Ethics approval for the Hemoglobin elevation in Erythropoietin Resistance with Oxpentifylline (HERO) trial has been obtained from the local Institutional Ethics Committee in all participating centres prior to study initiation and patient enrolment. The study will be performed in accordance with the 2000 Edinburgh, Scotland Revision of the Declaration of Helsinki, the National Health and Medical Research Committee (NHMRC) Statement on Human Experimentation, Joint NHMRC/AVCC Statement and Guidelines on Research Practice, applicable ICH guidelines and the Therapeutic Goods Administration (TGA) – Note for guidance on good clinical practice (CPMP/ICH/135/95) annotated with TGA. Application under the Clinical Trials Notification (CTN) scheme will be required for this protocol.
The study population includes adults (18 years or over) with stage 4 or 5 CKD (on dialysis or estimated GFR < 30 ml/min/1.73 m2) who are able to give informed consent and who have a haemoglobin concentration < 110 g/L for at least 3 months in spite of EPO dosage ≥ 200 IU/kg/week or DPO dosage ≥ 1 μg/kg/week for at least 1 month. Patients will be recruited by local investigators from participating renal units (outpatients and dialysis units) throughout Australia and New Zealand. The multicentre nature of the study will greatly enhance the generalisability of the trial.
Exclusion criteria include:
Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study.
Pregnancy or breast-feeding.
Known hypersensitivity to, or intolerance of, oxpentifylline or other methylxanthines, such as caffeine, theophylline or theobromine.
Active peptic ulcer disease.
Absolute or functional iron deficiency (ferritin < 100 μg/L and/or transferrin saturation < 20%).
Vitamin B12 or folate deficiency.
Parathyroid hormone level > 100 pmol/L.
Serum aluminium > 2 μmol/L.
Urea reduction ratio < 65% or single pool Kt/V < 1.0 (haemodialysis patients) or total weekly Kt/V < 1.7 (peritoneal dialysis patients).
Presence of systemic haematological disease (including antibody-mediated pure red cell aplasia) or known haemoglobinopathy
Major surgery, infection, acute myocardial infarction or malignancy within the last 3 months.
Melatonin treatment, androgen therapy or blood transfusion within the previous month.
Vitamin C therapy at dose greater than 100 mg/day or at a dose which has changed within the last 3 months.
Haemorrhagic stroke or severe haemorrhage within the last 3 months.
The study is an investigator-initiated, prospective, double-blind, randomized, placebo-controlled phase 3 trial. Patients will be randomised to one of two treatment groups in equal proportion (Fig. 1). To ensure adequate concealment of allocation, the randomization will be performed using a central computer and web-based link to the central database provided through the Australasian Kidney Trials Network (AKTN). Patients will be randomized in permuted blocks with stratification for centre and disease stage/dialysis type.
The experimental intervention will be oxpentifylline (400 mg daily per os; Trental®, Sanofi-Aventis, Sydney, Australia). Oxpentifylline is registered in Australia for treatment of intermittent claudication on the basis of chronic arterial occlusive disease of the limbs. The standard dose is 400 mg three times daily. The dose of oxpentifylline selected for this study (400 mg daily) is lower than the standard dose because the drug may accumulate in renal failure. Moreover, this dose has been shown to be efficacious without significant side effects in 23 ESKD patients studied by Cooper et al and Navarro et al
The control intervention will be placebo (1 tablet daily per os).
Iron supplementation will be performed according to usual protocol (note that randomisation will be stratified for centre). Vitamin B and folic acid supplementation are permitted. Melatonin and androgen therapy are proscribed during the study period. If the patient is taking vitamin C, the daily dose will be kept constant throughout the study period. Erythropoietin (EPO) or darbepoetin (DPO) dosages will not be increased during the study, and will only be reduced if haemoglobin levels rise above 125 g/L.
Patients, investigators and outcome assessors will be blinded to the treatment allocation.
The primary outcome measure will be the difference in haemoglobin concentration between the oxpentifylline and control groups at the end of the 4 month study period.
Secondary outcome measures include:
Difference in the dosage of erythropoiesis stimulating agents (ESA; either erythropoietin or darbepoetin) between the oxpentifylline and control groups at the end of the 4 month study period.
Difference in Key's index (ESA dosage divided by haemoglobin concentration) between the oxpentifylline and control groups at the end of the 4 month study period.
Difference in frequency of blood transfusion requirements between the oxpentifylline and control groups during the 4 month study period.
Occurrence of adverse events in the oxpentifylline and control groups during the 4 month study period.
Exploratory outcome measures that will be studied include the differences in serum concentrations of hepcidin and biomarkers of inflammation (TNF-α, interferon-γ, IL-6 and IL-1) and oxidative stress (isoprostanes, protein carbonyls, plasma catalase and glutathione peroxidase activity) between the oxpentifylline and control groups at the end of the 4 month trial.
