Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12608000199314
Ethics application status
Approved
Date submitted
26/03/2008
Date registered
14/04/2008
Date last updated
21/10/2021
Date data sharing statement initially provided
7/06/2021
Date results information initially provided
7/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
HERO Study - Handling Erythropoietin Resistance with Oxpentifylline
Scientific title
A randomised, placebo-controlled trial of oxpentifylline on erythropoietin resistance in patients with erythropoietin-resistant anaemia
Secondary ID [1] 252409 0
Nil
Universal Trial Number (UTN)
Trial acronym
HERO Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Erythropoietin-resistant anaemia 2961 0
Condition category
Condition code
Renal and Urogenital 3101 3101 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
400mg Oxpentifylline tablets daily for 4 months
Intervention code [1] 2694 0
Treatment: Drugs
Comparator / control treatment
Placebo that is undistingishable from the active treatment containing no active ingredients
Control group
Placebo

Outcomes
Primary outcome [1] 3992 0
A difference in Erythropoietin Resistance Index (ERI) between the oxpentifylline and placbo groups
Timepoint [1] 3992 0
4 months
Secondary outcome [1] 6712 0
Reduction to the dosage of erythropoietic stimulatory proteins (ESPs; either erythropoietin or darbepoetin);
Timepoint [1] 6712 0
4 months
Secondary outcome [2] 6713 0
Increase in Haemoglobin (Hb) concentration between oxpentifylline and placebo groups
Timepoint [2] 6713 0
4 months
Secondary outcome [3] 6714 0
Reduction in blood transfusion requirements
Timepoint [3] 6714 0
4 months
Secondary outcome [4] 6715 0
Occurrence of adverse events
Timepoint [4] 6715 0
4 months
Secondary outcome [5] 6716 0
A subgroup analysis will be performed to determine whether patients with significantly elevated C-reactive protein (CRP) levels are more likely to have oxpentifylline-responsive anaemia
Timepoint [5] 6716 0
4 months
Secondary outcome [6] 6717 0
Difference in serum hepcidin concentrations (measured using a liquid chromatography mass spectrometry)
Timepoint [6] 6717 0
4 months
Secondary outcome [7] 6718 0
Difference in levels of biomarkers of inflammation and oxidative stress (these tests will include cytokines tested using ELISAs, isoprostanes using liquid chromatography/mass spectrometry, protein carbonyls tested via an ELISA, and plasma catalase/glutathione peroxidase activity tested using spectrometry
Timepoint [7] 6718 0
4 months

Eligibility
Key inclusion criteria
1. Stage 4 or 5 chronic kidney disease 2. Haemoblobin concentration less than or equal to120 g/L 3. ERI greater than or equal to1.0 IU/kg/week/gHb for Erythopoietin (EPO) treated patients and greater than or equal to 0.005 micrograms/kg/week/g Hb for darbepoetin (DPO) treated patients. 4. Stable EPO or DPO dosage for at least 8 weeks. 5. 18 years or over. 6. Able to give informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study 2.Pregnancy or breast-feeding 3. Known hypersensitivity to, or intolerance of, oxpentifylline or other methylxanthines such as caffeine, theophylline or theobromine 4. History of major gastrointestinal bleeding or any gastrointestinal bleeding in the past 12 weeks. 5. Absolute or functional iron deficiency (ferritin less than 100 microg/L and/or transferrin saturation less than 20%)
6. Vitamin B12 or folate deficiency 7. Parathyroid hormone level greater than 100 pmol/L 8. Serum aluminium greater than 2 micromol/L 9. Urea reduction ratio less than 65% or single pool Kt/V less than 1.0 (haemodialysis patients) or total weekly Kt/V less than 1.7 (peritoneal dialysis patients) 10. Presence of systemic haematological disease (including antibody-mediated pure red cell aplasia) or known haemoglobinopathy 11. Active haemolysis 12. Any surgery within the last 6 weeks
13. Infection within 6 weeks of the last dose of antibiotic, acute myocardial infarction or malignancy within the last 6 weeks 14. Melatonin treatment, androgen therapy or blood transfusion within the previous 4 weeks 15. Vitamin C therapy at dose greater than 1000mg/day or at a dose which has changed within the last 12 weeks
16. Haemorrhagic stroke or severe haemorrhage within the last 12 weeks 17. Current immunosuppressant use, or immunosupression during previous 4 weeks

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients, investigators and outcome assessors will be blindeed to the treatment allocation. To ensure adequate concealment of allocation, the randomisation will be performed using a central computer and an interactive voice-response system (IVRS) or web-based link to the central database provided through the Australasian Kidney Trials (AKT) network.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomised as soon as practicable after the patient has signed the consent form. Randomisation will be stratified by centre and disease stage (stage 4 CKD, stage 5 CKD on haemodialysis, stage 5 CKD on peritoneal dialysis).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2008
Actual
22/06/2009
Date of last participant enrolment
Anticipated
Actual
24/08/2012
Date of last data collection
Anticipated
Actual
1/06/2013
Sample size
Target
110
Accrual to date
Final
53
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment postcode(s) [1] 613 0
2305
Recruitment postcode(s) [2] 614 0
7250
Recruitment postcode(s) [3] 615 0
2170
Recruitment postcode(s) [4] 616 0
3168
Recruitment postcode(s) [5] 617 0
4102
Recruitment postcode(s) [6] 618 0
5000
Recruitment postcode(s) [7] 619 0
0811
Recruitment postcode(s) [8] 620 0
7001
Recruitment postcode(s) [9] 621 0
3050
Recruitment postcode(s) [10] 622 0
3550
Recruitment postcode(s) [11] 623 0
2348
Recruitment postcode(s) [12] 624 0
2500
Recruitment postcode(s) [13] 801 0
4870
Recruitment postcode(s) [14] 802 0
6160
Recruitment postcode(s) [15] 803 0
4215
Recruitment postcode(s) [16] 804 0
4120
Recruitment outside Australia
Country [1] 825 0
New Zealand
State/province [1] 825 0

