- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02987465
Evaluating the Effect of Standard-of-care Erythropoiesis-stimulating Agents on Forearm Blood Flow in Nondialysis-dependent Subjects With Anaemia Associated With Chronic Kidney Disease. (OPERA-CKD)
An Observational, Open-label Pilot Study to Evaluate the Effect of Standard-of-care Erythropoiesis-stimulating Agents (Darbepoetin Alfa) on Forearm Blood Flow in Nondialysis-dependent Subjects With Anaemia Associated With Chronic Kidney Disease.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is a pilot proposal to understand the changes in physiology in patients undergoing scheduled therapy with Darbepoetin as part of their normal NHS care. It is therefore an observational pilot study of changes in physiology before and after Darbepoetin. Conventional erythropoiesis stimulating agents (ESAs) are widely used to improve haemoglobin production and reduce anaemia in subjects with chronic kidney disease (CKD). However, ESAs are associated with the development of hypertension and increased cardiovascular morbidity and mortality. A number of potential underlying pathophysiological mechanisms have been postulated, mostly concerning around altered sensitivity to, or circulating levels of, endogenous vasoactive mediators. However, the existing data are inconsistent. Hand et al. found that short-term therapy with recombinant erythropoietin was associated with a rise in blood pressure, and an increase in vasoconstrictor responsiveness to infused noradrenaline, but not to endothelin-1. Serum endothelin-1 levels were elevated compared to controls at baseline, but did not change after erythropoietin therapy. Other groups have reported that ESA administration increases plasma levels of endothelin-1, and that this is strongly correlated with the increase in mean arterial pressure (MAP). Human endothelial cells incubated in ESAs show decreased eNOS expression and endothelial nitric oxide (NO) production. Ex-vivo studies in resistance vessels of subjects with CKD found impaired endothelial function, as assessed by acetylcholine mediated vasodilatation, which was partially reversed by blockade of the endothelin receptor (ET-A). In vivo acute and chronic ESA administration also impairs endothelial function, which is often considered as a surrogate of nitric oxide bioavailability.
Recently, newer agents have been postulated as a novel alternative to ESAs for treating renal anaemia. However, cardiovascular effects are incompletely characterised. Studies elucidating the mechanisms for ESA induced vasoconstriction and possible effects that promote cardiovascular disease are necessary and it would be imperative to study whether the use of these novel agents avoids these effects, potentially making them a better alternative to ESAs.
This pilot study aims to determine the putative mechanisms which may be involved in the BP response to ESA use in patients with anaemia associated with CKD who are EPO naïve within the last 12 months. Information gained from this study will inform a larger clinical trial that is being planned. Healthy volunteers will be recruited to provide a baseline of normal responses to compare against.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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Cambridgeshire
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Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
- Addenbrooke's Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Up to 12 patients with anaemia associated with chronic kidney disease (CKD).
Up to 12 healthy volunteers.
Description
Inclusion Criteria CKD patients:
- Provided written informed consent to participate
- Be aged 18 years or over
- Clinically suitable for EPO (Darbepoetin) therapy as part of routine NHS standard of care for anaemia due to chronic kidney disease (CKD)
- No prior EPO treatment within the preceding 12 months
- Palpable brachial artery
Inclusion Criteria Healthy Volunteers:
- Provided written informed consent to participate
- Aged 18 years or over
- Blood pressure <140/90
- Normal haematology and renal function (defined as a normal creatinine and eGFR measured at any time in the last 6 months or at screening)
- Not on any regular prescribed medication
- Palpable brachial artery
Exclusion criteria CKD patients:
- Kidney transplant: Planned living-related kidney transplant within 26 weeks
- Patients on PDE5 inhibitors, alpha blockers, or nitrates (other than PRN GTN), unless they can be omitted until after the forearm study on the day of the visit
- MI or acute coronary syndrome in the preceding ≤ 4 weeks prior to screening
- Stroke or transient ischemic attack in the preceding ≤ 4 weeks prior to screening
- Known clinical diagnosis of Heart failure: NYHA Class III-IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
- Clinic Blood pressure: sustained BP > 170/100 mm Hg (on repeated measurements)
- Pregnancy - Non-sterilised, pre-menopausal women will undergo urinary beta-HCG testing at every visit and be given advice on contraceptive use in the PIS.
