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

Phase 2

Completed

Brief Summary: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
INC424 (ruxolitinib) - Study Treatment	ruxolitinib	Regularly transfused adult patients with thalassemia and spleen enlargement.

Primary Outcome Measures

Name	Time	Method
Change of Hematocrit Adjusted Volume of Red Blood Cells (RBC)	week 6 to week 30 interval	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).

Secondary Outcome Measures

Name	Time	Method
Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals	baseline, weeks 0 - 30	Change from baseline in pre-transfusion hemoglobin levels
Percentage Change in Spleen Length (cm) Below the Left Coastal Margin	baseline, weeks 1,2,3,4,6,12,18,24,30	Change of spleen length from baseline over time measured by palpitation by time
Pharmacokinetics (PK) Parameter of Cmin	week 2, week 12	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.
Percentage Change in Spleen Volume (cm3)	baseline, week 12, week 30	Change of spleen volume from baseline at week 12 and week 30 as measured by magnetic imaging resonance (MRI) or computed tomography (CT).
Pharmacokinetics (PK) Parameter of Cmax	Day 1, Week 2 (Day 15), Week 12 (Day 85)	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.