetic risk to APOL1 positive patients who do not know their genetic risk). A broader trial is needed to better determine the importance of APOL1 gene testing for improving the testing, diagnosis, and treatment of individuals at risk of CKD.

The primary aim is to determine the effect of participant and provider knowledge of a positive APOL1 status and accompanying guideline based clinical decision support (CDS) on blood pressure management on change in systolic blood pressure (SBP) from baseline to 3 months after randomization among the APOL1 positive participants. Secondary aims are to:

1. Determine the effect of participant and provider knowledge of a positive APOL1 status on the probability of documented CKD diagnosis.

2. Determine the effect of participant and provider knowledge of a positive APOL1 status on the probability of receiving a urine microalbumin/creatinine testing and ACE-I/ARB prescription based on results of the urine microalbumin level.

3. Explore cost effectiveness, mediators, moderators, psychobehavioral impact of results disclosure on participants, and effects of participant and provider knowledge of APOL1 status on provider treatment recommendations.

Approximately 6,750 participants of African ancestry age 18-70 with hypertension that either: 1) do not have diabetes and do not have CKD, or 2) have CKD. Participants with diabetes may be included as long as they also have CKD.

Population for Main Study:

Participants from Randomized Population (above) who test positive for APOL1

Main Study Analyses:

• To determine the effect of participant and provider knowledge of a positive APOL1 status on SBP, we will compare the change in SBP from baseline to 3 months of the Intervention - APOL1 positive group to the change in SBP from baseline to 3 months of the Control - APOL1 positive group using a two sided t-test, as appropriate, with an overall two-sided type I error of 0.05.
• The effect of knowledge of a positive APOL1 status on all secondary endpoints will be compared between Intervention - APOL1 positives to Control - APOL1 positives with the proportion difference test.
• Additional analyses will include analysis of time trends in SBP, subset analyses, and exploratory analyses of cost effectiveness, mediators, moderators, psychobehavioral impact of results disclosure on participants, and effects of knowledge of APOL1 status on provider treatment recommendations.

Conditions

Chronic Kidney Disease; Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Immediate Return of Results

Immediate return of results to inform participant of APOL1 status (either positive or negative).

Group Type: ACTIVE_COMPARATOR

Timing of return of results

Intervention Type: OTHER

Participants will be randomized to immediate versus delayed APOL1 return of results

Delayed Return of Results

Delayed return of results of APOL1 status (either positive or negative) after the completion of the 6 month final study visit.

Group Type: ACTIVE_COMPARATOR

Timing of return of results

Intervention Type: OTHER

Participants will be randomized to immediate versus delayed APOL1 return of results

Interventions

Timing of return of results

Participants will be randomized to immediate versus delayed APOL1 return of results

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Self reported African ancestry
• English Speaking
• Age 18-70 years
• Have diagnosis of hypertension: Diagnosis of hypertension is defined by either:

• ICD10 diagnosis codes (i.e., I10; I11.x; I12.x; I13.x; I16.x) OR
• On active antihypertensive therapy for indication of hypertension OR
• Having systolic blood pressure of 140 mm Hg or greater in at least 2 of the last 3 consecutive recorded values in the EHR OR
• Having hypertension in the patient's medical record problem list
• Have been seen at ≥1 time in past year at a participating primary care site
• Either: 1) do not have diabetes and do not have CKD, or 2) have CKD; Participants with diabetes may be included as long as they also have CKD.

CKD is defined by either: A) ICD10 codes (i.e., N18.x; E08.22; E09.22; E10.22; E11.22;E13.22 (exclude Z94.0; N18.6; Z99.2)) OR B) Microalbumin/proteinuria level >30 mg/g for 2 time periods ≥ 3 months. Values taken within 12 months of enrollment, unless 2 values are unavailable, then review within 24 months of enrollment. OR C) 15 ≤ eGFR ≤ 60 ml/min for 2 time periods ≥ 3 months. GFRs are taken within 12 months of enrollment, unless 2 values are unavailable, then review within 24 months.

Diabetes is defined by: HbA1c ≥ 6.5 at least one time in the last year OR ICD10 diagnosis codes OR Having diabetes in the patient's medical record problem list.

Exclusion Criteria

• Have diabetes, but no CKD.
• Are currently on dialysis (ICD 10 codes N18.6, Z99.2 and Z94.0)
• Have ESRD (eGFR<15 ml/min)
• Have a left ventricular assist device (LVAD)
• Have a terminal illness
• Have patient-reported known pregnancy at time of enrollment
• Have had a liver, kidney, or allogeneic bone marrow transplant
• Too cognitively impaired to provide informed consent and/or complete the study protocol
• Institutionalized or too ill to participate (i.e. incarcerated, psychiatric or nursing home facility)
• Plan to move out of the area within 6 months of enrollment
• Not a current patient seeing a provider who cares for their hypertension (i.e., family medicine, internal medicine, nephrology, HIV provider, cardiology, hypertension specialists) at a participating site
• Previously participated in the GUARDD pilot study OR have previously undergone APOL1 testing

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Human Genome Research Institute (NHGRI)

NIH

Sponsor Role: collaborator

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: collaborator

Indiana University School of Medicine

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hrishikesh Chakraborty, DrPH

Role: STUDY_DIRECTOR

Duke University

Carol Horowitz, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of Florida - Gainesville

Gainesville, Florida, United States

University of Florida - Jacksonville

Jacksonville, Florida, United States

Eskenazi Health

Indianapolis, Indiana, United States

Indiana University

Indianapolis, Indiana, United States

University Medical Center New Orleans

New Orleans, Louisiana, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

The Institute for Family Health

New York, New York, United States

Southeastern Healthcare

Lumberton, North Carolina, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Meharry Medical College

Nashville, Tennessee, United States

Nashville General Hospital

Nashville, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor Research Institute

Dallas, Texas, United States

Countries

United States

References

Eadon MT, Cavanaugh KL, Orlando LA, Christian D, Chakraborty H, Steen-Burrell KA, Merrill P, Seo J, Hauser D, Singh R, Beasley CM, Fuloria J, Kitzman H, Parker AS, Ramos M, Ong HH, Elwood EN, Lynch SE, Clermont S, Cicali EJ, Starostik P, Pratt VM, Nguyen KA, Rosenman MB, Calman NS, Robinson M, Nadkarni GN, Madden EB, Kucher N, Volpi S, Dexter PR, Skaar TC, Johnson JA, Cooper-DeHoff RM, Horowitz CR; GUARDD-US Investigators. Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension. Contemp Clin Trials. 2022 Aug;119:106813. doi: 10.1016/j.cct.2022.106813. Epub 2022 Jun 1.

Reference Type: BACKGROUND

PMID: 35660539 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U01HG010225

Identifier Type: NIH

Identifier Source: secondary_id

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U01HG007269

Identifier Type: NIH

Identifier Source: secondary_id

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U01HG010232

Identifier Type: NIH

Identifier Source: secondary_id

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U01HG010248

Identifier Type: NIH

Identifier Source: secondary_id

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U01HG010231

Identifier Type: NIH

Identifier Source: secondary_id

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U01HG010245

Identifier Type: NIH

Identifier Source: secondary_id

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PRO00102997

Identifier Type: -

Identifier Source: org_study_id