Clinical trial NCT03625648: Pentoxifylline in Diabetic Kidney Disease
Official title: CSP #2008 - Pentoxifylline in Diabetic Kidney Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Diabetic Kidney Disease
Keywords: Diabetic Kidney disease
pentoxifylline
PTX
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2018-08-10
Enrollment: 2510
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, placebo controlled
Primary purpose: TREATMENT

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: 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

Eligibility criteria: 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 regardless of the degree of albuminuria/proteinuria, or
   * Group II: eGFR 30 to less than 45 mL/min/1.73 m2 with UACR greater than or equal to (\>) 30 mg/g or UPCR greater than or equal to (\>) 150 mg/g, or
   * Group III: eGFR 45 to less than 60 mL/min/1.73 m2 with UACR greater than or equal to (\>) 300 mg/g or UPCR greater than or equal to (\>)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 greater than or equal to (\>) 30 mg/g, or
   * Group III: eGFR 45 to less than 60 mL/min/1.73 m2 with UACR greater than or equal to (\>) 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

Primary outcomes:
measure: Time to ESRD or death
timeFrame: 5 to 9 years
Secondary outcomes:
measure: Quality of life (KDQoL-SF)
timeFrame: 5 to 9 years
measure: Time until doubling of serum creatinine
timeFrame: 5 to 9 years
measure: Incidence of congestive heart failure hospitalization (CHF)
timeFrame: 5 to 9 years
measure: Incidence of a three-point MACE
timeFrame: 5 to 9 years
measure: Incidence of a peripheral vascular disease (PVD)
timeFrame: 5 to 9 years
measure: Percentage of participants with 50% reduction in UACR from baseline
timeFrame: 5 to 9 years
measure: Rate of change in eGFR per year during the study period
timeFrame: 5 to 9 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System, Little Rock, AR
state: Arkansas
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: Bay Pines
country: United States
facility: Bay Pines VA Healthcare System, Pay Pines, FL
state: Florida
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital, Tampa, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Iowa City
country: United States
facility: Iowa City VA Health Care System, Iowa City, IA
state: Iowa
city: Lexington
country: United States
facility: Lexington VA Medical Center, Lexington, KY
state: Kentucky
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Columbia
country: United States
facility: Harry S. Truman Memorial, Columbia, MO
state: Missouri
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis VA Medical Center John Cochran Division, St. Louis, MO
state: Missouri
city: Omaha
country: United States
facility: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
state: Nebraska
city: Albuquerque
country: United States
facility: New Mexico VA Health Care System, Albuquerque, NM
state: New Mexico
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Dayton
country: United States
facility: Dayton VA Medical Center, Dayton, OH
state: Ohio
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Columbia
country: United States
facility: Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
state: South Carolina
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center, Richmond, VA
state: Virginia
city: Salem
country: United States
facility: Salem VA Medical Center, Salem, VA
state: Virginia
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
city: Milwaukee
country: United States
facility: Clement J. Zablocki VA Medical Center, Milwaukee, WI
state: Wisconsin
Study officials:
affiliation: Edward Hines Jr. VA Hospital, Hines, IL
name: David J Leehey
role: STUDY_CHAIR
References:
citation: Leehey DJ, Carlson K, Reda DJ, Craig I, Clise C, Conner TA, Agarwal R, Kaufman JS, Anderson RJ, Lammie D, Huminik J, Polzin L, McBurney C, Huang GD, Emanuele NV. Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial. BMJ Open. 2021 Aug 16;11(8):e053019. doi: 10.1136/bmjopen-2021-053019.