Myelodysplastic SyndromesPhase 4NCT03598582
Biological Predictive Factors of Response to ESA in Low Risk MDS Patients
A Phase 4 study testing Epoetin Zeta in people with Myelodysplastic Syndromes, run by Association pour la recherche sur les Affections Malignes en Immunologie Sanguine.
Trial summary
In this trial, the investigators would like to understand why a small percentage of patients will be refractory to ESA (independently of International prognostic scoring system (IPSS) and % of blasts). Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Myelodysplastic Syndromes
- What is being tested?
- Epoetin Zeta
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- No sites listed yet
- Study dates
- 1 Jan 2013to 1 May 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- > 18y patients
- with MDS subtypes :
- refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess of blasts (RAEB) with <10 % blasts (according to FAB classification) CMML with white blood cell (WBC) <13.000/mm3
- RA, RARS, RCMD, RAEB-1, CMML-1 with WBC <13.000/mm3 (according to OMS classification), 5q- syndrome
- Low int-1 IPSS score
- With hemoglobin (Hb)<10 g/dL or red blood cell transfusion (RBC) transfusion dependent
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- treated by ESA according to national French recommendations
- without renal insufficiency
- with ECOG PERFORMANCE STATUS <2
Who cannot join
- higher risk MDS (IPSS intermediate-2 or high)
- CMML with >10 % of BM blasts or WBC>13.000/mm3
- Non-controlled hypertension
- Cardio-vascular disease :uncontrolled, angina pectoris, cardiac insufficiency,
- Renal insufficiency : Creatinine clearance<40ml/min
- EPO level>500UI/l
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- Systemic infection or inflammatory chronic disease
- Serum folates<2 ng/mL or vitamin B12 <200 pg/mL
- Other causes of anemia (eg hemolysis, hemorrhage, iron deficiency)
- Pregnancy (positive betaHCG) or nursing
- Women of childbearing age without effective contraception why?
- Hypersensitivity to Darbepoietin alfa or other ESA
- Patient unable to understand the protocol or to follow adequately
- History of epilepsy
- History of thrombosis
- Concomitant thalidomide or lenalidomide treatment
About this study
Official title: Biological Predictive Factors of Response to Erythropoiesis Stimulating Agent (ESA) in Low Risk Myelodysplastic Syndromes (MDS) Patients
In this trial, the investigators would like to understand why a small percentage of patients will be refractory to ESA (independently of International prognostic scoring system (IPSS) and % of blasts). In a retrospective study of the "Groupe Francophone des Myélodysplasies (GFM)" , the investigators showed that about 43% of patients are refractory or will relapse after initial response to ESA and it has been shown that these patients have a poorer survival. The investigators plan to give a 12-week treatment of Epoetin alfa or zeta in low risk MDS patients and measure different biological factors to predict response to ESA:
- evaluation by flow cytometry before and after treatment of the degree of dyserythropoiesis and dysgranulopoiesis which could explain the primary resistance or loss of response of a subset of patients,
- screening by molecular biology of predictive factors of response to ESA,
- Iron homeostasis will be measured via hepcidin, GDF-15 and ferritin levels.
Read the detailed description
Lower risk MDS patients, with LOW and INT-1 IPSS score, with anemia Hb<10g/dl, requiring or not Red blood cel (RBC) transfusions, treated by erythropoiesis stimulating agent (ESA) according to national French recommendations ( epoetin zeta 40000 UI/week in lower risk MDS, <10% blasts, with Hb<10g/dl and sEPO<500UI/l, for 12 weeks).
BM aspirates are collected prospectively at T0 and at W12 of ESA treatment.
BM aspirates will be collected prospectively at inclusion in all 70 patients, after 12 weeks, in 70 patients.
Fresh bone marrow samples will be centralized at Cochin hospital for flow cytometry analysis of dyserythropoiesis and gene sequencing (Hematology laboratory, Cochin, Paris). "Ogata flow cytometry score" will be assessed locally in Mulhouse, Creteil, Tours, Grenoble or Cochin. Patients have been reevaluated at week 12 by flow cytometry "Ogata score".
