ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

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]

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

Condition category

Condition code

Blood

Anaemia

Renal and Urogenital

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]

Treatment: Drugs

Comparator / control treatment

Not applicable

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

Haemoglobin levels will be assessed once a week for up to 15 weeks from the first study drug dose.

Secondary outcome [1]

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]

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]

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]

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]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

31/05/2013

Actual

Date of last participant enrolment

Anticipated

31/12/2013

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Xenetic Biosciences PLC

Address [1]

Greener House, 66-68 Haymarket
London SW1Y 4RF UK

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Commercial sector/Industry

Name [1]

Novotech (Australia) Pty Ltd

Address [1]

Level 3, 235 Pyrmont St, Pyrmont, NSW 2009

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

229 Greenhill Road
Dulwich
South Australia 5065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/04/2013

Approval date [1]

24/06/2013

Ethics approval number [1]

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

Prof Simon Roger

Address

Renal Research
37 William St, Gosford
2250, NSW, Australia

Country

Australia

Phone

+61 243 237977

Fax

+61 243 252522

sdroger@bigpond.net.au

Contact person for public queries

Name

Henry Hoppe

Address

Xenetic Biosciences PLC
Greener House, 66-68
Haymarket
London SW1Y 4RF UK

Country

United Kingdom

Phone

+4420 3021 1500

Fax

+4420 3021 1511

h.hoppe@xeneticbio.com

Contact person for scientific queries

Name

Henry Hoppe and/or Sanjay Jain

Address

Xenetic Biosciences PLC
Greener House, 66-68
Haymarket
London SW1Y 4RF UK

Country

United Kingdom

Phone

+4420 3021 1500

Fax

+4420 3021 1511

h.hoppe@xeneticbio.com and/or s.jain@xeneticbio.com

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

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Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Plain language summary	No		Summary results are not yet available

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