Evaluating the Safety of Long Term Dosing of Romiplostim (Formerly AMG 531) in Thrombocytopenic Subjects With Myelodysplastic Syndromes (MDS)

An Open Label Extension Study Evaluating the Safety of Long Term Dosing of Romiplostim in Thrombocytopenic Subjects With Myelodysplastic Syndromes (MDS)

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00472290

Enrollment

Registered

2007-05-11

Start date

2007-04-01

Completion date

2011-12-26

Last updated

2017-12-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hematology, MDS, Myelodysplastic Syndromes, Thrombocytopenia

Keywords

Hematology, MDS, Myelodysplastic Syndromes, Thrombocytopenia

Brief summary

This is an open label extension study of romiplostim for treatment of thrombocytopenia (platelet count ≤ 50 x 10\^9/L) in MDS subjects. The study is designed to assess the long-term safety of treatment with romiplostim, as measured by incidence of overall adverse events, the incidence of bleeding events, the utilization of platelet transfusions, and the duration of platelet response. The study will further describe the time to disease progression to acute myeloid leukemia (AML) and survival.

Interventions

DRUGRomiplostim (formerly AMG 531)

Subjects will begin the study at an initial dose of 750 µg. Except for: * Subject whose doses were escalated to doses higher than 750 µg AMG 531 weekly, and maintained a response per IWG guidelines for platelet response. * Subjects who were stable at a lower dose of AMG 531 on the previous study. Doses will be adjusted throughout the study based on individual subject's platelet count.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Subject completed a romiplostim study for the treatment of thrombocytopenia in subjects with MDS * Subject has an Eastern Cooperative Oncology (ECOG) performance status of 0 to 2 * Subject had a platelet count ≤ 50 x 10\^9/L since the final dose of investigational product in the parent study * Subject or his/her legally acceptable representative provided written informed consent before any study-specific procedures were initiated

Exclusion criteria

* Subject has been diagnosed with AML or has a blast count ≥ 10% by peripheral blood or bone marrow biopsy * Subject has a prior history of leukemia * Subject has a prior history of bone marrow or stem cell transplantation * Subject has a prior malignancy (other than in situ cervical cancer, controlled prostate cancer, or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for ≥ 3 years before randomization * Subject has active or uncontrolled infections * Subject has unstable angina, congestive heart failure \[New York Heart Association (NYHA) \> class II\], uncontrolled hypertension (diastolic \> 100 mmHg), uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction * Subject has a history of arterial thrombosis (eg, stroke or transient ischemic attack) in the past year * Subject has a history of venous thrombosis that currently requires anti-coagulation therapy * Subject received interleukin (IL)-11 within 4 weeks of screening * Subject previously received a thrombopoietic growth factor (other than romiplostim) * Subject has a known hypersensitivity to any recombinant E coli-derived product (eg, Infergen®, Neupogen®, Somatropin, Actimmune) * Subject is currently enrolled in investigational device or drug study(ies), has not yet completed at least 4 weeks since ending investigational device or drug study(ies) (other than parent romiplostim study), or subject is receiving other investigational agent(s)/device(s) * Subject is of child-bearing potential and is evidently pregnant (eg, positive human chorionic gonadotropin \[HCG\] test) or is breast feeding * Subject is not using adequate contraceptive precautions * Subject has any kind of disorder that compromises his/her ability to give written informed consent (and does not have a legally acceptable representative) or is unable to comply with study procedures

Design outcomes

Primary

Measure	Time frame
Overall Summary of Adverse Events	During treatment period from first dose of IP to End of Study visit, on Average 56 Weeks .
Incidence of Antibody (AB) Formation	During treatment period from first dose of IP to End of Study visit, on Average 56 Weeks.

Secondary

Measure	Time frame	Description
Weeks With Platelet Response Per Year	During the treatment period. The average duration of romiplostim exposure is 56 weeks.	During the time since the first dose of IP to the end of the treatment period. Platelet response was based on the modified IWG 2006 criteria (Cheson et al, 2006) and was defined as, in the absence of platelet transfusion: an absolute increase in platelet count of ≥ 30 x 10\^9/L for a subject starting with a platelet count of ≥ 20 x 10\^9/L; or an increase in platelet count from \< 20 x 10\^9/L to ≥ 20 x 10\^9/L and by at least 100% in a subject that started with a platelet count \< 20 x 10\^9/L.
Weekly Bleeding Events Per 100 Subject Years	During the treatment period. The average duration of romiplostim exposure is 56 weeks.	During the time since the first dose of IP to the end of the treatment period. A single bleeding event was defined as each individual bleeding episode that originated from a specific organ system (eg, gastrointestinal system or central nervous system). A bleeding event that continued for more than 7 days was counted as separate events every eighth day.
Duration of Platelet Response	During treatment period. The average duration of romiplostim exposure is 56 weeks.	Platelet response was based on the modified IWG 2006 criteria (Cheson et al, 2006) and was defined as, in the absence of platelet transfusion: an absolute increase in platelet count of ≥ 30 x 10\^9/L for a subject starting with a platelet count of ≥ 20 x 10\^9/L; or an increase in platelet count from \< 20 x 10\^9/L to ≥ 20 x 10\^9/L and by at least 100% in a subject that started with a platelet count \< 20 x 10\^9/L.
Time to First Platelet Response	During treatment period. The average duration of romiplostim exposure is 56 weeks.	Time since first dose of IP to the first platelet response. Platelet response was based on the modified IWG 2006 criteria (Cheson et al, 2006) and was defined as, in the absence of platelet transfusion: an absolute increase in platelet count of ≥ 30 x 10\^9/L for a subject starting with a platelet count of ≥ 20 x 10\^9/L; or an increase in platelet count from \< 20 x 10\^9/L to ≥ 20 x 10\^9/L and by at least 100% in a subject that started with a platelet count \< 20 x 10\^9/L.
Platelet Transfusion Events Per 100 Subject Years	During the treatment period. The average duration of romiplostim exposure is 56 weeks.	During the time since the first dose of IP to the end of the treatment period. A discrete platelet transfusion event was defined as any number of platelet transfusions administered within a 3-day period. Platelet transfusions administered more than 3 days apart were counted as separate platelet transfusion events.