Blood plasma will be been collected for analysis of GDF-15 and hepcidin, and sent to Cochin (Institut Cochin, Paris). Hepcidin level was measured by LC-MS/MS method in Louis Mourier Hospital.
Red score analysis was done in a centralized manner in Cochin, according to the methods described previously. Basically, it was evaluated on CD36, CD71 CV and Hb level according to the gender.
Genomic studies and Bioinformatic analysis Mutations in a selected panel of 39 genes will be screened in the 70 samples by a Next-Generation Sequencing (NGS) assay.
Sample size justification and Statistical analysis Sample size computation was based on the secondary endpoint which was the response rate. The investigators expected a response rate of 50-60%, therefore about 30 patients will be responders and 30 patients non responders. With 10%-15% of non evaluable biological data, n=70 patients should be included.
- Conditions
- Myelodysplastic Syndromes
- Being tested
- Epoetin Zeta
- Keywords
- myelodysplastic syndromes, erythropoiesis stimulating agents, factors of response
- Medical subject headings
- Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Epoetin ZetaDrug
Also called Retacrit
Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks.
Response has been evaluated at 12 weeks according to IWG 2006 criteria. Patients with response continued on epoetin zeta. In non-responders, the patients have been excluded from the protocol.
| Study group | Role | What they receive |
|---|---|---|
| epoetin zeta | Other | Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks. Receives: Drug: Epoetin Zeta |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of the Red score on the prediction of response to ESA
The flow cytometry (FCM) "Red score" described by Mathis et al, Leukemia 2013, ranges from 0 to 7 and includes CD36 and CD71 CV and Hb levels.
Measured: 5 years
Determination of Ogata FCM score on the prediction of response to ESA
The "Ogata FCM score" described by Ogata et al, Haematologica 2009, ranges from 0 to 4 and includes parameters of dysgranulopoiesis and excess of CD34+ blasts
Measured: 5 years
Determination of the number of molecular gene mutations on the prediction of response to ESA
Gene mutations numbers, assessed by next generation sequencing on a 39 gene panel
Measured: 5 years
Determination of GDF-15 levels on the prediction of response to ESA
Mean and median values of GDF15 (pg/ml) levels
Measured: 5 years
Determination of hepcidin levels on the prediction of response to ESA
Mean and median values of hepcidin (ng/ml)
Measured: 5 years
Secondary outcomes (1)
Response rate to ESA
Response rate will be evaluated by IWG 2006 criteria of erythroid response.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2018
- Study start1 Jan 2013
- Primary completion1 May 2017
- Study completion1 May 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Myelodysplastic SyndromesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- Association pour la recherche sur les Affections Malignes en Immunologie Sanguine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Sophie PARK, MD, PHD, Principal investigator, CHU Grenoble Alpes
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03598582
- Sponsor's protocol ID
- RETA
- Status last verified
- Jul 2018
- First submitted
- 26 May 2018
- Last updated
- 26 Jul 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biological Predictive Factors of Response to Erythropoiesis Stimulating Agent (ESA) in Low Risk Myelodysplastic Syndromes (MDS) Patients
- ClinicalTrials.gov ID
- NCT03598582
- Acronym / sponsor ID
- RETA
- Conditions
- Myelodysplastic Syndromes
- Keywords
- myelodysplastic syndromes, erythropoiesis stimulating agents, factors of response
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- Association pour la recherche sur les Affections Malignes en Immunologie SanguineUniversity, hospital or other
- Study start
- 1 Jan 2013 (actual)
- Primary completion
- 1 May 2017 (actual)
- Study completion
- 1 May 2018 (actual)
- First posted
- 26 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In this trial, the investigators would like to understand why a small percentage of patients will be refractory to ESA (independently of International prognostic scoring system (IPSS) and % of blasts). In a retrospective study of the "Groupe Francophone des Myélodysplasies (GFM)" , the investigators showed that about 43% of patients are refractory or will relapse after initial response to ESA and it has been shown that these patients have a poorer survival. The investigators plan to give a 12-week treatment of Epoetin alfa or zeta in low risk MDS patients and measure different biological factors to predict response to ESA:
- evaluation by flow cytometry before and after treatment of the degree of dyserythropoiesis and dysgranulopoiesis which could explain the primary resistance or loss of response of a subset of patients,
- screening by molecular biology of predictive factors of response to ESA,
- Iron homeostasis will be measured via hepcidin, GDF-15 and ferritin levels.
