Study of Efficacy and Safety of INC424 in Regularly Transfused Patients With Thalassemia.

Study Overview
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Brief Summary
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Patients with severe thalassemia (thalassemia major) present with severe anemia that required life-long transfusion therapy, spleen enlargement that led to increased transfusion requirement, and other serious complications as early death, growth retardation, bone deformations and iron overload due to blood transfusions. Splenectomy can significantly reduce transfusion requirement in thalassemia patients, but it is associated with an increased risk of serious complications such as sepsis and thrombosis. Preliminary preclinical and clinical data suggested that JAK2 inhibition, by reducing spleen size, could improve hemoglobin levels, thereby eliminating the need for splenectomy and reducing transfusion requirement and related iron overload.

Official Title
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A Single Arm, Multicenter, Phase IIa Study to Explore the Efficacy and Safety of Ruxolitinib (INC424) in Regularly Transfused Patients With Thalassemia

Conditions
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Thalassemia Major

Intervention / Treatment
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* Drug: ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with thalassemia on a regular and stable transfusion regimen (at least 2 RBC units within every 4-week interval for 24 weeks prior to Screening) and anticipated to receive the same transfusion regimen during the study. Patients with spleen enlargement at Screening, defined as spleen palpable below the costal margin and spleen volume of ≥ 450 cm3 as confirmed by MRI (or CT scan in applicable patients). Patients need to be on iron chelation treatment (deferoxamine or deferasirox) for at least four weeks prior to Screening Exclusion Criteria: Splenectomy prior to or planned during the study Active serious bacterial, mycobacterial, fungal, parasitic or viral infection which requires therapy (e.g., pneumonia, tuberculosis, systemic mycosis, herpes zoster) Hemoglobin <65 g/L (<4.0 mmol/L) at Screening Platelet count <75×109/L, absolute neutrophils count < 1.5×109/L at Screening. Estimated MDRD < 30 mL/min/1.73 m2 at Screening. ALT (SGPT) levels >5 times ULN at Screening. Hepatocellular disease such as hepatitis B (presence of HBs antigen), hepatitis C (presence of HCV RNA), liver cirrhosis. HIV positivity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INC424 (ruxolitinib) - Study Treatment<br>Regularly transfused adult patients with thalassemia and spleen enlargement. | Drug: ruxolitinib<br>* Ruxolitinib was taken at a starting dose of 10 mg twice daily with dose adjustments within the range of 5 to 25 mg twice daily.<br>* Other names: INC424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Hematocrit Adjusted Volume of Red Blood Cells (RBC) | Change of RBC transfusion requirement measured as percent change of the hematocrit-adjusted volume of transfused RBC and observed during within on-treatment interval (any time-points of RBC transfusion between week 6 and week 30 driven by the individual patient's need) compared to baseline (defined by pre-treatment interval between Week - 24 to start of treatment). | week 6 to week 30 interval | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Spleen Volume (cm3) | Change of spleen volume from baseline at week 12 and week 30 as measured by magnetic imaging resonance (MRI) or computed tomography (CT). | baseline, week 12, week 30 | 
| Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals | Change from baseline in pre-transfusion hemoglobin levels | baseline, weeks 0 - 30 | 
| Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Change of spleen length from baseline over time measured by palpitation by time | baseline, weeks 1,2,3,4,6,12,18,24,30 | 
| Pharmacokinetics (PK) Parameter of Cmin | C min of INC424 by actual dose administered from 10mg bid to 20mg bid. Plasma PK samples were collected at Day 15 (Week 2), and Day 85 (Week 12). Cmin was collected immediately prior to dosing. n= number of patients with valid PK samples as per definition of the PK analysis set. | week 2, week 12 | 
| Pharmacokinetics (PK) Parameter of Cmax | Cmax (1h) of INC424 by actual dose administered from 10mg bid to 20mg bid. Plasma PK samples were collected at Day 1, Week 2, and Week 12. Cmax was collected within a +/- 1 hour post dose. n= number of patients with valid PK samples as per definition of the PK analysis set. | Day 1, Week 2 (Day 15), Week 12 (Day 85) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thalassemia, thalassemia major, spleen enlargement, INC424, ruxolitinib