Long-term Study of Romiplostim in Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

Immune Thrombocytopenia Clinical Trial

Official title:

A Single Arm, Open-label, Long-term Efficacy and Safety Study of Romiplostim in Thrombocytopenic Pediatric Subjects With Immune Thrombocytopenia (ITP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02279173
• Other study ID #: 20101221
• Secondary ID: 2011-005019-96
• Status: Completed
• Phase: Phase 3
• Start date: December 10, 2014
• Est. completion date: August 8, 2019

Study information

• Verified date: June 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase 3b single arm, open label, multicenter study describing the percentage of time pediatric participants with ITP have a platelet response while receiving romiplostim, defined as a platelet count ≥ 50 x 10^9/L in the absence of ITP rescue medications for the past 4 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 203
• Est. completion date: August 8, 2019
• Est. primary completion date: August 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

Inclusion Criteria:

• Diagnosis of primary ITP according to The American Society of Hematology (ASH) Guidelines at least 6 months before screening, regardless of splenectomy status

• Age = 1 year and < 18 years of age

• Refractory to prior ITP therapy, relapsed after at prior ITP therapy, or be ineligible for other therapies. Examples of prior therapy include: corticosteroids, intravenous Immunoglobulin (IVIG), anti-D immunoglobulin, platelet transfusions.

• Platelet count = 30 x10^9/L or is experiencing uncontrolled bleeding

• Has provided informed consent before any study-specific procedure;

• Adequate hematologic, renal, and liver function during screening:

• Hemoglobin > 10.0 g/dL

• Serum creatinine = 1.5 x the upper limit of normal (ULN)

• Total serum bilirubin = 1.5 x the ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0 x the ULN

• For the EU, Switzerland and Turkey protocol supplement, subject must agree to a scheduled bone marrow biopsy and aspirate at Year 1 or Year 2 following romiplostim treatment and any unscheduled biopsies if clinically indicated

• For the EU, Switzerland and Turkey protocol supplement, a reticulin grade of 0, 1, 2, or 3 according to the modified Bauermeister grading scale, as assessed by central laboratory from a bone marrow biopsy performed within 1 year prior to planned first dose of romiplostim or consent to a pre-treatment bone marrow biopsy and aspirate prior to planned first dose of romiplostim

Exclusion Criteria:

• History of a bone marrow stem cell disorder (Any abnormal bone marrow findings other than those typical of ITP must be approved by Amgen before a subject may be enrolled)

• Prior bone marrow transplant or peripheral blood progenitor cell transplant

• Active or prior malignancy except non-melanoma skin cancers within the last 5 years

• History of myelodysplastic syndrome

• History of bleeding diathesis

• History of congenital thrombocytopenia

• History of Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV)

• History of systemic lupus erythematosus, Evans syndrome, or autoimmune neutropenia

• History of antiphospholipid antibody syndrome or known positive for lupus anticoagulant

• History of disseminated intravascular coagulation, hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura

• History of venous thromboembolism or thrombotic events

• Previous use of romiplostim or previous use of eltrombopag within 4 weeks of enrollment

• Previous use of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), recombinant human thrombopoietin (rHuTPO) or any other platelet producing agent

• Rituximab (for any indication) or 6-mercaptopurine within 8 weeks of enrollment, or anticipated use at any time during the study

• Splenectomy within 4 weeks of the screening visit

• Alkylating agents within 8 weeks before the screening visit or anticipated use during the time of the proposed study

• Vaccinations known to decrease platelet counts within 8 weeks before the screening visit

• Currently enrolled in another investigational device or drug study, or less than 30 days since ending investigational study

• Will have investigational procedures while enrolled on study

• Female subject of child bearing potential (defined as having first menses) not willing to use, in combination with her partner highly effective methods of birth control during treatment and for 1 month after the end of treatment

• Subject is pregnant or breast feeding, or might become pregnant within 1 month after the end of treatment

• Subject has known hypersensitivity to any recombinant Escherichia coli derived product (eg, Infergen®, Neupogen®, somatropin, and Actimmune®)

• Has previously enrolled into this study

• Will not be available for protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge

• Any kind of disorder that, may compromise the subject to give written informed consent and/or to comply with all required study procedures

Related Conditions & MeSH terms

• Immune Thrombocytopenia
• Purpura, Thrombocytopenic, Idiopathic
• Thrombocytopenia

