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Trial registered on ANZCTR


Registration number
ACTRN12617000216314
Ethics application status
Approved
Date submitted
7/12/2016
Date registered
9/02/2017
Date last updated
28/09/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase II dose escalation study of cyclophosphamide in haematopoietic stem cell transplantation in severe systemic sclerosis patients unfit for standard dose cyclophosphamide.
Scientific title
A Phase II dose escalation study of cyclophosphamide in haematopoietic stem cell transplantation in severe systemic sclerosis patients unfit for standard dose cyclophosphamide.
Secondary ID [1] 290706 0
The ASSURE study (Autologous Stem transplant in Scleroderma Using Reduced Exposure to cyclophosphamide)
Universal Trial Number (UTN)
Trial acronym
The ASSURE study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autoimmune disorder 301262 0
systemic sclerosis 301263 0
Condition category
Condition code
Inflammatory and Immune System 301022 301022 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible Patients with severe systemic sclerosis not deemed suitable for standard dose cyclophosphamide will be enrolled in the study . Dose finding study whereby 5 patients will be enrolled in cohort 1. Next cohort will be enrolled after 12 months re safety and efficacy. cohort 3 will start 12 moths after cohort 2 reviewed re safety and efficacy reviewed .

Cohort 1: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for the HSCT procedure. Patients will be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on hospital admission. Cyclophosphamide 12.5mg/kg is administered intravenously daily for 2 doses on Day -3, and Day-2 with hyperhydration (100-125 ml/hr isotonic fluid +/- intravenous mesna per 24 hours). Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered intravenously daily for 4 doses from Day -6 to day -3. A test dose of ATG 0.001mg given intradermal will be administered several hours before first dose on Day -6. Methylprednisolone 1mg/kg will be given intravenously for serum sickness prophylaxis on the days of ATG. A minimum of 2 x 106/kg CD34+ cells without manipulation will be infused on Day 0. All patients will receive standard intravenous antibiotics upon neutropenic fever after blood cultures and chest X ray. In order to prevent hypertensive crisis, all Systemic Sclerosis patients will receive captopril to a maximally tolerated dose to maintain systolic blood pressure at 100 systolic. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jejuni, candida albicans and Herpes Zoster respectively for 6 months.

Cohort 2: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for the HSCT procedure. Patients will be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on hospital admission. Cyclophosphamide 25mg/kg is administered intravenously daily for 2 doses on Day -3 and Day -2 with hyperhydration (100-125 ml/hr isotonic fluid +/- intravenous mesna per 24 hours). Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered intravenously once daily for 4 doses from Day -6 to Day -3. A test dose of ATG 0.001mg will be given intradermal on Day -6 several hours before the first dose.. Methylprednisolone 1mg/kg will be given intravenously for serum sickness prophylaxis on the same days as ATG. A minimum of 2 x 106/kg CD34+ cells without manipulation will be infused on Day 0. All patients will receive standard intravenous antibiotics upon neutropenic fever after blood cultures and chest X ray. In order to prevent hypertensive crisis, all Systemic Sclerosis patients will receive captopril to a maximally tolerated dose to maintain systolic blood pressure at 100 systolic. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jejuni, candida albicans and Herpes Zoster respectively for 6 months.

Cohort 3: Within 2-8 weeks of stem cell collection and cryopreservation the patients are to be admitted to St Vincents Hospital for the HSCT procedure. Patients will be placed in a single room and chemo-immunotherapy will be administered via a central venous line placed on Hospital admission. Cyclophosphamide 35mg/kg is administered intravenously daily for 2 doses on Day -3and Day-2 with hyperhydration (100-125 ml/hr isotonic fluid +/- intravenous mesna per 24 hours). Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered intravenously daily for 4 doses from Day -6 to Day-3. A test dose of ATG 0.001mg will be given intradermal several hours pro to first dose. Methylprednisolone 1mg/kg will be given intravenously for serum sickness prophylaxis on the days of ATG. A minimum of 2 x 106/kg CD34+ cells without manipulation will be infused on Day 0. All patients will receive standard intravenous antibiotics upon neutropenic fever after blood cultures and chest X ray. In order to prevent hypertensive crisis, all Systemic Sclerosis patients will receive captopril to a maximally tolerated dose to maintain systolic blood pressure at 100 systolic. Following engraftment, all patients will receive Bactrim 1600mg/800mg, Fluconazole and Valaciclovir for prophylaxis of pneumocystitis jejuni, candida albicans and Herpes Zoster respectively for 6 months.

Patient's regardless of the cohort have a blood test to evaluate any below normal blood results and physical assessment /reviewed by their treating physician weekly for 1 month, then fortnightly then monthly. Assessment using Rodnan skin score. Patient will also complete questionnaires ( VAS, HAQ and SF-36) at the following timepoints; pre HSCT, 3 months, 6 months, 12 months then yearly
Intervention code [1] 296594 0
Treatment: Drugs
Intervention code [2] 296595 0
Treatment: Other
Comparator / control treatment
none
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300436 0
transplant-related mortality
Timepoint [1] 300436 0
within first 100 days post-HSCT
Primary outcome [2] 300437 0
length of hospital stay by review of hospital records
Timepoint [2] 300437 0
number of days from admission to hospital discharge
Primary outcome [3] 300438 0
number of days receiving blood products assessed by review of medical records
Timepoint [3] 300438 0
number of days From HSCT to 100 days post-HSCT
Secondary outcome [1] 329982 0
IV antibiotic use assessed through review of medical records.
Timepoint [1] 329982 0
number of days From HSCT to 100 days post-HSCT
Secondary outcome [2] 329983 0
Assessment of adequacy of stem cell collection using low dose of cyclophosphamide by review of medical records
Timepoint [2] 329983 0
number of stem cell collected at time of plasmapheresis by review of medical records.
Secondary outcome [3] 329984 0
Efficacy of HSCT in lower dose Cyclophopshamide by reviewing physical assessment and assessing skin dexterity using Modified Rodman Skin Score recorded in medical records.
Timepoint [3] 329984 0
3, 6 and 12 months post HSCT
Secondary outcome [4] 331191 0
Measurement of engraftment assessed through blood tests taken daily until discharge and bone marrow biopsy (if applicable) and by review of medical records.
Timepoint [4] 331191 0
number of days From HSCT to 100 days post-HSCT
Secondary outcome [5] 331192 0
transfusion requirements assessed through review of medical records.
Timepoint [5] 331192 0
number of days From HSCT to 100 days post-HSCT
Secondary outcome [6] 331475 0
Efficacy of HSCT in lower dose Cyclophopshamide by patient competing questionnaires to measure pain using VAS scale and quality of life using HAQ and SF-36 questionnaires.
Timepoint [6] 331475 0
3, 6 and 12 months post HSCT

Eligibility
Key inclusion criteria
Able to provide informed written consent
Severe SSc either de novo or unresponsive to previous therapies requiring HSCT (in the opinion of the referring physician)
Age 16-65
ECOG 0,1,2,3.
Negative serology for HIV.
If hepatitis B positive– willing to take entacavir for 1 year
If hepatitis C positive – 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 HDCy using 200mg/kg due to pre-existing cardio-respiratory disease due to
Age greater than 60yrs
Cardiac LV Ejection Fraction less than 50%
Total Lung Capacity less than 50%
Resting mean pulmonary artery pressure (mPAP) greater than 25mmHg
mPAP greater than 30mm/hg after 500mls bolus
DLCO/VA less than 50%.
Abnormal Cardiac MRI
Cardiac event (eg: arrhythmia, episode of chest pain or dysopnoea) whilst harvesting haemopoietic stem cells using the conventional protocol of HDCy 2g/m2 (these patient would be withdrawn from the standard protocol and consented to the low dose cohorts).
Known stable coronary artery disease ( equal to 30% stenosis of a major coronary artery or previous therapy for coronary disease).
Minimum age
16 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Karnofsky 40% or less
Cardiac Ejection fraction less than 40%
mPAP greater than 50mmHg
DLCO/VA less than 30%
Unstable coronary artery disease

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 which results in significant neutropenia (less than 1000/ul) or thrombocytopenia (less than 100,000/ul).

Severe renal (serum creatinine greater than 200hmol/l) or liver disease (Bilirubin greater than 50umol/l or known cirrhosis)

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
Single group
Other design features
3 cohorts, enrol one cohort at a time
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Assuming a 10% adverse event (i.e death due to complications of HSCT) rate is unacceptable, an overall alpha of 0.05 and at least 80% power, a total sample of 15 with 5 participants in each of three cohorts is required.

Stopping rules for the trial are: 1 event in the first cohort, 2 events in the second (of the total 10 participants up to that point) and 3 events in the 15 total participants in the third stage.

This calculation is based on Fleming's procedure.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
7/12/2016
Date of last participant enrolment
Anticipated
10/12/2018
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
15
Accrual to date
10
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 7084 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 14813 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 295133 0
Government body
Name [1] 295133 0
NSW Health
Country [1] 295133 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
St Vincent's Hospital Sydney
390 Victoria st
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 293950 0
None
Name [1] 293950 0
Address [1] 293950 0
Country [1] 293950 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296480 0
St Vincent's Hospital Sydney Human Research Ethics Committee (HREC)
Ethics committee address [1] 296480 0
St Vincent's Hospital Sydney
Research Translational centre
97 105 Boundary st
Darlinghurst NSW 2010
Ethics committee country [1] 296480 0
Australia
Date submitted for ethics approval [1] 296480 0
21/11/2016
Approval date [1] 296480 0
29/11/2016
Ethics approval number [1] 296480 0
SVH 16 221

Summary
Brief summary
Patients with severe systemic sclerosis with cardiac complications requiring a stem cell transplant after their disorder progressing after standard treatment not deemed suitable for standard dose cyclophosphamide can be enrolled into an available cohort group to receive one of 3 different LOW doses of cyclophosphamide

This study aims to reduce Treatment related side effects by reducing the intensity of conditioning, in particular cyclophosphamide dosage, in order to offer the potential benefits of stem cell transplant to patients normally excluded from HSCT whilst potentially maintaining efficacy.

It is hypothesised that a lower dose cyclophosphamide stem cell transplant regimen of 12.5-35mg/kg/day in 3 cohorts will be tolerated with less toxicity than an historical cohort of 50mg/kg/day in patients with severe systemic sclerosis
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71018 0
A/Prof John Moore
Address 71018 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 71018 0
Australia
Phone 71018 0
+61 2 9355 5656
Fax 71018 0
+61 2 9355 5602
Email 71018 0
[email protected]
Contact person for public queries
Name 71019 0
Ms PAtricia Plenge
Address 71019 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 71019 0
Australia
Phone 71019 0
+61 2 9355 5656
Fax 71019 0
+61 2 9355 5735
Email 71019 0
[email protected]
Contact person for scientific queries
Name 71020 0
A/Prof John Moore
Address 71020 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 71020 0
Australia
Phone 71020 0
+61 2 9355 5656
Fax 71020 0
+61 2 9355 5602
Email 71020 0
[email protected]

No information has been provided regarding IPD availability


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.