Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria
Primary Purpose
HIV/AIDS, Albuminuria, Kidney Diseases
Status
Suspended
Phase
Phase 2
Locations
Nigeria
Study Type
Interventional
Intervention
Lisinopril
Placebo Oral Tablet
Sponsored by
About this trial
This is an interventional treatment trial for HIV/AIDS focused on measuring HIV/AIDS, sub-Saharan Africa, Kidney disease, Albuminuria, Genetic risk
Eligibility Criteria
Inclusion criteria:
- Participated in Study Aim 1
- 18-70 years of age
- HIV-positive (as documented by HIV-1 ELISA testing)
- On ART for a minimum of six (6) months AND having a suppressed plasma viral load result (< 20 copies/mL) within the past 6 months
- Average uACR between 30-300 mg/g (based on 2 uACRs [first morning voids], with the second obtained 4-8 weeks after the first specimen)(NOTE: All aim 1 screened patients having a uACR value > 300 mg/g will undergo urine dipstick analysis for aim 2 eligibility, and if their urine dipstick results reveals ≥ 2+ protein, then they will be considered ineligible (no additional uACR testing will be necessary to determine eligibility)
- eGFR = >60 ml/min/1.73m2 (using CKD-EPI-Cr-CyC equation) AND
- If female, non-pregnant (documentation of negative urine pregnancy test) and not breastfeeding/lactating
Exclusion criteria:
- Pregnant or currently breastfeeding
- eGFR of <60 ml/min/1.73m2 (using CKD-EPI-Cr-CyC equation)
- Average uACR > 300 mg/g (based on 2 uACRs [first morning voids], with the second obtained 4-8 weeks after the first specimen)
- K+ >5.0 meEq/L or reasons to be concerned about hyperkalemia
- Known history of Diabetes diabetes mellitus (would qualify for treatment with an ACEi/ARB)
- Poorly controlled hypertension (≥3 BP readings >160/110 in past 3 6 months)
- Known history of Congestive congestive heart failure (chronic)
- Average uACR (calculated on values obtained from 2 successive measures 4-8 weeks apart) of < 30 mg/g OR > 300 mg/g
- Relative symptomatic hypotension (BP <90/60)
- Currently receiving an ACEi and/or ARB; OR
- Lack of suitability as a study candidate (i.e. active substance use disorder, active use of potentially nephrotoxic medication(s) (i.e. traditional medicines, etc.) and/or consistent alcohol, drug, and/or traditional medication use, and/or history of poor compliance (i.e. multiple missed scheduled clinic appointments, etc.)
Sites / Locations
- Aminu Kano Teaching Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Active Medication (Intervention arm)
Placebo comparator (Control arm)
Arm Description
ACE-inhibitor lisinopril
Matched placebo
Outcomes
Primary Outcome Measures
Regression from microalbuminuria (uACR 30-300) to normoalbuminuria (uACR < 30 mg/g) by study arm
Reduction/improvement in degree/grade of albuminuria
Progression from microalbuminuria (uACR 30-300) to macroalbuminuria (uACR > 300 mg/g) by study arm
Progression/worsening in degree/grade of albuminuria
Mean change in urinary albumin to creatinine ratio (uACR)
Mean change in urinary albumin excretion
Secondary Outcome Measures
Doubling of serum creatinine from baseline
Worsening renal function (as measured by serum creatinine)
All-cause mortality
Survival
Proportion experiencing a 40% decline in eGFR
Proportion with 40% decline in eGFR (measured using CKD-EPI-Cr-CyC equation)
Mean change in eGFR over time
Mean change in eGFR (measured using CKD-EPI-Cr-CyC equation)
Change in clinical/performance status as ascertained via World Health Organization Quality of Life HIV (WHOQOL-HIV) scale
WHOQOL-HIV scale evaluates quality of life based on physical, psychological, social, environmental, and spiritual domains, as well as level of independence. We will use the 31-question version, with each question rated on a 5-point Likert scale. Scores of questions within each domain are averaged to get domain score, and final score is mean of domain scores multiplied by 4. Final score ranges from 4 to 20, with 20 being optimal.
Change in clinical/performance status as ascertained via Karnofsky Performance Score
Karnofsky Performance Score measures change in clinical/performance status with values ranging from 0 to 100, where 100 is perfect health and 0 is death.
Full Information
NCT ID
NCT03201939
First Posted
June 22, 2017
Last Updated
May 4, 2023
Sponsor
Vanderbilt University Medical Center
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Aminu Kano Teaching Hospital, SAIC-Frederick, Inc., Brigham and Women's Hospital
1. Study Identification
Unique Protocol Identification Number
NCT03201939
Brief Title
Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria
Official Title
Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Suspended
Why Stopped
DSMB recommendations--lab QC issues relate to urine albumin measurement (>2-year pause). DSMB approval obtained (3/24/2023) to re-open but will not enroll participants until new/separate funding obtained as this award ends in Feb. 2024.
