Conditions: Myelodysplastic Syndromes
Keywords: MDS classified as IPSS low/int-1
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
There are currently no licensed drugs in the EU to treat thrombocytopenia in MDS patients classified as IPSS low/int-1. Prior studies with romiplostim (a TPO receptor agonist) in MDS found that baseline concentration of TPO as well as transfusion history were predictive of subsequent response in a retrospective model. The current prospective study has the aim to explore whether both pretreatment variables (endogenous TPO, TPO-level, platelet transfusion history) can predict the response to subsequent short-term treatment with romiplostim.

Detailed description:
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies of the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis, progressive bone marrow failure, and the propensity to transform to acute myeloid leukemia (AML) (Malcovati et al., 2013).

There are currently no licensed drugs in the EU to treat thrombocytopenia in MDS patients classified as IPSS low/int-1. Prior studies with romiplostim (a TPO receptor agonist) in MDS found that baseline concentration of TPO as well as transfusion history were predictive of subsequent response in a retrospective model.

Classically, MDS is associated with apoptosis and excessive proliferation, resulting in a combination of a hyper-cellular marrow and peripheral cytopenia. The rationale for using romiplostim in MDS is to stimulate normal progenitor cells to increase platelet counts. Upon correction of thrombocytopenia, responding MDS patients should have a decreased risk of bleeding and a reduction in platelet transfusions (Giagounidis et al., 2014). This reduction in platelet transfusions may in turn decrease the risks of alloimmunization and the resultant morbidity and costs associated with that condition.

Arms:
arm 1: Stratification into group 1 if Score (Baseline-TPO Level and previous thrombocyte transfusions) are +3

TPO based model to predict subsequent response to romiplostim in MDS patients with IPSS Low/Int-1 according to a model developed by Sekeres et. al./ BJH 2014 arm 2: Stratification into group 2 if Score (Baseline-TPO Level and previous thrombocyte transfusions) are -1 or -2

TPO based model to predict subsequent response to romiplostim in MDS patients with IPSS Low/Int-1 according to a model developed by Sekeres et. al./ BJH 2014 arm 3: Stratification into group 3 if Score (Baseline-TPO Level and previous thrombocyte transfusions) are -6

TPO based model to predict subsequent response to romiplostim in MDS patients with IPSS Low/Int-1 according to a model developed by Sekeres et. al./ BJH 2014

Interventions: intervention 1: N-Plate / romiplostim
Intervention descriptions: intervention 1: medical intervention in 3 patient groups (MDS patients with IPSS Low/Int-1) that are stratified according to their baseline TPO-Level and previous transfusions

Protocol document:
Prot_SAP_000.pdf: 
Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 1 of 11 
 
SYNOPSIS 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Title of Study: 
Prospective validation of a predictive model of response to romiplostim in patients with IPSS low or 
intermediate-1 risk myelodysplastic syndrome (MDS) and thrombocytopenia – the EUROPE trial 
Substantial protocol changes:  
The study was conducted according to the Clinical Study Protocol version 3.0 dated 05 Mar 2015 
and the following amendments: 
• 
Version 4.0 dated 20 May 2015: included minor specifications of the AML progression, HI-N 
response definition and extension of the screening period 
• 
Version 5.0 dated 10 Jun 2017: included specification of visit assessments, statistical 
distributions of patients in the strata and instructions for reconstitution of the study drug 
• 
Version 6.0 dated 30 Aug 2019: re-calculation of sample size due to poor recruitment in two of 
the three study arms, update of addresses and contact information 
Investigators and study centre(s): 
Prof. Dr. Uwe Platzbecker 
Universitätsklinikum Dresden 
Medizinische Klinik und Poliklinik I 
 
 Dresden, Germany 
Prof. Dr. Aristoteles Giagounidis 
Marien Hospital Düsseldorf GmbH 
 
 
Innere Medizin und Hämatologie 
 
 Düsseldorf, Germany 
Prof. Dr. Georgia Metzgeroth 
Universitätsklinikum Mannheim 
Medizinische Klinik III Hämatologie und 
Internistische Onkologie 
 
