Pentoxifylline in Diabetic Kidney Disease (PTXRx)

September 5, 2023 updated by: VA Office of Research and Development

CSP #2008 - Pentoxifylline in Diabetic Kidney Disease

Pentoxifylline (PTX) is a medication that has been on the market since 1984 for use in disease in the blood vessels of the legs. There is some preliminary information that it may protect the kidneys from damage due to diabetes and other diseases. "Pentoxifylline in Diabetic Kidney Disease" is a study to bee conducted in 40 VA hospitals across the nation to determine definitively whether or not PTX can prevent worsening of kidney disease and delay death in patients with diabetic kidney disease.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Diabetic kidney disease (DKD) is the most frequent cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the U.S. and in U.S. Veterans. Control of blood pressure and reduction in proteinuria, for instance by blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptors blockers (ARBs), have led to some improvement in outcomes in recent years. However, many patients continue to progress to ESRD, requiring costly dialysis or transplantation and resulting in high mortality. Patients with ESRD on maintenance dialysis also have markedly impaired quality of life. Thus, novel treatments are needed for this disease.

The non-specific phosphodiesterase inhibitor pentoxifylline (PTX) was approved by the FDA in 1984 for the treatment of peripheral vascular disease. Therefore, this drug has been in clinical use for over 3 decades and has been found to have an excellent safety profile. Recent experimental and clinical data suggest that PTX, when added to usual care in patients with DKD, leads to a reduction in albuminuria and reduced inflammation, as evidenced by lower levels of inflammatory cytokines, and may decrease progression of renal disease. The available evidence thus suggests the possibility of the use of PTX as a valuable repurposing of an old drug in the treatment of DKD. However, a large scale multicenter randomized clinical trial is needed to determine whether this agent can reduce hard endpoints such as ESRD and death in patients with DKD.

The objective of this study is to test the hypothesis that PTX, when added to usual care, leads to a reduction in the incidence of ESRD and mortality in type-2 diabetic patients with DKD when compared to usual care plus placebo.

The primary endpoint will be time to ESRD or death. ESRD will be defined as need for chronic dialysis or renal transplantation.

Secondary efficacy endpoints will be: (1) quality of life as measured by the Kidney Disease Quality of Life Short Form (KDQoL-SF), (2) time until doubling of serum creatinine, (3) hospitalization for congestive heart failure (CHF), (4) a three-point MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) peripheral vascular disease (PVD), (6) percentage of participants with 50% reduction in UACR from baseline, (7) Rate of change in eGFR per year during the study period. Safety (serious adverse events and adverse events possibly or probably related to study drug, discontinuation of study drug) will also be analyzed as a secondary safety outcome.

The design will be simple with only 2 face-to-face visits (randomization and end of trial visits). The remaining quarterly contacts can be conducted by telephone collecting minimal targeted information. Laboratory testing specifically for the study will be done only at randomization, at 6 months and the end of the study, if needed. However, coordinators will assure that a serum creatinine will have been measured every 6 months as part of routine clinical care or, in rare instances where one has not been done, obtain this measurement. Other than randomization to PTX or matched placebo, patient care will be handled by usual providers according to recommended standards of care.

There will be a one-year ramp-up phase which will include 6 VA hospitals. The purpose of the ramp-up phase will be to optimize procedures prior to widespread implementation, including assessing the recruitment rate to determine whether the expected rate can be achieved and assessing the efficacy of central distribution of study drug/placebo.

In addition, the investigators will refine methods of recruitment, demonstrate that the proposed follow-up methods are working as intended, and address unforeseen problems. This will be followed by the full study at 40 sites (which includes the 6 ramp-up sites) and will involve 3 years of recruitment and 5 years of follow-up.

Sample size calculation, assuming a 26.6% event rate in the control group and 21.6% event rate in PTX group (corresponding to a 19% relative reduction), two-sided alpha = 0.05, 85% power, a 3-year enrollment period, a minimum 5-year follow-up period, and one proposed interim analysis indicates that 2510 participants will need to be randomized.