Participant flow

Recruitment details

This study was available to subjects who completed a previous romiplostim study for the treatment of thrombocytopenia in subjects with low or intermediate-1 risk MDS. First Subject Enrolled: 17-Jul-2007; Last Subject Enrolled: 15-Feb-2011

Participants by arm

Arm	Count
Romiplostim Subjects received subcutaneous dosing at 250, 500, 750, 1000, or 1500 mcg weekly or biweekly, with adjustments based on platelets. Romiplostim is supplied in a 5 mL single use vial as a sterile, white, preservative-free, lyophilized powder.	72
Total	72

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Administrative Decision	37
Overall Study	Adverse Event	6
Overall Study	Death	3
Overall Study	Disease Progression	4
Overall Study	Lack of Efficacy	1
Overall Study	Lost to Follow-up	1
Overall Study	Progression of Therapy-Related MDS	1
Overall Study	Protocol Specified Criteria	7
Overall Study	Requirement for alternative therapy	7
Overall Study	Withdrawal by Subject	5

Baseline characteristics

Characteristic	Romiplostim
Age, Continuous	68.9 Years STANDARD_DEVIATION 11.1
Baseline Platelet Count	27.6 10^9/L STANDARD_DEVIATION 15.5
Eastern Cooperative Oncology (ECOG) performance status 0: Fully active	42 Participants
Eastern Cooperative Oncology (ECOG) performance status 1: Can carry out light or sedentary work	25 Participants
Eastern Cooperative Oncology (ECOG) performance status 2: Capable of selfcare but unable to work	5 Participants
Eastern Cooperative Oncology (ECOG) performance status >=3: Capable of only limited selfcare or worse	0 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening MDS associated with isolated del(5q)	0 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening MDS-U: Myelodysplastic syndrome - unclassified	15 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening RAEB-1: Refractory Anemia with Excess Blasts-1	7 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening RAEB-2: Refractory Anemia with Excess Blasts-2	2 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening RA: Refractory Anemia	20 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening RARS: Refractory Anemia with Ringed Sideroblasts	1 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening RCMD:Refractory cytopenia w multilineage dysplasia	24 Participants
Myelodysplastic Syndromes World Health Organization Classification at Study Screening RCMD-RS: RCMD and ringed sideroblasts	3 Participants
Race/Ethnicity, Customized Black or African American	4 Participant
Race/Ethnicity, Customized Hispanic or Latino	3 Participant
Race/Ethnicity, Customized Other	4 Participant
Race/Ethnicity, Customized White or Caucasian	61 Participant
Sex: Female, Male Female	32 Participants
Sex: Female, Male Male	40 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	66 / 72
serious Total, serious adverse events	29 / 72

Outcome results

Primary

Incidence of Antibody (AB) Formation

Time frame: During treatment period from first dose of IP to End of Study visit, on Average 56 Weeks.

Population: Safety analysis includes subjects who took at least one dose of romiplostim.

Arm	Measure	Group	Value (NUMBER)	Dispersion
Romiplostim	Incidence of Antibody (AB) Formation	Positive binding AB to IP at or before baseline	5 Participant	94.7
Romiplostim	Incidence of Antibody (AB) Formation	Neutralizing AB to IP at or before baseline	0 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Binding AB positive to IP post-baseline only	5 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Persistent binding AB positive to IP	4 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Transient binding AB positive to IP	1 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Positive binding AB to TPO at or before baseline	4 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Neutralizing AB to TPO at or before baseline	0 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Binding AB positive to TPO post-baseline only	3 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Persistent binding AB positive to TPO	2 Participant	—
Romiplostim	Incidence of Antibody (AB) Formation	Transient binding AB positive to TPO	1 Participant	—

Primary

Overall Summary of Adverse Events

Time frame: During treatment period from first dose of IP to End of Study visit, on Average 56 Weeks .

Population: Safety analysis includes subjects who took at least one dose of romiplostim.

Arm	Measure	Group	Value (NUMBER)
Romiplostim	Overall Summary of Adverse Events	Subjects Reporting Any AE	71 Participant
Romiplostim	Overall Summary of Adverse Events	Subjects Reporting Any Treatment-related AE	19 Participant
Romiplostim	Overall Summary of Adverse Events	Subjects Reporting Any Treat-related Serious AE	4 Participant
Romiplostim	Overall Summary of Adverse Events	Subjects Reporting Any Serious AE	29 Participant
Romiplostim	Overall Summary of Adverse Events	Subjects Withdrew Study or Stop IP Due to AE	8 Participant

Secondary

Duration of Platelet Response

Platelet response was based on the modified IWG 2006 criteria (Cheson et al, 2006) and was defined as, in the absence of platelet transfusion: an absolute increase in platelet count of ≥ 30 x 10\^9/L for a subject starting with a platelet count of ≥ 20 x 10\^9/L; or an increase in platelet count from \< 20 x 10\^9/L to ≥ 20 x 10\^9/L and by at least 100% in a subject that started with a platelet count \< 20 x 10\^9/L.

Time frame: During treatment period. The average duration of romiplostim exposure is 56 weeks.