 Mannheim, Germany 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 2 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
PD Dr. Katharina Götze 
Klinikum Rechts der Isar TU München 
III Med. Klinik und Poliklinik 
 
 
 München, Germany 
Dr. Marie-Luise Hütter-Krönke 
Universitätsklinikum Ulm 
Zentrum für Innere Medizin 
Klinik für Innere Medizin III 
 
 Ulm, Germany 
PD Dr. Michael Heuser 
Medizinische Hochschule Hannover 
Klinik für Hämatologie, Hämostaseologie, 
Onkologie und Stammzelltransplantation 
 
 Hannover, Germany 
Dr. Stefani Parmentier 
Rems-Murr-Klinik Winnenden 
Abteilung für Hämatologie, Onkologie und 
Palliativmedizin 
 
 Winnenden, Germany 
PD Dr. Mathias Hänel 
Klinikum Chemnitz gGmbH 
Klinik für Innere Medizin III 
 
 Chemnitz, Germany 
PD Dr. Haifa Kathrin Al-Ali 
Universitätsklinikum Halle/Saale 
Klinik für Innere Medizin IV 
Onkologie/Hämatologie/ Hämostaseologie 
 
 
 Halle/Saale, Germany 
Pr Pierre Fenaux 
Service d´hématologie Sénior, Hôpital Saint-Louis 
 
 
 Paris, France 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 3 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Dr. Agnes Guerci-Bresler 
CHU Brabois 
Hématologie Clinique 
 
 Vandoeuvre-les-Nancy, France 
Dr. Marie-Pierre Gourin 
CHRU de Limoges – Hôpital Dupuytren 
Service d’Hématologie Clinique et Thérapie 
Cellulaire 
 
 Limoges, France 
Dr. Pascale Cony-Makhoul 
Centre Hospitalier Annecy Genevois 
Service d'Hématologie Clinique 
 
 Pringy, France 
Dr. Aspasia Stamatoullas 
Centre Henri Becquerel 
Département d’Hématologie 
 
 Rouen, France 
Pr Eric Wattel 
Centre Hospitalier Lyon-Sud 
Service d’Hématologie Clinique 
 
 
 Pierre-Bénite, France 
Pr Mathilde Hunault-Berger 
CHU d’Angers 
Service des Maladies du sang 
 
 Angers, France 
Dr. Bohrane Slama 
CH Henri Duffaut d'Avignon 
Service d’Hématologie Oncologie 
 
 Avignon, France 
Dr. Sophie Dimicoli-Salazar 
CHU de Haut-Lévèque 
Centre F. Magendie 
Service des Maladies du sang 
 
 Pessac, France 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 4 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Dr. Kamel Laribi 
CH Le Mans 
Service d'Onco-Hématologie 
 
 Le Mans, France 
Dr. Loic Fouillard 
Centre Hospitalier de Meaux 
Service d’Hématologie 
 
 Meaux, France 
Pr Sophie Park 
CHU de Grenoble 
Clinique Universitaire d’Hématologie 6eA 
 
 Grenoble, France 
Dr. Stefan Wickenhauser 
CHU de Nîmes 
Service d’Hématologie Clinique et Oncologie 
Médicale 
 
 Nîmes, France 
Dr. Laurence Legros 
Hôpital Archet 1 
Service d’Hématologie Clinique 
 
 
 Nice, France 
Dr. Stéphane Cheze 
CHU Côte de Nacre 
Service d’Hématologie Clinique 
 
 Caen, France 
Dr. Jose Miguel Torregrosa Diaz 
CHU de Poitiers 
Service Onco-Hématologie et Thérapie Cellulaire 
 
 Poitiers, France 
Pr Emmanuel Gyan 
Hôpital Bretonneau de Tours 
Service d’Hématologie Clinique 
 
 Tours, France 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 5 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Dr. Benoit Renzis 
CHU Estaing 
Service d’Hématologie Clinique 
 
 Clermont Ferrand, France 
Dr. Lisa Willems 
Hôpital Cochin 
Service d’Hématologie Clinique 
 
