Myelofibrosis
Conditions
Brief summary
This is a Phase IB, open-label, dose-finding study of the JAK 1 and 2 inhibitor ruxolitinib in patients with myelofibrosis (MF). The study consists of two periods: the core study period, comprising the dose escalation stage and the safety extension phase up to Week 24, then the extension study period beyond Week 24 and up to 3 years, to further characterize the safety and efficacy of ruxolitinib in this patient population. The dose escalation phase will enroll successive cohorts of patients who receive increasing doses of ruxolitinib until the maximum safe starting dose (MSSD) is determined. In the safety expansion phase, additional patients will be treated with ruxolitinib at the MSSD defined during dose escalation. The primary objective is to establish the MSSD of ruxolitinib in patients with MF and starting platelet counts \< 100 x 10 \^9/L
Interventions
DRUGRuxolitinib
Starting dose of ruxolitinib for cohort 1 in dose escalation phase - 5mg twice a day (BID) Doses will be increased a total of approximately 5mg for successive dosing cohorts based on baseline platelet count
Sponsors
Novartis
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Require treatment for MF and classified at least as intermediate risk level 1 defined by the International Working Group. * Platelet count \< 100x10 \^9/L at screening or at Study Day 1.
Exclusion criteria
* Received platelet transfusion within 14 days prior to Screening evaluations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities | 28 days | DLT was defined as the occurrence of any of the following treatment-related toxicities, occurring through Day 28: Any grade ≥ 2 hemorrhagic event ; Any grade thrombocytopenia requiring PLT transfusion; PLT count \< 25x109/L\*; Grade 4 neutropenia (absolute neutrophil count \< 0.5x109/L)\*; Grade ≥ 3 febrile neutropenia\*; Grade ≥ 2 total serum bilirubin with coincident direct bilirubin ≥ 0.5 mg/dL; Grade 3 non-hematologic toxicity for ≥ 7 consecutive days; Grade 4 non-hematologic toxicity. In the dose escalation stage in the core study period, the starting does in both strata was 5mg bid. Successive cohorts of newly enrolled patients received increasing doses of ruxolitinib until the Maximum Safe Starting Dose (MSSD) was determined. Initially, only patients with PLT counts 75-99 x10\^9/L (stratum 1) were allowed to be enrolled. Once safety was established in stratum 1 at the first 2 dose cohorts, eligible population was further expanded to patients with PLT counts 50-74 x10\^9/L (stratum 2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | 24 weeks | Participants achieving ≥ 50% reduction in palpable spleen length relative to study day 1 by treatment and stratum |
| Change in Spleen Length as Measure by Palpation Over Time | Day 8, 15, 22, 29, 43, 57, 85, 113, 141, 168, 252, 336, 420, 504, 588, 672, 756, 1008, 1092 | Defined as measurement of change in spleen length by palpation from baseline |
| PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | 24 weeks | To define the PK and C Reactive Protein relationship using PK Quartiles (AUC 0-12, ng\*h/mL) |
| Number of Treatment Emergent Adverse Events (TEAE's) | approximately 4 years | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. |
| PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | 24 weeks | To define the PK and Tissue Necrosis Factor Receptor 2 relationship using PK Quartiles (AUC 0-12, ng\*h/mL) |
| AUC 0-Inf | 0.25 to 0.75, 1 to 3, and 4 to 12 hours postdose on Day 1 and predose, 0.25 to 0.75 hours, and 1 to 3 hours postdose on Day 15, with a random sample on Days 29 and 57 | Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity |
| PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | 24 weeks | To define the PK and Interleukin 1 Receptor Antagonist relationship relationship using PK Quartiles (AUC 0-12, ng\*h/mL) |
Countries
Austria, China, France, Germany, Italy, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted from 03-Mar-2011 to 31-Dec-2019 globally. Participants with MF and baseline PLT of 75 to \< 100 × 109/L are enrolled in Stratum 1;and 50 to \< 75 × 109/L are enrolled in Stratum 2.. The study has a core period (up to week 24) consisting of 2 phases (dose escalation and safety expansion) followed by an extension period (up to 3 years). Participants received increasing doses of ruxolitinib until the Maximum Safe Starting Dose (MSSD) was determined
Pre-assignment details
A total of 69 participants enrolled in the study with 44 in Stratum 1 (cohorts 1,2,3,4,5) and 25 in Stratum 2 (Cohorts 1,2,3).
Participants by arm
| Arm | Count |
|---|---|
| Stratum 1 : Cohort 1 Ruxolitinib was administered at 5 mg bid in Participants with baseline Platelet counts of 75-99x10\^9/L | 5 |
| Stratum 1 : Cohort 2 Ruxolitinib was administered at 5 mg q.AM / 10 mg q.PM in Participants with baseline Platelet counts of 75-99 x10\^9/L | 3 |
| Stratum 1 : Cohort 3 Ruxolitinib was administered to cohort 3 at 10 mg bid in Participants with baseline Platelet counts of 75-99 x10\^9/L | 20 |
| Stratum 1 : Cohort 4 Ruxolitinib was administered at 10 mg q.AM / 15 mg q.PM) in Participants with baseline Platelet counts of 75-99 x10\^9/L | 4 |
| Stratum 1 : Cohort 5 Ruxolitinib was administered at 15 mg bid in Participants with baseline Platelet counts of 75-99 x10\^9/L | 12 |
| Stratum 2 : Cohort 1 Ruxolitinib was administered at 5 mg bid in participants with baseline Platelet counts of 50-74x10\^9/L | 3 |
| Stratum 2 : Cohort 2 Ruxolitinib was administered at 5 mg q.AM / 10 mg q.PM) in participants with baseline Platelet counts of 50-74 x10\^9/L | 4 |
| Stratum 2 : Cohort 3 Ruxolitinib was administered at 10 mg bid in participants with baseline Platelet counts of 50-74 x10\^9/L | 18 |
| Stratum 2 : Cohort 4 Ruxolitinib was administered at 10 mg q.AM / 15 mg q.PM in participants with baseline Platelet counts of 50-74 x10\^9/L | 0 |
| Stratum 2 : Cohort 5 Ruxolitinib was administered at 15 mg bid in participants with baseline Platelet counts of 50-74 x10\^9/L | 0 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 | 1 | 5 | 1 | 2 | 5 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 2 | 1 | 0 | 1 | 0 | 4 | 0 | 0 |
| Overall Study | Noncompliance with study drug | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 | 2 | 0 | 0 | 2 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 0 | 2 | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Stratum 2 : Cohort 3 | Stratum 2 : Cohort 2 | Stratum 2 : Cohort 1 | Stratum 1 : Cohort 5 | Stratum 1 : Cohort 4 | Stratum 1 : Cohort 3 | Stratum 1 : Cohort 1 | Stratum 1 : Cohort 2 |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 66.4 years STANDARD_DEVIATION 11.81 | 68.0 years STANDARD_DEVIATION 11.66 | 72.5 years STANDARD_DEVIATION 6.95 | 67.3 years STANDARD_DEVIATION 11.06 | 75.8 years STANDARD_DEVIATION 3.3 | 70.4 years STANDARD_DEVIATION 8.91 | 63.0 years STANDARD_DEVIATION 14.71 | 63.00 years STANDARD_DEVIATION 7.78 | 54.00 years STANDARD_DEVIATION 4 |
| ECOG Performance Status 0 | 24 Participants | 4 Participants | 1 Participants | 0 Participants | 6 Participants | 1 Participants | 9 Participants | 1 Participants | 2 Participants |
| ECOG Performance Status 1 | 32 Participants | 10 Participants | 2 Participants | 2 Participants | 4 Participants | 1 Participants | 9 Participants | 3 Participants | 1 Participants |
| ECOG Performance Status 2 | 13 Participants | 4 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 19 Participants | 3 Participants | 3 Participants | 1 Participants | 5 Participants | 1 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 46 Participants | 13 Participants | 0 Participants | 2 Participants | 7 Participants | 3 Participants | 15 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized White Asian | 12 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 11 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White Missing | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White Other | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White White | 51 Participants | 16 Participants | 3 Participants | 2 Participants | 11 Participants | 4 Participants | 8 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Female | 36 Participants | 7 Participants | 3 Participants | 2 Participants | 4 Participants | 2 Participants | 12 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 33 Participants | 11 Participants | 1 Participants | 1 Participants | 8 Participants | 2 Participants | 8 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 3 | 3 / 20 | 1 / 4 | 0 / 12 | 1 / 3 | 0 / 4 | 4 / 18 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 20 / 20 | 4 / 4 | 12 / 12 | 3 / 3 | 4 / 4 | 18 / 18 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 2 / 5 | 2 / 3 | 10 / 20 | 4 / 4 | 5 / 12 | 3 / 3 | 3 / 4 | 9 / 18 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities
DLT was defined as the occurrence of any of the following treatment-related toxicities, occurring through Day 28: Any grade ≥ 2 hemorrhagic event ; Any grade thrombocytopenia requiring PLT transfusion; PLT count \< 25x109/L\*; Grade 4 neutropenia (absolute neutrophil count \< 0.5x109/L)\*; Grade ≥ 3 febrile neutropenia\*; Grade ≥ 2 total serum bilirubin with coincident direct bilirubin ≥ 0.5 mg/dL; Grade 3 non-hematologic toxicity for ≥ 7 consecutive days; Grade 4 non-hematologic toxicity. In the dose escalation stage in the core study period, the starting does in both strata was 5mg bid. Successive cohorts of newly enrolled patients received increasing doses of ruxolitinib until the Maximum Safe Starting Dose (MSSD) was determined. Initially, only patients with PLT counts 75-99 x10\^9/L (stratum 1) were allowed to be enrolled. Once safety was established in stratum 1 at the first 2 dose cohorts, eligible population was further expanded to patients with PLT counts 50-74 x10\^9/L (stratum 2).
