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Trial registered on ANZCTR


Registration number
ACTRN12620000171910p
Ethics application status
Submitted, not yet approved
Date submitted
24/12/2019
Date registered
17/02/2020
Date last updated
17/02/2020
Date data sharing statement initially provided
17/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised trial of third-party virus-specific T cells in patients with untreated viral infection after an allogeneic stem cell transplantation
Scientific title
A randomised trial of most closely HLA-matched third-party donor-derived virus-specific cytotoxic T-lymphocytes in patients with untreated viral infection post-allogeneic stem cell transplantation to reduce number of days in hospital
Secondary ID [1] 300154 0
None
Universal Trial Number (UTN)
NA
Trial acronym
R3R
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Cytomegalovirus (CMV) infection 315691 0
Epstein Barr Virus (EBV) infection 315692 0
Condition category
Condition code
Infection 313978 313978 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1 to 4 sequential intravenous infusions of 2x10^7/m^2 Tcells directed at each CMV and EBV. Hence, the total dose is 4x10^7/m^2 Tcells.
Patients randomised to receive investigational product will receive at least 1 infusion. Patients will be assessed for eligibility for subsequent infusions after 21 days post each infusion. Patients will be eligible for a subsequent infusion if the CMV virus titre is >1000IU/ml blood or EBV virus titre is 5000 copies/ml blood or if there is ongoing clinical and/or radiological and/or virological infection in the organ system(S) affected by the virus that led to the initial infection. EBV associated post-transplant lymphoproliferative disease (PTLD) will also deem a patient eligible.
If the patient is eligible, they will receive a subsequent infusion at the same dose. A total of 4 infusions may be given to any one patient randomised to the investigational product arm.
If a patient requires additional doses, they will be contacted to arrange suitable appointment times. Infusions will be documented in medical records.
Intervention code [1] 316427 0
Treatment: Other
Comparator / control treatment
Best available therapy which usually entails antivirals for CMV or Rituximab for EBV as per site protocols where available or treating clinician's discretion.
Control group
Active

Outcomes
Primary outcome [1] 322391 0
Number of inpatient days based on medical records
Timepoint [1] 322391 0
12 months post-transplant
Secondary outcome [1] 378302 0
Number of days as an inpatient based on medical records
Timepoint [1] 378302 0
12 months post randomisation
Secondary outcome [2] 378303 0
Overall survival
Timepoint [2] 378303 0
12 months post transplant
Secondary outcome [3] 378304 0
Safety of Tcell infusion by measuring type and severity of adverse events.
Adverse events may include tachycardia, hypotension, fever, graft-versus host disease (GVHD) which will be assessed by measuring observations (ie: temperature using thermometer, blood pressure using digital sphygmomanometer, SpO2 using digital saturation probe, respiratory rate monitoring rise and fall of chest over 1 minute and heart rate from digital saturation probe) at infusion and doctor review of GVHD.
Timepoint [3] 378304 0
7 days post infusions
Secondary outcome [4] 378305 0
Non-relapse mortality (Relapse is determined according to usual criteria for the underlying disease that transplant was indicated for)
Timepoint [4] 378305 0
12 months post tranplant
Secondary outcome [5] 378306 0
Rate of malignant disease based on standard of care medical review and assessment, documented in medical records
Timepoint [5] 378306 0
12 months post transplant
Secondary outcome [6] 378307 0
Clinical response measured as viral response/recurrence of viral infection based of viral titre in blood or clinical assessment recorded in medical records
Timepoint [6] 378307 0
12 months post infusion
Secondary outcome [7] 378308 0
Use of antiviral drugs based on medical records
Timepoint [7] 378308 0
12 months post infusion
Secondary outcome [8] 378309 0
Number of hospital days based on medical records
Timepoint [8] 378309 0
12 months post transplant
Secondary outcome [9] 378310 0
Graft function based on medical records
Timepoint [9] 378310 0
12 months post transplant
Secondary outcome [10] 378311 0
Specific Tcell immunity to pathogens based on laboratory analysis (using blood sample)
Timepoint [10] 378311 0
12 months post infusions
Secondary outcome [11] 378312 0
Correlation of response with degree of human leukocyte antigen (HLA) matching based on number of days for infection to resolve. (Based on infusion product release information and medical records)
Timepoint [11] 378312 0
12 months post infusion
Secondary outcome [12] 378313 0
Incidence of acute GVHD based on medical records
Timepoint [12] 378313 0
100 days post transplant
Secondary outcome [13] 378314 0
Incidence of chronic GVHD based on medical records
Timepoint [13] 378314 0
12 months post infusion
Secondary outcome [14] 378315 0
Quality of life using the Functional Assessment of Cancer Therapy – Bone Marrow Transplant (FACT-BMT Version 4).
Timepoint [14] 378315 0
12 months post transplant