 Paris, France 
MUDr. Anna Jonásková 
Charles University General Hospital 
 
Praha 2, 12800, Czech Republic 
Publication (reference) 
Platzbecker U, Kubasch AS, Giagounidis A, et al. Biomarkers of response to romiplostim in patients 
with lower-risk myelodysplastic syndrome (MDS) and thrombocytopenia – results of the EUROPE 
trial by the EMSCO network. Blood 2019; 134 (Suppl 1): 2998. 
Kubasch AS, Giagounidis A, Metzgeroth G, et al. A molecular-based response prediction model to 
romiplostim in patients with lower-risk MDS and severe thrombocytopenia. Blood 2020; 136  
(Suppl 1): 44-45. 
Kubasch AS, Giagounidis A, Metzgeroth G, et al. Prospective Validation of a Biomarker-Driven 
Response Prediction Model to Romiplostim in Lower-Risk Myelodysplastic Syndromes – Results of 
the EUROPE Trial by EMSCO In preparation, submission to Leukemia planned for 04/2022 
Studied period (years): 
6 
Phase of development: 
date of first enrolment: 
21 May 2015 
Phase II 
date of last completed: 
01 Jul 2021 
Objectives: 
Primary: to investigate prospectively whether the current thrombopoietin (TPO) level based 
response model can predict response to romiplostim in thrombocytopenic patients with 
international prognostic scoring system (IPSS) low/int-1 MDS 
Secondary: Safety, bleeding events, acute myeloid leukemia (AML) evolution, peripheral blasts 
during therapy, identification of molecular parameters associated with response and progression 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 6 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Methodology: 
The study consisted of a screening period, a treatment period of max 4 months which was extended 
to a total of 1 year for patients identified as responders, and a 12-months follow-up period for all 
study participants. During the study, efficacy as well as safety and tolerability of the study 
medication were investigated. 
Number of patients (planned and analysed): 
Planned: at least 80 screened for a total enrollment of 75 patients 
Analysed: 77 in the Full Analysis Set (FAS), 51 and 39 in the Per-Protocol Set (PPS) for the first and 
second treatment period, respectively 
Diagnosis and main criteria for inclusion: 
Male and female patients at an age of 18 or older diagnosed with IPSS low and int-1 MDS with 
thrombocytopenia 
Test product product, dose and mode of administration, batch number: 
Active ingredient: Romiplostim 
Name of finished product: Nplate® 500 µg powder for solution for injection 
Dose, route of administration and duration of treatment: Starting dose 750 µg once a week 
(7d ± 2d), subcutaneous injection, 4 months maximum duration for non-responders, for responders 
treatment period was extended for up to 1 year (8 months extension period). The dose was adjusted 
based on the subject’s platelet count. 
Batch numbers: 1055969, 1066887, 1073336, 1077714, 1081835, 1088132, 1099012 
Marketing authorization number(s): EU/1/08/497/002 
Duration of treatment: 
During the first 16 weeks of treatment, 27 patients (35%) consistently received the full romiplostim 
dose of 750 μg without need for dose reduction. In 6 patients (7.8%), dose was adapted to 500 µg 
and in 1 patient (1.3%) to 125 µg. In 43 patients (55.8%), treatment was temporarily stopped for 
multiple reasons and later on reinitiated. In the second treatment period (Week 16 to Week 52) 8 
patients (10.4%) consistently received the full dose, in 3 patients (3.9%) the dose was reduced to 
250 µg and in 66 patients (85.7%) dosing was stopped. The median duration of treatment exposure 
was 145 days (range 12 - 576 days). 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 7 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Reference therapy, dose and mode of administration, batch number: 
N/A 
Criteria for evaluation: 
Primary endpoint:  
• 
Hematologic improvement of platelets (HI-P) after 4 months on therapy 
Safety: 
• 
Cumulative hematologic improvement of platelets (HI-P), erythrocytes (HI-E) and neutrophils 
(HI-N) 
• 
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 (AEs) including clinically significant changes 
in laboratory values 
Statistical methods: 
All statistical analyses followed the procedures specified in the Clinical Study Protocol (Version 6.0, 
dated 30 Aug 2019) and the Statistical Analysis Plan (Version 1.0, dated 06 Jul 2020). 
Summary statistics are presented for the total number of patients and by model groups.  
All continuous variables are summarized using the following statistics: n (non-missing sample size), 
number of missing values (Missing), arithmetic mean (Mean), standard deviation, (STD), median 
(Median), maximum (Max) and minimum (Min) and 95%-confidence interval (CI) for the mean. 
All hypothesis were tested against two-sided alternatives. Only hypotheses concerning the 
comparison of model groups with respect to response rates were tested against one-sided 
alternatives. The level of significance was set to 5%.  
If not stated otherwise, all analyses are based on FAS and PPS and the following test procedures 
were applied: 
Categorical variables with two categories were analyzed using Fisher’s exact test to compare 
proportions between model groups. Variables with more than two categories were compared by 
Pearson’s Chi-square test. Additionally, contingency coefficient ccorr was calculated. 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 8 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Continuous variables were analyzed by the following procedure:  
The Shapiro-Wilk Test was applied in order to check the hypothesis of normality distribution. In case 
of non-rejection of the normality hypothesis the model groups were compared by an analysis of 
covariance (ANCOVA) procedure which includes “group” as fixed effect and the baseline values as 