Time frame: 28 days
Population: Dose Determining Set. Dose was not escalated to enroll participants in Stratum-2 : Cohorts 4 and 5.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum 1 : Cohort 1 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 1 : Cohort 2 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 1 : Cohort 3 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 1 : Cohort 4 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 1 : Cohort 5 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 2 : Cohort 1 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 2 : Cohort 2 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Stratum 2 : Cohort 3 | Number of Participants With Dose Limiting Toxicities | 1 Participants |
Secondary
AUC 0-Inf
Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity
Time frame: 0.25 to 0.75, 1 to 3, and 4 to 12 hours postdose on Day 1 and predose, 0.25 to 0.75 hours, and 1 to 3 hours postdose on Day 15, with a random sample on Days 29 and 57
Population: Results are summarized by strata; dose relationship is accounted for by PK quartile grouping.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum 1 : Cohort 1 | AUC 0-Inf | 1027 nM*hr | Standard Deviation 357 |
| Stratum 1 : Cohort 2 | AUC 0-Inf | 1930 nM*hr | Standard Deviation 562 |
| Stratum 1 : Cohort 3 | AUC 0-Inf | 3756 nM*hr | Standard Deviation 916 |
Secondary
Change in Spleen Length as Measure by Palpation Over Time
Defined as measurement of change in spleen length by palpation from baseline
Time frame: Day 8, 15, 22, 29, 43, 57, 85, 113, 141, 168, 252, 336, 420, 504, 588, 672, 756, 1008, 1092
Population: Change in spleen length measurement as compared to baseline are summarized by time and by stratum as specified in the SAP.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 57 | -4.5 cm | Standard Deviation 2.98 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 252 | -5.5 cm | Standard Deviation 4.4 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 29 | -4.4 cm | Standard Deviation 3.14 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 336 | -5.1 cm | Standard Deviation 4.64 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 85 | -4.5 cm | Standard Deviation 3.53 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 420 | -6.1 cm | Standard Deviation 4.8 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 8 | -2.8 cm | Standard Deviation 2.73 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 504 | -5.7 cm | Standard Deviation 4 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 113 | -4.7 cm | Standard Deviation 3.29 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 588 | -4.7 cm | Standard Deviation 5.24 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 43 | -4.6 cm | Standard Deviation 2.74 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 672 | -5.8 cm | Standard Deviation 5.33 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 141 | -4.9 cm | Standard Deviation 3.24 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 756 | -5.7 cm | Standard Deviation 5.22 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 15 | -3.3 cm | Standard Deviation 2.7 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 1008 | -7.6 cm | Standard Deviation 3.93 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 168 | -5.2 cm | Standard Deviation 3.73 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 1092 | -6.8 cm | Standard Deviation 1.71 |
| Stratum 1 : Cohort 1 | Change in Spleen Length as Measure by Palpation Over Time | Day 22 | -5.2 cm | Standard Deviation 2.87 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 1092 | -4.2 cm | Standard Deviation 5.81 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 8 | -3.7 cm | Standard Deviation 2.98 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 15 | -5.4 cm | Standard Deviation 4.4 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 22 | -5.4 cm | Standard Deviation 4.81 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 29 | -6.0 cm | Standard Deviation 4.23 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 43 | -5.8 cm | Standard Deviation 4.31 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 57 | -5.6 cm | Standard Deviation 4.52 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 85 | -5.2 cm | Standard Deviation 4.32 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 113 | -6.0 cm | Standard Deviation 4.74 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 141 | -6.7 cm | Standard Deviation 4.43 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 168 | -5.0 cm | Standard Deviation 4.78 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 252 | -3.6 cm | Standard Deviation 6.67 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 336 | -5.3 cm | Standard Deviation 4.86 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 420 | -4.9 cm | Standard Deviation 5.75 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 504 | -4.9 cm | Standard Deviation 4.91 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 588 | -5.4 cm | Standard Deviation 5.61 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 672 | -4.4 cm | Standard Deviation 6.6 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 756 | -6.0 cm | Standard Deviation 6.03 |
