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

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

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.

Study Overview

• Status: Completed
• Conditions: Thalassemia Major
• Intervention / Treatment: Drug: ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Greece
  • GR
    • Athens, GR, Greece, GR-115 27
      • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90146
      • Novartis Investigative Site
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INC424 (ruxolitinib) - Study Treatment; Regularly transfused adult patients with thalassemia and spleen enlargement.	Drug: ruxolitinib; 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.; Other Names: INC424

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2014
• Primary Completion (Actual): April 12, 2016
• Study Completion (Actual): April 12, 2016

Study Registration Dates

• First Submitted: January 28, 2014
• First Submitted That Met QC Criteria: January 28, 2014
• First Posted (Estimate): January 30, 2014

Study Record Updates

• Last Update Posted (Actual): July 17, 2017
• Last Update Submitted That Met QC Criteria: June 19, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: INC424; ruxolitinib; thalassemia; thalassemia major; spleen enlargement
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: CINC424X2201; 2013-002812-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No