Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis
Brief summary
Evaluate the safety, tolerability and pharmacokinetics of AIN457 when administered as a single dose (intravenous infusion) in patients with active rheumatoid arthritis in combination with a stable dose of methotrexate. And to compare efficacy on the dose groups.
Interventions
BIOLOGICALAIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.
DRUGPlacebo
Placebo to AIN457
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients with active rheumatoid arthritis in combination with a stable dose of methotrexate aged 18-75 years may participate in this trial. * Post menopausal or surgically sterile female patients are allowed. Women of child-bearing potential may participate if they are on a stable dose of methotrexate and if they are practicing effective contraception for at least 6 months prior to screening, willing to use 2 forms of contraception, including at least 1 barrier method during the study and for at least 2 months following the completion/discontinuation of the study. * Patients must have a diagnosis of active rheumatoid arthritis of stages I, II or III (ACR 1987 revised classification for criteria for RA). Disease duration of at least 6 months prior to randomization is essential;
Exclusion criteria
* Current treatment with anti-TNF-α or anti IL-1 therapy (or other biological therapy). * Patients with congestive heart failure or poorly controlled diabetes mellitus (HbA1c value ≥10%). * Presence of any major chronic inflammatory autoimmune diseases like psoriasis, psoriatic arthritis, spondyloarthropathy, inflammatory bowel disease or SLE that can mimic rheumatoid arthritis diagnosis or that can interfere with efficacy evaluation in the study. * History of renal trauma, glomerulonephritis or patient with one kidney. * Pregnant or breastfeeding women will be excluded. * A positive tuberculin skin test. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics PK of AIN457: T1/2 in Parts 2 and 3 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| Pharmacokinetics PK of AIN457: Vz in Parts 2 and 3 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| Pharmacokinetics PK of AIN457: CL in Parts 2 and 3 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| Percentage of Parts 2 and 3 Participants Who Achieved American College of Rheumatology Response of 20 (ACR20) | Day 43 | Clinical response to treatment was assessed according to ACR20 criteria. A participant was defined as an ACR20 responder if the following 3 conditions were met: 1) ≥20% improvement in the number of tender joints, 2) ≥20% improvement in the number of swollen joint and 3) ≥20% improvement in three of the following five domains: patient global assessment, physician global assessment, patient pain assessment, health assessment questionnaire (HAQ) and acute phase reactant. |
| Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99 and 113. |
| PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| Pharmacokinetics PK of AIN457: Tmax in Parts 2 and 3 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| Pharmacokinetics PK of AIN457: Cmax in Parts 2 and 3 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
| Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | Day 113 | Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Activity Score (DAS28) of Parts 2 and 3 Participants | Day 43 | The DAS28 is a composite score based on tender and swollen joint counts, C reactive protein (CRP) concentrations, and the participant's global disease activity based on a visual analogue scale (VAS). The tender joint count (based on 28 joints) was calculated by scoring several different aspects of tenderness as assessed by pressure and joint manipulation on physical examination. The information on various types of tenderness was then collapsed into a single tender versus non-tender dichotomy, and the number of joints that were classified as tender was recorded. The swollen joint count was calculated in the same manner. For CRP concentrations, blood samples were collected and sent to a central laboratory for assessment. For the VAS assessment, the participant used a 100 mm horizontal VAS to assess the severity of his or her arthritis where 0 = none and 100 = most severe. DAS28 scores range from \<2.6 (disease remission) to \>5.1 (high disease activity). |
| Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70 | Day 43 | Clinical response to treatment was assessed according to ACR50 and ACR70 criteria. A participant was defined as an ACR50 or ACR70 responder if the following 3 conditions were met: 1) improvement of ≥50% or ≥ 70%, respectively, in the number of tender joints, 2) improvement of ≥50% or ≥ 70%, respectively, in the number of swollen joints and 3) improvement of ≥50% or ≥ 70%, respectively, in three of the following five domains: patient global assessment, physician global assessment, patient pain assessment, health assessment questionnaire (HAQ) and acute phase reactant |
Countries
Belgium, Germany, Netherlands, Singapore, Spain, United States
Participant flow
Recruitment details
Part 1: single dose escalation - sequential cohorts of patients and healthy volunteers received AIN457A or placebo. Part 2: multiple dose escalation - sequential cohorts of patients received 2 doses of AIN457A or placebo. Part 3: patients received 2 doses of AIN457 10 mg/kg (or the maximum tolerated dose) or placebo.
