The objective of this trial is to investigate whether Eltrombopag added to standard immunosuppressive treatment increases the rate of early (at three months) complete response and blood counts and can be use as front-line therapy for SAA treatment.
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Rate of Complete response (defined as Hb >10 g/dL, ANC > 1,000/*L and Plt
>100,000 *L) at 3 months since start of treatment in untreated severe AA
patients.
Secondary outcome
1. Time to first hematological response (complete or partial) described by a
cumulative incidence curve (see paragraph 9.6)
2. Time to best hematological response, described by a cumulative incidence
curve (see paragraph 9.6)
3. Time to complete response (see paragraph 9.6)
4. Rates of hematological response (overall, complete, partial) at 6, 12, 18
and 24 months
5. Overall survival (OS) probability; OS is defined as time from treatment
starting (day 1) to death, or last follow-up for patients alive
6. Event-free survival (EFS) probability; EFS is defined as time from treatment
starting to either relapse, death, treatment failure or clonal evolution
(whichever occurs first), or last follow-up for patients alive in response
7. Cumulative incidence of relapse, from first hematological response (complete
or partial) (see paragraph 9.6)
8. Cumulative incidence of clonal evolution (as defined below, see 9.5): AML,
MDS or karyotypic abnormalities (see paragraph 9.6)
9. Cumulative incidence of PNH population occurrence and clinical hemolytic PNH
occurrence (see paragraph 9.6)
10. Cumulative incidence of discontinuation of immunosuppressive therapy
11. Rate of CsA-independent hematological response at 24 months
12. Need for transfusions (packed red cell units and platelet units) and number
of transfusions required from treatment.
13. Need for any supportive care, including hospitalization
14. Quality of life (as assessed by the validated EORTC QLQ-C30
questionnaire)(changes over time and differences between treatment arms)
15. Safety and tolerability of the investigational treatment, including SAE
Background summary
Severe aplastic anemia (SAA) is an hematological disease of the bone marrow
resulting in an impairment of the production of blood cells. As a result of
this disease you are suffering from a lack of all blood cells, possibly leading
to clinical sign and symptoms that may affect your well-being, and may result
in medical complications. Aplastic anemia, especially in its severe form, is
considered a life-threatening disease. Thus, patients diagnosed with SAA
require a prompt and adequate treatment which aims to restore the functioning
of the bone marrow, and thus to reduce the risk of potentially fatal
complications.
The current standard IST for SAA is based on the association of anti-thymocyte
globulin (ATG) and cyclosporine A (CsA). It is well demonstrated that this
treatment may result in clinical response in about two thirds of patients, with
improvement of blood counts beginning around 3 months from the treatment start,
and possibly further improving over time. Recent data have demonstrated that
one specific type of ATG (horse-ATG, commercial brand ATGAM from Pfizer) seems
superior to the other commercially available ATGs, and thus ATGAM, is currently
the recommended preferred ATG for front-line IST in SAA. However, all patients
should continue maintenance IST with CsA for at least 12 months, possibly
tapered very slowly in the subsequent months, even if irrespective of this
long-term maintenance IST about one third of patient may relapse.
Recently, a new drug, eltrombopag, has been investigated for the treatment of
SAA. eltrombopag, is a compound which stimulates the functioning of the bone
marrow independently from IST. It has recently been demonstrated that
eltrombopag has a positive effect as well on the blood cell production.
Study hypothesis: that the experimental treatment will increase the 3 months
response rate up to 21% (by 3 folds, based on the 7%expected in the control
groups at 3 months after treatment start.
Study objective
The objective of this trial is to investigate whether Eltrombopag added to
standard immunosuppressive treatment increases the rate of early (at three
months) complete response and blood counts and can be use as front-line therapy
for SAA treatment.
Study design
Prospective, randomized, multi-center phase III study.
Intervention
Two treatment arms, A and B, where subjects randomisized to arm A will receive
the standard treatment for SAA (hATG+CsA) whereas subjects randomized to arm B
will receive the experimental treatment (hATG+CsA+eltrombopag).
Study burden and risks
The persons who are approached by their treating physician for possible
participation in the RACE trial are diagnosed with severe aplastic anemia and
are not eligible for a bone marrow transplant.I
If they decide to participate in this study, they are assured that they will
receive the, at the moment, best possible treatment for SAA (standard
treatment). This treatment is exactly the same as the treatment that SAA
patients will receive who do not participate in the RACE study. participation
in this study not only offers patients the best treatment for SAA, but also the
possibility of receiving the standard treatment + a drug which has proven to
stimulate the bone marrow function.
The treatments have side effects such as nausea, headache, increased blood
pressure and reduction of kidney- and liver function. The side effects of CsA
are related to increased CsA dose and will therefore be closely monitored to
prevent overdose. ATGAM may, due to its immunesuppressing pharmacological
effect, theoretically lead to an increased risk of infections.