Intervention

Drug:
• Romiplostim
Romiplostim subcutaneous weekly injection

Locations

Country	Name	City	State
Australia	Research Site	Parkville	Victoria
Australia	Research Site	Randwick	New South Wales
Australia	Research Site	South Brisbane	Queensland
Belgium	Research Site	Brussels
Belgium	Research Site	Bruxelles
Belgium	Research Site	Gent
Belgium	Research Site	Leuven
Belgium	Research Site	Liege
Brazil	Research Site	Belem	Pará
Brazil	Research Site	Jau	São Paulo
Brazil	Research Site	Sao Paulo	São Paulo
Brazil	Research Site	Sao Paulo	São Paulo
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Olomouc
Czechia	Research Site	Ostrava-Poruba
Czechia	Research Site	Praha 5
France	Research Site	Montpellier cedex 05
France	Research Site	Nice Cedex 3
France	Research Site	Paris
France	Research Site	Vandoeuvre les Nancy
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Szeged
Israel	Research Site	Beer Sheva
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Petach Tikvah
Israel	Research Site	Tel Aviv
Israel	Research Site	Tel Hashomer
Mexico	Research Site	Monterrey	Nuevo León
Poland	Research Site	Bydgoszcz
Poland	Research Site	Lodz
Poland	Research Site	Olsztyn
Poland	Research Site	Zabrze
Russian Federation	Research Site	Krasnodar
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saratov
Russian Federation	Research Site	Volgograd
South Africa	Research Site	Durban	KwaZulu-Natal
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Parktown	Gauteng
South Africa	Research Site	Tygerberg	Western Cape
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	Esplugues de Llobregat	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Valencia	Comunidad Valenciana
Switzerland	Research Site	Basel
Switzerland	Research Site	St. Gallen
Switzerland	Research Site	Zuerich
Turkey	Research Site	Adana
Turkey	Research Site	Antalya
Turkey	Research Site	Izmir
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Edinburgh
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United States	Research Site	Atlanta	Georgia
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Columbus	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Fort Worth	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Iowa City	Iowa
United States	Research Site	Kansas City	Missouri
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Nashville	Tennessee
United States	Research Site	New York	New York
United States	Research Site	Peoria	Illinois
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Roseville	California

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Czechia,  France,  Hungary,  Israel,  Mexico,  Poland,  Russian Federation,  South Africa,  Spain,  Switzerland,  Turkey,  United Kingdom, 

References & Publications (2)

Grainger J, Bussel JB, Tarantino MD, Cooper N, Beam D, Despotovic JM, Maschan A, Wang K, Eisen M, Bowers C. A Single-Arm, Long-Term Efficacy and Safety Study of Subcutaneous Romiplostim in Children with Immune Thrombocytopenia. Blood Adv. 2022 Apr 12. pii: bloodadvances.2021006014. doi: 10.1182/bloodadvances.2021006014. [Epub ahead of print] — View Citation

