Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000292673
Ethics application status
Approved
Date submitted
8/12/2022
Date registered
17/03/2023
Date last updated
23/06/2024
Date data sharing statement initially provided
17/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A multi-centre Phase 2 study exploring optimal dosing and scheduling of cyclophosphamide in systemic sclerosis patients undergoing haematopoietic stem cell transplantation.
Scientific title
A multi-centre Phase 2 study exploring optimal dosing and scheduling of cyclophosphamide in systemic sclerosis patients undergoing haematopoietic stem cell transplantation.
Secondary ID [1] 306779 0
None
Universal Trial Number (UTN)
Trial acronym
The 2-ASSURE study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
systemic sclerosis 326904 0
Condition category
Condition code
Inflammatory and Immune System 324105 324105 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Once the screening/baseline assessments are completed, patients return to the local centre for further review and discuss the results from the series of baseline/standard of care assessments. These assessments will be used to determine the level of disease involvement and whether an Autologous Haematopoietic Stem Cell Transplant (AHSCT) would be suitable. If patient is suitable to receive a AHSCT, the patient will be asked to sign the consent form. The results from their cardiac and respiratory assessments, age and co-morbidities will be used to determine which treatment arm would be appropriate for them as outlined below:

-Patients who have normal cardiac screening, age less than 50 and no major co-morbidities will receive a standard dose of cyclophosphamide in the conditioning within one of two separate cohorts using a standard dose regimen.
-Those who have heart disease, age greater than 50 or significant co-morbidities/poor performance status will receive a low dose regimen utilising cyclophosphamide and enroll into one of two cohorts using a low dose regimen either with/ without rituximab.

All patients (low and standard dose cohorts) will undergo stem cell collection following 1g/m2 cyclophosphamide after informed written consent using 2-ASSURE Patient Information Consent Forms. The following day, patients will be discharged from the ward and daily filgrastim 10mcg/kg for 10-12 days will be administered until a minimum haematopoietic stem cells is detected on blood tests as per standard of care (SOC) . These stem cells are collected then be cryopreserved as per standard operating procedures in the Haematology Department.

Regardless of the treatment being given, although cardiac monitoring during treatment is not mandated, it is highly recommended to be performed due to the known cyclophosphamide induced cardiac toxicity. If monitoring is not available, daily cardiology review is encouraged. A 12-lead ECG, NTproBNP and Troponin-I will be performed daily pre and during conditioning until D+6 post transplant, and an echocardiogram performed at D-6 and D-1 pre transplant (D-6, D-1pre transplant and D+5 post transplant in standard dose cohort 2). Any abnormal results found on cardiac enzyme, echocardiogram, ECG or other assessments performed throughout the study will need to be actioned/ addressed at the discretion of the local treating haematology and cardiology teams. An electronic copy of the echocardiographic scans (coded with the participants study number) will also be sent to the central site (SVH) to be centrally analysed post-hoc. Patients are to be weighed twice per day. Ongoing accrual of patients from Cohort 1 to Cohort 2 will only occur after safety requirements have been approved by the Independent Safety and Data Monitoring Committee (SDMC).

Standard dose Cohort 1 will enrol total of 10 Participants, who will be admitted to Hospital for the HSCT procedure. This group will have 50mg/kg of cyclophosphamide for 4 dose before stem cell infusion. Patients will ideally be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on or before D-6 pre transplant. Intravenous cyclophosphamide 50mg/kg/day is administered on D-5, D-4, D-3, D-2 pre transplant with hyperhydration and mesna. Rabbit anti-thymocyte globulin, Thymoglobuline (ATG) will be administered pre transplant at a dose of 0.5mg/kg on D-5, 1mg/kg on D-4 and 1.5mg/kg on D-3, D-2 and D-1 pre transplant. Methylprednisolone 1mg/kg will be given as serum sickness prophylaxis on the days of ATG. intravenous fluids be kept to a minimum, Mesna only given in 250mls, thymoglobuline in 500mls and IV hydration limited to two x 12hour bags of plasmalyte (or equivalent) per 24 hour period. Frusemide 40mg will be given after each dose of cyclophosphamide and an additional 40mg is advised if weight increases by 2kg or more on evening weight.