| Stratum 1 : Cohort 2 | Change in Spleen Length as Measure by Palpation Over Time | Day 1008 | -8.0 cm | Standard Deviation 4.55 |
Secondary
Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length
Participants achieving ≥ 50% reduction in palpable spleen length relative to study day 1 by treatment and stratum
Time frame: 24 weeks
Population: All participants who had spleen assessment at week 24. Multiple dose cohorts within the strata are grouped according to total daily dose ranges as specified in Statistical Analysis Plan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum 1 : Cohort 1 | Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | 3 Participants |
| Stratum 1 : Cohort 2 | Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | 6 Participants |
| Stratum 1 : Cohort 3 | Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | 4 Participants |
| Stratum 1 : Cohort 4 | Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | 1 Participants |
| Stratum 1 : Cohort 5 | Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | 3 Participants |
Secondary
Number of Treatment Emergent Adverse Events (TEAE's)
Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment.
Time frame: approximately 4 years
Population: Full Analysis Population; Multiple dose cohorts within the strata are combined based on the total dose levels as specified in Statistical Analysis Plan
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum 1 : Cohort 1 | Number of Treatment Emergent Adverse Events (TEAE's) | 8 Participants |
| Stratum 1 : Cohort 2 | Number of Treatment Emergent Adverse Events (TEAE's) | 20 Participants |
| Stratum 1 : Cohort 3 | Number of Treatment Emergent Adverse Events (TEAE's) | 16 Participants |
| Stratum 1 : Cohort 4 | Number of Treatment Emergent Adverse Events (TEAE's) | 7 Participants |
| Stratum 1 : Cohort 5 | Number of Treatment Emergent Adverse Events (TEAE's) | 18 Participants |
Secondary
PK- C Reactive Protein Levels by PK Quartile (AUC0-12)
To define the PK and C Reactive Protein relationship using PK Quartiles (AUC 0-12, ng\*h/mL)
Time frame: 24 weeks
Population: Results are summarized by strata, as dose relationship is accounted for by PK quartiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 2 Day 1 | 9.5 micrograms/mL | Standard Deviation 0.707 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 3 Day 29 | 2.76 micrograms/mL | Standard Deviation 4.66 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 2 Day 29 | 10.2 micrograms/mL | Standard Deviation 23.8 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 3 Day 168 | 7.7 micrograms/mL | Standard Deviation 14.9 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 1 Day 168 | 7.6 micrograms/mL | Standard Deviation 8 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 4 Day 1 | 0.96 micrograms/mL | Standard Deviation 1.05 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 2 Day 168 | 8.37 micrograms/mL | Standard Deviation 12.8 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 4 Day 29 | 1.87 micrograms/mL | Standard Deviation 1.43 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 1 Day 29 | 21.2 micrograms/mL | Standard Deviation 31.5 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 4 Day 168 | 4.88 micrograms/mL | Standard Deviation 9.01 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 3 Day 1 | 6.85 micrograms/mL | Standard Deviation 7.28 |
| Stratum 1 : Cohort 1 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 1 Day 1 | 14 micrograms/mL | Standard Deviation 5.73 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 2 Day 1 | 7.7 micrograms/mL | — |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 1 Day 1 | 12 micrograms/mL | — |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 1 Day 29 | 2.6 micrograms/mL | Standard Deviation 2.05 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 1 Day 168 | 5.51 micrograms/mL | Standard Deviation 4.98 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 2 Day 29 | 1.84 micrograms/mL | Standard Deviation 173 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 2 Day 168 | 2.41 micrograms/mL | Standard Deviation 1.45 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 3 Day 1 | 6.5 micrograms/mL | — |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 3 Day 29 | 7.36 micrograms/mL | Standard Deviation 9.06 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 3 Day 168 | 4.98 micrograms/mL | Standard Deviation 5.1 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 4 Day 1 | 5.4 micrograms/mL | — |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 4 Day 29 | 12.4 micrograms/mL | Standard Deviation 17.8 |
| Stratum 1 : Cohort 2 | PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | Quartile 4 Day 168 | 4.9 micrograms/mL | — |
Secondary
PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12)
To define the PK and Interleukin 1 Receptor Antagonist relationship relationship using PK Quartiles (AUC 0-12, ng\*h/mL)
Time frame: 24 weeks
