Dose finding study for Polysialylated Erythropoietin (PSA-EPO) in Chronic Kidney Disease (CKD) subjects
A Phase 2, Open Label, Multicentre, Sequential Dose Finding Study to Evaluate the Safety, Pharmacodynamics and Pharmacokinetics of Multiple Doses of Polysialylated Erythropoietin [PSA-EPO; PSA-epoetin alfa; ErepoXen (registered trade name)] Administered Subcutaneously in Chronic Kidney Disease (CKD) Subjects Not on Dialysis and Not Receiving Erythropoiesis Stimulating Agents (PSA-EPO-06)
Xenetic Biosciences PLC
90 participants
May 31, 2013
Interventional
Conditions
Summary
Anaemia associated with Chronic Kidney Disease (CKD) is due to the inability of the diseased kidneys to produce adequate amounts of endogenous erythropoietin (EPO), as well as, the shortened lifespan of red blood cells (RBCs), iron and other nutritional deficiencies, infection, and inflammation. The prevalence of anaemia increases with progressive deterioration of renal function, and affects more than 90% of people with end stage renal disease. Anaemia is associated with increased mortality, increased likelihood of hospitalization, reduced cognitive function and exercise capacity, and increased left ventricular hypertrophy and heart failure. Treatment of anaemia reduces morbidity and may improve quality of life (QoL). Erythropoietin Stimulating Agents have been established as an effective treatment for anaemia associated with CKD and have improved the management of anaemia over alternatives such as blood transfusion. The first approved recombinant human erythropoietin, epoetin alfa, is administered 2-3 times/week for maximum efficacy. Darbepoetin alfa, has a longer half life allowing for less frequent dosing. Methoxy-polyethylene glycol-epoetin beta is a pegylated product that can be administered once monthly. PSA-EPO is a polysialylated form of erythropoietin (EPO), which is being developed for the treatment of anaemia of CKD. It is thought that polysialylation might produce an improved form of EPO, requiring a lower frequency of injection, have a slower onset of action than EPO, and potentially avert some of the side effects noted for EPO (e.g., thrombotic cardiovascular events). This is a phase 2, open-label, multi-centre and sequential dose finding trial with up to 6 treatment cohorts of 12 pre-dialysis participants per cohort will enrol between 24 and 90 participants >18 years of age with anaemia secondary to CKD, and not had treatment with an ESA in the prior 10 weeks. Two dose level cohorts are initially planned to be sequentially enrolled. Depending on the observed safety profile and pharmacological response, up to four additional open-label cohorts of 12 participants per cohort may be subsequently added to study additional and/or repeat dose levels of PSA-EPO, as determined by a safety review committee. Each participant will receive an open-label dose of PSA-EPO every 2 weeks in the correction phase, and every 4 weeks once the target haemoglobin level has been achieved, for a total of up to 8 doses. The first cohort will receive a starting dose of 1 microgram/kg body weight administered subcutaneously every two weeks. Each participant who completes the study is expected to participate for at least 17 weeks following the screening and attend weekly visits (unless advised differently by the local principal investigator) during that time.
Eligibility
Inclusion Criteria9
- Subjects willing to give the written informed consent,
- Males and females aged >18 years. Female subjects of childbearing potential and male subjects with partners of childbearing potential must agree to the use of a double method of contraception while in the study and for 45 days after study discontinuation.
- Established chronic kidney disease stage 3 or 4, unlikely to require dialysis for at least 16 weeks,
- Two separate haemoglobin (Hb) values of greater than or equal to 8g/dL and less than or equal to 10 g/dL determined using the provided haemoglobin point of care device, Hemacue(TM) within 14 days and at least 2 days apart prior to first study drug administration,
- Serum ferritin greater than or equal to 100 microgram/L or transferrin saturation of greater than or equal to 20% within 2 weeks prior to study drug administration,
- Serum (or red cell) folate and Vitamin B12 levels > lower limit of normal within 4 weeks prior to study drug administration.
- White blood cell count greater than or equal to 3 x 10*9/L within 4 weeks prior to study drug administration,
- Platelet count greater than or equal to 140 x 10*9/L within 4 weeks prior to study drug administration, and
- Weight greater than or equal to 45 (maximum 140) kg within 4 weeks prior to study drug administration.
Exclusion Criteria23
- Previous exposure to any Erythropoietin Stimulating Agents (ESA) within 10 weeks prior to the planned administration of the study drug (PSA-EPO-06)
- Red blood cell transfusion within 12 weeks prior to study drug administration
- More than one dose of intravenous iron within 2 weeks prior to Screening
- Life expectancy <12 months,
- Past history of intolerance to ESA therapy,
- Known intolerance to parenteral iron therapy,
- High likelihood of early withdrawal or interruption of the study due to any medical or social factor,
- C-reactive protein (CRP) >30 mg/L within 4 weeks prior to study drug administration,
- Immunosuppressive therapy within 12 weeks prior to the planned administration of the study drug,
- Grand mal seizure within 6 months prior to the planned study drug administration,
- Uncontrolled arterial hypertension (systolic pressure >180 mm Hg, diastolic pressure > 105 mm Hg) within 6 weeks prior to the planned administration of the study drug,
- Chronic congestive heart failure (NYHA Class III-IV),
- Severe hyperparathyroidism (defined as >10 times upper limit of normal or >150 pmol/L),
- Major surgery within 12 weeks prior to the planned administration of the study drug (subjects due to dialysis access creation can be enrolled),
- Systemic blood diseases (sickle cell disease, myelodysplastic syndrome, myeloma, and haemolytic anaemia),
- Systemic inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.),
- Acute inflammatory disease or infection requiring antibiotics during the screening period,
- Positive for Hepatitis B, C, HIV or syphilis,
- Malignant disease within the past 5 years, or requiring therapy at the time of subject enrolment and in the course of the study (except for non melanoma skin cancer which is not an exclusion criterion),
- Hepatic enzyme (ALT and AST) levels exceeding twice the upper limit of normal,
- Pregnancy or breastfeeding,
- Participation in any other investigational drug study within 4 weeks prior to the planned administration of the drug,
- Prior haemodialysis or peritoneal dialysis treatment
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Interventions
Eligible participants will be initially enrolled in the starting cohort dose level of 1 microgram/kg body weight of PSA-EPO given as a subcutaneous injection every 2 weeks for 8 doses (15 weeks). The injection will be given by study site staff experienced in administering subcutaneous injections. Once the haemoglobin levels reaches a target level of 10-12g/dL, dosing may be changed to every 4 weeks. After review of the Week 8 safety data of six or more subjects in this cohort and if no safety concerns are identified, enrolment of the next cohort of 12 subjects at either a higher dose level or lower dose level. Two dose level cohorts are initially planned to be sequentially enrolled. Depending on the observed safety profile and pharmacological response, up to four additional open-label cohorts (up to 6 treatment cohorts in total) of 12 participants per cohort may be subsequently added to study additional and/or repeat (confirmatory) dose levels of PSA-EPO, as determined by a safety review committee (SRC). A higher or lower dose level will be determined by the review of haemoglobin levels and safety data by the SRC.
Locations(1)
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ACTRN12613000504718