Standard dose Cohort 2 will enrol total of 10 Participants, who will be admitted to Hospital for the HSCT procedure. This group will have 200mg/kg Cyclophosphamide given as 50mg/kg for 2 doses before and 2 doses after stem cells infusion. Patients will ideally be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on or before D-6 pre transplant. Intravenous cyclophosphamide 50mg/kg/day is administered on D-5, D-4 pre transplant with hyperhydration and mesna. ATG will be administered pre transplant at a dose of 0.5mg/kg on D-5, 1mg/kg on D-4 and 1.5mg/kg on D-3, D-2 and D-1 pre transplant. Methylprednisolone 1mg/kg will be given as serum sickness prophylaxis on the days of ATG. Intravenous cyclophosphamide 50mg/kg/day is administered again on D+3, D+4 post transplant with hyperhydration and mesna. It is advised that intravenous fluids be kept to a minimum, Mesna only given in 250mls, thymoglobuline in 500mls and IV hydration limited to two x 12hour bags of plasmalyte (or equivalent) per 24 hour period. Frusemide 40mg will be given after each dose of cyclophosphamide and an additional 40mg is advised if weight increases by 2kg or more on evening weight.

Low dose Cohort 1 arm will enrol total of 10 Participants, who will be admitted to Hospital for the HSCT procedure. This group will have 100mg/kg Cyclophosphamide and Rituximab. Patients will ideally be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on or before D-6 pre transplant. Intravenous cyclophosphamide 25mg/kg/day is administered D-5, D-4, D-3, D-2 pre transplant with hyperhydration and mesna. ATG will be administered pre transplant at a dose of 0.5mg/kg on D-5, 1mg/kg on D-4 and 1.5mg/kg on D-3, D-2 and D-1 pre transplant. Methylprednisolone 1mg/kg will be given as serum sickness prophylaxis on the days of ATG. Rituximab 500mg will be administered D-6 pre transplant and D+1 post transplant. It is advised that intravenous fluids be kept to a minimum, Mesna only given in 250mls, ATG in 500mls and IV hydration limited to two x 12hour bags of plasmalyte (or equivalent) per 24 hour period. Frusemide 40mg will be given after each dose of cyclophosphamide and an additional 40mg is advised if weight increases by 2kg or more on evening weight.

Low dose Cohort 2 arm will enrol total of 10 Participants, who will be admitted to Hospital for the HSCT procedure. This group will have 140mg/kg Cyclophosphamide with no Rituximab. Patients will ideally be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on or before D-6 pre transplant. Intravenous cyclophosphamide 35mg/kg/day is administered on D-5, D-4, D-3, D-2 pre transplant with hyperhydration and mesna. It is advised that intravenous fluids be kept to a minimum, Mesna only given in 250mls, ATG in 500mls and IV hydration limited to two x 12hour bags of plasmalyte (or equivalent) per 24 hour period. Frusemide 40mg will be given after each dose of cyclophosphamide and an additional 40mg is advised if weight increases by 2kg or more on evening weight.

All treatment arms will have a minimum number of stem cells will be infused on Day 0 as per institutional guidelines.

All patients will receive standard of care intravenous antibiotics upon neutropenic fever as per institutional guidelines after blood cultures and chest X ray. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jiroveci pneumonia, candida albicans and Herpes Zoster respectively for 6 months post transplant. Serum sickness from ATG may occur from D+8 post transplant onwards, if fever persists (usually with arthralgia and rash) despite IV antibiotics then corticosteroids 0.5-1mg/kg can be used in addition to IV antibiotics. Weekly serial monitoring and Treatment for viral infections from Day+21 post transplant until Day +90 post transplant is recommended. Treatment for viral infections is as per institute’s practice. Adequate prophylaxis for hepatitis B seropositive donors/recipients is recommended as per the institute’s practice. Treatment of post-transplant infections and neutropenic fever is as per the institution’s guidelines.

