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Trial registered on ANZCTR


Registration number
ACTRN12613000721707
Ethics application status
Approved
Date submitted
14/06/2013
Date registered
1/07/2013
Date last updated
12/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Eltrombopag and Early Refractory Immune Thrombocytopenia (ITP)
Scientific title
A Multicentre, single arm, open label study evaluating the efficacy and safety of Eltrombopag (Revolade TM)) in patients with early refractory Immune Thrombocytopenia within 6 months of diagnosis
Secondary ID [1] 282669 0
NIL
Universal Trial Number (UTN)
U1111-1144-4732
Trial acronym
SPRITE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Immune Thrombocytopenia 289371 0
Condition category
Condition code
Blood 289703 289703 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open label study, all patients will receive an oral tablet dose daily of eltrombopag based on their platelet
count and ethnicity (patients from Japan have been shown to have an increased eltrombopag serum level by
approximately 80% compared to Cuacasian patients). All patients will receive the study drug for 12 weeks and
assessed for bleeding episodes and platelet count. Patients deemed to have responded will stay on eltrombopag
with the opportunity to dose reduce to the lowest possible dose whilst maintaining a response over time. The study
will run for 130 weeks (2 1/2 years) for those who continue to respond and the availability of the medication to
patients beyond that.

The starting dose of eltrombopag will depend on the patients platelet count. If the patient platelet count is less than 10 (x109/L) they will commence on Eltrombopag 75mg (or 50mg if they are of East Asian heritage) per day. If the platelet count is greater than 10 (x109/L) they will commence on Eltrombopag 50mg (or 25mg if of East Asian heritage) per day. This dose may be adjusted up to a maximum of Eltrombopag 150mg (or 100mg for patients of East Asian heritage) per day. Once the patient platelet count is stable the steroid dose and the eltrombopag dose is reduced to the lowest possible dose while maintaining acceptable platelet levels.

All patients with early refractory ITP will remain on a minimum steroid dose of oral prednisolone 25mg daily for 2 weeks after the initiation of Eltrombopag. The prednisolone can be progressively weaned to zero over the subsequent 6 weeks if clinically appropriate.
Patients with relapsed ITP will remain on Prednisolone, 10mg or less for 2 weeks after the initiation of Eltrombopag. The prednisolone can be progressively weaned to zero over the subsequent 6 weeks if clinically appropriate. Subsequent relapse of ITP to MR in this context in patients who have demonstrated steroid response in the past should be managed with resumption of prednisolone to a maximum of 10mg/day; dose escalation of Eltrombopag will only be considered in this context if MR is not achieved or there are steroid complications (e.g., unstable diabetes).

Patients will be monitored weekly for the first 12 weeks and assessed for bleeding episodes and adverse events by physical examination and laboratory testing, inlcuding full blood counts. After this time patients deemed to have responded to treatment will be assess monthly. Patients will be expected to return unused or empty medication containers for drug accountability purposes.
Intervention code [1] 287333 0
Treatment: Drugs
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 289802 0
Overall response rate (ORR) at Week 12, as defined by the proportion of patients achieving a CR, PR and MR. Note that achievement of at least a MR is thought to be clinically relevant.
Timepoint [1] 289802 0
Week 12 of treatment with eltrombopag
Secondary outcome [1] 303266 0
Time to response (TTR), defined as time from first Eltrombopag to time of onset of MR/PR/CR;
Timepoint [1] 303266 0
time of onset of MR/PR/CR
Secondary outcome [2] 303267 0
CR, PR and MR rates to Eltrombopag treatment at Week 4,8 and 26 by assessment of bleeding episodes and platelet count
Timepoint [2] 303267 0
Week 4,8 and 26
Secondary outcome [3] 303268 0
Time to CR, PR, and MR by assessment of bleeding episodes and platelet count
Timepoint [3] 303268 0
Week 4, 8 and 26
Secondary outcome [4] 303269 0
Duration of CR, PR, and MR by assessment of bleeding episodes and platelet count
Timepoint [4] 303269 0
at assessment points week 12, 26, 52, 110.
Secondary outcome [5] 303270 0
Time to initiation of new ITP therapy and/or increase in dose of existing ITP therapy, including date on which decision made in relation to splenectomy. This will be determined by bleeding episodes, platelet count and requirement to initiatate other ITP therapy.
Timepoint [5] 303270 0
week 12, week 25, week 52
Secondary outcome [6] 303272 0
Therapeutic Response (Minimal/Partial/Complete reduction of concomitant ITP therapy) by assessing patients overall condition including bleeding episodes and platelet count
Timepoint [6] 303272 0
week 26
Secondary outcome [7] 303273 0
Incidence and severity of adverse events on Eltrombopag up to the end of week 12. Expected adverse events that may occur include abnormal liver function, nausea and vomiting, rash, myalgia, musculoskeletal pain, back pain, pharangytis and urinary tract infection, thrombotic/thromboembolic complications, bleeding following eltrombopag discontinuation and bone marrow reticulin formation and risk of bone marrow fibrosis.
Timepoint [7] 303273 0
Day 84 + 30 days by assessing the patients overall condition with physical examination and blood tests
Secondary outcome [8] 303274 0
The natural history of ITP in response to tapering of Eltrombopag after 26 weeks in patients with at least a stable PR, defined as a platelet greater than 50x109/L on a stable or reducing dose of Eltrombopag over the prior 8 weeks
Timepoint [8] 303274 0
8 weeks post reducing dose, after 26 weeks

