Clinical trial NCT04191824: Genetic Testing to Understand and Address Renal Disease Disparities Across the United States
Official title: Genetic Testing to Understand and Address Renal Disease Disparities Across the United States
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Kidney Disease
Hypertension
Keywords: Kidney Disease
Genetic testing
APOL1
Genomics
Renal Disease
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Human Genome Research Institute (NHGRI)
name: Icahn School of Medicine at Mount Sinai
name: University of Florida
name: Indiana University School of Medicine
name: Vanderbilt University Medical Center
First posted: 2019-12-10
Enrollment: 6789
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Immediate versus delayed return of Apolipoprotein L1 (APOL1) genetic testing results to provider and participant.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Systolic Blood Pressure From Baseline to 3 Months for APOL1 Positive Participants.
timeFrame: Baseline to 3 month study visit
Secondary outcomes:
measure: Change in Number of Participants With Urine Microalbuminuria/Proteinuria Orders
timeFrame: Baseline to 6 month study visit
measure: Number of Participants With Documented Order of Microalbuminuria/Proteinuria Tests
timeFrame: From baseline to 6 month study visit
measure: Number of Participants With a Change in Documented Diagnosis for Stage 3 CKD and Above
timeFrame: From baseline to 6 month study visit
measure: Number of Participants With Documented Diagnosis of CKD Stage 3 and Above
timeFrame: From baseline to 6 month study visit
measure: Number of Participants With a Change in Documented Diagnosis for Any Stage CKD
timeFrame: From baseline to 6 month study visit
measure: Number of Participants With Documented Diagnosis of All Stages of CKD
timeFrame: From baseline to 6 month study visit
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Gainesville
country: United States
facility: University of Florida - Gainesville
state: Florida
city: Jacksonville
country: United States
facility: University of Florida - Jacksonville
state: Florida
city: Indianapolis
country: United States
facility: Eskenazi Health
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: The Institute for Family Health
state: New York
city: Lumberton
country: United States
facility: Southeastern Healthcare
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Meharry Medical College
state: Tennessee
city: Nashville
country: United States
facility: Nashville General Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Research Institute
state: Texas
Study officials:
affiliation: Duke University
name: Hrishikesh Chakraborty, DrPH
role: STUDY_DIRECTOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Carol Horowitz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.