If this study is successful and PTX is found to reduce the incidence of ESRD and/or death, this will reduce the personal and financial burden of renal replacement therapy (dialysis/transplantation) for Veterans with diabetic kidney disease

Study Type

Interventional

Enrollment (Estimated)

2510

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85012
        • Recruiting
        • Phoenix VA Health Care System, Phoenix, AZ
        • Contact:
    • Arkansas
      • Little Rock, Arkansas, United States, 72205-5484
        • Recruiting
        • Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
        • Contact:
    • California
      • Loma Linda, California, United States, 92357
      • Long Beach, California, United States, 90822
      • Palo Alto, California, United States, 94304-1207
        • Recruiting
        • VA Palo Alto Health Care System, Palo Alto, CA
        • Contact:
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Rocky Mountain Regional VA Medical Center, Aurora, CO
        • Contact:
    • Florida
      • Bay Pines, Florida, United States, 33744-0000
        • Recruiting
        • Bay Pines VA Healthcare System, Pay Pines, FL
        • Contact:
      • Gainesville, Florida, United States, 32608-1135
        • Recruiting
        • North Florida/South Georgia Veterans Health System, Gainesville, FL
        • Contact:
      • Tampa, Florida, United States, 33612
        • Recruiting
        • James A. Haley Veterans' Hospital, Tampa, FL
        • Contact:
    • Georgia
      • Decatur, Georgia, United States, 30033
        • Recruiting
        • Atlanta VA Medical and Rehab Center, Decatur, GA
        • Contact:
        • Contact:
    • Illinois
      • Hines, Illinois, United States, 60141-3030
        • Recruiting
        • Edward Hines Jr. VA Hospital, Hines, IL
        • Contact:
        • Study Chair:
          • David J Leehey
    • Iowa
      • Iowa City, Iowa, United States, 52246-2292
        • Recruiting
        • Iowa City VA Health Care System, Iowa City, IA
        • Contact:
    • Kentucky
      • Lexington, Kentucky, United States, 40502
    • Michigan
      • Ann Arbor, Michigan, United States, 48105-2303
        • Recruiting
        • VA Ann Arbor Healthcare System, Ann Arbor, MI
        • Contact:
    • Minnesota
      • Minneapolis, Minnesota, United States, 55417
        • Recruiting
        • Minneapolis VA Health Care System, Minneapolis, MN
        • Contact:
        • Contact:
    • Missouri
      • Columbia, Missouri, United States, 65201-5275
        • Recruiting
        • Harry S. Truman Memorial, Columbia, MO
        • Contact:
      • Kansas City, Missouri, United States, 64128-2226
      • Saint Louis, Missouri, United States, 63106-1621
        • Recruiting
        • St. Louis VA Medical Center John Cochran Division, St. Louis, MO
        • Contact:
    • Nebraska
      • Omaha, Nebraska, United States, 68105-1873
        • Recruiting
        • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
        • Contact:
        • Contact:
    • New Mexico
      • Albuquerque, New Mexico, United States, 87108-5153
        • Recruiting
        • New Mexico VA Health Care System, Albuquerque, NM
        • Contact:
    • North Carolina
      • Durham, North Carolina, United States, 27705-3875
        • Recruiting
        • Durham VA Medical Center, Durham, NC
        • Contact:
    • Ohio
      • Cincinnati, Ohio, United States, 45220
      • Dayton, Ohio, United States, 45428
        • Active, not recruiting
        • Dayton VA Medical Center, Dayton, OH
    • Oregon
      • Portland, Oregon, United States, 97207-2964
        • Recruiting
        • VA Portland Health Care System, Portland, OR
        • Contact:
        • Contact:
          • Alexandra
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-4551
        • Active, not recruiting
        • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
    • South Carolina
      • Columbia, South Carolina, United States, 29209-1638
        • Recruiting
        • Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
        • Contact:
    • Tennessee
      • Memphis, Tennessee, United States, 38104
    • Texas
      • Dallas, Texas, United States, 75216-7167
        • Recruiting
        • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
        • Contact:
      • Houston, Texas, United States, 77030-4211
      • San Antonio, Texas, United States, 78229-4404
        • Recruiting
        • South Texas Health Care System, San Antonio, TX
        • Contact:
    • Utah
      • Salt Lake City, Utah, United States, 84148
    • Virginia
      • Richmond, Virginia, United States, 23249-0001
        • Recruiting
        • Hunter Holmes McGuire VA Medical Center, Richmond, VA
        • Contact:
      • Salem, Virginia, United States, 24153-6404
        • Recruiting
        • Salem VA Medical Center, Salem, VA
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98108
        • Recruiting
        • VA Puget Sound Health Care System Seattle Division, Seattle, WA
        • Contact:
        • Contact:
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53295-0001
        • Recruiting
        • Clement J. Zablocki VA Medical Center, Milwaukee, WI
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

