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Kidney DiseasePhase 3VA NEPHRON-DNCT00555217

VA NEPHRON-D: Diabetes iN Nephropathy Study

A Phase 3 study testing losartan and lisinopril in people with Kidney Disease and Nephropathy, run by US Department of Veterans Affairs at 31 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. The overall rate of ESRD secondary to diabetes has risen 68% since 1992. Medications that block the renin angiotensin system have been shown to decrease the progression of diabetic nephropathy. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Kidney Disease, Nephropathy, Type 2 Diabetes
What is being tested?
losartan and lisinopril
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,448 participants
Where
31 sitesin 2 countries
Study dates
Jul 2008to Oct 2014
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Type 2 diabetes
  • Albuminuria >300mg/gram creatinine
  • Stage 2 or 3 CKD (eGFR 30 to <90 mg/min/1.73m*2 )
  • Able to give informed consent
  • Telephone contact available

Who cannot join

  • History of intolerance to ACEI or ARB
  • Serum potassium level >5.5 meq/L
  • Receiving sodium polystyrene sulfonate (Kayexalate)
  • Pregnancy, breast feeding, planning to become pregnant or sexually active and not using birth control
  • Renal transplant recipient
  • Suspected non-diabetic kidney disease
Show all 17Show fewer
  • Inability to discontinue current use of ACEI/ARB combination
  • Current use of Lithium
  • Severe (end-stage) comorbid disease
  • Prisoner
  • Age <18
  • Estimated glomerular filtration rate (GFR) <30 or >=90 ml/min/1.73m*m
  • HbA1c >10.5%
  • Patient refusal
  • Participation in a concurrent interventional study
  • Blood pressure >180/95
  • Unwilling to stop any proscribed medications after enrollment

Trial locations and contacts

31 sites in 2 countries.

31 sites in 2 countries

United States30 sites

  • New Mexico VA Health Care System, Albuquerque

    Albuquerque, New Mexico, 87108-5153

  • VA Maryland Health Care System, Baltimore

    Baltimore, Maryland, 21201

  • VA Western New York Healthcare System at Buffalo

    Buffalo, New York, 14215

  • Ralph H Johnson VA Medical Center, Charleston

    Charleston, South Carolina, 29401-5799

  • VA Medical Center, Cleveland

    Cleveland, Ohio, 44106

  • WJB Dorn Veterans Hospital, Columbia

    Columbia, South Carolina, 29209

  • VA North Texas Health Care System, Dallas

    Dallas, Texas, 75216

  • VA Medical Center, Durham

    Durham, North Carolina, 27705

  • VA New Jersey Health Care System, East Orange

    East Orange, New Jersey, 07018

  • North Florida/South Georgia Veterans Health System

    Gainesville, Florida, 32608

  • Edward Hines, Jr. VA Hospital

    Hines, Illinois, 60141-5000

  • Richard Roudebush VA Medical Center, Indianapolis

    Indianapolis, Indiana, 46202-2884

  • VA Medical Center, Iowa City

    Iowa City, Iowa, 52246-2208

  • VA Medical Center, Kansas City MO

    Kansas City, Missouri, 64128

  • Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock

    Little Rock, Arkansas, 72205-5484

  • VA Medical Center, Loma Linda

    Loma Linda, California, 92357

  • VA Medical Center, Memphis

    Memphis, Tennessee, 38104

  • VA Medical Center, Miami

    Miami, Florida, 33125

  • Zablocki VA Medical Center, Milwaukee

    Milwaukee, Wisconsin, 53295-1000

  • VA Medical Center, Minneapolis

    Minneapolis, Minnesota, 55417

  • VA Medical Center

    Nashville, Tennessee, 37212-2637

  • VA Medical Center, Omaha

    Omaha, Nebraska, 68105-1873

  • VA Palo Alto Health Care System

    Palo Alto, California, 94304-1290

  • Carl T. Hayden VA Medical Center

    Phoenix, Arizona, 85012

  • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

    Pittsburgh, Pennsylvania, 15240

  • VA Medical Center, Portland

    Portland, Oregon, 97201

  • Hunter Holmes McGuire VA Medical Center

    Richmond, Virginia, 23249

  • VA Medical Center, St Louis

    St Louis, Missouri, 63106

  • James A. Haley Veterans Hospital, Tampa

    Tampa, Florida, 33612

  • VA Connecticut Health Care System (West Haven)

    West Haven, Connecticut, 06516

Other trials in United States

Puerto Rico1 site

  • VA Medical Center, San Juan

    San Juan, 00921

Other trials in Puerto Rico

About this study

Official title: CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D Study)

Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. The overall rate of ESRD secondary to diabetes has risen 68% since 1992. Medications that block the renin angiotensin system have been shown to decrease the progression of diabetic nephropathy. The use of an angiotensin receptor blocker (ARB) has been shown to decrease the risk of progression of kidney disease in two studies of individuals with Type 2 diabetes and proteinuria. Despite the use of an ARB, the incidence of renal failure remained high in the treated group in both studies. The combination of an angiotensin converting enzyme inhibitor (ACEI) and ARB can lead to more complete blockade of the renin angiotensin system. In diabetic kidney disease, combination therapy has been shown to decrease proteinuria in short-term studies. Although there are encouraging results for improvement in proteinuria there are no data on progression of kidney disease for the use of combination of ACEI and ARB therapy in patients with diabetes. In addition, there could be an increased risk of serious hyperkalemia in individuals with diabetes who receive combination ACEI and ARB. The investigators therefore propose a randomized double blind multi-center clinical trial to assess the effect of combination of ACEI and ARB in patients with diabetes and proteinuria on progression of kidney disease.

Read the detailed description

Primary Hypothesis:

To evaluate the combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB) vs. standard treatment with angiotensin receptor blocker on the progression of kidney disease in individuals with Type 2 diabetes and overt nephropathy.

The primary outcome is a composite endpoint of reduction in estimated GFR of 30 ml/min/1.73m*m in individuals with an estimated baseline GFR greater than or equal to 60 ml/min/1.73m*m; reduction in estimated GFR of greater than 50% in individuals with an estimated baseline GFR less than 60 mL/min/1.73m*m; progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR less than 15 ml/min/1.73m*m) or death.

Secondary outcome: a renal composite endpoint, defined as; reduction in estimated GFR of more than 50% (for individuals with a baseline estimated GFR less than 60 ml/min/1.73m*m); reduction in estimated GFR of more than 30 ml/min/1.73m*m (for individuals with a baseline estimated GFR greater than or equal to 60 ml/min/1.73m*m) or progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR of less than 15 ml/min/1.73m*m).

Tertiary outcomes are cardiovascular events (cardiovascular mortality, myocardial infarction, cerebrovascular accident, admission for heart failure), change in albuminuria at 12 months and decline in slope of kidney function.

Study Abstract:

The study is a multi-center, prospective, randomized, parallel group trial to test the efficacy of the combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotension receptor blocker (ARB) vs. standard treatment with angiotension receptor blocker on the combined end-point. The primary outcome is a composite endpoint of reduction in estimated GFR of 30 ml/min/1.73m*m in individuals with an estimated GFR greater than or equal to 60 ml/min/1.73m*m; reduction in estimated GFR of greater than 50% in individuals with an estimated GFR less than 60 ml/min/1.73m*m; progression to end-stage renal disease (defined as need for dialysis, renal transplant or en eGFR less than 15 ml/min/1.73m*m)or death. The study population is individuals with type 2 diabetes and overt nephropathy.

Eligible subjects who consent to participate will be randomized into either the combination therapy arm or the mono therapy arm. The randomization will be stratified by site and within sites by baseline albuminuria (< 1 vs. greater than or equal to 1 gram/gram creatinine) and eGFR (< 60 vs. greater than or equal to 60 ml/min/1.73m*m). All participants will receive open label therapy with losartan, an ARB, as standard of care. Patients not treated with an ACEI or ARB will be initiated on losartan; patients treated with an ACEI or ARB other than losartan (the study ARB) will be converted to losartan (the study ARB) and the dose titrated to 100 mg/day. Individuals who tolerate ARB 100mg/day criteria will be randomized in a 1:1 ratio to the addition of blinded lisinopril (the study ACEI) or placebo. The medication (lisinopril or placebo) will be titrated from an initial dose of 10 mg/day to a target dose of 40 mg/day. After each adjustment in dose, serum chemistries will be evaluated for kidney function and potassium levels. Subjects will be enrolled over a period of 4.25 years and the maximum length of follow-up is 6.25 years. The planned study duration is 6.25 years with 4.25 years of accrual and 6.25 years of follow-up for all enrolled patients. The intervention was stopped on November 7, 2012 for safety concerns after an interim analysis. Patients are still under passively follow-up without intervention.

Being tested
losartan, lisinopril
Keywords
kidney disease, nephropathy, type 2 diabetes, hyperkalemia, acute kidney injury
Medical subject headings
Kidney Diseases, Diabetes Mellitus, Type 2, Hyperkalemia, Acute Kidney Injury

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • losartanDrug

    50 or 100mg/day

  • lisinoprilDrug

    10, 20 or 40 mg/day

Study groups in NCT00555217
Study groupRoleWhat they receive
Combination of ARB and ACEIExperimentalCombination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB)
Receives: Drug: losartan; Drug: lisinopril
Monotherapy ARBActive comparatorMono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)
Receives: Drug: losartan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. A Composite Endpoint of Reduction in Estimated GFR of 30ml/Min/1.73m*m in Individuals w/a Baseline Estimated GFR >= 60 ml/Min/1.73m*m, Reduction in Estimated GFR >50% in Individuals w/ Baseline Estimated GFR <60ml/Min/1.73m*m; ESRD or Death

    Time to the first event of reduction in estimated GFR of 30ml/min/1.73m*m in individuals w/a baseline estimated GFR >= 60 ml/min/1.73m*m, reduction in estimated GFR >50% in individuals w/ baseline estimated GFR <60ml/min/1.73m*m; ESRD or death.