Funding & Sponsors
Funding source category [1] 3218 0
Charities/Societies/Foundations
Name [1] 3218 0
Roche Foundation for Anaemia Research(RoFAR)
Country [1] 3218 0
Switzerland
Funding source category [2] 3219 0
Commercial sector/Industry
Name [2] 3219 0
Janssen-Cilag Pty Limited
Country [2] 3219 0
Australia
Funding source category [3] 3220 0
Commercial sector/Industry
Name [3] 3220 0
Amgen Australia Pty Ltd
Country [3] 3220 0
Australia
Funding source category [4] 267247 0
Government body
Name [4] 267247 0
NHMRC Project Grant 2011
Country [4] 267247 0
Australia
Primary sponsor type
University
Name
Australasian Kidney Trials Network
Address
University of Queensland
Ground floor, Bldg 33, Princess Alexandra Hospital
Ipswich Rd, Woolloongabba QLD 4102
Country
Australia
Secondary sponsor category [1] 2885 0
None
Name [1] 2885 0
Address [1] 2885 0
Country [1] 2885 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5204 0
University of Queensland
Ethics committee address [1] 5204 0
The University of Queensland
Brisbane QLD 4072 Australia
Ethics committee country [1] 5204 0
Australia
Date submitted for ethics approval [1] 5204 0
Approval date [1] 5204 0
06/07/2007
Ethics approval number [1] 5204 0
2007000701

Summary
Brief summary
Low red blood cell counts (anaemia) occur in the vast majority of patients with chronic kidney disease. In most cases, these low red blood cell counts respond to treatment with medications, such as erythropoietin (Eprex®) or darbepoietin alpha (Aranesp®). However, about 10-15% of patients continue to be anaemic even with appropriate treatment. Such patients are at increased risk of being hospitalized, developing complications such as heart failure, and dying. A number of small studies have suggested that a drug called oxpentifylline (Trental®) is very good at safely raising red blood cell counts in persistently anaemic patients. However, this drug has not yet been properly tested in a controlled trial (that is, where the drug is given to 1 group of patients, but not another).
Trial website
www.aktn.org.au
Trial related presentations / publications
A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis stimulating agent hyporesponsiveness in anemic patients with CKD: the handling erythropoietin resistance with oxpentifylline (HERO) trial. David W. Johnson, Elaine M. Pascoe, Sunil V. Badve, Kim Dalziel, Alan Cass, Philip Clarke, Paolo Ferrari, Stephen P McDonald, Alicia T. Morrish, Eugenie Pedagogos, Vlado Perkovic, Donna Reidlinger, Anish Scaria, Rowan Walker, Liza A. Vergara, Carmel M. Hawley, on behalf offor the HERO Study Collaborative Group. American Journal of Kidney Diseases (AJKD) published online 9 Aug 2014 DOI: 10.1053/j.ajkd.2014.06.020; http://www.sciencedirect.com/science/article/pii/S0272638614009871
Public notes

Contacts
Principal investigator
Name 28465 0
Prof David Johnson
Address 28465 0
Australasian Kidney Trials Network (UQ) Ground floor, Bldg 33 Princess Alexandra Hospital 199 Ipswich Road WOOLLOONGABBA QLD 4102
Country 28465 0
Australia
Phone 28465 0
+61 7 3176 5463
Fax 28465 0
Email 28465 0
[email protected]
Contact person for public queries
Name 11622 0
Ms Laura Robison
Address 11622 0
Australasian Kidney Trials Network, Centre for Health Services Research
Faculty of Medicine, The University of Queensland
Level 5, Translational Research Institute
37 Kent Street, Woolloongabba
Brisbane Qld 4102 Australia
Country 11622 0
Australia
Phone 11622 0
+61 401696408
Fax 11622 0
07 3176 5663
Email 11622 0
[email protected]
Contact person for scientific queries
Name 2550 0
Prof David Johnson
Address 2550 0
Department of Nephrology,
Princess Alexandra Hospital
Ipswich Rd
Woolloongabba QLD 4102
Country 2550 0
Australia
Phone 2550 0
61 7 3240 5080
Fax 2550 0
Email 2550 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11928Statistical analysis plan https://aktn.org.au/hero 



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Am J Kidney Dis. 65(1):49-57

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAssociation between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial.2017https://dx.doi.org/10.1111/nep.12815
EmbaseA randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients with CKD: The handling erythropoietin resistance with oxpentifylline (HERO) trial.2015https://dx.doi.org/10.1053/j.ajkd.2014.06.020
EmbaseAssociation between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease: A secondary analysis of the HERO trial.2015https://dx.doi.org/10.1186/s40697-015-0066-5
Dimensions AIOxpentifylline versus placebo in the treatment of erythropoietin-resistant anaemia: a randomized controlled trial2008https://doi.org/10.1186/1471-2369-9-8
N.B. These documents automatically identified may not have been verified by the study sponsor.