- Any other reason for exclusion from this study in the opinion of the Principal Investigator
Exclusion Criteria Healthy Volunteers:
- Any condition which, in the opinion of the investigator, precludes enrolment
- Undergoing investigation for any serious medical condition
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Chronic Kidney Disease patients
Up to 12 patients with anaemia associated with CKD.
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Darbepoetin is not a study drug and is prescribed as part of routine treatment of anaemia in CKD1.
Darbepoetin is licensed for use for the treatment of anaemia in the context of CKD.
It will be provided as part of the standard clinical care of the renal patients in this study.
Healthy Volunteers will not be treated with Darbepoetin.
Acetylcholine is being used as a challenge agent in this study and assesses NO-mediated vasodilation
Noradrenaline is being used as a challenge agent in this study and is an endogenous a1 adrenoceptor agonist
BQ 123 is being used as a challenge agent in this study and is an (Endothelin A) ETA receptor agonist.
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Healthy Volunteers
Up to 12 healthy subjects will be recruited such that age and gender are similar to the CKD patients.
These subjects will be recruited as negative controls for a baseline assessment of healthy physiology.
These subjects will not be treated with Darbepoetin.
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Acetylcholine is being used as a challenge agent in this study and assesses NO-mediated vasodilation
Noradrenaline is being used as a challenge agent in this study and is an endogenous a1 adrenoceptor agonist
BQ 123 is being used as a challenge agent in this study and is an (Endothelin A) ETA receptor agonist.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Response to intra-arterial acetylcholine
Time Frame: CKD patients: Measured at baseline and at the end of the 6 week treatment period
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Change in forearm blood flow responses as measured by venous occlusion plethysmography, in response to intra-arterial acetylcholine
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CKD patients: Measured at baseline and at the end of the 6 week treatment period
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Response to intra-arterial Noradrenaline
Time Frame: CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Change in forearm blood flow responses, as measured by venous occlusion plethysmography, in response to intra-arterial Noradrenaline
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CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Response to intra-arterial BQ123
Time Frame: CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Change in forearm blood flow responses as measured by venous occlusion plethysmography, in response to intra-arterial BQ123
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CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Change in mean arterial blood pressure
Time Frame: CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Change in mean arterial blood pressure, systolic blood pressure and diastolic blood pressure post-Darbepoetin-Alfa over 6 weeks of treatment
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CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Changes in Arterial stiffness
Time Frame: CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Changes in arterial stiffness post-darbepoetin-alfa
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CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Correlations between individual challenge agent
Time Frame: CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Correlations between individual challenge agent forearm blood flow responses and change in blood pressure
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CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Forearm blood flow responses to Acetylcholine, Noradrenaline and BQ123 in patients with CKD compared to healthy volunteers
Time Frame: Healthy Volunteers: Measured at baseline; CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Change in forearm blood flow responses to Acetylcholine, Noradrenaline and BQ123 in patients with anaemia associated with CKD at baseline compared to healthy volunteers
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Healthy Volunteers: Measured at baseline; CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Responses to Acetylcholine, Noradrenaline and BQ123 in patients with CKD post-Darbepoetin compared to healthy volunteers
Time Frame: Healthy Volunteers: Measured at baseline; CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Change in forearm blood flow responses to Acetylcholine, Noradrenaline and BQ123 in patients with anaemia associated with CKD post-Darbepoetin compared to healthy volunteers
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Healthy Volunteers: Measured at baseline; CKD patients: Measured at baseline before treatment with Darbepoetin and then at the end of the 6 week treatment period with Darbepoetin
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Joseph Cheriyan, MBCHB, MA, FRCP, Cambridge University Hospitals NHS Foundation Trust
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Urologic Diseases
- Disease Attributes
- Renal Insufficiency
- Chronic Disease
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Cardiovascular Diseases
- Kidney Diseases
- Renal Insufficiency, Chronic
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Cholinergic Agents
- Adrenergic alpha-Agonists
- Adrenergic Agonists
- Cholinergic Agonists
- Hematinics
- Sympathomimetics
- Vasoconstrictor Agents
- Darbepoetin alfa
- Norepinephrine
- Acetylcholine
Other Study ID Numbers
- OPERA-CKD (AO94224)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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