Eligibility
Key inclusion criteria
ALL of the following criteria must be met to be eligible:
1. Documented diagnosis of ITP (by exclusion) according to the ASH guidelines,
2. Age greater than or equal to 18 years,
3. Primary refractory ITP with a platelet count less than 30x109/L despite an average daily dose of at least 1mg/kg (or 75mg in patients greater than 75kg) prednisolone for at least 2 weeks OR
Recurrent ITP after an initial response to steroids which requires 10mg or more of prednisolone per day and, or, recurrent doses of IVIG to maintain a platelet count of 30x109/L or greater (within 6 months of diagnosis, noting that above this threshold, steroid toxicity with prolonged therapy is unacceptable).
4. Failure of prior splenectomy will NOT be an inclusion criteria, noting that (a) splenectomy will not be appropriate in some patients due to surgical risk and (b) particularly in younger patients, avoiding splenectomy may be desirable if the natural history of acute ITP in a subset is ultimately to resolve
Patients with ITP fulfilling the above criteria in the setting of HIV with CD4 count greater than 0.5x109/L undetectable viral load are eligible, as will be patients with secondary causes of ITP such as auto-immune disorders, lymphoproliferative disease and hepatitis C, subject to the exclusion criteria below.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients presenting with any of the following will be excluded from the study:
1. Failure or inability to provide informed consent.
2. Geographic inaccessibility prohibiting follow-up.
3. Treatment with rituximab within 8 weeks prior to consent.
4. Predicted survival of less than 12 months.
5. Patients with multisystem autoimmune disease, lymphoproliferative disorders or hepatitis C anticipated who receive disease specific therapy within the first 12 weeks (e.g., chemotherapy, cyclophosphamide, anti-viral therapy)
6. Drug-induced thrombocytopenia.
7. Known hypersensitivity to thrombopoietin Receptor agonists.
8. Pregnant or breast-feeding.
9. Reproductive potential but not willing to adhere to adequate contraception from screening and for one year after first dose of Eltrombopag.
10. HIV with CD4 count less than 500 and detectable viral load.
11. Symptomatic clinical significant arterial or venous thrombosis within 6 weeks prior to consent. Note that patients requiring anti-platelet or anti-thrombotic therapy for an event prior to 6 weeks will be eligible, with the intention that this therapy will be resumed once the platelet count reaches an appropriate level (in the order of 50x109/L for most patients). However, patients at very high risk of thrombosis e.g., antiphospholipid syndrome with prior thromboses or multiple thrombophilia risk factors will not be eligible
12. Participation in another clinical trial with any investigational drug within 30 days prior to study screening.

