Pentoxifylline in Diabetic Kidney Disease

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

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 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