A. Inclusion Criteria:

  1. Type 2 diabetes.

  2. Meet one of the following categories at a time that is greater than 90 days prior to randomization

    • Group I: eGFR 15 to less than 30 mL/min/1.73 m2, or
    • Group II: eGFR 30 to less than 45 mL/min/1.73 m2 with UACR > 30 mg/g or UPCR > 150 mg/g, or
    • Group III: eGFR 45 to less than 60 mL/min/1.73 m2 with UACR > 300 mg/g or UPCR > 500 mg/g

  3. Participants need to be in one of the following categories at the time of randomization:

    • Group I: eGFR 15 to less than 30 mL/min/1.73 m2

      , or

    • Group II: eGFR 30 to less than 45 mL/min/1.73 m2 with UACR > 30 mg/g, or
    • Group III: eGFR 45 to less than 60 mL/min/1.73 m2 with UACR > 300 mg/g

Participants must be a United States Veteran, currently receiving care at a VA hospital with a local study team.

Exclusion Criteria:

  1. Type 1 diabetes
  2. History of non-diabetic kidney disease
  3. Severe comorbid conditions expected to reduce life expectancy to less than 1 year, as determined by LSI
  4. Active substance abuse, homelessness, or other condition that is likely to result in participant non,ompliance as determined by the LSI
  5. Previous organ or bone marrow transplant
  6. Pregnancy, breast feeding or female of child-bearing potential unwilling to use a reliable form of contraception
  7. A recent (within 3 months) cerebral hemorrhage
  8. Current use of oral pentoxifylline
  9. Hypersensitivity to pentoxifylline or any of the components of the formulation
  10. Current use of systemic ketorolac, oral or IV (contraindicated with pentoxifylline)
  11. Current use of riociguat (contraindicated with pentoxifylline)
  12. Current use of dialysis
  13. Unable to provide informed consent
  14. or any condition that in the opinion of the LSI would make the potential participant non-compliant

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Drug: Placebo
placebo
Experimental: PTX
Active drug
Drug: Pentoxifylline
The non-specific phosphodiesterase inhibitor pentoxifylline (PTX) was approved by the FDA in 1984 for the treatment of peripheral vascular disease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to ESRD or death
Time Frame: 5 to 9 years
ESRD will be defined as need for chronic dialysis or renal transplantation.
5 to 9 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of life (KDQoL-SF)
Time Frame: 5 to 9 years
Quality of life as measured by the Kidney Disease Quality of Life Short Form (KDQoL-SF)
5 to 9 years
Time until doubling of serum creatinine
Time Frame: 5 to 9 years
Time until doubling of serum creatinine
5 to 9 years
Incidence of congestive heart failure hospitalization (CHF)
Time Frame: 5 to 9 years
The risk of a CHF hospitalization will be based on the participant-time data, specifically, the number of events per years.
5 to 9 years
Incidence of a three-point MACE
Time Frame: 5 to 9 years
The risk of a MACE event will be based on participant-time data, specifically, the number of events per participant years.
5 to 9 years
Incidence of a peripheral vascular disease (PVD)
Time Frame: 5 to 9 years
The risk of a PVD event will be based on participant-time data, specifically, the number of events per participant years.
5 to 9 years
Percentage of participants with 50% reduction in UACR from baseline
Time Frame: 5 to 9 years
Percentage of participants with 50% reduction in UACR from baseline
5 to 9 years
Rate of change in eGFR per year during the study period
Time Frame: 5 to 9 years
Rate of change in eGFR per year during the study period.
5 to 9 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Study Chair: David J Leehey, Edward Hines Jr. VA Hospital, Hines, IL

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 18, 2019

Primary Completion (Estimated)

January 3, 2028

Study Completion (Estimated)

July 8, 2030

Study Registration Dates

First Submitted

July 26, 2018

First Submitted That Met QC Criteria

August 8, 2018

First Posted (Actual)

August 10, 2018

Study Record Updates

Last Update Posted (Actual)

September 6, 2023

Last Update Submitted That Met QC Criteria

September 5, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2008 (Ministry of Health)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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