Pre-assignment details
In parts 1 and 2, participants were randomized 3:1 to receive AIN457A or placebo. In part 3, participants were randomized 1:1 to receive AIN457A or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - AIN457A 0.3 mg/kg AIN457A 0.3 mg/kg was administered intravenously as a single dose. | 6 |
| Part 1 - AIN457A 1.0 mg/kg AIN457A 1.0 mg/kg was administered intravenously as a single dose. | 6 |
| Part 1 - AIN457A 3.0 mg/kg AIN457A 3.0 mg/kg was administered intravenously as a single dose. | 6 |
| Part 1 - AIN457A 10 mg/kg AIN457A 10.0 mg/kg was administered intravenously as a single dose. | 6 |
| Part 1 - Placebo Placebo to AIN457A was administered intravenously as a single dose. | 8 |
| Parts 2 and 3 - AIN457A 1.0 mg/kg AIN457A 1.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22. | 6 |
| Parts 2 and 3 - AIN457A 3.0 mg/kg AIN457A 3.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22. | 6 |
| Parts 2 and 3 - AIN457A 10 mg/kg AIN457A 10.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22. | 26 |
| Parts 2 and 3 - Placebo Placebo to AIN457A was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22. | 26 |
| Part 1 - Healthy Volunteers - AIN457A 3 mg/kg AIN457A 3.0 mg/kg was administered intravenously as a single dose. | 3 |
| Part 1 - Healthy Volunteers - AIN457A 10 mg/kg AIN457A 10 mg/kg was administered intravenously as a single dose. | 3 |
| Part 1 - Healthy Volunteers - Placebo Placebo to AIN457A was administered intravenously as a single dose. | 2 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Parts 2 and 3 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 |
| Parts 2 and 3 | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Parts 2 and 3 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1 - AIN457A 0.3 mg/kg | Part 1 - AIN457A 1.0 mg/kg | Part 1 - AIN457A 3.0 mg/kg | Part 1 - AIN457A 10 mg/kg | Part 1 - Placebo | Parts 2 and 3 - AIN457A 1.0 mg/kg | Parts 2 and 3 - AIN457A 3.0 mg/kg | Parts 2 and 3 - AIN457A 10 mg/kg | Parts 2 and 3 - Placebo | Part 1 - Healthy Volunteers - AIN457A 3 mg/kg | Part 1 - Healthy Volunteers - AIN457A 10 mg/kg | Part 1 - Healthy Volunteers - Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.6 Years STANDARD_DEVIATION 8.04 | 58.8 Years STANDARD_DEVIATION 13.61 | 51.2 Years STANDARD_DEVIATION 9.5 | 63.2 Years STANDARD_DEVIATION 9.45 | 57.8 Years STANDARD_DEVIATION 3.41 | 60.8 Years STANDARD_DEVIATION 8.66 | 56.0 Years STANDARD_DEVIATION 12 | 49.9 Years STANDARD_DEVIATION 8.53 | 49.8 Years STANDARD_DEVIATION 15.19 | 26.7 Years STANDARD_DEVIATION 10.02 | 22.3 Years STANDARD_DEVIATION 2.31 | 42.5 Years STANDARD_DEVIATION 10.61 | 46.07 Years STANDARD_DEVIATION 10.83 |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 7 Participants | 5 Participants | 3 Participants | 19 Participants | 20 Participants | 0 Participants | 0 Participants | 1 Participants | 75 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 7 Participants | 6 Participants | 3 Participants | 3 Participants | 1 Participants | 29 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 | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 6 | 2 / 6 | 5 / 6 | 2 / 6 | 4 / 8 | 5 / 6 | 4 / 6 | 19 / 26 | 13 / 26 | 1 / 3 | 1 / 2 | 0 / 3 |
| serious Total, serious adverse events | 1 / 6 | 0 / 6 | 1 / 6 | 0 / 6 | 0 / 8 | 0 / 6 | 1 / 6 | 0 / 26 | 2 / 26 | 0 / 3 | 0 / 2 | 0 / 3 |
Outcome results
Primary
Percentage of Parts 2 and 3 Participants Who Achieved American College of Rheumatology Response of 20 (ACR20)
Clinical response to treatment was assessed according to ACR20 criteria. A participant was defined as an ACR20 responder if the following 3 conditions were met: 1) ≥20% improvement in the number of tender joints, 2) ≥20% improvement in the number of swollen joint and 3) ≥20% improvement in three of the following five domains: patient global assessment, physician global assessment, patient pain assessment, health assessment questionnaire (HAQ) and acute phase reactant.
