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Trial registered on ANZCTR


Registration number
ACTRN12617001008314
Ethics application status
Approved
Date submitted
5/07/2017
Date registered
12/07/2017
Date last updated
10/12/2019
Date data sharing statement initially provided
10/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
An Australian multicentre trial to compare the safety and efficacy of intravenous immunoglobulin replacement therapy with subcutaneous immunoglobulin replacement therapy (Hizentra®) to treat immunoglobulin deficiency in patients with chronic lymphocytic leukaemia (CLL)
Scientific title
An Australian multicentre prospective randomised study to compare the safety and efficacy of intravenous immunoglobulin replacement therapy with subcutaneous immunoglobulin replacement therapy (Hizentra®) to treat acquired hypogammaglobulinaemia in patients with chronic lymphocytic leukaemia (CLL)
Secondary ID [1] 292378 0
Nil known
Universal Trial Number (UTN)
U1111-1198-8691
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukaemia 303932 0
Condition category
Condition code
Cancer 303286 303286 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention 1 - 12 months
0.2g per ml (20%) sub cutaneous immunoglobulin (SCIg) weekly, switching from intravenous immunoglobulin (IVIg), subject’s current monthly IVIg dose divided by 4 (range: 0.05 – 0.15g/kg), n= 30
Intervention 2 - 12 months
0.2g per ml (20%) sub cutaneous immunoglobulin (SCIg) fortnightly, switching from intravenous immunoglobulin (IVIg), subject’s current monthly IVIg dose divided by 2 (0.1 – 0.3g/kg), n=30

Adherence/fidelity will be established with an initial 2-4 week in hospital training period where patients are educated on self administration of sub cutaneous immunoglobulin. From then on there will be a scheduled review by an investigator at 3, 6, 9 and 12 months where adherence and complications will be discussed, blood tests will also be taken to assess immunoglobulin levels. Doctors and nursing staff will be available by appointment at any time in between scheduled reviews.
Intervention code [1] 298547 0
Treatment: Drugs
Comparator / control treatment
Control - 12 months
Intravenous immunoglobulin (IVIg) monthly, continue the subject’s current monthly IVIg dose (range: 0.2 – 0.6g/kg), n= 30
Control group
Active

Outcomes
Primary outcome [1] 302670 0
The maintenance of a trough level of total serum immunoglobulin G of 4-6g/L during a 12 month period determined by blood tests
Timepoint [1] 302670 0
Over a 12 month period after randomisation with blood tests at month 1 then at months 2, 3, 6, 9 and 12 (i.e. study completion)
Secondary outcome [1] 336718 0
The composite secondary outcome of assessment of the maintenance of specific aspects of the immune system: immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin G (IgG) subclasses, and immunoglobulin E (IgE), and specific antibody levels to herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), influenza, pneumococcus, pertussis, haemophilia influenza type B (HIB), respiratory syncytial virus (RSV), rubella, hepatitis B and hepatitis C determined by blood tests
Timepoint [1] 336718 0
Over a 12 month period after randomisation with blood tests at commencement then at months 3, 6 and 12 (i.e. study completion)
Secondary outcome [2] 336779 0
The composite secondary outcome of assessment of the type and frequency of infection - i.e. bacterial and viral infections, varicella zoster infection (shingles), septicaemia, including need for antibiotics and hospitalisations for IV antibiotics determined by patient report at 3 monthly review
Timepoint [2] 336779 0
Over a 12 month period after randomisation with review at month 3, 6, 9 and 12 (i.e. study completion)
Secondary outcome [3] 336780 0
Safety – reported adverse reactions occurring during or following the immunoglobulin infusions or injections determined by patient report at 3 monthly review
Timepoint [3] 336780 0
Over a 12 month period after randomisation with review at month 3, 6, 9 and 12 (i.e. study completion)
Secondary outcome [4] 336781 0
The composite secondary outcome of assessing patient reported outcomes (PROs), including quality of life assessments, over the course of treatment determined by using the EuroQol EQ-5D-5L, EORTC QLQ-C30 and SF-36 tools
Timepoint [4] 336781 0
Over a 12 month period after randomisation with review at month 3, 6, 9 and 12 (i.e. study completion)
Secondary outcome [5] 336782 0
Total cost analysis will be conducted based on product costs, consumable costs and hours of staff time in delivery of therapy and education of patients. In addition, the costs of any change in the frequency of admission to hospital will be calculated in bed days.
Timepoint [5] 336782 0
Over a 12 month period after randomisation