covariate. Estimates of effects, 95%-confidence limits and p-values were calculated.  
If the hypothesis of normally distributed data was rejected, the ANCOVA procedure was based on 
Blom transformed ranks.  
Comparisons to baseline by treatment group were performed as paired t-tests. In case of non-
normal data Wilcoxons signed rank test based on intra-individual differences was applied. 
Sensitivity analysis were optionally be performed for continuous variables by including the 
grouping/stratification variables in an ANCOVA model to estimate the impact and possibly correct 
treatment effects: 
For categorical variables a logistic regression was performed including the specified effects as 
factors. Estimates of effects/odd ratios (OR) in the regression model, 95%-confidence limits and p-
values were calculated.  
The statistical model was consecutively reduced by the non-significant effect with the highest p-
value until the model contained only significant effects besides the model group effect. 
Summary – Conclusions: 
Efficacy Results: 
The primary efficacy endpoint was the rate of hematologic improvement of platelets (HI-P) defined 
as an absolute increase of platelet count to ≥ 30/nL for patients starting at > 20/nL or an increase of 
platelets from < 20/nL to > 20/nL and by at least 100%, according to International Working group 
(IWG) 2006 criteria lasting for ≥ 8 weeks after at least 16 Weeks of romiplostim treatment. 
In general, there was an increase in platelets observed during treatment with romiplostim which 
was more pronounced in Group A as compared to Group B+C. The median peak increase in platelet 
count for responders was higher in Group A than in Group B+C (FAS Group A: 291 /nL [95% CI 250 - 
491]; Group B+C: 108 /nL [95% CI -30.2 - 662]) and time to first peak increase was substantially 
shorter (FAS Group A: 34.0 days [95% CI 33.8 – 113]; Group B+C: 287 days [95% CI 134 - 353]). 
Among the FAS population 32 patients were HI-P responders at Week 16, 24 in Group A and 8 in 
Group B+C. In the PPS, a total of 29 patients showed HI-P response with 21 in Group A and 8 in 
Group B+C. A statistically significant difference was observed in the frequency of responders 
between Group A and Group B+C (p< 0.001). Further, the duration of HI-P was significantly longer 
for patients in Group A (median 351 days [95% CI 349 - 352]) than in Group B+C (median 315 days 
[95% CI 292 - 338]); p=0.006. 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 9 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
Model prediction 
According to a previously published model of response to thrombopoietin receptor agonist (TPO-
RA), patients were assigned into two different cohorts at the time of screening based on previous 
PTE and centrally assessed TPO serum levels (Group A: TPO < 500 ng/L and PTE < 6 units/past year; 
Group B+C: TPO > 500 ng/L, and/or PTE ≥ 6 units/past year).  
Applying data derived from the present study, the predicted model was not confirmed, neither for 
FAS nor PPS. 
Based on data from this study a new response prediction model was developed where the SRSF2 
mutation status and Hb level at baseline were significantly linked to HI-P, which achieved an overall 
accuracy of 70% for a correct romiplostim response prediction. The presence of an SRSF2 mutation 
was identified as a significant predictor of response to romiplostim treatment (p=0.016, logistic 
regression). In patients with an SRSF2 mutation, the probability to achieve HI-P was 65% compared 
to 33% in patients with SRSF2 wildtype. Comparing responders versus non-responders, no 
significant changes were found of variant allelic burden of variants detected pre- and post-
romiplostim treatment, which underlines the safety of romiplostim in this therapeutic setting and 
no expansion or stimulation of malignant clones. 
Safety Results: 
Hematologic improvement of neutrophils (HI-N) 
Neutrophil response was only regarded for patients with pretreatment level < 1.0 /nL. Of these, only 
3 patients allocated to Group A achieved HI-N and continued treatment after Week 16. The median 
peak increase in neutrophil count for responders in the FAS was 8.58 /nL [95% CI 6.51 – 10.2] and 
the median time to peak increase was 99.0 days [95% CI -149 - 430]. Median duration of HI-N 
response in Group A was 62 days [95% CI 50.8 – 73.2]. No HI-N was observed in Group B+C. None 
of the patients achieved HI-N after Week 16. 
Hematologic improvement of erythrocytes (HI-E) 
HI-E response was only regarded for patients with pretreatment hemoglobin (Hb) level < 11 g/dL 
who received less than four units of red blood cells (RBCs) within 8 weeks of cycle 1 day 1 (including 
patients not transfused).  
In general, there was an increase in Hb observed during treatment with romiplostim which was less 
pronounced in Group A as compared to Group B+C. Among the FAS population 7 patients were HI-
E responders at Week 16, 1 in Group A and 6 in Group B+C. At EOS the number of responders in 
Group B+C had increased to 12. Thus, at end of study the proportion of patients who achieved HI-E 
was significantly larger in Group B+C compared to Group A. 
The median peak increase in Hb for responders was higher in Group A than in Group B+C (FAS Group 
A: 6.05 g/dL [95% CI n.a.]; Group B+C: 3.25 g/dL [95% CI 2.00 – 5.20]) and time to first peak increase 
was longer (FAS Group A: 217 days [95% CI n.a.]; Group B+C: 194 days [95% CI 134 - 285]). However, 
it has to be noted that Group A includes 1 responder only. The duration of response was not 
significantly different between the groups. 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 10 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
 