Patients will be reviewed fortnightly as an outpatient in the first 6 weeks after hospital discharge or as required clinically up to D+100 post transplant. These visits will be to assess post HSCT clinical parameters such as the risk of infection (particularly viral infections) and are standard of care. All patients will have standardized follow up visits back to the transplant unit performed at D+100 post transplant then 6, 12, 24 months post transplant and then yearly up to 10 years (in order to assess long-term safety and efficacy. Patients will also be assessed in the event of relapse of disease. During stem cell collection phase and from D+100 post transplant onwards, all patients will have specific monitoring of their disease using disease specific questionnaires and Quality of Life (QOL) assessments. Clinical assessments at each visit will include scleroderma and standard of care clinical assessment. Laboratory investigations at each visit include standard of care blood and urine tests, namely FBC, UEC, LFT, ESR, CRP, CMP, ANA, ENA, RNA polymerase III antibodies (if positive at baseline), CK, iron studies, NTproBNP, troponin I, urine protein: creatinine, urine casts and red cell morphology. Assessment of gonadal function will occur at baseline and 3, 6, 12, 24 months post transplant and then yearly following AHSCT.
Intervention code [1] 323953 0
Treatment: Other
Intervention code [2] 325092 0
Treatment: Drugs
Comparator / control treatment
Data collected form previous studies enrolling scleroderma patient will be used to evaluate whether remission and disease activity correlates with immunological parameters including Human Leukocyte Antigen (HLA) class/single nucleotide polymorphism (SNP)s, immune reconstitution flow cytometry studies, haemopoietic stem cell graft analysis, cytokine assays, blood proteomic and biomarkers of end-organ function (eg cardiac enzymes), molecular biology assays including immune response, gene expression and measures of lymphocyte diversity.

Participants enrolled in A Single Centre Phase II Study Of Haematopoietic Stem Cell Transplantation For Severe Auto-Immune Diseases (ACTRN12613000339752) AND Phase II dose escalation study of cyclophosphamide in haematopoietic stem cell transplantation in severe systemic sclerosis patients unfit for standard dose cyclophosphamide studies (ACTRN12617000216314) from 2010 to 2021 will have their data reviewed for comparison with this study.
Control group
Historical

Outcomes
Primary outcome [1] 331907 0
determine safety of stem cell transplant for severe scleroderma patients by measuring transplant related mortality (TRM) using medical records in standard dose cyclophosphamide arm
Timepoint [1] 331907 0
reviewed at 100 days post transplant
Primary outcome [2] 331909 0
determine safety of stem cell transplant for severe scleroderma patients by measuring transplant related mortality (TRM) using medical records in Low dose cyclophosphamide arm
Timepoint [2] 331909 0
reviewed at 100 days post transplant
Secondary outcome [1] 411555 0
Overall survival post transplant
Timepoint [1] 411555 0
assessed at one, two, five and ten years post transplant
Secondary outcome [2] 411556 0
transplant related mortality (TRM) compared to historical controls
Timepoint [2] 411556 0
assessed at one, two, five and ten years post transplant then assessed at the conclusion of the study
Secondary outcome [3] 411557 0
Disease response by measuring changing in skin score using Modified Rodnan skin score (mRSS) assessment tool from baseline
Timepoint [3] 411557 0
Assessed at six month, one, two and five years post transplant
Secondary outcome [4] 411558 0
Disease response by measuring changes in lung function from baseline without the need for further immunosuppression using the following test/tools: spirometry, .lung function test to calculate lung volume (ie the total lung capacity/ residual volume) and lung diffusion capacity
Timepoint [4] 411558 0
Assessed at six month, one, two and five years post transplant
Secondary outcome [5] 411559 0
The incidence of recurrence of disease – defined as greater than 25% increase and 5 points in skin score from baseline or best result post Autologous Stem cell Transplant (AHSCT), whichever is better post transplant using medical records
Timepoint [5] 411559 0
Analysed at 6 months, yearly up to 10 years post transplant
Secondary outcome [6] 411560 0
The incidence of recurrence of disease measured by a decline in lung function using the following test/tools: spirometry, .lung function test to calculate lung volume (ie the total lung capacity/ residual volume) and lung diffusion capacity
Timepoint [6] 411560 0
Analysed at 6 months, yearly up to 10 years post transplant
Secondary outcome [7] 411561 0
Assessment of adequacy of stem cell collection using 1g/m2 compared to historical controls using medical records and data from studies conducted at St Vincent's Hospital
Timepoint [7] 411561 0
assessed at the conclusion of the study
Secondary outcome [8] 411562 0
Measurement of response to transplant ( ie engraftment, length of stay, transfusion requirements and IV antibiotic use) compared to historical controls using medical records and data from studies conducted at St Vincent's Hospital
Timepoint [8] 411562 0
assessed at the conclusion of the study
Secondary outcome [9] 411563 0
Assessment of immune reconstitution of immune subsets post transplant compared to historical controls using medical records and previous studies conducted at St Vincent's Hospital
Timepoint [9] 411563 0
assessed at the conclusion of the study
Secondary outcome [10] 411564 0
Clinical and laboratory measurement of fertility post transplant through reviewing medical record
Timepoint [10] 411564 0
Assessed 3, 6, 12 monthly then yearly up to 10 years post-transplant
Secondary outcome [11] 416895 0
The incidence of recurrence of disease by measuring cardiac function using echocardiogram, cardiac magnetic scan or Right heart catheter assessment.
Timepoint [11] 416895 0
Analysed at 6 months, yearly up to 10 years post transplant