Tarantino MD, Despotovic J, Roy J, Grainger J, Cooper N, Beam D, Raj A, Maschan A, Kim J, Eisen M. Romiplostim treatment for children with immune thrombocytopenia: Results of an integrated database of five clinical trials. Pediatr Blood Cancer. 2020 Nov;67(11):e28630. doi: 10.1002/pbc.28630. Epub 2020 Sep 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Time With a Platelet Response During the First 6 Months of Treatment	Platelet response was defined as a platelet count of = 50 x 10?/L with no rescue medication use for ITP in the past 4 weeks.; Monthly platelet response was calculated based on the median platelet count during each month. For each participant, the percentage of time with platelet response during the first 6 months was calculated as the number of months a platelet response was observed divided by the total number of months response was assessed.	Week 2 to Month 6, platelet response was assessed every week.
Primary	Percentage of Participants Who Developed Collagen After Exposure to Romiplostim	The percentage of participants who developed collagen as evidenced by trichrome staining, defined as a Grade 4 on the modified Bauermeister grading scale: Grade 0: No reticulin fibers demonstrable; Grade 1: Occasional fine individual fibers and foci of a fine fiber network; Grade 2: Fine fiber network throughout most of the section; no coarse fibers; Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining); Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining)	Year 1 (Cohort 1) and year 2 (Cohort 2)
Primary	Percentage of Participants With Increased Modified Bauermeister Grade	The percentage of participants with an increased modified Bauermeister grade defined as an increase by = 2 severity grades or an increase to grade 4 (i.e., grade 0 to 2-4, grade 1 to 3-4, grade 2 to 4, or grade 3 to 4 over baseline). The modified Bauermeister grading scale: Grade 0: No reticulin fibers demonstrable; Grade 1: Occasional fine individual fibers and foci of a fine fiber network; Grade 2: Fine fiber network throughout most of the section; no coarse fibers; Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining); Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining); Participants without an evaluable baseline result were assumed to have a baseline modified Bauermeister score of 0.	Baseline, year 1 (Cohort 1) and year 2 (Cohort 2)
Primary	Percentage of Participants Who Developed Bone Marrow Abnormalities	The percentage of participants with bone marrow abnormalities (eg, myelodysplastic syndrome, monosomy 7) based on analysis of bone marrow biopsy and aspirate samples using cytogenetics and fluorescence in situ hybridization.	Year 1 (Cohort 1) and year 2 (Cohort 2)
Secondary	Percentage of Time With a Platelet Response During the Overall Treatment Period	Platelet response was defined as a platelet count of = 50 x 10?/L with no rescue medication use in the past 4 weeks.; Monthly platelet response was calculated based on the median platelet count during each month. For each participant, the percentage of time with platelet response was calculated as the number of months a platelet response was observed divided by the total number of months response was assessed.	From week 2 to the end of the treatment period, 36 months
Secondary	Percentage of Time With an Increase in Platelet Count = 20 x 10? Cells/L Above Baseline	The percentage of time with an increase in platelet count = 20 x 10? cells/L above baseline from week 2 until the end of the treatment period without rescue medication use within the past 4 weeks.; For each participant, the percentage of time with an increase in platelet count = 20 x10? cells/L above baseline was calculated as the number of months the median platelet count was = 20 x10? cells/L above baseline divided by the total number of months assessed.	Baseline and from week 2 to month 36
Secondary	Number of Participants Reporting Use of Rescue Medications for ITP During the Treatment Period	Rescue medication is defined as any medication or transfusion, other than romiplostim and excluded medications, that is administered after enrollment to the participant with the intent of raising platelet counts or to prevent bleeding and includes concomitant medications for ITP in which the dose and/or schedule was increased. Permitted rescue medications included the following: corticosteroids; platelet transfusions; Intravenous immunoglobulin (IVIG); azathioprine; anti-D immunoglobulin; danazol	From first dose of romiplostim to the end of the treatment period, 36 months
Secondary	Number of Participants Who Developed Anti-Romiplostim or Anti-Thrombopoietin Neutralizing Antibodies	Blood samples were first tested for the presence of binding antibodies to romiplostim or the peptide portion of romiplostim, and to endogenous thrombopoietin (eTPO). Samples testing positive for binding antibodies were then tested for neutralizing antibodies by assessing their ability to neutralize romiplostim and/or eTPO in a cell-based bioassay.; Participants who developed neutralizing antibodies are those who had a postbaseline positive result with a negative or no result at baseline. Transient is defined as a negative result at the participant's last time point tested within the study period.	Week 12, week 52 and every 24 weeks thereafter up to month 36
Secondary	Number of Participants With Adverse Events	An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant, which does not necessarily have a causal relationship with study treatment.; A serious adverse event (SAE) was defined as an AE that met at least 1 of the following criteria: fatal; life threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event Adverse events were graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grading scale, where Grade 1 = mild AE; Grade 2 = moderate AE; Grade 3 = severe AE; Grade 4 = life-threatening or disabling; Grade 5 = death related to AE.	SAEs were collected from Screening through end-of-study follow-up (up to 38 months). Nonserious AEs were collected from first to last dose of study drug during the treatment period (up to 36 months).
Secondary	Percentage of Participants Who Developed Increased Reticulin	The percentage of participants with increased reticulin as evidenced by silver staining and defined as any increase from baseline in the modified Bauermeister grade: Grade 0: No reticulin fibers demonstrable; Grade 1: Occasional fine individual fibers and foci of a fine fiber network; Grade 2: Fine fiber network throughout most of the section; no coarse fibers; Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining); Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining); Participants without an evaluable baseline result were assumed to have a baseline modified Bauermeister score of 0.	Baseline, year 1 (Cohort 1) and year 2 (Cohort 2)

External Links

•   AmgenTrials clinical trials website