Eligibility
Key inclusion criteria
• Recipients of HLA matched or mismatched peripheral blood, bone marrow or cord blood myeloablative or non-myeloablative allogeneic stem cell transplantation for any indication within 6 months of transplant
• Reactivation or infection with CMV (cytomegalovirus) or EBV (Epstein barr virus) or EBV associated PTLD (post-transplant lymphoproliferative disorder) within 180 days following allogeneic stem cell transplantation must be present as determined by:
o For CMV
- CMV detectable by antigen detection, PCR or culture in peripheral blood or tissue biopsy or by immunohistochemical staining on tissue biopsy specimen
o For EBV
- Elevated EBV detectable in peripheral blood by PCR (polymerase chain reaction) or
- Presence of documented EBV related PTLD diagnosed by tissue biopsy or
- Elevated EBV detectable in the blood by PCR and clinical or imaging findings consistent with EBV lymphoma
• Patients must satisfy criteria for initiation of treatment within 180 days following allogeneic stem cell transplantation
o For CMV
- Most recent PCR in peripheral blood greater than or equal to 1,000 international units/ml (IU/ml) (3 log10) OR
- Positive antigen detection, PCR or culture in tissue in association with clinical symptoms and/or signs consistent with CMV tissue infection
o For EBV
- At least one post-transplant PCR in peripheral blood within two weeks greater than or equal to 10,000 viral genome copies/ml or two post-transplant PCRs in peripheral blood greater than or equal to 5,000 viral genome copies/ml if separated by an interval of at least 72 hours with the most recent value higher than the previous value
- Positive antigen detection, PCR or culture in tissue in association with clinical symptoms and/or signs and/or tissue biopsy or flow cytometry consistent with EBV tissue infection or EBV associated post-transplant lymphoproliferative disease
• Patients must not have received more than 7 days of prior treatment dose pharmacological anti-viral therapy for treatment of CMV or EBV infection Treatment dose pharmacological therapy is defined as:
o For CMV
- IV (intravenous) ganciclovir or oral valganciclovir at treatment dose or foscarnet at full dose or high dose acyclovir or one of its derivatives or brincidofovir or letermovir or maribivir at treatment doses (doses of aciclovir of 800 mg bd or valaciclovir 1 g/day or famciclovir 250mg bd or below will not be considered treatment dose)
o For EBV infection or EBV associated PTLD
- One dose of rituximab or other anti-CD20 antibody 7 days treatment with cytotoxic chemotherapy
- adequate hepatic and renal function (< 3 x upper limit of normal for AST (SGOT), ALT (SGPT), < 2 x upper limit of normal for total bilirubin, serum creatinine) unless abnormalities are considered to be due to the infection/PTLD being treated

• ECOG status 0 to 3 or Lansky score 30-100
• Patient (or legal representative) has given informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Use of anti-lymphocyte globulin (ALG, ATG, Campath or other broad spectrum lymphocyte antibody) given in the 4 weeks immediately prior to infusion or planned within 4 weeks after infusion unless anti-lymphocyte globulin levels in blood shown to be below the lympholytic threshold prior to infusion.
• Active grade II or greater graft versus host disease within 1 week prior to infusion.
• Prednisone or methylprednisolone at a dose of > 1 mg/kg (or equivalent in other steroid preparations) administered within 48 hours prior to cell infusion.
• Dose of prednisone or methylprednisolone (if administered) not maintained at a stable level for 48 hours prior to T cell infusion
• ECOG status 4 or Lansky score <30
• Privately insured in or outpatients in New South Wales participating centres

