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Pentoxifylline in Diabetic Kidney Disease (PTXRx)

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ClinicalTrials.gov Identifier: NCT03625648
Recruitment Status : Recruiting
First Posted : August 10, 2018
Last Update Posted : March 8, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE July 26, 2018
First Posted Date  ICMJE August 10, 2018
Last Update Posted Date March 8, 2021
Actual Study Start Date  ICMJE November 18, 2019
Estimated Primary Completion Date January 3, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 8, 2018)
Time to ESRD or death [ Time Frame: 5 to 9 years ]
ESRD will be defined as need for chronic dialysis or renal transplantation.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2019)
  • 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)
  • Time until doubling of serum creatinine [ Time Frame: 5 to 9 years ]
    Time until doubling of serum creatinine
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2018)
  • Quality of life [ Time Frame: 5 to 9 years ]
    Quality of life as measured by the Kidney Disease Quality of Life Short Form (KDQoL-SF)
  • Time until doubling of serum creatinine [ Time Frame: 5 to 9 years ]
    Time until doubling of serum creatinine
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pentoxifylline in Diabetic Kidney Disease
Official Title  ICMJE CSP #2008 - Pentoxifylline in Diabetic Kidney Disease
Brief Summary 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.
Detailed Description

As a consequence of the COVID-19 pandemic, and after consultation with the appropriate research oversight, regulatory and monitoring entities, screening and enrollment has been placed on temporary administrative hold as of 03/17/2020. VA ORD has allowed sites to resume after a detailed and thorough risk assess for each local VA was completed and sent to ORD for approval.

Once a local site has been approved, the study sponsor will allow for resumption of research activities once the local facility/study team deems prepared to being.

Some sites are on Administrative Hold from ORD due to COVID-19 until further notice while others have begun.

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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 3 face-to-face visits (randomization, titration 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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Double-blind, placebo controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Kidney Disease
Intervention  ICMJE
  • Drug: Pentoxifylline
    The non-specific phosphodiesterase inhibitor pentoxifylline (PTX) was approved by the FDA in 1984 for the treatment of peripheral vascular disease.
  • Drug: Placebo
    placebo
Study Arms  ICMJE
  • Experimental: PTX
    Active drug
    Intervention: Drug: Pentoxifylline
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 8, 2018)
2510
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 8, 2030
Estimated Primary Completion Date January 3, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Type-2 diabetes
  • Chronic Kidney Disease, stage 3 or 4 (eGFR 15-60 mL/min/1.73 m2) at the time of randomization and on one or more occasions 3 months or more prior to randomization
  • Participants need to be in one of the following categories at the time of randomization and on one or more occasions 3 months or more prior to randomization:

    • eGFR 15 to less than 30 mL/min/1.73 m2, or
    • eGFR 30 to less than 45 mL/min/1.73 m2 with UACR > 30 mg/g*, or
    • eGFR 45 to less than 60 mL/min/1.73 m2 with UACR > 300 mg/g**
    • *For screening purposes only, UPCR > 150 mg/g acceptable.
    • **For screening purposes only, UPCR > 500 mg/g acceptable.

Exclusion Criteria:

  • Type 1 diabetes
  • Known non-diabetic kidney disease
  • Severe comorbid conditions (expected to reduce life expectancy to less than 1 year, as determined by LSI)
  • Previous organ or bone marrow transplant
  • Pregnancy, breast feeding or females of child-bearing potential who are unwilling to use a reliable form of contraception
  • Presence of recent (within 3 months) cerebral hemorrhage
  • Currently using oral PTX
  • Hypersensitivity to PTX or any of the components of the formulation
  • Current use of ketorolac (contraindicated with PTX )
  • Current use of riociguat (contraindicated with PTX)
  • Unable to provide informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Douglas E Lammie, MPH RD (708) 202-8387 ext 25746 douglas.lammie@va.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03625648
Other Study ID Numbers  ICMJE 2008
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: David J Leehey Edward Hines Jr. VA Hospital, Hines, IL
PRS Account VA Office of Research and Development
Verification Date March 2021

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