    Measured: From enrollemnt to time of first primary event, up to 4.5 years

Secondary outcomes (1)

  1. A Renal Composite Endpoint, Defined as; Reduction in Estimated GFR of >50% (for Individuals With Baseline GFR <60) or Reduction in GFR of >30 (for Individuals With Baseline GFR >= GFR 60) or ESRD.

    Time to the first event of reduction in estimated GFR of >50% (for individuals with baseline GFR <60) or reduction in GFR of >30 (for individuals with baseline GFR >= GFR 60) or ESRD.

    Measured: From enrollment to time of first event, up to 4.5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Nov 2007 (estimated)
  2. Study startJul 2008
  3. Primary completionSep 2014
  4. Study completionOct 2014

Why it stopped: It was stopped primarily because of safety concerns along with low conditional power to detect a treatment effect on the primary outcome.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Care provider
Enrolment
1,448 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00555217
Sponsor's protocol ID
565
Acronym
VA NEPHRON-D
Status last verified
May 2015
First submitted
7 Nov 2007
Last updated
29 May 2015
Data monitoring committee
Yes

Publications

  • Fried LF, Duckworth W, Zhang JH, O'Connor T, Brophy M, Emanuele N, Huang GD, McCullough PA, Palevsky PM, Seliger S, Warren SR, Peduzzi P; VA NEPHRON-D Investigators. Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D). Clin J Am Soc Nephrol. 2009 Feb;4(2):361-8. doi: 10.2215/CJN.03350708. Epub 2008 Dec 31.

    PubMed 19118120

  • Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O'Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903. doi: 10.1056/NEJMoa1303154. Epub 2013 Nov 9.

    PubMed 24206457

  • Fried LF, Emanuele N, Zhang JH. Combined angiotensin inhibition in diabetic nephropathy. N Engl J Med. 2014 Feb 20;370(8):779. doi: 10.1056/NEJMc1315504. No abstract available.

    PubMed 24552328

  • Chen SS, Seliger SL, Fried LF. Complete inhibition of the renin-angiotensin-aldosterone system; where do we stand? Curr Opin Nephrol Hypertens. 2014 Sep;23(5):449-55. doi: 10.1097/MNH.0000000000000043.

    PubMed 25014549

  • Zimering MB, Zhang JH, Guarino PD, Emanuele N, McCullough PA, Fried LF; Investigators for the VA NEPHRON-D. Endothelial cell autoantibodies in predicting declining renal function, end-stage renal disease, or death in adult type 2 diabetic nephropathy. Front Endocrinol (Lausanne). 2014 Aug 11;5:128. doi: 10.3389/fendo.2014.00128. eCollection 2014.

    PubMed 25157242

  • Tamargo CL, Coca SG, Thiessen Philbrook H, Hu DG, Ix JH, Shlipak MG, Fried LF, Gutierrez OM, Waikar SS, Schrauben SJ, Schelling JR, Ganz P, Kimmel PL, Greenberg JH, Deo R, Takakura A, Vasan RS, Bonventre JV, Parikh CR. The distal nephron biomarkers associate with diabetic kidney disease progression. JCI Insight. 2025 Jun 23;10(12):e186836. doi: 10.1172/jci.insight.186836. eCollection 2025 Jun 23.

    PubMed 40548378

  • Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2024 Apr 29;4(4):CD006257. doi: 10.1002/14651858.CD006257.pub2.

    PubMed 38682786

  • Huang Y, Fried LF, Kyriakides TC, Johnson GR, Chiu S, Mcdonald L, Zhang JH. Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial. Clin Trials. 2019 Feb;16(1):81-89. doi: 10.1177/1740774518813121. Epub 2018 Nov 16.

    PubMed 30445841

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing losartan and lisinopril in people with Kidney Disease and Nephropathy, run by US Department of Veterans Affairs at 31 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 29 May 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 31 sites in United States, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 May 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

A Composite Endpoint of Reduction in Estimated GFR of 30ml/Min/1.73m*m in Individuals w/a Baseline Estimated GFR >= 60 ml/Min/1.73m*m, Reduction in Estimated GFR >50% in Individuals w/ Baseline Estimated GFR <60ml/Min/1.73m*m; ESRD or Death (time frame: From enrollemnt to time of first primary event, up to 4.5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00555217, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2015.

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