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

Rheumatoid Arthritis Clinical Trial

Official title:

A Randomized, Double Blind, Placebo-controlled, Dose Escalation Study of the Safety, Tolerability and Pharmacokinetics of AIN457 in Rheumatoid Arthritis Patients With Pharmacodynamics Assessed in an Expanded Cohort at the Maximum Tolerated Dose

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00669942
• Other study ID #: CAIN457A2101
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: April 29, 2008
• Last updated: March 27, 2015
• Start date: December 2005
• Est. completion date: November 2008

Study information

• Verified date: March 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationEuropean Union: European Medicines AgencySingapore: Health Sciences Authority
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: November 2008
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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-a 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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Biological:
• AIN457
AIN457A is a fully human recombinant IgG1 antibody that targets and neutralizes IL-17A.

Drug:
• Placebo
Placebo to AIN457

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Merksem
Germany	Novartis Investigative Site	Bad Nauheim
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Muenchen
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Nijmegen
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Guadalajara
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
United States	Novartis Investigative Site	Anniston	Alabama
United States	Novartis Investigative Site	Bend	Oregon
United States	Novartis Investigative Site	Duncansville	Pennsylvania
United States	Novartis Investigative Site	Largo	Florida
United States	Novartis Investigative Site	Madisonville	Kentucky
United States	Novartis Investigative Site	Ocala	Florida
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Palm Harbor	Florida
United States	Novartis Investigative Site	Port Orange	Florida
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Germany,  Netherlands,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Day 43	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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.	Day 113	No
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	Day 43	No
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).	Day 43	No