Study Start Date
February 2024 (Anticipated)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
February 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Aminu Kano Teaching Hospital, SAIC-Frederick, Inc., Brigham and Women's Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
In this study, the Investigators plan to determine the optimal means to prevent or slow the progression of kidney disease among genetically at-risk northern Nigerian HIV-infected adults. Based on data from studies of diabetic kidney disease that used medications that block the renin angiotensin aldosterone system (RAAS), we plan to evaluate whether or not RAAS inhibition (using a widely available medication that blocks RAAS) in HIV-infected adults produces similarly promising results.
Detailed Description
Individuals of African descent have a much higher risk for glomerular diseases. Specifically, there are two risk variants in the chromosome 22 APOL1 gene (G1/G2) and persons possessing 2 copies of these risk variants (G1/G1, G1/G2, or G2/G2), referred to as the high-risk (HR) genotype, are at high risk for non-diabetic kidney disease. Kopp et al. have shown that the APOL1 high-risk genotype confers sizeable odds ratios (OR) for FSGS (OR = 17), HIVAN (OR = 29 in the US; 89 in S. Africa), and hypertension-attributed end stage kidney disease (OR = 7). The presence of these risk variants is highest in West Africa, and specifically in Nigeria among persons of Hausa, Fulani, and Igbo descent. In the setting of untreated HIV infection, we have estimated that ~50% of individuals carrying the APOL1 HR genotype will develop chronic kidney disease (CKD). However, there is limited availability of dialysis and kidney transplantation in Nigeria, and most individuals will die soon after developing ESKD. Markers of kidney disease include microalbuminuria, proteinuria, and/or reduced estimated glomerular filtration rate (eGFR). All 3 have been associated with increased mortality in HIV+ adults. Increased urinary albumin excretion has diagnostic and prognostic value in the identification and confirmation of renal disease, and changes in albuminuria can be useful in assessing treatment efficacy as well as disease progression. Microalbuminuria, i.e., urine albumin to creatinine ratio (uACR) in the 30-300 mg/g range, is likely the earliest stage of CKD, analogous to diabetic microalbuminuria. The renin-angiotensin aldosterone system (RAAS) is the central player in the pathophysiology of CKD and blocking RAAS with angiotensin converting enzyme inhibitors (ACEi) is a well-recognized strategy to slow or halt renal disease progression in diabetics with CKD. To determine whether the presence of APOL1 HR genotype alters or predicts responsiveness to conventional therapy and if the addition of an ACEi to standard antiretroviral therapy (ART) reduces the risk for renal complications among West African adults, we will screen 2,600 HIV+ ART-experienced adults; to conduct the following Specific Aims:
To determine the prevalence of APOL1 renal risk variants and assess whether APOL1 HR status correlates with prevalent albuminuria, eGFR, and/or prevalent CKD in a West African population.
To assess whether RAAS inhibition (with the ACEi lisinopril) in addition to ART, compared to the existing standard-of-care (SOC), will significantly reduce the incidence of additional kidney disease manifestations. We will randomize ART-experienced (6+ months) adults with prevalent microalbuminuria (uACR 30-300 mg/g) and an eGFR of > 30 ml/min/1.73m2 to lisinopril (n=140) vs. SOC (n=140); and
To determine whether the APOL1 HR genotype is associated with worse longitudinal renal outcomes in Nigerians with prevalent albuminuria.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV/AIDS, Albuminuria, Kidney Diseases, Genetic Predisposition
Keywords
HIV/AIDS, sub-Saharan Africa, Kidney disease, Albuminuria, Genetic risk
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Double-blind, placebo-controlled RCT
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind, placebo-controlled RCT
Allocation
Randomized
Enrollment
280 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Active Medication (Intervention arm)
Arm Type
Active Comparator
Arm Description
ACE-inhibitor lisinopril
Arm Title
Placebo comparator (Control arm)
Arm Type
Placebo Comparator
Arm Description
Matched placebo
Intervention Type
Drug
Intervention Name(s)
Lisinopril
Other Intervention Name(s)
Intervention arm
Intervention Description
ACE-inhibitor (lisinopril)(intervention arm
Intervention Type
Other
Intervention Name(s)
Placebo Oral Tablet
Other Intervention Name(s)
Control arm
Intervention Description
Comparator placebo (control arm)
Primary Outcome Measure Information:
Title
Regression from microalbuminuria (uACR 30-300) to normoalbuminuria (uACR < 30 mg/g) by study arm
Description
Reduction/improvement in degree/grade of albuminuria
Time Frame
2 years
Title
Progression from microalbuminuria (uACR 30-300) to macroalbuminuria (uACR > 300 mg/g) by study arm
Description
Progression/worsening in degree/grade of albuminuria
Time Frame
2 years
Title
Mean change in urinary albumin to creatinine ratio (uACR)
Description
Mean change in urinary albumin excretion
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Doubling of serum creatinine from baseline
Description
Worsening renal function (as measured by serum creatinine)
Time Frame
2 years
Title
All-cause mortality
Description
Survival
Time Frame
2 years
Title
Proportion experiencing a 40% decline in eGFR
Description
Proportion with 40% decline in eGFR (measured using CKD-EPI-Cr-CyC equation)
Time Frame
2 years
Title
Mean change in eGFR over time
Description
Mean change in eGFR (measured using CKD-EPI-Cr-CyC equation)
Time Frame
2 years
Title
Change in clinical/performance status as ascertained via World Health Organization Quality of Life HIV (WHOQOL-HIV) scale
Description
WHOQOL-HIV scale evaluates quality of life based on physical, psychological, social, environmental, and spiritual domains, as well as level of independence. We will use the 31-question version, with each question rated on a 5-point Likert scale. Scores of questions within each domain are averaged to get domain score, and final score is mean of domain scores multiplied by 4. Final score ranges from 4 to 20, with 20 being optimal.