Time frame: Day 43
Population: The analysis was performed on the 10 mg and placebo treatment arms of the parts 2 and 3 participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Percentage of Parts 2 and 3 Participants Who Achieved American College of Rheumatology Response of 20 (ACR20) | 46 percentage of participants |
| Parts 2 and 3 - Placebo | Percentage of Parts 2 and 3 Participants Who Achieved American College of Rheumatology Response of 20 (ACR20) | 27 percentage of participants |
Primary
Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Parts 2 and 3 participants who received AIN457A at 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | AUCinf | 808.6 day*ug/mL | Standard Deviation 251.01 |
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | AUClast | 746.4 day*ug/mL | Standard Deviation 209.2 |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | AUCinf | 2843 day*ug/mL | Standard Deviation 481.49 |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | AUClast | 2704 day*ug/mL | Standard Deviation 467.6 |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | AUCinf | 8371 day*ug/mL | Standard Deviation 2505.8 |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants | AUClast | 7815 day*ug/mL | Standard Deviation 2102 |
Primary
Pharmacokinetics PK of AIN457: CL in Parts 2 and 3 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Parts 2 and 3 participants who received AIN457A at 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: CL in Parts 2 and 3 Participants | 0.1834 Liters/day | Standard Deviation 0.042822 |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: CL in Parts 2 and 3 Participants | 0.1775 Liters/day | Standard Deviation 0.034075 |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: CL in Parts 2 and 3 Participants | 0.1994 Liters/day | Standard Deviation 0.063454 |
Primary
Pharmacokinetics PK of AIN457: Cmax in Parts 2 and 3 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Parts 2 and 3 participants who received AIN457A at 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: Cmax in Parts 2 and 3 Participants | 23.54 ug/mL | Standard Error 3.1588 |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: Cmax in Parts 2 and 3 Participants | 97.78 ug/mL | Standard Error 15.543 |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: Cmax in Parts 2 and 3 Participants | 322.2 ug/mL | Standard Error 96.719 |
Primary
Pharmacokinetics PK of AIN457: T1/2 in Parts 2 and 3 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Parts 2 and 3 participants who received AIN457A at 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: T1/2 in Parts 2 and 3 Participants | 25.60 Day | Standard Deviation 6.31 |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: T1/2 in Parts 2 and 3 Participants | 23.89 Day | Standard Deviation 3.2335 |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: T1/2 in Parts 2 and 3 Participants | 23.68 Day | Standard Deviation 6.3048 |
Primary
Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99 and 113.
Time frame: Day 113
Population: Part 1 participants who received AIN457A at 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis. One participant in the 0.3 mg/kg arm was not analyzed due to an atypical PK profile.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants | 0.09028 day |
| Parts 2 and 3 - Placebo | Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants | 0.08472 day |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants | 0.1253 day |
| Part 1 - AIN457A 10 mg/kg | Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants | 0.1260 day |
Primary
Pharmacokinetics PK of AIN457: Tmax in Parts 2 and 3 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Parts 2 and 3 participants who received AIN457A at 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: Tmax in Parts 2 and 3 Participants | 21.08 day |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: Tmax in Parts 2 and 3 Participants | 21.08 day |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: Tmax in Parts 2 and 3 Participants | 21.09 day |
Primary
Pharmacokinetics PK of AIN457: Vz in Parts 2 and 3 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Parts 2 and 3 participants who received AIN457A at 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Pharmacokinetics PK of AIN457: Vz in Parts 2 and 3 Participants | 6.514 Liter | Standard Deviation 1.1542 |
| Parts 2 and 3 - Placebo | Pharmacokinetics PK of AIN457: Vz in Parts 2 and 3 Participants | 6.062 Liter | Standard Deviation 1.0189 |
| Part 1 - AIN457A 3.0 mg/kg | Pharmacokinetics PK of AIN457: Vz in Parts 2 and 3 Participants | 6.382 Liter | Standard Deviation 1.1336 |
Primary
PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Part 1 participants who received AIN457A at 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis. One participant in the 0.3 mg/kg arm was not analyzed due to an atypical PK profile.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUCinf | 141.3 day*ug/mL | Standard Deviation 48.781 |
| Parts 2 and 3 - AIN457A 10 mg/kg | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUClast | 132.7 day*ug/mL | Standard Deviation 42.824 |
| Parts 2 and 3 - Placebo | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUCinf | 430.7 day*ug/mL | Standard Deviation 48.281 |
| Parts 2 and 3 - Placebo | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUClast | 415.6 day*ug/mL | Standard Deviation 42.793 |
| Part 1 - AIN457A 3.0 mg/kg | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUClast | 1097 day*ug/mL | Standard Deviation 291.59 |
| Part 1 - AIN457A 3.0 mg/kg | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUCinf | 1148 day*ug/mL | Standard Deviation 330.89 |
| Part 1 - AIN457A 10 mg/kg | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUClast | 3936 day*ug/mL | Standard Deviation 697.65 |
