E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with IPSS low or intermediate-1 risk myelodysplastic syndrome (MDS) and thrombocytopenia |
Patients atteints d'un syndrome myélodysplasique de risque faible ou intermédiaire-1 selon l'IPSS et de thrombocytopénie |
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E.1.1.1 | Medical condition in easily understood language |
Patients with low or intermediate-1 risk myelodysplastic syndrome (MDS) and decrease in functional platelet cells |
Patients atteints d'un syndrome myélodysplasique de risque faible ou intermédiaire-1 et de thrombocytopénie |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068361 |
E.1.2 | Term | MDS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to investigate prospectively whether the current TPO level based response model can predict response to romiplostim in thrombocytopenic patients with IPPS low/int-1 MDS |
Étudier de manière prospective l’existence d’un modèle prédictif de réponse au Romiplostim en fonction du dosage initial de TPO et de l’historique transfusionnel chez les patients thrombopéniques SMD de risque faible ou int-1 selon l’IPSS |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are Safety, bleeding events, AML evolution, peripheral blasts during therapy,
identification of molecular parameters associated with response and progression |
Évaluer:
- La toxicité et la tolérance au produit
- Les évènements hémorragiques
- Le taux de transformation en LAM
- L’évolution du pourcentage de blastes circulants pendant la période de traitement
- Identifier les paramètres moléculaires associés à une réponse ou à la progression
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet the following inclusion criteria tobe eligible for the study,
1. Must understand and voluntarily sign an informed consent form
2. Age > 18 years at the time of signing the informed consent form
3. Must be able to adhere to the study visit schedule and other protocol requirements
4. Diagnosis of MDS using the WHO classification for myeloid neoplasms (Vardiman et al, 2002) as assessed during the screening period
5. Per MDS IPSS, low or intermediate-1 risk MDS as assessed during the screening period
6. The mean of the 2 platelet counts taken within 4 weeks prior to stratification must be:
• ≤ 30 x 109/L (with no individual count > 30 x 109/L during the screening period), with or without a history of bleeding associated with the diagnosis of MDS, OR
• < 50 x 109/L (with no individual count >60 x 109/L during the screening period), with a history of bleeding associated with the diagnosis of MDS
(A standard of care platelet count taken prior to Informed consent may be used as 1 of the 2 counts taken within 4 weeks prior to randomization)
7. Adequate liver function, as evidenced by ALT ≤ 3 times the laboratory normal range, AST ≤ 3 times the laboratory normal range and total bilirubin ≤ 2 times the laboratory normal range
8. Bone marrow aspirate (central diagnostics) with cytogenetics (local) within 8 weeks of starting first dose of investigational product
9. Female subjects of childbearing potential† must:
o Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy and for 4 weeks after the end of study drug therapy, even if she has amenorrhoea |
Les patients doivent remplir tous les critères suivants pour participer à l’étude :
- Les patients doivent comprendre et signer le consentement éclairé
- Les patients doivent être capables de se rendre aux visites médicales nécessaires à cette étude et adhérer au suivi protocolaire
- Âge 18 ans et plus
- SMD (OMS 2008), risque faible ou int-1 avec blastes médullaires < 5%
- 2 bilans plaquettaires disponibles dans les 4 semaines avant la stratification et à distance de 7 jours minimum depuis la dernière transfusion de plaquettes: Un des 2 bilans peut être antérieur à la date de signature du consentement.
