To evaluate the efficacy of romiplostim for the treatment of thrombocytopenia in subjects with international prognostic scoring system (IPSS) low or intermediate-1 risk MDS as measured by the number of clinically significant bleeding events.
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the incidence of clinically significant bleeding
events. A clinically significant bleeding event is defined as any bleeding
event of grade >= 2 per the modified WHO bleeding scale.
Secondary outcome
The key secondary endpoint is the incidence of platelet transfusion events. A
discrete platelet transfusion event is any number of platelet transfusions
administered within a 3-day period. Transfusions administered for more than 3
consecutive days will be counted as separate transfusion events every 4th day.
Transfusions given in the absence of any bleeding when the platelet count is
>10 x 109/L will be captured but will not be counted as a platelet transfusion
event for the purpose of this endpoint.
The remaining secondary efficacy endpoints are:
• The overall number of bleeding events
• The total number of units of platelets transfused
• The incidence of platelet hematologic improvement (HI-P) per MDS IWG 2006
guidelines
• The duration of platelet hematologic improvement (HI-P) in the absence of
platelet transfusions per MDS IWG 2006 guidelines
• Overall survival
• Incidence of patient-reported bleeding events (Th-Symptoms)
The safety endpoints are:
• The incidence and severity of all adverse events including clinically
significant changes in laboratory values
• The incidence of disease progression to acute myelogenous leukemia (AML)
• The incidence of neutralizing romiplostim antibody formation and antibodies
that cross-react with eTPO
Background summary
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic
malignancies of the pluripotent hematopoietic stem cells. Patients often
present with complications related to anemia (fatigue), neutropenia
(infections) and/or thrombocytopenia (bleeding). The prognosis of MDS patients
is poor. Patients die either from complications associated with cytopenias
(infections and bleeding) or transformation to acute myeloid leukaemia (AML).
The therapeutic options for MDS remain limited. Even as disease modulating
agents are approved for the treatment of MDS, supportive care remains an
important treatment option for patients with MDS. Currently there are no
thrombopoietic agents indicated for use in MDS. Therefore, platelet
transfusions are the only available treatment option (despite the associated
risks).
Romiplostim increases platelet production via the thrombopoietin (TPO) receptor
and has been shown to be well tolerated and effective in increasing platelet
counts in animals, healthy volunteers, patients with Immune Thrombocytopenic
Purpura (ITP), and in patients with MDS.
Study objective
To evaluate the efficacy of romiplostim for the treatment of thrombocytopenia
in subjects with international prognostic scoring system (IPSS) low or
intermediate-1 risk MDS as measured by the number of clinically significant
bleeding events.
Study design
This is a Phase 2, multicenter, randomized, double blind, placebo controlled
study designed to assess the efficacy and safety of romiplostim (formerly, AMG
531) treatment in thrombocytopenic MDS subjects.
The study is composed of a 26-week placebo controlled test treatment period
(romiplostim versus Placebo), a 2 to 4 week interim wash-out period, a 24-week
placebo controlled extended treatment period, and a 4-week follow-up period.
During the interim wash-out period, a bone marrow biopsy will be performed in
the absence of growth factor to assess changes in the marrow. In the extended
treatment period, safety assessments will continue and subjects will be allowed
to receive any standard of care treatments for MDS. Subjects will be followed
for survival for an additional 60 months following the End of Study (EOS)
visit. The End of Trial is defined as the time when the last subject has
finished the 60 months of survival follow-up.
Intervention
Approximately 240 thrombocytopenic subjects with IPSS low or intermediate-1
risk MDS will be randomized in a 2:1 allocation to receive romiplostim or
placebo weekly via subcutaneous injection during a 26-week test treatment
period and subsequent 24-week extended treatment period.
Study burden and risks
Patients will have extra visits when participating in this study, they will be
treated weekly with romiplostim or placebo as subcuteneous injection, they will
have bone marrow biopsies taken and they will complete patient diaries and
questionnaires.
Because romiplostim is an investigational drug that has only been given to a
limited number of humans (more than 300), not all potential side effects are
currently known. The symptoms most frequently reported are headaches and
flu-like symptoms.
