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Trial registered on ANZCTR


Registration number
ACTRN12624000567527
Ethics application status
Approved
Date submitted
10/03/2024
Date registered
6/05/2024
Date last updated
6/05/2024
Date data sharing statement initially provided
6/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II Trial to Evaluate the Safety and Efficacy of clazakizumab for the desensitisation of highly sensitized patients on the deceased donor kidney transplant waiting list
Scientific title
A Phase II Trial to Evaluate the Safety and Efficacy of clazakizumab for the desensitisation of highly sensitized patients on the deceased donor kidney transplant waiting list
Secondary ID [1] 311704 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
End stage kidney disease 333174 0
Condition category
Condition code
Renal and Urogenital 329864 329864 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Clazakizumab 12.5mg subcutaneously every 4 weeks for up to 52 weeks, unless the individual receives a kidney transplant during the period of treatment. If they receive a transplant then Clazakizumab 12.5mg subcutaneously every 4 weeks is continued if they have ever had an antibody against donor HLA, otherwise it is stopped at the time of transplant. If it is continued after transplant then it is stopped 3 months after transplant if no donor specific antibody is detectable and there is no antibody-mediated rejection on a surveillance biopsy. If clazakizumab is not stopped at 3 months then it is stopped at 6 months after transplant.
Intervention code [1] 328166 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 337640 0
In each subject, the number and proportion of HLA antibodies that have a fall in MFI of greater than 50% or fall to MFI less than 1500
Timepoint [1] 337640 0
During treatment at baseline and 2, 4, 6, 8, 10, 12 (primary timepoint) months
Secondary outcome [1] 432633 0
The proportion of subjects who had a fall in HLA antibodies determined by any of a greater than 50% fall in MFI or to MFI less than 1500
Timepoint [1] 432633 0
During treatment at baseline and 2, 4, 6, 8, 10, 12 months.
Secondary outcome [2] 432634 0
Proportion of subjects who had HLA antigens removed from list of exclusions due to a fall in the corresponding antibody
Timepoint [2] 432634 0
At end of 12 months treatment period or the final HLA antigen exclusion list prior to transplant if that is prior to 12 months
Secondary outcome [3] 432635 0
The number of HLA antigens removed from the list of exclusions for each subject due to a fall in the corresponding antibody
Timepoint [3] 432635 0
At end of 12 months treatment period or the final HLA antigen exclusion list prior to transplant if that is prior to 12 months
Secondary outcome [4] 432636 0
Change in HLA antibody relative intensity scale score
Timepoint [4] 432636 0
During treatment at baseline and 2, 4, 6, 8, 10, 12 months
Secondary outcome [5] 432637 0
Change in HLA antibody titre
Timepoint [5] 432637 0
During treatment at baseline and at 2, 4, 6, 8, 10, 12 months
Secondary outcome [6] 432638 0
Proportion of subjects who had their calculated panel reactive antibody (cPRA) score reduced to less than 98%
Timepoint [6] 432638 0
At end of 12 months treatment period or the final calculation prior to transplant if that is prior to 12 months
Secondary outcome [7] 432639 0
Change in cPRA of each subject
Timepoint [7] 432639 0
At end of 12 months treatment period or the final calculation prior to transplant if that is prior to 12 months
Secondary outcome [8] 432640 0
Proportion of subjects transplanted during the study
Timepoint [8] 432640 0
Monthly from baseline to 12 months during the treatment period
Secondary outcome [9] 432641 0
Proportion of subjects transplanted during the study whose donor was excluded prior to the study due to the presence of donor specific antibody (DSA)
Timepoint [9] 432641 0
Monthly from baseline to 12 months during the treatment period
Secondary outcome [10] 432642 0
Rate and timing of antibody mediated rejection (clinical or subclinical) within the first year after transplant
Timepoint [10] 432642 0
Monthly from the time of transplant to 12 months after transplant
Secondary outcome [11] 432643 0
Rate and timing of T cell-mediated rejection within the first year after transplant
Timepoint [11] 432643 0
Monthly from the time of transplant to 12 months after transplant
Secondary outcome [12] 432644 0
Kidney function at 3 and 12 months after transplant
Timepoint [12] 432644 0
3 and 12 months after kidney transplant
Secondary outcome [13] 432645 0
Patient and graft survival at 12 months
Timepoint [13] 432645 0
12 months after transplant
Secondary outcome [14] 432646 0
BK or cytomegalovirus (CMV) infections in the first 12 months after transplant
Timepoint [14] 432646 0
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months after transplant
Secondary outcome [15] 432647 0
Other opportunistic infections in the first 12 months after transplant
Timepoint [15] 432647 0
Monthly until 12 months after transplant
Secondary outcome [16] 432648 0
HLA antibody including DSA MFI levels after transplant
Timepoint [16] 432648 0
Week 1 and 2, month 1, 2, 3, 6, 9, 12 after transplant
Secondary outcome [17] 432649 0
HLA antibody including DSA relative intensity scale score after transplant
Timepoint [17] 432649 0
Week 1 and 2, month 1, 2, 3, 6, 9, 12 after transplant
Secondary outcome [18] 432650 0
Incidence of de novo DSA formation in the first 12 months after transplant
Timepoint [18] 432650 0
Week 1 and 2, month 1, 2, 3, 6, 9, 12 after transplant
Secondary outcome [19] 432651 0
Incidence of de novo DSA formation in the first 12 months after transplant
Timepoint [19] 432651 0
At the time of transplant
Secondary outcome [20] 432652 0
Surveillance biopsy results at 2-3 and 12 months
Timepoint [20] 432652 0
At 2-3 months and 12 months after transplant
Secondary outcome [21] 432653 0
Molecular microscope (MMDx) biopsy analysis if light microscopy is abnormal
Timepoint [21] 432653 0
At the time of biopsy if the biopsy is abnormal and was performed within 12 months of transplant
Secondary outcome [22] 432654 0
Graft survival at 12 months
Timepoint [22] 432654 0
12 months after transplant
Secondary outcome [23] 432655 0
Overall patient survival at 12 months
Timepoint [23] 432655 0
12 months after transplant
Secondary outcome [24] 432656 0
Other clazakizumab safety
Timepoint [24] 432656 0
Monthly for the duration of treatment with clazakizumab plus monthly for 12 months after kidney transplantation in those who are transplanted
Secondary outcome [25] 432657 0
Change in IgG levels (total and subclass)
Timepoint [25] 432657 0
Baseline, 2, 4, 6, 8, 10, 12 months during treatment, plus every 3 months in those who receive a kidney transplant
Secondary outcome [26] 432658 0
Change in B cell and T cell and other immune cell subsets
Timepoint [26] 432658 0
Baseline, 2, 4, 6, 8, 10, 12 months during treatment, plus every 3 months in those who receive a kidney transplant
Secondary outcome [27] 432659 0
Change in donor specific B cell and plasma cell numbers
Timepoint [27] 432659 0
Baseline, 2, 4, 6, 8, 10, 12 months during treatment, plus monthly in those who receive a kidney transplant