Avec taux de plaquettes ≤ 30 G/L, sans aucun résultat supérieur à 30 G/L pendant la période de screening associé ou non à un antécédent hémorragique lié au SMD
OU
Avec un taux de plaquettes < 50 G/L, sans aucun résultat supérieur à 60 G/L pendant la période de screening ET associé à un antécédent hémorragique lié au SMD
- Une fonction hépatique adéquate définie par : ALAT & ASAT ≤ 3 x LSN et Bilirubine totale ≤ 2 x LSN
- Un myélogramme et un caryotype dans les 8 semaines avant la première administration du Romiplostim (sous réserve de disponibilité du matériel nécessaire à la relecture centralisée)
- Les femmes en âge de procréer doivent:
Utiliser une contraception efficace sans interruption (4 semaines minimum avant et 2 mois après la période de traitement par Romiplostim)
Accepter de réaliser un test de grossesse (sensibilité minimal à 25mUI/ml) dans les 3 jours minimum avant le début de traitement
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating females
2. IPSS intermediate-2 or high-risk
3. ≥ 5% blasts in the bone marrow as determined by central morphology during screening
4. Previous treatment with any thrombopoietic growth factor
5. Prior history of hematopoietic stem cell transplantation
6. Active or uncontrolled disease including infections or cancer
7. Unstable angina, congestive heart failure (NYHA > class II), uncontrolled hypertension
8. History of arterial thrombosis (eg, stroke or transient ischemic attack) within the past year
9. History of venous thrombosis that currently requires anti-coagulation therapy
10. Received IL-11 within 4 weeks of the first dose of investigational product
11. Receipt of G-CSF, peg-G-CSF, or GM-CSF within 4 weeks of the first dose of investigational product
12. Planned receipt of peg-G-CSF or GM-CSF after the first dose of investigational product
13. Subjects of reproductive potential who are not using adequate contraceptive precautions, in the judgment of the investigator. The sponsor recommends double barrier contraception is used for all applicable patients enrolled on this study. A double barrier method is defined as 2 methods of contraception, for example 2 actual barrier methods, or 1 actual barrier method and 1 hormonal method.
14. Known hypersensitivity to any recombinant E coli-derived product (eg, Infergen, Neupogen, Somatropin, and Actimmune)
15. Inability to comply with study procedures.
16. Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s)
17. Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study.
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- Femmes enceintes ou allaitantes
- SMD de score IPSS int-1 avec blastose médullaire ≥ 5%, int-2 ou haut risque
- Taux de blastes médullaires au screening ≥ 5% sur la relecture centralisée
- Traitement antérieur par un facteur de croissance de la thrombopoïétine (TPO) ou autre agoniste TPO
- Antécédents de greffe de cellules souches hématopoïétiques, de leucémie, d’anémie aplasique ou de pathologie de la moelle osseuse autre que le SMD
- Maladie active ou non contrôlée (incluant infections ou cancer)
- Angine de poitrine instable, insuffisance cardiaque congestive (NYHA > II), hypertension non contrôlée
- Antécédent de thrombose artérielle dans l’année précédant le screening
- Antécédent de thrombose veineuse nécessitant un traitement par anticoagulant
- Antécédent de traitement par VIDAZA (IV, SC)
- Traitement par REVLIMID, agent stimulant l’érythropoïèse, ou facteurs de croissance (Peg-GSCF, GCSF, GM-CSF, IL-11), sans wash out de 4 semaines avant la 1ère administration de Romiplostim
- Hypersensibilité ou allergie à un produit dérivé de la bactérie E. coli (Nplate, Infergen, Neupogen, Somatropin, Actimmune)
- Patient sans wash-out de 30 jours au minimum depuis la dernière administration d’un traitement à l’étude
- Condition médicale ou psychiatrique empêchant le suivi de l’essai
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E.5 End points |
E.5.1 | Primary end point(s) |
• Hematologic improvement of platelets (HI-P) after 4 months on therapy |
Amélioration plaquettaire après 4 mois de traitement |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 4 months on therapy |
après 4 mois de traitement |
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E.5.2 | Secondary end point(s) |
• Cumulative hematologic improvement of platelets (HI-P), erythrocytes (HI-E) and neutrophils (HI-N)
• The incidence of disease progression to higher stage MDS or AML
• Increase of peripheral blasts during therapy
• Association of the presence of certain mutations with disease progression in a retrospective analysis
• Incidence of bleeding events
• Type, incidence and severity of all adverse events including clinically significant changes in laboratory values
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- Les améliorations plaquettaires, érythroïdes ou neutrophiles
- L’incidence de progression en LAM ou SMD de haut risque
- L’augmentation de la blastose sanguine
- L’association entre la présence de certaine mutation et la progression de la maladie (Analyse rétrospective)
- L’incidence des évènements hémorragiques
- Le type, l’incidence et la sévérité des évènements indésirables
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of study for all patients |
sortie d'étude de tous les patients |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
tous les patients recevront le traitement par Romiplostim, stratification en 3 groupes |
each patient receives IMP (Romiplostim), patients are stratified into 3 groups |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 48 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |