Role of Antibiotic Therapy or Immunoglobulin On iNfections in hAematoLogy: Immunoglobulin Stopping or Extension

Haematological Malignancy Clinical Trial

— RATIONALISE  

Official 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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05678621
• Other study ID #: TRU-RLS-21
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 30, 2022
• Est. completion date: April 2027

Study information

• Verified date: April 2024
• Source: Monash University
• Contact: Prof Zoe McQuilten
• Phone: +61 3 9903 0379
• Email: zoe.mcquilten[@]monash.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: April 2027
• Est. primary completion date: April 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

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.

Related Conditions & MeSH terms

• Agammaglobulinemia
• Haematological Malignancy
• Hematologic Neoplasms
• Hypogammaglobulinemia
• Infections
• Neoplasms

Intervention

Drug:
• trimethoprim-sulfamethoxazole (co-trimoxazole)
Doxycycline is an alternative for participants with hypersensitivity to co-trimoxazole.
• amoxycillin/clavulanic acid and ciprofloxacin
clindamycin is an alternative to amoxycillin/clavulanic acid for participants with hypersensitivity to penicillin.
• Immunoglobulins
Intravenous monthly immunoglobulin or subcutaneous weekly immunoglobulin

Locations

Country	Name	City	State
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Concord Hospital	Concord	New South Wales
Australia	Canberra Hospital	Garran	Australian Capital Territory
Australia	Austin Hospital	Heidelberg	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Sunshine Hospital	St Albans	Victoria
Australia	Royal North Shore	St Leonards	New South Wales

Sponsors (1)

Lead Sponsor	Collaborator
Monash University

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		12 months following randomisation
Secondary	Proportion of patients who develop at least 1 Grade 3 or higher infection(s) from randomisation to 12 months.		12 months following randomisation
Secondary	Proportion of patients with one or more clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) to 12 months.		12 months following randomisation
Secondary	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.		12 months following randomisation
Secondary	Proportion of patients with one or more microbiologically documented bacterial infections.		12 months following randomisation
Secondary	Number of microbiologically documented bacterial infections.		12 months following randomisation
Secondary	Time free from hospitalisation and antimicrobials with therapeutic intent.		12 months following randomisation
Secondary	Proportion of patients with one or more treatment-related adverse events		12 months following randomisation
Secondary	Number of treatment-related adverse events.		12 months following randomisation
Secondary	Proportion of patients with fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms isolated.		12 months following randomisation
Secondary	Number of infections with fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms isolated.		12 months following randomisation
Secondary	Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months	QoL will be assessed using the EORTC QLQ-C30 questionnaire.	Randomisation and 3, 6, 9 and 12 months following randomisation.
Secondary	Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months	QoL will be assessed using the Functional Assessment of Cancer Therapy - Neutropenia (FACT-N) questionnaire.	Randomisation and 3, 6, 9 and 12 months following randomisation.
Secondary	Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months	QoL will be assessed using the EQ-5D-5L questionnaire.	Randomisation and 3, 6, 9 and 12 months following randomisation.
Secondary	Costs associated with allocated treatment arm and infections during study	Costs associated with each treatment arm with be aggregated into Australian dollars. Aggregate costs will be calculated based on the following data sources: medical records, infection-related hospitalisations (using unit costs based on unlinked data from the Victorian Admitted Episodes Dataset, Victorian Emergency Minimum Dataset and the Victorian Cost Data Collection), Medicare Benefits Scheme (MBS), Pharmaceutical Benefits Scheme (PBS) and Australian Immunisation Registry (AIR) data.	12 months following randomisation
Secondary	Cost effectiveness of the allocated treatment arm	Differences in costs and Quality Adjusted Life Years (QALYs) for each of the treatment arms will be aggregated into a cost effectiveness ratio. The following data sources will be used to calculate this outcome measure: the EORTC QLQ-C30 questionnaire will be used to calculate QALYS. Costs will be calculated based on the following data sources: medical records, infection-related hospitalisations (using unit costs based on unlinked data from the Victorian Admitted Episodes Dataset, Victorian Emergency Minimum Dataset and the Victorian Cost Data Collection), Medicare Benefits Scheme (MBS), Pharmaceutical Benefits Scheme (PBS) and Australian Immunisation Registry (AIR) data.	12 months following randomisation
Secondary	Trough IgG level at 3, 6, 9 and 12 months from baseline.		3, 6, 9 and 12 months from baseline
Secondary	Proportion of patients in immunoglobulin cessation treatment arms who restart Ig over 12 months.		12 months following randomisation
Secondary	Covid anti-spike protein levels at baseline, 3, 6, 9, and 12 months.		3, 6, 9 and 12 months following baseline