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Trial registered on ANZCTR


Trial ID
ACTRN12613000504718
Ethics application status
Approved
Date submitted
29/04/2013
Date registered
7/05/2013
Date last updated
14/10/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Dose finding study for Polysialylated Erythropoietin (PSA-EPO) in Chronic Kidney Disease (CKD) subjects
Scientific title
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)
Secondary ID [1] 282423 0
None
Universal Trial Number (UTN)
U1111-1140-1573
Trial acronym
PSA-EPO-06
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia in Chronic Kidney Disease 288993 0
Condition category
Condition code
Blood 289337 289337 0 0
Anaemia
Renal and Urogenital 289338 289338 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 287046 0
Treatment: Drugs
Comparator / control treatment
Not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 289450 0
To determine the range of doses of PSA-EPO administered subcutaneously that increases and maintains a haemoglobin levels at 10-12 g/dL in CKD subjects not on dialysis. This will be done by monitoring haemogloblin levels in participants.
Timepoint [1] 289450 0
Haemoglobin levels will be assessed once a week for up to 15 weeks from the first study drug dose.
Secondary outcome [1] 302499 0
To evaluate the safety profile of up to 8 doses of PSA-EPO administered subcutaneously in CKD subjects not on dialysis. This will be done by monitoring safety (presence of adverse events, changes in laboratory data, changes in physical examination and vital signs) in participants. Possible adverse events may include: increase in blood pressure, headache, irritation at injection site, nausea, vomiting, fever and diarrhoea.
Timepoint [1] 302499 0
Safety will be assessed once a week during the treatment period (15 weeks) and fortnightly during the follow up period up until all adverse events have stabilised. In case of severe adverse events (SAEs), if any, safety will be assessed hourly/daily by local principal investigator during the treatment period until SAEs have stabilised.
Secondary outcome [2] 302500 0
To evaluate the pharmacokinetic (PK) profile of up to 8 doses of PSA-EPO administered subcutaneously in a subset of CKD subjects not on dialysis. This will be assessed through the collection and analysis of blood samples collected from participants.
Timepoint [2] 302500 0
Blood samples for pharmacokinetics will be collected from a subgroup of participants each time they receive PSA-EPO and 2, 4, 6, 8, 10 and 12 days after the day they receive the first dose of PSA-EPO. A maximum of 15 samples of 3mL each at each time points up to 15 weeks from the first study drug dose.
Secondary outcome [3] 302554 0
To evaluate the pharmacodynamic (PD) profile of up to 8 doses of PSA-EPO administered subcutaneously in a subset of CKD subjects not on dialysis. This will be assessed on the data collected for safety evaluations including weekly haemoglobin level, weekly reticulocyte level, red cell count, haematocrit and iron studies.
Timepoint [3] 302554 0
Haemoglobin, reticulocyte, red cell count and haematocrit will be assessed weekly during the treatment period (15 weeks). Iron studies will be assessed monthly during the treatment period (15 weeks).