For both drug belonging to the standard treatment, it is accounted that the
subject will experience the same side effects when they decide not to
participate in this study because the standard treatment is equal to the SAA
treatment that patients receive outside of the protocol.
Eltrombopag is generally well tolerated and it has shown an acceptable toxicity
profile. The most common toxicity of eltrombopag pertains to the liver, with
mild to moderate increase of liver testings; for this reasons your biochemical
parameters will be accurately monitored during the study. Nausea, vomiting,
headache are other common adverse events, whereas thromboembolic events are
possible but eventually associated with high platelet counts. Changes can occur
in blood and bone marrow, which can lead to the development of cancer. Patients
will be checked during the study on this changes.
After inclusion of the subject in the study there will be a screening visit to
ensure that the subject is eligible to participate in the study (Pregnancy
test, DEB test). There will be additionally tests performed, next to the
standard SAA diagnosis and physical examination, including: bone marrow
aspirate and biopsy and blood draws. Bone marrow biopsies will be performed at
3 additional visits (6 months; 12 months; and 24 months). If the patient is in
CR at 3 months, this will be confirmed by an additional bone marrow biopsy.
Especially the bone marrow biopsies may be experienced as painful by the
patient. However, this treatment is part of the standard treatment of SAA
patients outside this study.
There will be 22 visits in total during two years of the study. During these
visits blood is drawn from the subject. This is standard for SAA treatment but
the amount of visits is higher when taking part in this study. The volume of
blood drawn from the subject shall thus be higher, as well for additional
testing (genetically) to provide better insights in SAA and to monitor the
treatment progression. The subject has given consent for these additional
samples before inclusion in the study
On four different timepoints during the study (screening visit,6 months, 12
months, 24 months) the subject will be asked to complete a "quality of life"
questionnaire. Questions cover global health status, physical, emotional and
social well being, pain and financial difficulties due to treatment or disease.
This questionnaire may be experienced as emotionally hard since the subject is
confronted with his or her disease (SAA).
Possibly, the subject experiences a disappointment when he or she is randomized
in the standard treatment arm or when there is no complete response after
treatment with eltrombopag.
In case that the subject is randomized in treatment arm A (standard treatment
arm) and there has been no signs of complete response after 6 months, then this
subject will be eligible to receive a treatment with eltrombopag, outside of
the protocol. In the case of relapse or partial response to treatment after 3
months of a subject randomized in treatment arm B (experimental arm), a second
round of treatment with eltrombopag will be started.
Rijnsburgerweg 10
Leiden 2333 AA
NL
Rijnsburgerweg 10
Leiden 2333 AA
NL
Listed location countries
Age
Inclusion criteria
1.Diagnosis of severe or very severe aplastic anemia, defined by ;* At least two of the following:;* Absolute neutrophil counts <0.5 x 10(9)/L (severe) or ;<0.2 x 10(9)/L (very severe);* Platelet counts <20 x 10(9)/L;* Reticulocyte counts <60 x 10(9)/L;* Hypocellular bone marrow (<30% cellularity), without evidences of fibrosis or malignant cells;2.Age * 15 years;;3.Written informed consent;4. Willing and able to comply with all of the requirements and visits in the protocol;5. Understands that they can be randomised to either treatment arm;6. Negative pregnancy test for women of child bearing age;7. Written acceptance to use contraception (hormonal or barrier method of birth control; abstinence) for the entire duration of study participation.
Exclusion criteria
1.Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab);2.Eligibility to a sibling allogeneic stem cell transplantation ;3.Evidence of a myelodysplastic syndrome, defined by the presence of myelodysplastic features, excess of blasts or karyotypic abnormalities typical of MDS (according to revised WHO 2008 ;criteria) , as well as other primitive marrow disease. Patients with diagnosis of AA with cytogenetic abnormalities which are recurrent in MDS (according to revised WHO 2008 criteria) should be included in this category, and are not eligible for the study; patients with del(20q), +8 and *Y are not included in this category, and thus are eligible for this study. The list of karyotypic abnormalities which qualifies for the diagnosis of MDS are listed in the Appendix 1.;4.History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita) ;5.History of malignant tumors with active disease within 5 years from enrollment and/or previous chemo-rediotherapy;6.Previous history of stem cell transplantation;7.Treatment with cyclosporin A; <4 weeks of cyclosporin A treatment before enrollment, wash out period of 2 weeks before enrollment;8.CMV viremia, as defined by positive PCR or pp65 test;9.WHO performance status *3;10.Pregnant or breast feeding patients;11.Patients with hepatic, renal or cardiac failure, or any other life-;threatening concurrent disease;12.Patients with HIV infection;13.Patients without social health care assistance;14.Participation in another clinical trial within 1 month before the start of this trial;15.Subjects with known hypersensitivity to any of the component medications
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000363-40-NL |
| ClinicalTrials.gov | NCT02099747 |
| CCMO | NL50426.058.15 |