Full blood counts will be measured monthly, as per usual clinical practice. Iron studies will be measured every 2 months. Patients will receive a medical review every 2 months. An individual patient's participation in the study will cease at the end of the 4 month study period. If, before this time, the patient experiences severe anaemia (< 65 g/L), symptomatic anaemia or the patient's attending physician believes that additional therapy is required (eg blood transfusion), they will be considered to have reached an end-point and will be withdrawn from study medication, but will still have blood counts measured monthly and followed for study outcomes.
The number and proportion of subjects who report treatment-emergent adverse events will be summarized for each treatment group. Treatment emergent events include events that start on or after Day 0 of the study [that is the first day of Study Drug administration], and were not present at baseline, or were present at baseline, but increased in severity after the start of the study. The Medical Dictionary for Regulatory Activities [MedDRA] Terminology will be used to classify all adverse events with rESAect to System Organ Class [SOC], high level group term (HLGT), and preferred term.
Prospective power calculations based on unpaired t-test comparisons indicate that the study will have adequate statistical power (90% probability) to detect a clinically significant increase in haemoglobin concentration of 10 g/L, assuming alpha = 0.05 and a population standard deviation of 12 g/L, if 62 patients were recruited in the study (31 in each group). Allowing for a 5% drop-out rate and a 20% non-compliance rate, we aim to recruit a total of 110 patients (55 in each group) across all centres. We anticipate that this will require a recruitment period of 6 months.
Differences between the intervention and control groups with respect to the primary outcome measure (haemoglobin level at 4 months) will be measured by comparison of the mean haemoglobin in each group, adjusted for baseline values (analysis of covariance). Data will be analysed on an intention to treat basis. For patients withdrawing before the end of the 4 month study, their haemoglobin at the time of withdrawal will be taken as their final haemoglobin. A sub-analysis will be performed to determine whether patients with significantly elevated C-reactive protein (CRP) levels (above the local laboratory's reference range) are more likely to have oxpentifylline-responsive anaemia. The data will be analysed by t-test and by repeated measures analysis of covariance. Because of power considerations and the relatively short duration of the study, no interim analysis is planned.
Secondary analyses will be performed by repeated measures analysis of covariance with and without adjustment for baseline characteristics. The analyses used for secondary outcome measures will include unpaired t-test (Key's index), Mann-Whitney U-test (ESA dosage) and chi square test (blood transfusion requirement, adverse drug reactions).
Categorical baseline characteristics (e.g. sex, race, comorbid illnesses, etc) will be summarized with the number and percent of subjects in each treatment group with the characteristic. Quantitative characteristics (e.g. age and weight) will be summarized by mean and standard deviation or median [interquartile range], depending on data distribution. The number and percent of subjects who are randomized, treated with randomized Study Drug, require intervention, prematurely discontinue, and complete the study will be summarized. Fisher's exact test or the Chi-square test will be used to assess treatment group differences in the proportions of subjects who require intervention and who complete the study. The number and percent of subjects will be summarized for each reason for premature discontinuation.
BMC Nephrology © 2008 Johnson et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Professor Johnson has received consultancy fees and speaker's honoraria from Sanofi-Aventis (manufacturer of oxpentifylline). He has also received consultancy fees, speaker's honoraria, research grants and conference travel sponsorships from Amgen, Janssen-Cilag and Roche (all manufacturers of erythropoiesis stimulating agents).
Dr. Hawley has received conference travel sponsorships from Amgen and Janssen- Cilag.
Professor Ferrari has received speaker's honoraria and conference travel sponsorships from Amgen, Roche and Janssen-Cilag.
Dr McDonald has received speaker's honoraria, and conference travel sponsorships from Amgen and Janssen-Cilag (manufacturers of erythropoiesis stimulating agents).
Associate Professor Alan Cass has received speaker's honoraria and research grants from Amgen, Janssen-Cilag and Roche.
The remaining authors declare that they have no financial competing interests.
Non-Financial Competing Interests
The authors declare that they have no non-financial competing interests.
DJ: Principal Investigator; conceived study; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. CH: Trial Management Committee member; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. BR: Trial Management Committee member; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. EB: Trial Management Committee member; participated in design and co-ordination; provided statistical advice; helped to draft manuscript; read and approved the final manuscript. CT: Trial Management Committee member; participated in design and co-ordination; provided statistical advice; helped to draft manuscript; read and approved the final manuscript. RB: Trial Management Committee member; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. PF: Trial Management Committee member; conceived hepcidin sub-study; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. SM: Trial Management Committee member; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. EP: Trial Management Committee member; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript. AC: Trial Management Committee member; participated in design and co-ordination; helped to draft manuscript; read and approved the final manuscript.
Cite this: Oxpentifylline Versus Placebo in the Treatment of Erythropoietin-resistant Anaemia: A Randomized Controlled Trial - Medscape - Aug 01, 2008.