Eligibility
Key inclusion criteria
For those patients who will receive standard dose regimens (200mg/kg cyclophosphamide):
• Able to provide informed written consent
• 2013 ACR/EULAR classification criteria for SSc
• Disease duration is 5 years from first non-Raynaud’s manifestation
• Progressive interstitial lung disease [ILD] (ILD defined as typical findings on a HRCT chest as determined by a radiologist, with greater than 10% of lung involvement) – where progression is defined between two timepoints as a relative FVC decline of 10%, or a relative FVC decline of 5–9% in association with a DLCO relative decline of 15%, or radiological progression on HRCT
AND/OR
• mRSS is equal to 15 with dSSc skin pattern and progression over the previous 3-12 months of greater than 25% and 5 mRSS points
AND
• Patient has trialled 3-6 months of highly active therapy at discretion of local site (for example, but not limited to: MMF, rituximab, nintedanib, tocilizumab, cyclophosphamide, methotrexate, azathioprine)
• Age 16-49
• Karnofsky grade greater than 60%.
• Negative serology for HIV.
• If hepatitis B +ve - willing to take entacavir for 1 year
• If hepatitis C +ve - must be cleared by anti-viral therapy prior to HSCT
• Negative pregnancy test.
• Absence of severe chronic infection.
• Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age.
• Cardiac LV Ejection Fraction greater than 50%
• Resting mean pulmonary artery pressure (mPAP) equal to 20mmHg
• mPAP less than 30mm/hg after 500mls bolus
• DLCO equal to 40%.
• Normal Cardiac MRI

For those patients who will receive a low dose conditioning with cyclophosphamide 100mg-140mg/kg with/without rituximab:

