End Stage Renal Disease
Conditions
Keywords
Anemia, ESRD
Brief summary
Chronic kidney disease (CKD) patients have increased levels of inflammation and oxidative stress, which in turn contribute to anemia and cardiovascular disease. Pentoxifylline is known to have anti-inflammatory and anti-oxidant properties, and has shown promise in improving the treatment of patients with anemia. This study will examine the use of pentoxifylline for the treatment of anemia in chronic kidney disease.
Detailed description
Treatment of the anemia of renal failure has been revolutionized by the use of erythropoietin and other ESAs (erythropoiesis-stimulating agent). Concerns with ESA use include a substantial number of End Stage Renal Disease (ESRD) patients with ESA-resistant anemia, and a growing body of evidence of potential negative effects of high doses of ESA use, including increased mortality and increased rate of tumor growth in cancer patients. There are only a couple of small studies in the literature examining the effects of pentoxifylline on anemia in patients with renal failure. The results are limited by the very small number of patients. There is clearly a need for a larger, prospective, clinical trial of pentoxifylline in ESRD patients, not limited to those with ESA-resistant anemia. This would be the first prospective, randomized clinical trial of this size to study pentoxifylline for the treatment of anemia in chronic kidney disease.
Interventions
DRUGErythropoietin
Standard of Care
DRUGPentoxifylline
400 mg qd po for 6 months
Sponsors
Fresenius Medical Care North America
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, aged ≥18 years; * Able to comply with the study procedures and medication; * Written informed consent given; * On a stable in-center hemodialysis regimen (at least 3 times per week) for ≥ 12 weeks prior to screening; * Subject must have been on a stable (\< 25% change) erythropoietin dose with an average of ≥ 15,000 and \<55,000 units/week of treatment for ≥ 14 days prior to screening visit; * Two hemoglobin measurements must meet the following criteria: (1) Taken ≥ 2 weeks apart; (2) Between 10 and 12 g/dL, inclusive; (3) Within 1 g/dL of each other; and (4) Occurred within 30 days prior to screening visit; * If subject is a female and of childbearing potential (pre-menopausal and not surgically sterile), subject is willing to use an effective contraceptive method throughout study, which includes abstinence, barrier methods, hormones, or IUDs; * Life expectancy of 12 months or greater; * Most recent single pool Kt/V ≥1.2, taken within 45 days prior to screening visit; * Stable nutrition status with all albumin levels ≥ 3.0 g/dL within the 30 days prior to screening visit.
Exclusion criteria
* Participation in any clinical trial using an investigational product or device during the 30 days preceding the Screening Visit; * Currently undergoing nocturnal hemodialysis; * A significant history of alcohol, drug or solvent abuse in the opinion of the investigator; * Serum iPTH \> 800 pg/mL within 90 days prior to screening visit; * Dysrhythmia or severe cardiac disease: CHF Class III-IV; unstable cardiovascular diagnosis (for example MI, CABG, PTCA, CVA, and TIA) within 90 days prior to screening visit; * Significant concurrent liver disorder \[Aspartate transaminase (AST) or alanine transaminase (ALT) values \> 3 times upper limit of normal (ULN) within 30 days prior to screening\]; * Platelet count \< 130x109 within 30 days prior to screening visit or on the day of the screening visit; * Known hypersensitivity to, or intolerance of, Pentoxifylline or other methylxanthines, such as caffeine, theophylline or theobromine; * Currently taking pentoxifylline, warfarin, theophylline, aminophylline, dyphylline, or oxtriphylline; * Absolute or functional iron deficiency \[transferrin saturation (TSAT) \<20%\] within 45 days prior to screening; * Recent or severe hemorrhage per PI discretion; * Significant bleeding episode or prolonged bleeding from dialysis access per PI judgment within the 3 months prior to screening; * Melatonin treatment, androgen therapy or blood transfusion within 30 days prior to screening; * Vitamin C therapy at dose greater than 100 mg/day or at a dose which has changed within the last 3 months; * Current active cancer (excluding basal cell carcinoma of the skin); * Poorly controlled hypertension per PI judgment within 4 weeks prior to screening; * Known HIV positive status; * Significant GI disorders where absorption of an oral medication might, in the opinion of the Investigator, be impaired; * Anticipated live donor kidney transplant or any other planned major surgery over the study duration; * History of poor adherence to hemodialysis or medical regimen; * Any active clinically significant infection or evidence of an underlying infection; * Currently on immunosuppressive drug regimen other than a stable, low dose of steroids, per PI judgment; * Any disease or condition, physical or psychological that, in the opinion of the investigator, would compromise the safety of the subject or the likelihood of achieving reliable results or increase the likelihood of the subject being withdrawn.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Erythropoietin Dose | Baseline and 6 months | Erythropoietin dose is amount needed to maintain a hemoglobin between 11 and 12 mg/dL. |
Secondary
| Measure | Time frame |
|---|---|
| Examine the EPO Resistance Index (Erythropoietin Dose/kg/Week/Hgb) or ERI Over Time | 6 months |
| Observe Changes in Markers of Inflammation Including But Not Limited to TNF-α and IL-6 | 6 months |
Countries
United States
Participant flow
Recruitment details
This study was conducted at Fresenius Medical Care North America Dialysis clinics between August 2010 and October 2011.
Pre-assignment details
There was no wash out or run in period for this trial.68 subjects signed informed consent, and 48 subjects were randomized.13 of the 20 screen failures were due to exclusionary lab values, 3 due to excluded medications, and 3 were due to other exclusion criteria, 1 due to unrelated SAE. Zero patients withdrew consent prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Erythropoietin Plus Pentoxifylline Standard of care prescribed erythropoietin dose plus 400mg oral pentoxifylline once a day. | 24 |
| Erythropoietin Alone Standard of care prescribed erythropoietin dose. | 24 |
| Total | 48 |
Baseline characteristics
| Characteristic | Erythropoietin Alone | Erythropoietin Plus Pentoxifylline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 5 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 19 Participants | 35 Participants |
| Age Continuous | 57 years STANDARD_DEVIATION 14 | 56 years STANDARD_DEVIATION 12 | 56 years STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 24 participants | 24 participants | 48 participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 24 | 24 / 24 |
| serious Total, serious adverse events | 12 / 24 | 12 / 24 |
Outcome results
Primary
Change in Erythropoietin Dose
Erythropoietin dose is amount needed to maintain a hemoglobin between 11 and 12 mg/dL.
Time frame: Baseline and 6 months
Population: The number of patients for analysis was based on those patient who had completed 6 months of treatment. The analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin Plus Pentoxifylline | Change in Erythropoietin Dose | -8700 Units EPO | Standard Deviation 12586 |
| Erythropoietin Alone | Change in Erythropoietin Dose | -2988 Units EPO | Standard Deviation 10232 |
p-value: >0.05ANCOVA
Secondary
Examine the EPO Resistance Index (Erythropoietin Dose/kg/Week/Hgb) or ERI Over Time
Time frame: 6 months
Secondary
Observe Changes in Markers of Inflammation Including But Not Limited to TNF-α and IL-6
Time frame: 6 months