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Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria

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ClinicalTrials.gov Identifier: NCT03201939
Recruitment Status : Not yet recruiting
First Posted : June 28, 2017
Last Update Posted : June 13, 2019
Sponsor:
Collaborators:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Aminu Kano Teaching Hospital
SAIC-Frederick, Inc.
Information provided by (Responsible Party):
C. William Wester, Vanderbilt University Medical Center

Tracking Information
First Submitted Date  ICMJE June 22, 2017
First Posted Date  ICMJE June 28, 2017
Last Update Posted Date June 13, 2019
Estimated Study Start Date  ICMJE August 12, 2019
Estimated Primary Completion Date February 6, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 28, 2018)
  • Regression from microalbuminuria (uACR 30-300) to normoalbuminuria (uACR < 30 mg/g) by study arm [ Time Frame: 2 years ]
    Reduction/improvement in degree/grade of albuminuria
  • Progression from microalbuminuria (uACR 30-300) to macroalbuminuria (uACR > 300 mg/g) by study arm [ Time Frame: 2 years ]
    Progression/worsening in degree/grade of albuminuria
  • Mean change in urinary albumin to creatinine ratio (uACR) [ Time Frame: 2 years ]
    Mean change in urinary albumin excretion
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2017)
  • Regression from microalbuminuria (uACR 30-300) to normoalbuminuria (uACR < 30 mg/g) by study arm [ Time Frame: 2 years ]
    Reduction/improvement in degree/grade of albuminuria
  • Progression from microalbuminuria (uACR 30-300) to macroalbuminuria (uACR > 300 mg/g) by study arm [ Time Frame: 2 years ]
    Progression/worsening in degree/grade of albuminuria
Change History Complete list of historical versions of study NCT03201939 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2018)
  • Doubling of serum creatinine from baseline [ Time Frame: 2 years ]
    Worsening renal function (as measured by serum creatinine)
  • All-cause mortality [ Time Frame: 2 years ]
    Survival
  • Proportion experiencing a 40% decline in eGFR [ Time Frame: 2 years ]
    Proportion with 40% decline in eGFR (measured using CKD-EPI-Cr-CyC equation)
  • Mean change in eGFR over time [ Time Frame: 2 years ]
    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 [ Time Frame: baseline, 1 year, 2 years ]
    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 [ Time Frame: baseline, 1 year, 2 years ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2017)
  • Mean change in urinary albumin to creatinine ratio (uACR) [ Time Frame: 2 years ]
    Mean change in urinary albumin excretion
  • Doubling of serum creatinine from baseline [ Time Frame: 2 years ]
    Worsening renal function (as measured by serum creatinine)
  • All-cause mortality [ Time Frame: 2 years ]
    Survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria
Official Title  ICMJE Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria
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:

  1. 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.
  2. 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
  3. To determine whether the APOL1 HR genotype is associated with worse longitudinal renal outcomes in Nigerians with prevalent albuminuria.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Double-blind, placebo-controlled RCT
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double-blind, placebo-controlled RCT
Primary Purpose: Treatment
Condition  ICMJE
  • HIV/AIDS
  • Albuminuria
  • Kidney Diseases
  • Genetic Predisposition
Intervention  ICMJE
  • Drug: Lisinopril
    ACE-inhibitor (lisinopril)(intervention arm
    Other Name: Intervention arm
  • Other: Placebo Oral Tablet
    Comparator placebo (control arm)
    Other Name: Control arm
Study Arms  ICMJE
  • Active Comparator: Active Medication (Intervention arm)
    ACE-inhibitor lisinopril
    Intervention: Drug: Lisinopril
  • Placebo Comparator: Placebo comparator (Control arm)
    Matched placebo
    Intervention: Other: Placebo Oral Tablet
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 28, 2018)
280
Original Estimated Enrollment  ICMJE
 (submitted: June 26, 2017)
200
Estimated Study Completion Date  ICMJE August 31, 2023
Estimated Primary Completion Date February 6, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Gender Based Eligibility: Yes
Gender Eligibility Description: Both males and females eligible
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: C. William Wester, MD, MPH +001-615-875-0145 william.wester@vumc.org
Contact: Donna J. Ingles, MS, MPH +001-615-343-3555 donna.j.ingles@vumc.org
Listed Location Countries  ICMJE Nigeria
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03201939
Other Study ID Numbers  ICMJE Vanderbilt_University MC
U01DK112271 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
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.
Responsible Party C. William Wester, Vanderbilt University Medical Center
Study Sponsor  ICMJE Vanderbilt University Medical Center
Collaborators  ICMJE
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Aminu Kano Teaching Hospital
  • SAIC-Frederick, Inc.
Investigators  ICMJE
Principal Investigator: C. William Wester, MD, MPH Vanderbilt University Medical Center
Principal Investigator: Muktar H. Aliyu, MD, DrPH Vanderbilt University Medical Center
PRS Account Vanderbilt University Medical Center
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP