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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05678621




Registration number
NCT05678621
Ethics application status
Date submitted
11/02/2022
Date registered
10/01/2023
Date last updated
19/04/2024

Titles & IDs
Public title
Role of Antibiotic Therapy or Immunoglobulin On iNfections in hAematoLogy: Immunoglobulin Stopping or Extension
Scientific title
A Randomised Controlled Trial of Continuing Immunoglobulin Therapy, or Stopping With or Without Prophylactic Antibiotics, on Infection Rate in Patients With Acquired Hypogammaglobulinemia Secondary to Haematological Malignancies.
Secondary ID [1] 0 0
TRU-RLS-21
Universal Trial Number (UTN)
Trial acronym
RATIONALISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Haematological Malignancy 0 0
Hypogammaglobulinemia 0 0
Condition category
Condition code
Infection 0 0 0 0
Studies of infection and infectious agents
Infection 0 0 0 0
Other infectious diseases
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Blood 0 0 0 0
Other blood disorders
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - trimethoprim-sulfamethoxazole (co-trimoxazole)
Treatment: Drugs - amoxycillin/clavulanic acid and ciprofloxacin
Treatment: Drugs - Immunoglobulins

Experimental: ARM A: Stop immunoglobulin (Ig) and commence prophylactic oral antibiotics - Once daily trimethoprim-sulfamethoxazole (co-trimoxazole) 160mg/800mg. Nb: Doxycycline 100mg daily as an alternative for participants with hypersensitivity to co-trimoxazole.

Duration: 12 months. Route: PO

Experimental: ARM B: Stop immunoglobulin (without prophylactic antibiotics) - Participants will be prescribed amoxycillin/clavulanic acid 1750-2000mg/250mg and ciprofloxacin 750 mg, to keep at home for initial use if symptoms of infection develop, with immediate review by their treating clinical team, or nearest emergency department or medical practitioner with phone contact to treating team if most practical.

Nb: clindamycin 600 mg is permitted as an alternative to amoxycillin/clavulanic acid for participants with hypersensitivity to penicillin.

Duration: 12 months. Route: PO

Active comparator: ARM C: Continue immunoglobulin - Participants will continue treatment with their current Ig replacement schedule. Participants will receive either Intravenous Ig (IVIg) or Subcutaneous Ig (SCIg)

* IVIg: Participants will be treated in accordance with the Criteria for Clinical Use of Immunoglobulin in Australia. Monthly (every 4 weeks ± 1 week) dose of 0.4g/kg, modified to achieve an Immunoglobulin G (IgG) trough level of at least lower limit of age-specific serum IgG reference range. In the first month of therapy, if IgG \<4g/L then an additional (loading) dose of 0.4g/kg may be given at the clinician's discretion.
* SCIg: Subcutaneous immunoglobulin weekly may be used in patients who meet local criteria for home based self-administration in centres with established SCIg programs. A loading IVIg dose may be given in the first month if required. Thereafter, dosing at 100mg/kg/week, modified to achieve an IgG steady state level of at least the lower limit of the serum reference range.

Duration: 12 months.


Treatment: Drugs: trimethoprim-sulfamethoxazole (co-trimoxazole)
Doxycycline is an alternative for participants with hypersensitivity to co-trimoxazole.

Treatment: Drugs: amoxycillin/clavulanic acid and ciprofloxacin
clindamycin is an alternative to amoxycillin/clavulanic acid for participants with hypersensitivity to penicillin.

Treatment: Drugs: Immunoglobulins
Intravenous monthly immunoglobulin or subcutaneous weekly immunoglobulin
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free survival (EFS), defined as time from randomisation until occurrence of a Grade 3 or higher infection (as defined by CTCAE Version 5), or death from any cause.
Timepoint [1] 0 0
12 months following randomisation
Secondary outcome [1] 0 0
Proportion of patients who develop at least 1 Grade 3 or higher infection(s) from randomisation to 12 months.
Timepoint [1] 0 0
12 months following randomisation
Secondary outcome [2] 0 0
Proportion of patients with one or more clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) to 12 months.
Timepoint [2] 0 0
12 months following randomisation
Secondary outcome [3] 0 0
Number of clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) to 12 months. Data collected from medical records will inform this outcome measure.
Timepoint [3] 0 0
12 months following randomisation
Secondary outcome [4] 0 0
Proportion of patients with one or more microbiologically documented bacterial infections.
Timepoint [4] 0 0
12 months following randomisation
Secondary outcome [5] 0 0
Number of microbiologically documented bacterial infections.
Timepoint [5] 0 0
12 months following randomisation
Secondary outcome [6] 0 0
Time free from hospitalisation and antimicrobials with therapeutic intent.
Timepoint [6] 0 0
12 months following randomisation
Secondary outcome [7] 0 0
Proportion of patients with one or more treatment-related adverse events
Timepoint [7] 0 0
12 months following randomisation
Secondary outcome [8] 0 0
Number of treatment-related adverse events.
Timepoint [8] 0 0
12 months following randomisation
Secondary outcome [9] 0 0
Proportion of patients with fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms isolated.
Timepoint [9] 0 0
12 months following randomisation
Secondary outcome [10] 0 0
Number of infections with fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms isolated.
Timepoint [10] 0 0
12 months following randomisation
Secondary outcome [11] 0 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months
Timepoint [11] 0 0
Randomisation and 3, 6, 9 and 12 months following randomisation.
Secondary outcome [12] 0 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months
Timepoint [12] 0 0
Randomisation and 3, 6, 9 and 12 months following randomisation.
Secondary outcome [13] 0 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months
Timepoint [13] 0 0
Randomisation and 3, 6, 9 and 12 months following randomisation.
Secondary outcome [14] 0 0
Costs associated with allocated treatment arm and infections during study
Timepoint [14] 0 0
12 months following randomisation
Secondary outcome [15] 0 0
Cost effectiveness of the allocated treatment arm
Timepoint [15] 0 0
12 months following randomisation
Secondary outcome [16] 0 0
Trough IgG level at 3, 6, 9 and 12 months from baseline.
Timepoint [16] 0 0
3, 6, 9 and 12 months from baseline
Secondary outcome [17] 0 0
Proportion of patients in immunoglobulin cessation treatment arms who restart Ig over 12 months.
Timepoint [17] 0 0
12 months following randomisation
Secondary outcome [18] 0 0
Covid anti-spike protein levels at baseline, 3, 6, 9, and 12 months.
Timepoint [18] 0 0
3, 6, 9 and 12 months following baseline