Based on data from previous studies with romplostim received to date, other
side effects can be:
an increase in the number of platelets to above the normal level
(thrombocytosis); after stopping the treatment with romiplostim, the shortage
of platelets can worsen temporarily for a short period of time; antibodies
against romiplostim can be formed; an allergic reaction to romiplostim can
occur; increased fibers (reticulin) in the bone marrow and there is the risk of
a temporary increase in the number of blast cells in the bone marrow.
The usual risks that are associated with drawing blood are discomfort, pain,
redness, swelling, and/or bruising where the blood is taken. Sometimes bleeding
can occur at the place where blood is drawn. Fainting and infections are rare
occurrences.
The subcutaneous injections of romiplostim/placebo may cause momentary
discomfort and possible bruising. One subject reported a mild tingling
sensation on the injection place.
Minervum 7061
Breda 4817ZK
NL
Minervum 7061
Breda 4817ZK
NL
Listed location countries
Age
Inclusion criteria
Inclusion Criteria:
•Diagnosis of MDS using the WHO classification
•Per MDS IPSS, low or intermediate-1 risk MDS
•The mean of the two platelet counts taken within 4 weeks prior to randomization must be:
o<= 20 x 109/L, with no individual count >30 x 109/L, with or without a history of bleeding, OR
o<= 50 x 109/L, with no individual count >60 x 109/L with a history of bleeding.
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
•Subjects must be *18 and <= 90 years of age at the time of informed consent. Subjects between 85 and 90 years of age must have been diagnosed with MDS <= 5 years from study start.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
•Adequate liver function, as evidenced by ALT <= 3 times the laboratory normal range, AST <= 3 times the laboratory normal range and total bilirubin <= 2.0 times the laboratory normal range (Adequate liver function for patients with a confirmed diagnosis of Gilbert*s Disease evidenced by ALT <= 3 times the laboratory normal range, and AST <= 3 times the laboratory normal range).
•A serum creatinine concentration <= 2 mg/dl (<= 176.8 *mol/L)
•Bone marrow biopsy and aspirate with cytogenetics within 3 months of starting first dose of investigational product
•Subject or his/her legally acceptable representative provided written informedconsent before any study-specific procedures were initiated (see section 12.1)
Exclusion criteria
Exclusion Criteria:
• Have ever received any disease-modifying treatment for MDS
• Previously diagnosed with intermediate-2 or high risk MDS using the IPSS
• Prior history of leukemia, aplastic anemia, or other non-MDS related bone marrow stem cell disorder
• Prior history of hematopoietic stem cell transplantation
• Persistent peripheral blood monocytosis (>= 3 months with an absolute monocyte count >1,000/*L)
• Prior malignancy (other than in situ cervical cancer, non-melanoma skin cancer, or in situ carcinoma) unless treated with curative intent and without evidence of disease for ³ 3 years before randomization
• Active or uncontrolled infections
• Unstable angina, congestive heart failure (NYHA > class II), uncontrolled hypertension (diastolic >100 mmHg), uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction
• History of arterial thrombosis (eg, stroke or transient ischemic attack) within the past year
• History of venous thrombosis that currently requires anti-coagulation therapy
• Received IL-11 within 4 weeks of the first dose of investigational product
• Have previously received any thrombopoietic growth factor
• Receipt of G-CSF, peg-G-CSF, or GM-CSF within 4 weeks of the first dose of investigational product
• Planned receipt of peg-G-CSF or GM-CSF after the first dose of investigational product
• Pregnant or breast feeding
• Subjects of reproductive potential who are not using adequate contraceptive precautions, in the judgment of the investigator. Amgen recommends double barrier contraception is used for all applicable patients enrolled on this study. A double barrier method is defined as two methods of contraception, for example 2 actual barrier methods, or one actual barrier method and one hormonal method.
• Known hypersensitivity to any recombinant E coli-derived product (eg, Infergen*, Neupogen*, Somatropin, and Actimmune)
• Previously enrolled in this study
• Inability to comply with study procedures
• Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s)
Design
Recruitment
Medical products/devices used
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 | EUCTR2007-007258-75-NL |
| ClinicalTrials.gov | NCT00472290 |
| CCMO | NL23719.091.08 |