Detailed description
Lower risk MDS patients, with LOW and INT-1 IPSS score, with anemia Hb<10g/dl, requiring or not Red blood cel (RBC) transfusions, treated by erythropoiesis stimulating agent (ESA) according to national French recommendations ( epoetin zeta 40000 UI/week in lower risk MDS, <10% blasts, with Hb<10g/dl and sEPO<500UI/l, for 12 weeks).
BM aspirates are collected prospectively at T0 and at W12 of ESA treatment.
BM aspirates will be collected prospectively at inclusion in all 70 patients, after 12 weeks, in 70 patients.
Fresh bone marrow samples will be centralized at Cochin hospital for flow cytometry analysis of dyserythropoiesis and gene sequencing (Hematology laboratory, Cochin, Paris). "Ogata flow cytometry score" will be assessed locally in Mulhouse, Creteil, Tours, Grenoble or Cochin. Patients have been reevaluated at week 12 by flow cytometry "Ogata score".
Blood plasma will be been collected for analysis of GDF-15 and hepcidin, and sent to Cochin (Institut Cochin, Paris). Hepcidin level was measured by LC-MS/MS method in Louis Mourier Hospital.
Red score analysis was done in a centralized manner in Cochin, according to the methods described previously. Basically, it was evaluated on CD36, CD71 CV and Hb level according to the gender.
Genomic studies and Bioinformatic analysis Mutations in a selected panel of 39 genes will be screened in the 70 samples by a Next-Generation Sequencing (NGS) assay.
Sample size justification and Statistical analysis Sample size computation was based on the secondary endpoint which was the response rate. The investigators expected a response rate of 50-60%, therefore about 30 patients will be responders and 30 patients non responders. With 10%-15% of non evaluable biological data, n=70 patients should be included.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| epoetin zeta | Other | Drug: Epoetin ZetaPatients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks. |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- > 18y patients
- with MDS subtypes :
- With hemoglobin (Hb)<10 g/dL or red blood cell transfusion (RBC) transfusion dependent
- treated by ESA according to national French recommendations
- without renal insufficiency
Key exclusion criteria (16 listed)
- higher risk MDS (IPSS intermediate-2 or high)
- CMML with >10 % of BM blasts or WBC>13.000/mm3
- Non-controlled hypertension
- Cardio-vascular disease :uncontrolled, angina pectoris, cardiac insufficiency,
- Renal insufficiency : Creatinine clearance<40ml/min
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Epoetin ZetaAlso: RetacritPatients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks. Response has been evaluated at 12 weeks according to IWG 2006 criteria. Patients with response continued on epoetin zeta. In non-responders, the patients have been excluded from the protocol. | Drug | epoetin zeta |
Primary outcome
Determination of the Red score on the prediction of response to ESA
Time frame: 5 years
The flow cytometry (FCM) "Red score" described by Mathis et al, Leukemia 2013, ranges from 0 to 7 and includes CD36 and CD71 CV and Hb levels.
Determination of Ogata FCM score on the prediction of response to ESA
Time frame: 5 years
The "Ogata FCM score" described by Ogata et al, Haematologica 2009, ranges from 0 to 4 and includes parameters of dysgranulopoiesis and excess of CD34+ blasts
Determination of the number of molecular gene mutations on the prediction of response to ESA
Time frame: 5 years
Gene mutations numbers, assessed by next generation sequencing on a 39 gene panel
Determination of GDF-15 levels on the prediction of response to ESA
Time frame: 5 years
Mean and median values of GDF15 (pg/ml) levels
Determination of hepcidin levels on the prediction of response to ESA
Time frame: 5 years
Mean and median values of hepcidin (ng/ml)
1 secondary outcome
Response rate to ESA
Time frame: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jul 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sophie PARK, MD, PHD principal investigator
CHU Grenoble Alpes
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Epoetin Zeta in people with Myelodysplastic Syndromes, run by Association pour la recherche sur les Affections Malignes en Immunologie Sanguine.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of the Red score on the prediction of response to ESA (time frame: 5 years). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jul 2018.