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 18 years of age
2. Diagnosis of chronic lymphocytic leukaemia (CLL), multiple myeloma (MM) or non-Hodgkin lymphoma (NHL).
3. Patients must be receiving Ig (IV or subcutaneous - SCIg) replacement for prevention of bacterial infections due to hypogammaglobulinaemia for longer than 6 consecutive months.
4. Patient is eligible for trial of Ig cessation in the opinion of the treating clinician and local investigator.
5. Life expectancy greater than 12 months.
6. Able to give informed consent, and willing and able to comply with each of the treatment arms.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior or planned allogeneic haematopoietic stem cell transplantation.
2. Major infection (Grade 3 or higher) in preceding 3 months, and/or current active infection requiring antimicrobial treatment.
3. Already receiving daily antibiotic prophylaxis for the purpose of preventing bacterial infection (Note: patients may receive antiviral, antifungal and Pneumocystis jirovecii pneumonia (PJP) prophylaxis).
4. Intolerance of all trial antibiotic options in either arm A or arm B.
5. Communication, compliance or logistical issues that are likely to limit patient's ability to take prophylactic or emergency antibiotics, or to obtain urgent medical attention for symptoms of infection.
6. Pregnant or breastfeeding.
7. Severe renal impairment (estimated or measured creatinine clearance of less than 30 mL/min).
8. Previous splenectomy.
9. Previous participation in this trial.
10. Treating team deems enrolment in the study is not in the best interests of the patient.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/11/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/04/2027
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,VIC
Recruitment hospital [1] 0 0
Canberra Hospital - Garran
Recruitment hospital [2] 0 0
Concord Hospital - Concord
Recruitment hospital [3] 0 0
Royal North Shore - St Leonards
Recruitment hospital [4] 0 0
Monash Medical Centre - Clayton
Recruitment hospital [5] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [6] 0 0
The Alfred Hospital - Melbourne
Recruitment hospital [7] 0 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 0 0
2605 - Garran
Recruitment postcode(s) [2] 0 0
2139 - Concord
Recruitment postcode(s) [3] 0 0
2065 - St Leonards
Recruitment postcode(s) [4] 0 0
3168 - Clayton
Recruitment postcode(s) [5] 0 0
3084 - Heidelberg
Recruitment postcode(s) [6] 0 0
3004 - Melbourne
Recruitment postcode(s) [7] 0 0
3021 - St Albans

Funding & Sponsors
Primary sponsor type
Other
Name
Monash University
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The aim of the study is to find out if patients with blood cancers receiving immunoglobulin (Ig) for the purpose of preventing infections can safety stop immunoglobulin after six months of therapy, and take oral antibiotics instead to prevent serious infections.

Patients may be eligible to join this study if they are aged 18 years or above, have an acquired hypogammaglobulinaemia secondary to a haematological malignancy, and have been receiving intravenous or subcutaneous Ig for longer than 6 consecutive months.

Participants will be randomised (allocated by chance) to one of three treatment groups, as follows:

* Stop immunoglobulin (IVIg or SCIg) and be given oral antibiotics to take every day (ARM A)
* Stop immunoglobulin (IVIg or SCIg) and be given oral antibiotics to keep at home to use as soon as symptoms of an infection develop (ARM B)
* Continue receiving immunoglobulin (IVIg or SCIg) - this is the usual care group (ARM C)

The duration of each treatment is for 12 months from study entry.

Participants will be asked to attend a screening/baseline visit so that their treating clinician can assess their eligibility for the trial and collect baseline data. If eligible for the trial, participants will then be randomly allocated to one of the three treatment groups.

Once randomised, active participation in the study will last for 13 months. During this period, participants will be asked to return to the hospital for a study visit every 3 months, with monthly telephone visits to check-in on your progress between each in-person visit. Participants will also be asked to complete a study diary, recording treatment compliance and signs/symptoms of infection experienced throughout the study period.

Types of assessments and data collected will include: Medical history, demographics, physical examination, blood tests, stool sample, quality of life questionnaires, information about your general health, hospitalisations, medications and procedures. In order to assess and compare the cost-effectiveness of the treatment groups, the study team will also request authorisation from participants to access their Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS), and Australian Immunisation Register (AIR) data.
Trial website
https://clinicaltrials.gov/study/NCT05678621
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Prof Erica Wood
Address 0 0
Monash University
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Prof Zoe McQuilten
Address 0 0
Country 0 0
Phone 0 0
+61 3 9903 0379
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05678621