Population: Results are summarized by strata, as dose relationship is accounted for by PK quartiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 1 Day 1 | 188 picograms/mL | Standard Deviation 116 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 1 Day 29 | 267 picograms/mL | Standard Deviation 334 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 1 Day 168 | 592 picograms/mL | Standard Deviation 532 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 2 Day 1 | 179 picograms/mL | Standard Deviation 43.1 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 2 Day 29 | 524 picograms/mL | Standard Deviation 519 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 2 Day 168 | 557 picograms/mL | Standard Deviation 504 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 3 Day 1 | 319 picograms/mL | Standard Deviation 288 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 3 Day 29 | 304 picograms/mL | Standard Deviation 327 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 3 Day 168 | 549 picograms/mL | Standard Deviation 531 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 4 Day 1 | 120 picograms/mL | Standard Deviation 40.3 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 4 Day 29 | 604 picograms/mL | Standard Deviation 647 |
| Stratum 1 : Cohort 1 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 4 Day 168 | 562 picograms/mL | Standard Deviation 758 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 4 Day 29 | 475 picograms/mL | Standard Deviation 464 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 1 Day 1 | 105 picograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 3 Day 1 | 191 picograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 1 Day 29 | 588 picograms/mL | Standard Deviation 730 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 4 Day 1 | 148 picograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 1 Day 168 | 379 picograms/mL | Standard Deviation 419 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 3 Day 29 | 452 picograms/mL | Standard Deviation 529 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 2 Day 1 | 133 picograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 4 Day 168 | 378 picograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 2 Day 29 | 600 picograms/mL | Standard Deviation 649 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 3 Day 168 | 960 picograms/mL | Standard Deviation 792 |
| Stratum 1 : Cohort 2 | PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | Quartile 2 Day 168 | 334 picograms/mL | Standard Deviation 322 |
Secondary
PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12)
To define the PK and Tissue Necrosis Factor Receptor 2 relationship using PK Quartiles (AUC 0-12, ng\*h/mL)
Time frame: 24 weeks
Population: Results are summarized by strata, as dose relationship is accounted for by PK quartiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 1 Day 1 | 24 nanograms/mL | Standard Deviation 19.8 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 1 Day 29 | 20.5 nanograms/mL | Standard Deviation 19.7 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 1 Day 168 | 14 nanograms/mL | Standard Deviation 4.24 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 2 Day 1 | 13.5 nanograms/mL | Standard Deviation 0.707 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 2 Day 29 | 14.9 nanograms/mL | Standard Deviation 6.62 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 2 Day 168 | 36.1 nanograms/mL | Standard Deviation 22.9 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 3 Day 1 | 21 nanograms/mL | Standard Deviation 9.9 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 3 Day 29 | 12.9 nanograms/mL | Standard Deviation 4.32 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 3 Day 168 | 13.3 nanograms/mL | Standard Deviation 5.8 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 4 Day 1 | 15 nanograms/mL | Standard Deviation 4.24 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 4 Day 29 | 15.7 nanograms/mL | Standard Deviation 9.13 |
| Stratum 1 : Cohort 1 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 4 Day 168 | 14.3 nanograms/mL | Standard Deviation 7.67 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 4 Day 29 | 24.6 nanograms/mL | Standard Deviation 17.4 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 1 Day 1 | 6.2 nanograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 3 Day 1 | 47 nanograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 1 Day 29 | 25.7 nanograms/mL | Standard Deviation 14.4 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 4 Day 1 | 24 nanograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 1 Day 168 | 22.6 nanograms/mL | Standard Deviation 12.6 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 3 Day 29 | 13.7 nanograms/mL | Standard Deviation 11.6 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 2 Day 1 | 8.2 nanograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 4 Day 168 | 11 nanograms/mL | — |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 2 Day 29 | 12.3 nanograms/mL | Standard Deviation 7.67 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 3 Day 168 | 12.4 nanograms/mL | Standard Deviation 7.99 |
| Stratum 1 : Cohort 2 | PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | Quartile 2 Day 168 | 18.4 nanograms/mL | Standard Deviation 12.6 |