Cumulative rate of hematologic improvement 
None of the patients achieved simultaneous response of HI-P, HI-E and HI-N. 
Disease progression 
In the FAS, disease progression was reported for 10% of patients until end of study (EOS) and 25% 
until end of follow-up (FU). Progression free survival was not significantly different between the 
model groups. 
Association of the presence of certain mutations with disease progression 
Mutations were analyzed in 75 of 77 patients. There was no statistically significant difference 
observed in counts of mutations between HI-P responders and non-responders. A weak correlation 
was found between the presence of ASXL1 and disease progression. 
Increase of peripheral blasts during therapy 
The increase over time in peripheral blasts was significantly higher in Group A than in Group B+C 
(FAS p=0.001, PPS p=0.018). 
Bleeding events 
In total, 221 bleeding events were reported in the first treatment period until Week 16, 158 events 
in Group A and 63 events in Group B+C. From Week 20 through Week 52, a total of 64 events were 
documented, 49 in Group A and 15 in Group B+C. Most of the events were Grade 1. 
Safety endpoints 
A total of 658 treatment-emergent AEs (TEAEs) were recorded in 70 patients (91%), i.e. 499 events 
in 49 patients of Group A (96%) and 159 events in 21 patients of Group B+C (81%).  
Overall, 99 out of the 658 TEAEs (15%) were assessed as likely or possibly related to the study 
medication romiplostim. The most frequent drug-related TEAEs were leukocytosis (7 patients, 
9.1%), blast cells present/increased (6 patients, 7.8%), hematoma (4 patients, 5.2%), anemia 
(3 patients, 3.9%) and arthralgia (3 patients, 3.9%). 
A total of 35 SAEs were documented in 20 patients (26%), 23 events in 12 patients of Group A (24%) 
and 12 events in 8 patients of Group B+C (31%). Seven patients (9%) experienced a serious adverse 
event (SAE) that was assessed as related to the study medication including AML (2 cases), asthenia, 
mucosal hemorrhage, drug-specific antibody, monocyte count increased, viral rash, cerebrovascular 
accident and pulmonary embolism (1 case each). 
During treatment, 6 patients (7.8%) had transient appearance of centrally assessed peripheral blasts 
to >10%, which was reversible after romiplostim interruption and 2 patients (2.6%) progressed to 
AML. Thirteen patients (17%) had Grade 2 or higher bleeding events. 
Except for leukocytosis, monocytosis and increase of peripheral blasts, no significant trends or 
general changes in safety laboratory parameters were observed that might be caused by the study 
medication romiplostim. One TEAE of hyperkalemia was documented and assessed as related to the 
study medication. One event of increased C-reactive protein was reported as SAE and assessed as 
not related to the study medication. 