Eligibility
Key inclusion criteria
1. Age 18-70 years at the time of screening.
2. Highly sensitized:
a. with a cPRA of greater than 98% based on their current unacceptable HLA antigens on the transplant waiting list.
b. Must remain highly sensitized with a cPRA greater than 95% after altering unacceptable HLA antigens to only include those to which they have current antibodies detected by Luminex screening with an MFI greater than 1500 or lower if it is an antibody against a repeat HLA mismatch from a previous transplant, if it appears likely that an anti-HLA antibody is binding multiple different Luminex beads leading to an apparent lowering of the MFI or if a previous surrogate flow cytometric crossmatch was positive due to that antibody.
3. Must have end-stage kidney disease and currently be active on the deceased donor kidney transplant waiting list for greater than 12 months.
4. Written informed consent obtained from subject (or legally acceptable representative).
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participant is unable or unwilling to comply with study procedures in the opinion of the Investigator.
2. Requiring multi-organ transplant.
3. Pregnant, breastfeeding, or unwillingness to practice highly effective birth control during the study and for 5 months after last dose of study medication.
4. History of anaphylaxis.
5. Abnormal liver function test (LFTs) (alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/bilirubin greater than 1.5 times the upper limit of normal) at screening or other significant liver disease.
6. Latent or active tuberculosis:
a. Chest X-ray (CXR) in the past 6 months showing evidence of latent or active tuberculosis. If CXR is not available, it must be performed at screening.
and/or
b. Positive QuantiFERON-TB Gold test at screening.
7. Human Immunodeficiency Virus (HIV) positive at screening.
8. Presence of hepatitis B surface antigen (HBsAg) at screening
9. Hepatitis C virus (HCV) RNA positive at screening.
10. History of inflammatory bowel disease (except fully excised and recovered from the surgery for ulcerative colitis), clinically significant diverticular disease (unless fully excised and recovered from the surgery) or history of GI perforation.
11. Neutropenia (less than 1,000/mm3) or thrombocytopenia (less than 100,000/mm3) at screening.
12. Active infections requiring systemic (IV or oral) antimicrobial agents.
13. History or current opportunistic infection, including (but not limited to) the following: a nontuberculous mycobacterial infection, pneumocystis, aspergillosis, and toxoplasmosis.
14. Active viral infections such as CMV, EBV, JCV, and polyoma BK.
15. Current participation in an investigational drug trial.
16. Administration of a live vaccine within 6 weeks of screening, including but not limited to the following:
a. Adenovirus [Adenovirus vaccine live oral type 7]
b. Varicella [Varivax]
c. Hepatitis A [VAQTA]
d. Rotavirus [Rotashield]
e. Yellow fever [Y-F-Vax]
f. Measles and mumps live virus vaccine
g. Measles, mumps, and rubella vaccine [MMR-II]
h. Sabin oral polio vaccine
i. Rabies vaccines [IMOVAX Rabies I.D., RabAvert])
j. Present or previous (within 5 years) malignancy except for basal cell carcinoma, fully excised squamous cell carcinoma of the skin, non-recurrent (within 5 years) cervical carcinoma in-situ, DCIS following completion of therapy or T1a renal cell carcinoma.
17. Presence of a condition or abnormality (i.e., clinically significant endocrine, autoimmune, metabolic, neurological, psychiatric/psychological, renal, gastrointestinal, hepatic, and hematological or any other system abnormalities that are uncontrolled with standard treatment) that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