• Able to provide informed written consent
• 2013 ACR/EULAR classification criteria for SSc
• Disease duration of 5 years from first non-Raynaud’s manifestation
• Progressive interstitial lung disease [ILD] (ILD defined as typical findings on a HRCT chest as determined by a radiologist, with greater than 10% of lung involvement) – where progression is defined between two timepoints as a relative FVC decline of 10%, or a relative FVC decline of 5–9% in association with a DLCO relative decline of 15%, or radiological progression on HRCT
AND/OR
• mRSS equal to 15 with dSSc skin pattern and progression over the previous 3-12 months of greater than 25% and 5 mRSS points
AND
• Patient has trialled 3-6 months of highly active therapy at discretion of local site (for example, but not limited to: MMF, rituximab, nintedanib, tocilizumab, cyclophosphamide, methotrexate, azathioprine)
• Age 50-70 or less than 50 yrs with poor Karnofsky or cardio-respiratory compromise (as per below).
• Karnofsky grade greater than 40%
• Negative serology for HIV.
• If hepatitis B +ve - willing to take entecavir for 1 year
• If hepatitis C +ve – must be cleared by anti-viral therapy prior to HSCT
• Negative pregnancy test.
• Absence of severe chronic infection.
• Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age.
• Ineligible for 200mg/kg cyclophosphamide due to:
o Cardiac LV Ejection Fraction less than 50%
o Resting Pulmonary arterial systolic pressure (PASP) greater than 40mmHg or greater than 45mmHg after 500mls bolus
o Resting Mean pulmonary arterial pressure (mPAP) greater than 20 mmHg or mPAP greater than 30mmHg after 500mls bolus
o Decrease or lack of augmentation of CO after fluid challenge
o Pulmonary vascular resistance greater than 3 Wood units
o Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) less than 40%
o Abnormal Cardiac MRI, eg D-sign of septal bounce or Myocarditis
o Known stable coronary artery disease (greater than 29% stenosis of a major coronary artery or previous therapy for coronary disease).
o Cardiac event (eg: arrhythmia, episode of chest pain, admission to hospital for cardio-respiratory compromise) whilst harvesting haemopoietic stem cells using the protocol of HDCy 1g/m2 (these patients would be withdrawn from the standard protocol and consented to the low dose cohorts).
o Significant smoking history (ever)
Minimum age
16 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
All patients
• Karnofsky 30% or less
• Left ventricular ejection fraction less than 40%
• Constrictive pericarditis or cardiac tamponade
• Uncontrolled severe arrhythmia
• Unstable or severe unrevascularised coronary artery disease
• Pulmonary arterial systolic pressure (PASP) greater than 60mmHg
• Mean pulmonary arterial pressure (mPAP) greater than 40mmHg at rest or mPAP greater than 50mmHg with 500mL fluid bolus
• Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) less than 30%
• Respiratory failure as defined in the endpoints (use of continuous oxygen or partial pressure of oxygen (pO2) less than 60 mmHg or partial pressure of carbon dioxide (pCO2) greater than 50mmHg without oxygen)
• Unwilling to cease smoking permanently prior to mobilisation for at least 12 weeks
• Prior history of malignancy or other current medical condition which in the opinion of the investigators would restrict the ability of the patient to tolerate the procedure.
• Unable to provide informed consent and/or the diagnosis of mental and cognitive deficits which can interfere with the capability of providing the informed consent.
• Major bone marrow failure or condition (such as myelodysplasia) which results in significant neutropenia (less than 1000/ul) or thrombocytopenia (less than 100,000/ul).
• Severe renal disease creatinine clearance less than 40mL/min (measured or estimated)
• Severe liver disease (Bilirubin greater 50umol/l or known cirrhosis)
• Gastric antral vascular ectasia (GAVE) with active bleeding ( For inclusion, patients with GAVE must have treated disease eg with argon laser and have no active bleeding). Immediate pre-conditioning endoscopy should be considered in those with a history of GAVE or anaemia/iron deficiency.
• Gut involvement with systemic sclerosis resulting in malabsorption, chronic diarrhoea or low BMI (less than 20) which in the opinion of the investigators would restrict the ability of the patient to tolerate the procedure
• Uncontrolled infection.

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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
27/03/2023
Actual
21/08/2023
Date of last participant enrolment
Anticipated
1/12/2025
Actual
Date of last data collection
Anticipated
3/12/2035
Actual
Sample size
Target
40
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 22706 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 22707 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 22708 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 22710 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 22711 0
Dandenong Hospital- Monash Health - Dandenong
Recruitment postcode(s) [1] 37985 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 37986 0
5000 - Adelaide
Recruitment postcode(s) [3] 37987 0
6150 - Murdoch
Recruitment postcode(s) [4] 37989 0
3084 - Heidelberg
Recruitment postcode(s) [5] 37990 0
3175 - Dandenong

Funding & Sponsors
Funding source category [1] 311116 0
Hospital
Name [1] 311116 0
St Vincent's Hospital, Sydney
Country [1] 311116 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
390 Victoria St Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 313859 0
None
Name [1] 313859 0
Address [1] 313859 0
Country [1] 313859 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310645 0
St Vincent's Hospital, Sydney
Ethics committee address [1] 310645 0
Ethics committee country [1] 310645 0
Australia
Date submitted for ethics approval [1] 310645 0
26/09/2022
Approval date [1] 310645 0
22/03/2023
Ethics approval number [1] 310645 0
2022/ETH01757

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

Contacts
Principal investigator
Name 118378 0
A/Prof John Moore
Address 118378 0
St Vincent's Hospital, Sydney
390 Victoria St Darlinghurst NSW 2010
Country 118378 0
Australia
Phone 118378 0
+61 2 9355 5656
Fax 118378 0
Email 118378 0
[email protected]
Contact person for public queries
Name 118379 0
Patricia Plenge
Address 118379 0
St Vincent's Hospital, Sydney
390 Victoria St Darlinghurst NSW 2010
Country 118379 0
Australia
Phone 118379 0
+61 2 83824957
Fax 118379 0
Email 118379 0
[email protected]
Contact person for scientific queries
Name 118380 0
Patricia Plenge
Address 118380 0
St Vincent's Hospital, Sydney
390 Victoria St Darlinghurst NSW 2010
Country 118380 0
Australia
Phone 118380 0
+61 2 83824957
Fax 118380 0
Email 118380 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not at this stage


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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