Thalassemia Major
Conditions
Keywords
thalassemia, thalassemia major, spleen enlargement, INC424, ruxolitinib
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.
Interventions
DRUGruxolitinib
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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. |
Countries
Greece, Italy, Lebanon, Thailand, Turkey (Türkiye)
Participant flow
Pre-assignment details
Approximately 30 patients were planned to be enrolled in the study. 30 patients were analyzed in the full analysis, PK, and safety sets; 27 patients were analyzed in the per-protocol set.
Participants by arm
| Arm | Count |
|---|---|
| INC424 (Ruxolitinib) - Study Treatment Regularly transfused adult patients with thalassemia and spleen enlargement | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Patients/guardian decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | INC424 (Ruxolitinib) - Study Treatment |
|---|---|
| Age, Continuous | 25.9 years STANDARD_DEVIATION 6.83 |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 30 |
| serious Total, serious adverse events | 6 / 30 |
Outcome results
Primary
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).
Time frame: week 6 to week 30 interval
Population: Per-Protocol Set (PPS) consisted of a subset of patients in the Safety Set who were compliant with requirements of the Study Protocol. Patients were excluded from the PPS if: they had no or incomplete history of RBC transfusions within 24 weeks prior to the first dose of ruxolitinib or discontinued treatment with ruxolitinib prior to Week 18.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| INC424 (Ruxolitinib) - Study Treatment | Change of Hematocrit Adjusted Volume of Red Blood Cells (RBC) | -5.934 % change of hematocrit-adjusted volume | Standard Deviation 22.1681 |
Secondary
Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals
Change from baseline in pre-transfusion hemoglobin levels
Time frame: baseline, weeks 0 - 30
Population: The Safety Set consists of all patients who received at least one dose of ruxolitinib. All safety data was analyzed using the Safety set. The FAS and Safety set are identical in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals | Weeks 0 - 6 ) | 0.43 percentage change of hemoglobin levels | Standard Deviation 10.135 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals | Weeks 6 - 12 | 2.87 percentage change of hemoglobin levels | Standard Deviation 10.555 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals | Weeks 12 - 18 | 2.78 percentage change of hemoglobin levels | Standard Deviation 11.081 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals | Weeks 18 - 24 | -0.56 percentage change of hemoglobin levels | Standard Deviation 9.76 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Mean Pre-transfusion Hemoglobin by 6 Week Time Intervals | Weeks 24 - 30 | 0.06 percentage change of hemoglobin levels | Standard Deviation 14.321 |
Secondary
Percentage Change in Spleen Length (cm) Below the Left Coastal Margin
Change of spleen length from baseline over time measured by palpitation by time
Time frame: baseline, weeks 1,2,3,4,6,12,18,24,30
Population: The Safety Set consists of all patients who received at least one dose of ruxolitinib. All safety data was analyzed using the Safety set. The FAS and Safety set are identical in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 1 | -11.19 percentage change in spleen length | Standard Deviation 15.376 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 2 | -22.11 percentage change in spleen length | Standard Deviation 23.604 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 3 | -25.01 percentage change in spleen length | Standard Deviation 24.178 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 4 | -26.94 percentage change in spleen length | Standard Deviation 25.343 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 6 | -33.85 percentage change in spleen length | Standard Deviation 25.251 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 12 | -49.29 percentage change in spleen length | Standard Deviation 26.792 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 18 | -56.32 percentage change in spleen length | Standard Deviation 29.994 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 24 | -56.93 percentage change in spleen length | Standard Deviation 29.552 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Length (cm) Below the Left Coastal Margin | Week 30 | -57.40 percentage change in spleen length | Standard Deviation 36.97 |
Secondary
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).
Time frame: baseline, week 12, week 30
Population: The Safety Set consisted of all patients who received at least one dose of ruxolitinib. All safety data was analyzed using the Safety set. The FAS and Safety set are identical in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Volume (cm3) | % change from baseline at Week 12 | -19.733 percentage change | Standard Deviation 16.0539 |
| INC424 (Ruxolitinib) - Study Treatment | Percentage Change in Spleen Volume (cm3) | % change from baseline at Week 30 | -26.829 percentage change | Standard Deviation 16.6936 |
Secondary
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.
Time frame: Day 1, Week 2 (Day 15), Week 12 (Day 85)
Population: The PK analysis set includes all patients with at least one evaluable PK sample at any visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC424 (Ruxolitinib) - Study Treatment | Pharmacokinetics (PK) Parameter of Cmax | Day 1 | 58.2000 ng/mL | Standard Deviation 0 |
| INC424 (Ruxolitinib) - Study Treatment | Pharmacokinetics (PK) Parameter of Cmax | Week 12 | 0.00 ng/mL | Standard Deviation 0 |
| INC424 (Ruxolitinib) - Study Treatment | Pharmacokinetics (PK) Parameter of Cmax | Week 2 | 56.7000 ng/mL | Standard Deviation 0 |
| 15mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Day 1 | 126.8000 ng/mL | Standard Deviation 58.70337 |
| 15mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Week 12 | 107.2100 ng/mL | Standard Deviation 50.07525 |
| 15mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Week 2 | 125.400 ng/mL | Standard Deviation 40.61805 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Week 2 | 0.00 ng/mL | Standard Deviation 0 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Day 1 | 0.00 ng/mL | Standard Deviation 0 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Week 12 | 245.6900 ng/mL | Standard Deviation 50.00362 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Day 1 | 0.00 ng/mL | Standard Deviation 0 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Week 12 | 185.0000 ng/mL | Standard Deviation 97.58074 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmax | Week 2 | 0.00 ng/mL | Standard Deviation 0 |
Secondary
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.
Time frame: week 2, week 12
Population: The PK analysis set includes all patients with at least one evaluable PK sample at any visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC424 (Ruxolitinib) - Study Treatment | Pharmacokinetics (PK) Parameter of Cmin | Week 12 (Day 85) | 9.1300 ng/mL | Standard Deviation 7.61039 |
| INC424 (Ruxolitinib) - Study Treatment | Pharmacokinetics (PK) Parameter of Cmin | Week 2 (Day 15) | 7.5800 ng/mL | Standard Deviation 7.57959 |
| 15mg Bid | Pharmacokinetics (PK) Parameter of Cmin | Week 2 (Day 15) | NA ng/mL | — |
| 15mg Bid | Pharmacokinetics (PK) Parameter of Cmin | Week 12 (Day 85) | 18.5400 ng/mL | Standard Deviation 23.9994 |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmin | Week 2 (Day 15) | NA ng/mL | — |
| 20mg Bid | Pharmacokinetics (PK) Parameter of Cmin | Week 12 (Day 85) | 20.2300 ng/mL | Standard Deviation 25.98617 |