Double Blind, Placebo-controlled, Study of the Safety, Tolerability and Pharmacokinetics of AIN457 in Rheumatoid Arthritis Patients

Phase 1

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Placebo
Biological: AIN457

Registration Number: NCT00669942

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 104

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/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1 - Placebo	Placebo	Placebo to AIN457A was administered intravenously as a single dose.
Parts 2 and 3 - AIN457A 3.0 mg/kg	AIN457	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.
Part 1 - Healthy Volunteers - AIN457A 3 mg/kg	AIN457	AIN457A 3.0 mg/kg was administered intravenously as a single dose.
Part 1 - AIN457A 0.3 mg/kg	AIN457	AIN457A 0.3 mg/kg was administered intravenously as a single dose.
Parts 2 and 3 - AIN457A 1.0 mg/kg	AIN457	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.
Part 1 - AIN457A 3.0 mg/kg	AIN457	AIN457A 3.0 mg/kg was administered intravenously as a single dose.
Part 1 - AIN457A 10 mg/kg	AIN457	AIN457A 10.0 mg/kg was administered intravenously as a single dose.
Part 1 - AIN457A 1.0 mg/kg	AIN457	AIN457A 1.0 mg/kg was administered intravenously as a single dose.
Parts 2 and 3 - AIN457A 10 mg/kg	AIN457	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.
Parts 2 and 3 - Placebo	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.
Part 1 - Healthy Volunteers - AIN457A 10 mg/kg	AIN457	AIN457A 10 mg/kg was administered intravenously as a single dose.
Part 1 - Healthy Volunteers - Placebo	Placebo	Placebo to AIN457A was administered intravenously as a single dose.

Primary Outcome Measures

Name	Time	Method
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.
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: 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.
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: 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.
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: 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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

Name	Time	Method
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