Eligibility
Key inclusion criteria
1. Diagnosis of chronic lymphocytic leukaemia (CLL) according to NCI/IWCLL criteria
2. IgG < 6.5 g/L prior to commencement of IVIg
3. Recurrent episodes of non-neutropenic bacterial infection (>2 infections per year requiring antibiotics, or severe non-neutropenic bacterial infection (requiring hospitalisation and IV antibiotics
4. Currently receiving, and stable on IVIg as per the National Blood Authority, State Australian Red Cross Blood Transfusion Service, and local institutional approved guidelines for the provision of IVIg, or patients requiring commencement of immunoglobulin replacement therapy according to standard guidelines
5. An ECOG performance status score of 0-2 at Screening
6. Able to comply with study protocol procedures and a minimum of 1 month of follow-up
7. Able to provide written informed consent
8. Adequate level of physical and mental capacity to allow self-administration of SCIg following a training period
9. Ability to adhere to a self-administration treatment plan
10. Life expectancy of at least 12 months
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with CLL who are not hypogammaglobulinaemic and hence ineligible for immunoglobulin replacement under Australian National Blood Authority Guidelines.
2. Transformation of CLL to aggressive NHL (Richter’s transformation)
3. Ongoing requirement for treatment with high dose corticosteroids at a dose equivalent to or greater than 30 mg/day prednisolone
4. Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying leukaemia):
a. AST or ALT greater than or equal to 2.5 × ULN
b. Total bilirubin greater than or equal to 3 × ULN
5. One or more individual organ / system impairment score(s) of 4 as assessed by the CIRS definition (i.e. extremely severe problem and/or immediate treatment required and/or organ failure and/or severe functional impairment)
6. Prior diagnosis of malignancy, unless:
a. the malignancy has been treated with a curative intent and there is no evidence of recurrence or
b. in remission without treatment for greater than or equal to 2 years prior to study enrolment
7. Previous severe adverse reaction to IVIg requiring inpatient monitoring
8. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
9. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalisation (relating to the completion of the course of antibiotics, except if for tumour fever) within 4 weeks prior to the start of Cycle 1
10. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

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



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
For this non-inferiority trial, 90 patients (30 per arm) are proposed. Assuming a standard deviation of approximately 1 (this standard deviation estimate is generated from a cohort of known CLL patient with hypogammaglobuliaemia) then a minimum of 66 patients (i.e. 22 patients in each arm) are required to be 95% sure that the lower limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will be above the non-inferiority limit of -1g/L. A single sided t-test will be conducted to test the primary endpoint.
Pharmaco-economic analysis will be conducted to compare the cost of IVIg versus SCIg therapy on a monthly and annual basis.
To evaluate safety, the number of patients reporting adverse events will be recorded and compared between the three arms.
The overall health-related QOL scores obtained from the EuroQol EQ-5D-5L, EORTC QLQ-C30, five individual EORTC QLQ-C30 subscales, and the SF-36 modified questionnaire will be summarised descriptively at baseline and each subsequent assessment time point for each treatment arm separately. Overall patterns of change in QOL across the course of the study may be investigated using general linear mixed modelling; this will also allow investigation of associations between patient and treatment characteristics with QOL.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
24/07/2017
Actual
19/09/2017
Date of last participant enrolment
Anticipated
28/06/2019
Actual
7/05/2018
Date of last data collection
Anticipated
28/02/2020
Actual
Sample size
Target
90
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 8488 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 8489 0
St George Hospital - Kogarah
Recruitment hospital [3] 8490 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 16575 0
2065 - St Leonards
Recruitment postcode(s) [2] 16576 0
2217 - Kogarah
Recruitment postcode(s) [3] 16577 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 296924 0
Commercial sector/Industry
Name [1] 296924 0
CSL-Behring
Country [1] 296924 0
Australia
Primary sponsor type
Individual
Name
Professor Stephen Mulligan
Address
c/o Professor Stephen Mulligan
Royal North Shore Hospital
Reserve Rd
St Leonards
NSW 2065
Country
Australia
Secondary sponsor category [1] 295931 0
None
Name [1] 295931 0
Address [1] 295931 0
Country [1] 295931 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298130 0
North Shore Local Health District
Ethics committee address [1] 298130 0
Ethics committee country [1] 298130 0
Australia
Date submitted for ethics approval [1] 298130 0
15/11/2016
Approval date [1] 298130 0
08/02/2017
Ethics approval number [1] 298130 0
RESP/16/292

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

Contacts
Principal investigator
Name 76098 0
Prof Stephen Mulligan
Address 76098 0
Royal North Shore Hospital
Reserve Rd
St Leonards
NSW 2065
Country 76098 0
Australia
Phone 76098 0
+61 2 99267111
Fax 76098 0
Email 76098 0
mulligan@sydney.edu.au
Contact person for public queries
Name 76099 0
Stephen Mulligan
Address 76099 0
Royal North Shore Hospital
Reserve Rd
St Leonards
NSW 2065
Country 76099 0
Australia
Phone 76099 0
+61 2 99267111
Fax 76099 0
Email 76099 0
mulligan@sydney.edu.au
Contact person for scientific queries
Name 76100 0
Stephen Mulligan
Address 76100 0
Royal North Shore Hospital
Reserve Rd
St Leonards
NSW 2065
Country 76100 0
Australia
Phone 76100 0
+61 2 99267111
Fax 76100 0
Email 76100 0
mulligan@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



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.