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
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/05/2024
Actual
Date of last participant enrolment
Anticipated
5/05/2025
Actual
Date of last data collection
Anticipated
10/05/2027
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26247 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 42216 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 316033 0
Charities/Societies/Foundations
Name [1] 316033 0
John Perrett Bequest
Country [1] 316033 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
Country
Australia
Secondary sponsor category [1] 318189 0
None
Name [1] 318189 0
Address [1] 318189 0
Country [1] 318189 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314855 0
The Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 314855 0
https://www.thermh.org.au/research/researchers/ethics
Ethics committee country [1] 314855 0
Australia
Date submitted for ethics approval [1] 314855 0
Approval date [1] 314855 0
17/09/2021
Ethics approval number [1] 314855 0

Summary
Brief summary

Kidney transplantation improves the survival and quality of life of people with end-stage kidney disease (ESKD) compared to remaining on dialysis. One of the major barriers preventing some people with ESKD from receiving a transplant is the presence of antibodies against a broad range of HLA antigens found in the community. Transplantation in the presence of antibodies directed against the HLA type of the donor (donor specific antibody, DSA) is associated with an increased risk of antibody-mediated rejection, development of transplant glomerulopathy and graft loss. To minimise this risk, many deceased donor kidney transplant allocation systems allow potential recipients to avoid donors with HLA antigens to which the recipient has detectable antibodies. There is therefore an unmet need for a strategy to reduce the number of HLA-specific antibodies in these highly sensitised patients. This study will specifically investigate whether Clazakizumab is effective at reducing HLA antibody levels, whether this allows some HLA types to be removed from the list deemed unacceptable and whether this increases the chance of transplantation. It will also study the safety of this intervention and the outcomes of the transplants performed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 132942 0
A/Prof Peter Hughes
Address 132942 0
Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia
Country 132942 0
Australia
Phone 132942 0
+61 3 9342 7116
Fax 132942 0
Email 132942 0
Peter.Hughes@mh.org.au
Contact person for public queries
Name 132943 0
Peter Hughes
Address 132943 0
Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia
Country 132943 0
Australia
Phone 132943 0
+61 3 9342 7116
Fax 132943 0
Email 132943 0
Peter.Hughes@mh.org.au
Contact person for scientific queries
Name 132944 0
Peter Hughes
Address 132944 0
Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia
Country 132944 0
Australia
Phone 132944 0
+61 3 9342 7116
Fax 132944 0
Email 132944 0
Peter.Hughes@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Researchers requesting individual patient data will be considered on a case by case basis, all of the individual participant data collected during the trial, after de-identification, may be shared.
When will data be available (start and end dates)?
From 12 months after publication of all study results for a period of 15 years.
Available to whom?
Researchers who provide a methodologically sound proposal will be assessed on a case-by-case basis by a panel of study investigators. Applications for trial data can be made through correspondence with the Principal Investigator.
Available for what types of analyses?
Data analyses will be considered on a case by case basis and could include re-analysis of trial results and secondary outcomes analysis.
How or where can data be obtained?
Proposals will be assessed on a case-by-case basis by a panel of study investigators. Applications for trial data can be made through correspondence with the Principal Investigator at peter.hughes@mg.org.au.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21841Study protocol  Peter.Hughes@mh.org.au



Results publications and other study-related documents

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