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)
The person who determines if a subject is eligible for inclusion in the trial is unaware of treatment allocation when the decision is made to register a patient to the trial.
Allocation is emailed to the site after the patient meets all eligibility and is registered to the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratification by participating site and by disease risk
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
NA
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Approximately 30% of patients undergoing HSCT (haemopoietic stem cell transplant) require treatment for CMV, EBV or EBV associated PTLD. We would therefore need to recruit from 420 allogeneic HSCT recipients over 3 years for this study. The participating centres perform around 400 allogeneic HSCT annually. Over 3 years, we expect approximately 360 viral reactivations requiring treatment. Therefore assuming a dropout or non-recruitment rate of 60%, we would recruit from 144 patients to the study over 3 years. Sample size is 144 patients.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 15554 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 15555 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 15556 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 15557 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 15558 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [6] 15559 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 28928 0
3050 - Parkville
Recruitment postcode(s) [2] 28929 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 28930 0
2065 - St Leonards
Recruitment postcode(s) [4] 28931 0
4029 - Herston
Recruitment postcode(s) [5] 28932 0
6150 - Murdoch
Recruitment postcode(s) [6] 28933 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 304593 0
Government body
Name [1] 304593 0
Office for Health and Medical Research
Address [1] 304593 0
73 Miller Street
North Sydney NSW 2060
Australia
Country [1] 304593 0
Australia
Primary sponsor type
Government body
Name
Western Sydney Local Health District
Address
Darcy Rd, Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 304883 0
None
Name [1] 304883 0
Address [1] 304883 0
Country [1] 304883 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 305015 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 305015 0
WSLHD Research and Education Network,
Westmead Hospital,
Hawkesbury Road,
Westmead NSW 2145
Ethics committee country [1] 305015 0
Australia
Date submitted for ethics approval [1] 305015 0
06/11/2019
Approval date [1] 305015 0
Ethics approval number [1] 305015 0

Summary
Brief summary
The study will involve patients who have a CMV or EBV infection requiring treatment following allogeneic blood or marrow transplantation. Patients with CMV or EBV requiring therapy will be randomly allocated to receive best available therapy or to best available therapy plus infusions of immune cells directed at CMV and EBV.
The aim of the study is to assess whether the combination of best available therapy and immune cells improved the outcomes for patients.
Trial website
Not applicable
Trial related presentations / publications
Not applicable
Public notes

Contacts
Principal investigator
Name 98974 0
Prof David Gottlieb
Address 98974 0
Clinical Trials Office,
Corner Hawkesbury and Darcy Roads, Westmead Hospital
Westmead, NSW, 2145
Country 98974 0
Australia
Phone 98974 0
+61 2 8890 9269
Fax 98974 0
+61 2 9689 3700
Email 98974 0
david.gottlieb@sydney.edu.au
Contact person for public queries
Name 98975 0
Ms Elissa Atkins
Address 98975 0
Clinical Trials Office,
Corner Hawkesbury and Darcy Roads, Westmead Hospital
Westmead, NSW, 2145
Country 98975 0
Australia
Phone 98975 0
+61 2 8890 9269
Fax 98975 0
+61 2 9689 3700
Email 98975 0
Elissa.Atkins@health.nsw.gov.au
Contact person for scientific queries
Name 98976 0
Prof David Gottlieb
Address 98976 0
Clinical Trials Office,
Corner Hawkesbury and Darcy Roads, Westmead Hospital
Westmead, NSW, 2145
Country 98976 0
Australia
Phone 98976 0
+61 2 8890 9269
Fax 98976 0
+61 2 9689 3700
Email 98976 0
david.gottlieb@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
IPD will not be available as there is a risk of patients being re-identifiable by those outside the study team.
What supporting documents are/will be available?
No other documents available
Summary results
No Results