Eligibility
Key inclusion criteria
1. Subjects willing to give the written informed consent,
2. 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.
3. Established chronic kidney disease stage 3 or 4, unlikely to require dialysis for at least 16 weeks,
4. 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,
5. 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,
6. Serum (or red cell) folate and Vitamin B12 levels > lower limit of normal within 4 weeks prior to study drug administration.
7. White blood cell count greater than or equal to 3 x 10*9/L within 4 weeks prior to study drug administration,
8. Platelet count greater than or equal to 140 x 10*9/L within 4 weeks prior to study drug administration, and
9. Weight greater than or equal to 45 (maximum 140) kg within 4 weeks prior to study drug administration.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous exposure to any Erythropoietin Stimulating Agents (ESA) within 10 weeks prior to the planned administration of the study drug (PSA-EPO-06)
2. Red blood cell transfusion within 12 weeks prior to study drug administration
3. More than one dose of intravenous iron within 2 weeks prior to Screening
4. Life expectancy <12 months,
5. Past history of intolerance to ESA therapy,
6. Known intolerance to parenteral iron therapy,
7. High likelihood of early withdrawal or interruption of the study due to any medical or social factor,
8. C-reactive protein (CRP) >30 mg/L within 4 weeks prior to study drug administration,
9. Immunosuppressive therapy within 12 weeks prior to the planned administration of the study drug,
10. Grand mal seizure within 6 months prior to the planned study drug administration,
11. 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,
12. Chronic congestive heart failure (NYHA Class III-IV),
13. Severe hyperparathyroidism (defined as >10 times upper limit of normal or >150 pmol/L),
14. Major surgery within 12 weeks prior to the planned administration of the study drug (subjects due to dialysis access creation can be enrolled),
15. Systemic blood diseases (sickle cell disease, myelodysplastic syndrome, myeloma, and haemolytic anaemia),
16. Systemic inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.),
17. Acute inflammatory disease or infection requiring antibiotics during the screening period,
18. Positive for Hepatitis B, C, HIV or syphilis,
19. 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),
20. Hepatic enzyme (ALT and AST) levels exceeding twice the upper limit of normal,
21. Pregnancy or breastfeeding,
22. Participation in any other investigational drug study within 4 weeks prior to the planned administration of the drug,
23. Prior haemodialysis or peritoneal dialysis treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Eligible participants will be initially enrolled in the starting cohort dose level of 1 microgram/kg body weight of PSA-EPO given every 2 weeks for up to 8 doses. 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.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A sample size of 12 subjects per cohort was selected for this exploratory study. Results from this initial study will be used to characterize the subject population and to assist with the design of subsequent clinical studies. No formal statistical calculation of sample size has been performed;
however, the number of subjects enrolled in this study is standard for this type of study and should be sufficient to generate meaningful safety, PK and PD data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment outside Australia
Country [1] 5051 0
New Zealand
State/province [1] 5051 0

Funding & Sponsors
Funding source category [1] 287183 0
Commercial sector/Industry
Name [1] 287183 0
Xenetic Biosciences PLC
Address [1] 287183 0
Greener House, 66-68 Haymarket
London SW1Y 4RF UK
Country [1] 287183 0
United Kingdom
Primary sponsor type
Commercial sector/Industry
Name
Xenetic Biosciences PLC
Address
Greener House, 66-68 Haymarket
London SW1Y 4RF UK
Country
United Kingdom
Secondary sponsor category [1] 285947 0
None
Name [1] 285947 0
Address [1] 285947 0
Country [1] 285947 0
Other collaborator category [1] 277370 0
Commercial sector/Industry
Name [1] 277370 0
Novotech (Australia) Pty Ltd
Address [1] 277370 0
Level 3, 235 Pyrmont St, Pyrmont, NSW 2009
Country [1] 277370 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289179 0
Bellberry Limited
Ethics committee address [1] 289179 0
229 Greenhill Road
Dulwich
South Australia 5065
Ethics committee country [1] 289179 0
Australia
Date submitted for ethics approval [1] 289179 0
24/04/2013
Approval date [1] 289179 0
24/06/2013
Ethics approval number [1] 289179 0
2013-04-177

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39626 0
Prof Simon Roger
Address 39626 0
Renal Research
37 William St, Gosford
2250, NSW, Australia
Country 39626 0
Australia
Phone 39626 0
+61 243 237977
Fax 39626 0
+61 243 252522
Email 39626 0
sdroger@bigpond.net.au
Contact person for public queries
Name 39627 0
Dr Henry Hoppe
Address 39627 0
Xenetic Biosciences PLC
Greener House, 66-68
Haymarket
London SW1Y 4RF UK
Country 39627 0
United Kingdom
Phone 39627 0
+4420 3021 1500
Fax 39627 0
+4420 3021 1511
Email 39627 0
h.hoppe@xeneticbio.com
Contact person for scientific queries
Name 39628 0
Dr Henry Hoppe and/or Sanjay Jain
Address 39628 0
Xenetic Biosciences PLC
Greener House, 66-68
Haymarket
London SW1Y 4RF UK
Country 39628 0
United Kingdom
Phone 39628 0
+4420 3021 1500
Fax 39628 0
+4420 3021 1511
Email 39628 0
h.hoppe@xeneticbio.com and/or s.jain@xeneticbio.com