| Part 1 - AIN457A 10 mg/kg | PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants | AUCinf | 4080 day*ug/mL | Standard Deviation 768.87 |
Primary
PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Part 1 participants who received AIN457A at 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis. One participant in the 0.3 mg/kg arm was not analyzed due to an atypical PK profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants | 8.772 ug/mL | Standard Deviation 1.802 |
| Parts 2 and 3 - Placebo | PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants | 35.22 ug/mL | Standard Deviation 18.755 |
| Part 1 - AIN457A 3.0 mg/kg | PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants | 70.95 ug/mL | Standard Deviation 9.9472 |
| Part 1 - AIN457A 10 mg/kg | PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants | 211.8 ug/mL | Standard Deviation 36.837 |
Primary
PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Part 1 participants who received AIN457A at 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis. One participant in the 0.3 mg/kg arm was not analyzed due to an atypical PK profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants | 0.2249 Liters/day | Standard Deviation 0.11196 |
| Parts 2 and 3 - Placebo | PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants | 0.2110 Liters/day | Standard Deviation 0.064415 |
| Part 1 - AIN457A 3.0 mg/kg | PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants | 0.2077 Liters/day | Standard Deviation 0.08088 |
| Part 1 - AIN457A 10 mg/kg | PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants | 0.1999 Liters/day | Standard Deviation 0.049375 |
Primary
PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Part 1 participants who received AIN457A at 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants | 23.21 day | Standard Deviation 6.8285 |
| Parts 2 and 3 - Placebo | PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants | 22.27 day | Standard Deviation 2.8478 |
| Part 1 - AIN457A 3.0 mg/kg | PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants | 23.47 day | Standard Deviation 5.7952 |
| Part 1 - AIN457A 10 mg/kg | PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants | 23.94 day | Standard Deviation 4.2566 |
Primary
PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Time frame: Day 113
Population: Part 1 participants who received AIN457A at 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg were included in this analysis. One participant in the 0.3 mg/kg arm was not analyzed due to an atypical PK profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants | 7.043 Liters | Standard Deviation 2.0197 |
| Parts 2 and 3 - Placebo | PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants | 6.756 Liters | Standard Deviation 2.2186 |
| Part 1 - AIN457A 3.0 mg/kg | PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants | 6.506 Liters | Standard Deviation 0.83822 |
| Part 1 - AIN457A 10 mg/kg | PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants | 6.699 Liters | Standard Deviation 0.83967 |
Secondary
Disease Activity Score (DAS28) of Parts 2 and 3 Participants
The DAS28 is a composite score based on tender and swollen joint counts, C reactive protein (CRP) concentrations, and the participant's global disease activity based on a visual analogue scale (VAS). The tender joint count (based on 28 joints) was calculated by scoring several different aspects of tenderness as assessed by pressure and joint manipulation on physical examination. The information on various types of tenderness was then collapsed into a single tender versus non-tender dichotomy, and the number of joints that were classified as tender was recorded. The swollen joint count was calculated in the same manner. For CRP concentrations, blood samples were collected and sent to a central laboratory for assessment. For the VAS assessment, the participant used a 100 mm horizontal VAS to assess the severity of his or her arthritis where 0 = none and 100 = most severe. DAS28 scores range from \<2.6 (disease remission) to \>5.1 (high disease activity).
Time frame: Day 43
Population: The analysis was performed on the 10 mg and placebo treatment arms of the parts 2 and 3 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Disease Activity Score (DAS28) of Parts 2 and 3 Participants | 4.306 scores on a scale | Standard Error 1.4787 |
| Parts 2 and 3 - Placebo | Disease Activity Score (DAS28) of Parts 2 and 3 Participants | 4.598 scores on a scale | Standard Error 1.2618 |
Secondary
Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70
Clinical response to treatment was assessed according to ACR50 and ACR70 criteria. A participant was defined as an ACR50 or ACR70 responder if the following 3 conditions were met: 1) improvement of ≥50% or ≥ 70%, respectively, in the number of tender joints, 2) improvement of ≥50% or ≥ 70%, respectively, in the number of swollen joints and 3) improvement of ≥50% or ≥ 70%, respectively, in three of the following five domains: patient global assessment, physician global assessment, patient pain assessment, health assessment questionnaire (HAQ) and acute phase reactant
Time frame: Day 43
Population: The analysis was performed on the 10 mg and placebo treatment arms of the parts 2 and 3 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Parts 2 and 3 - AIN457A 10 mg/kg | Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70 | ACR50 | 27 Percentage of participants |
| Parts 2 and 3 - AIN457A 10 mg/kg | Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70 | ACR70 | 8 Percentage of participants |
| Parts 2 and 3 - Placebo | Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70 | ACR50 | 15 Percentage of participants |
| Parts 2 and 3 - Placebo | Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70 | ACR70 | 8 Percentage of participants |