Protocol code: 440/47 
Synopsis EUROPE Clinical Study Report 
EudraCT-No: 2013-004328-12 
CSR Synopsis (Version 1.0, 28 Jun 2022)  
based on Clinical Study Report Version 1.0; 21 Jun 2022  
page 11 of 11 
Name of Sponsor/Company: 
Individual Study Table 
Referring to Part of the 
Dossier 
(For National Authority Use 
only) 
GMIHO 
Gesellschaft 
für 
Medizinische 
Innovation 
– 
Hämatologie und Onkologie 
mbH 
Name of Finished Product: 
Volume: 
Nplate® 
N/A 
Name of Active Ingredient: 
Page: 
Romiplostim 
N/A 
No trends or general changes in vital parameters were observed during treatment with romiplostim. 
The following TEAEs were reported as possibly related to the study medication romiplostim: weight 
decreased 1 event, hypertension 5 events. No SAE was reported. 
During study treatment one patient died from a thrombocytopenia that was assessed as not related 
to the study medication romiplostim. Twelve cases of death were documented during the follow-
up period. 
Conclusion: 
Thirty-two patients (41.6%) achieved hematologic improvement of platelets (HI-P), while neutrophil 
(HI-N) and erythroid (HI-E) response were observed in 3 (3.9%) and 7 (9.1%) patients. Results 
confirm and extend observations of previous studies showing a high clinical efficacy in a large subset 
of patients. The median duration of response with 351 days in Group A and 315 days in Group B+C 
is encouraging, particularly considering that 31% of included patients were relapsed or refractory 
to at least one prior treatment line. 
Results from this study could not confirm previous reports that platelet response significantly 
correlated with baseline endogenous TPO levels and platelet transfusion history. Based on data 
from this study a new response prediction model was developed where the SRSF2 mutation status 
and Hb level at baseline were significantly linked to HI-P, which achieved an overall accuracy of 70% 
for a correct romiplostim response prediction. The presence of an SRSF2 mutation was identified as 
a significant predictor of response to romiplostim treatment (p=0.016, logistic regression). In 
patients with an SRSF2 mutation, the probability to achieve HI-P was 65% compared to 33% in 
patients with SRSF2 wildtype. Interestingly, comparing responders vs. non-responders, no 
significant changes were found of variant allelic burden of variants detected pre- and post-
romiplostim treatment, which underlines the safety of romiplostim in this therapeutic setting and 
no expansion or stimulation of malignant clones. 
In conclusion, this prospective study did not confirm the predictive value of TPO levels and PTE on 
the response to romiplostim in patients with LR-MDS. Nevertheless, romiplostim is safe and highly 
efficacious in a large subset of patients. Further prospective and controlled studies are warranted 
to specify the definitive role of TPO-RA in the treatment landscape of LR-MDS. The newly developed 
response prediction model including SRSF2 mutation status may help identifying patients with the 
highest likelihood of response also in future clinical trials. To avoid overfitting of variables and to 
confirm the results, the new response prediction model needs to be validated in an external 
independent cohort. 
In summary, the study confirms the safety and efficacy of romiplostim in LR-MDS patients and may 
allow to better define subgroups of patients with a high likelihood of response.