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)
all patients will receive the standard doses of eltrombopag as appropriate for their platelet count and ethnicity
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The overall response rate (ORR) at week 12 is calculated as the number of patients who achieve an overall response at week 12 divided by the number of patients registered on the study who have either had a week 12 assessment or discontinued for any reason before week 12.
Recruitment will be paused after the 19th patient has been registered in the first stage, unless a sufficient number of responders (7 or more) have already been reported to thereby warrant continuation of recruitment into the second stage. If the trial terminates for futility at the end of the first stage, the maximum likelihood estimate (MLE) of the ORR will be reported.
If the trial continues to the second stage, recruitment will continue until 39 patients have been registered and evaluated for the primary efficacy endpoint. This number represents a feasible sample size, with respect to cost and accrual, but it is acknowledged that it is not sufficient to provide tight confidence intervals for the ORR. Nevertheless, analysis suggests that if 17 or more of the 39 patients respond, it can be concluded, with 95% confidence that the true ORR exceeds 30%.
If the second stage is completed, the p-value for the one-sided test and a 90% two-sided confidence interval will be reported as well as the ORR rates observed in each stage and the MLE of the ORR (Koyama, T. and Chen, H. (2008) Proper inference from Simon’s two-stage designs. Statistics in Medicine, 27, pp. 3145-3154).
The secondary endpoints that are also response rates will be analyzed in the same manner as the primary endpoint. Time-to-event endpoints and durations of response will be summarized using the Kaplan-Meier method. Details will be given in the Statistical Analysis Plan that will be established prior to the date of the database lock for the analysis of the pThe null hypothesis (H0) for the primary endpoint is that the ORR is 30% or less. The alternative hypothesis (H1) is that the ORR is greater than 30% and we require at least 80% power for rejection of the null hypothesis when the actual ORR is greater than or equal to 50%, a rate which we regard as an encouraging activity profile. A one-sided binomial test at the 5% significance level will be used to test:
H0: ORR equals 30% VERSUS H1: ORR greater than 30%
A Simon’s two-stage minimax design will be used for this trial. The total sample size is 39 patients. The trial will be stopped after the first stage of 19 patients should less than or equal to 6 patients achieve the primary endpoint by week 12. The design provides a 5% probability (alpha) that the trial will erroneously conclude that Eltrombopag is sufficiently promising when the true response rate is actually less than or equal to 30%, and a 20% probability (80% power) that the trial will erroneously reject Eltrombopag for further study if the true response rate is actually greatert han or equal to 50%.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/07/2013
Actual
27/02/2014
Date of last participant enrolment
Anticipated
1/06/2016
Actual
9/02/2016
Date of last data collection
Anticipated
6/08/2018
Actual
7/08/2018
Sample size
Target
39
Accrual to date
Final
39
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 1125 0
The Alfred - Prahran
Recruitment hospital [2] 1126 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 1127 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 6963 0
3004 - St Kilda Road Melbourne
Recruitment postcode(s) [2] 6964 0
3168 - Clayton
Recruitment postcode(s) [3] 6965 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 287450 0
Commercial sector/Industry
Name [1] 287450 0
Novartis Pharmaceuticals Australia Pty Limited Oncology
Country [1] 287450 0
Australia
Primary sponsor type
Hospital
Name
Alfred Health
Address
Commercial Road
Melbourne 3004
VICTORIA
Country
Australia
Secondary sponsor category [1] 286193 0
None
Name [1] 286193 0
Address [1] 286193 0
Country [1] 286193 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289426 0
The Alfred Health Human Ethics Committee
Ethics committee address [1] 289426 0
Commercial Road
Melbrourne 3004
VICTORIA
Ethics committee country [1] 289426 0
Australia
Date submitted for ethics approval [1] 289426 0
19/06/2013
Approval date [1] 289426 0
20/09/2013
Ethics approval number [1] 289426 0
HREC/13/Alfred/12

Summary
Brief summary
The aim of this study is to assess the effectiveness and safety of using Eltrombopag in patients with early refractory
ITP. Early refractory ITP is when the ITP is not responding to standard therapy within 6 months of diagnosis.
Eltrombopag is approved in Australia to treat severe chronic ITP however it is not approved for use in early refractory
ITP. Personal experience provided by doctors who have used this medication indicate that as well as being effective
in treating patients with chronic severe ITP, it might also be effective when treating patients in the earlier stages of
ITP when initial steroid therapy is no longer adequately working.
This is an open label study, all patients will receive an oral tablet dose daily of eltrombopag based on their platelet
count and ethnicity (patients from Japan have been shown to have an increased eltrombopag serum level by
approximately 80% compared to Caucasian patients). All patients will receive the study drug for 12 weeks and
assessed for bleeding episodes and platelet count. Patients deemed to have responded will stay on eltrombopag
with the opportunity to dose reduce to the lowest possible dose whilst maintaining a response over time. The study
will run for 130 weeks (2 1/2 years) for those who continue to respond and there will be availability of the medication to
patients beyond that. Overall response will be assessed at week 12 and defined as the achievement of CR, PR and MR. Time to response and duration of response and alternative treatment free survival will also be assessed. Therapeutic
response will be assessed at week 26.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40750 0
A/Prof Huyen Tran
Address 40750 0
Ronald Sawers Heamophilia Centre
Level 1 South Block
The Alfred
Commercial Road
Melbourne 3004
VICTORIA
Country 40750 0
Australia
Phone 40750 0
+61 3 9076 2179
Fax 40750 0
Email 40750 0
[email protected]
Contact person for public queries
Name 40751 0
Christine Mazis
Address 40751 0
Malignant heamatology and Stem Cell Transplantation Service
The Alfred
Level 1 South Block
Commercial Road
Melbrourne 3004
VICTORIA
Country 40751 0
Australia
Phone 40751 0
+61 3 9076 7136
Fax 40751 0
Email 40751 0
[email protected]
Contact person for scientific queries
Name 40752 0
Huyen Tran
Address 40752 0
Ronald Sawers Heamophilia Centre
Level 1 South Block
The Alfred
Commercial Road
Melbourne 3004
VICTORIA
Country 40752 0
Australia
Phone 40752 0
+61 3 9076 2179
Fax 40752 0
Email 40752 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



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