Time Frame
baseline, 1 year, 2 years
Title
Change in clinical/performance status as ascertained via Karnofsky Performance Score
Description
Karnofsky Performance Score measures change in clinical/performance status with values ranging from 0 to 100, where 100 is perfect health and 0 is death.
Time Frame
baseline, 1 year, 2 years
10. Eligibility
Sex
All
Gender Based
Yes
Gender Eligibility Description
Both males and females eligible
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria:
Participated in Study Aim 1
18-70 years of age
HIV-positive (as documented by HIV-1 ELISA testing)
On ART for a minimum of six (6) months AND having a suppressed plasma viral load result (< 20 copies/mL) within the past 6 months
Average uACR between 30-300 mg/g (based on 2 uACRs [first morning voids], with the second obtained 4-8 weeks after the first specimen)(NOTE: All aim 1 screened patients having a uACR value > 300 mg/g will undergo urine dipstick analysis for aim 2 eligibility, and if their urine dipstick results reveals ≥ 2+ protein, then they will be considered ineligible (no additional uACR testing will be necessary to determine eligibility)
eGFR = >60 ml/min/1.73m2 (using CKD-EPI-Cr-CyC equation) AND
If female, non-pregnant (documentation of negative urine pregnancy test) and not breastfeeding/lactating
Exclusion criteria:
Pregnant or currently breastfeeding
eGFR of <60 ml/min/1.73m2 (using CKD-EPI-Cr-CyC equation)
Average uACR > 300 mg/g (based on 2 uACRs [first morning voids], with the second obtained 4-8 weeks after the first specimen)
K+ >5.0 meEq/L or reasons to be concerned about hyperkalemia
Known history of Diabetes diabetes mellitus (would qualify for treatment with an ACEi/ARB)
Poorly controlled hypertension (≥3 BP readings >160/110 in past 3 6 months)
Known history of Congestive congestive heart failure (chronic)
Average uACR (calculated on values obtained from 2 successive measures 4-8 weeks apart) of < 30 mg/g OR > 300 mg/g
Relative symptomatic hypotension (BP <90/60)
Currently receiving an ACEi and/or ARB; OR
Lack of suitability as a study candidate (i.e. active substance use disorder, active use of potentially nephrotoxic medication(s) (i.e. traditional medicines, etc.) and/or consistent alcohol, drug, and/or traditional medication use, and/or history of poor compliance (i.e. multiple missed scheduled clinic appointments, etc.)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
C. William Wester, MD, MPH
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Muktar H. Aliyu, MD, DrPH
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aminu Kano Teaching Hospital
City
Kano
Country
Nigeria
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Investigative team will work with study biostatisticians, DSMB members, and collaborators to release analysis scripts (with publications) and devise an IPD sharing plan at/near study completion.
IPD Sharing Time Frame
Approximately 6 months after collection of the final patient data.
IPD Sharing Access Criteria
Deidentified data will be available after the conclusion of the study for investigators who are approved by the trial leadership at VUMC, AKTH, and NIH.
Citations:
PubMed Identifier
33901548
Citation
Wudil UJ, Aliyu MH, Prigmore HL, Ingles DJ, Ahonkhai AA, Musa BM, Muhammad H, Sani MU, Nalado AM, Abdu A, Abdussalam K, Shepherd BE, Dankishiya FS, Burgner AM, Ikizler TA, Wyatt CM, Kopp JB, Kimmel PL, Winkler CA, Wester CW. Apolipoprotein-1 risk variants and associated kidney phenotypes in an adult HIV cohort in Nigeria. Kidney Int. 2021 Jul;100(1):146-154. doi: 10.1016/j.kint.2021.03.038. Epub 2021 Apr 24.
Results Reference
background
PubMed Identifier
31182139
Citation
Aliyu MH, Wudil UJ, Ingles DJ, Shepherd BE, Gong W, Musa BM, Muhammad H, Sani MU, Abdu A, Nalado AM, Atanda A, Ahonkhai AA, Ikizler TA, Winkler CA, Kopp JB, Kimmel PL, Wester CW. Optimal management of HIV- positive adults at risk for kidney disease in Nigeria (Renal Risk Reduction "R3" Trial): protocol and study design. Trials. 2019 Jun 10;20(1):341. doi: 10.1186/s13063-019-3436-y.
Results Reference
background
Learn more about this trial
Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria
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