Phase 3 Trial Design: Splenectomized Patients
Nplate®: High level of evidence with two phase 3 trials in non-splenectomized and splenectomized patients.
A 6-month pivotal phase 3 trial established the efficacy of Nplate® in splenectomized patients[3][6]
Review the parallel 6-month phase 3 trial in non-splenectomized patients.
Endpoints[3][6]:
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Primary endpoint:
- — Durable platelet response, defined as weekly platelet responses during at least 6 of the last 8 weeks of treatment
in the 24-week study, in the absence of rescue therapy at any time during this study.
- — Durable platelet response, defined as weekly platelet responses during at least 6 of the last 8 weeks of treatment
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Select secondary endpoints:
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— Overall platelet response, defined as durable plus transient rates of platelet response
- A transient platelet response was defined as four or more weekly platelet responses without a durable platelet response from weeks 2 to 25, excluding platelet counts within 8 weeks of rescue therapy.
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— Number of weekly platelet responses
- A weekly platelet response was defined as a platelet count ≥ 50 x 109/L, excluding platelet counts within 8 weeks of rescue therapy.
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— Proportion of patients requiring rescue therapy
- Rescue therapies included corticosteroids, IVIG, platelet transfusions, and anti-D immunoglobulin and were permitted for bleeding, wet purpura, or if the patient was at immediate risk for hemorrhage.[6]
- Rescue therapy was defined as an increased dose of concurrent ITP drug, or the use of any new drug or platelet transfusion to increase platelet counts. Examples of rescue therapies include IVIG, steroids, anti-D, and platelet transfusion.
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— Overall platelet response, defined as durable plus transient rates of platelet response
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Baseline Characteristics of Splenectomized Patients in the Phase 3 Trial[3][6]
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INDICATION
Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts.
Important Safety Information
Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia
- In Nplate® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression from MDS to acute myelogenous leukemia (AML) has been observed.
- Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
Thrombotic/Thromboembolic Complications
- Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate®. Nplate® should be used with caution in patients with ITP and chronic liver disease.
- To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L.
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis
- Nplate® administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate®.
- In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.
- If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis.
Worsened Thrombocytopenia after Cessation of Nplate®
- In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days.
- Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines.
Lack or Loss of Response to Nplate®
- Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neutralizing antibodies to Nplate®.
- To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO).
- Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
Laboratory Monitoring
- Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose.
- Obtain CBCs, including platelet counts, weekly for at least two weeks following discontinuation of Nplate®.
Adverse Reactions
- In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity.
- Most common adverse reactions (≥ 5% higher patient incidence in Nplate® versus placebo) were Arthralgia (26%, 20%), Dizziness (17%, 0%), Insomnia (16%, 7%), Myalgia (14%, 2%), Pain in Extremity (13%, 5%) , Abdominal Pain (11%, 0%), Shoulder Pain (8%, 0%), Dyspepsia (7%, 0%), and Paresthesia (6%, 0%).
Please see Prescribing Information and Medication Guide
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THE NPLATE® FIRST STEP™ PROGRAM
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Clinical studies have evaluated the safety and efficacy of Nplate® treatment in adult patients with chronic ITP. Nplate® clinical trials have been conducted in both splenectomized and non-splenectomized patients, with some patients receiving Nplate® treatment for > 5 years.
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