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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

End stage kidney disease

Condition category

Condition code

Renal and Urogenital

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

During treatment at baseline and 2, 4, 6, 8, 10, 12 (primary timepoint) months

Secondary outcome [1]

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]

During treatment at baseline and 2, 4, 6, 8, 10, 12 months.

Secondary outcome [2]

Proportion of subjects who had HLA antigens removed from list of exclusions due to a fall in the corresponding antibody

Timepoint [2]

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]

The number of HLA antigens removed from the list of exclusions for each subject due to a fall in the corresponding antibody

Timepoint [3]

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]

Change in HLA antibody relative intensity scale score

Timepoint [4]

During treatment at baseline and 2, 4, 6, 8, 10, 12 months

Secondary outcome [5]

Change in HLA antibody titre

Timepoint [5]

During treatment at baseline and at 2, 4, 6, 8, 10, 12 months

Secondary outcome [6]

Proportion of subjects who had their calculated panel reactive antibody (cPRA) score reduced to less than 98%

Timepoint [6]

At end of 12 months treatment period or the final calculation prior to transplant if that is prior to 12 months

Secondary outcome [7]

Change in cPRA of each subject

Timepoint [7]

At end of 12 months treatment period or the final calculation prior to transplant if that is prior to 12 months

Secondary outcome [8]

Proportion of subjects transplanted during the study

Timepoint [8]

Monthly from baseline to 12 months during the treatment period

Secondary outcome [9]

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]

Monthly from baseline to 12 months during the treatment period

Secondary outcome [10]

Rate and timing of antibody mediated rejection (clinical or subclinical) within the first year after transplant

Timepoint [10]

Monthly from the time of transplant to 12 months after transplant

Secondary outcome [11]

Rate and timing of T cell-mediated rejection within the first year after transplant

Timepoint [11]

Monthly from the time of transplant to 12 months after transplant

Secondary outcome [12]

Kidney function at 3 and 12 months after transplant

Timepoint [12]

3 and 12 months after kidney transplant

Secondary outcome [13]

Patient and graft survival at 12 months

Timepoint [13]

12 months after transplant

Secondary outcome [14]

BK or cytomegalovirus (CMV) infections in the first 12 months after transplant

Timepoint [14]

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months after transplant

Secondary outcome [15]

Other opportunistic infections in the first 12 months after transplant

Timepoint [15]

Monthly until 12 months after transplant

Secondary outcome [16]

HLA antibody including DSA MFI levels after transplant

Timepoint [16]

Week 1 and 2, month 1, 2, 3, 6, 9, 12 after transplant

Secondary outcome [17]

HLA antibody including DSA relative intensity scale score after transplant

Timepoint [17]

Week 1 and 2, month 1, 2, 3, 6, 9, 12 after transplant

Secondary outcome [18]

Incidence of de novo DSA formation in the first 12 months after transplant

Timepoint [18]

Week 1 and 2, month 1, 2, 3, 6, 9, 12 after transplant

Secondary outcome [19]

Incidence of de novo DSA formation in the first 12 months after transplant

Timepoint [19]

At the time of transplant

Secondary outcome [20]

Surveillance biopsy results at 2-3 and 12 months

Timepoint [20]

At 2-3 months and 12 months after transplant

Secondary outcome [21]

Molecular microscope (MMDx) biopsy analysis if light microscopy is abnormal

Timepoint [21]

At the time of biopsy if the biopsy is abnormal and was performed within 12 months of transplant

Secondary outcome [22]

Graft survival at 12 months

Timepoint [22]

12 months after transplant

Secondary outcome [23]

Overall patient survival at 12 months

Timepoint [23]

12 months after transplant

Secondary outcome [24]

Other clazakizumab safety

Timepoint [24]

Monthly for the duration of treatment with clazakizumab plus monthly for 12 months after kidney transplantation in those who are transplanted

Secondary outcome [25]

Change in IgG levels (total and subclass)

Timepoint [25]

Baseline, 2, 4, 6, 8, 10, 12 months during treatment, plus every 3 months in those who receive a kidney transplant

Secondary outcome [26]

Change in B cell and T cell and other immune cell subsets

Timepoint [26]

Baseline, 2, 4, 6, 8, 10, 12 months during treatment, plus every 3 months in those who receive a kidney transplant

Secondary outcome [27]

Change in donor specific B cell and plasma cell numbers

Timepoint [27]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - City campus - Parkville

Recruitment postcode(s) [1]

3050 - Parkville

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

John Perrett Bequest

Address [1]

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal Melbourne Hospital

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Melbourne Hospital Human Research Ethics Committee

Ethics committee address [1]

https://www.thermh.org.au/research/researchers/ethics

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

17/09/2021

Ethics approval number [1]

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

A/Prof Peter Hughes

Address

Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia

Country

Australia

Phone

+61 3 9342 7116

Fax

[email protected]

Contact person for public queries

Name

Peter Hughes

Address

Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia

Country

Australia

Phone

+61 3 9342 7116

Fax

[email protected]

Contact person for scientific queries

Name

Peter Hughes

Address

Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia

Country

Australia

Phone

+61 3 9342 7116

Fax

[email protected]

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 [email protected].

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
21841	Study protocol			[email protected]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

Documents added manually

Documents added automatically