Efficacy, Safety and Tolerability of AIN457 in Patients With Rheumatoid Arthritis (RA) Taking Methotrexate (MTX)

Rheumatoid Arthritis Clinical Trial

Official title:

A 16-week Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Dose-finding Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous Secukinumab (AIN457) Followed by an Extension Phase up to a Total of 60 Weeks in Patients With Active Rheumatoid Arthritis Despite Stable Treatment With Methotrexate

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00928512
• Other study ID #: CAIN457F2201
• Secondary ID: 2009-011000-34
• Status: Completed
• Phase: Phase 2
• First received: June 25, 2009
• Last updated: October 7, 2015
• Start date: July 2009
• Est. completion date: March 2011

Study information

• Verified date: October 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBelgium: Federal Agency for Medicinal Products and Health ProductsCzech Republic: State Institute for Drug ControlGermany: Paul-Ehrlich-InstitutHungary: National Institute of PharmacyJapan: Pharmaceuticals and Medical Devices AgencyKorea: Food and Drug AdministrationPoland: Ministry of HealthRussia: Ministry of Health of the Russian FederationSlovakia: State Institute for Drug ControlTaiwan: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study will assess at Week 16 the efficacy and safety of AIN457 at different doses in patients with active RA despite stable MTX therapy. Treatment will continue up to Week 48 with a safety follow-up at Week 60 to assess the long term efficacy and safety of AIN457 treatment in combination with MTX in RA.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 237
• Est. completion date: March 2011
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Presence of RA classified by ACR 1987 revised criteria. Patients with active RA should have been on MTX for at least 3 months and must currently be treated with a stable dose of MTX (> or =7.5 mg/week - < or = 25 mg/week) for at least 4 weeks

• At Baseline: Disease activity criteria defined by > or = 6 out of 28 tender joints and > or = 6 out of 28 swollen joints WITH either Screening value of hsCRP > or = 10 mg/L OR ESR > or = 28 mm/1st hr

Exclusion Criteria:

• RA patients functional status class IV classified according to the ACR 1991 revised criteria

• Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone, or morphine)

• Any therapy by intra-articular injections (e.g. corticosteroid) required for treatment of acute RA flare within 4 weeks before randomization

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Secukinmab
Secukinumab was supplied as a 150mg lyophiized cake in individual glass vials each. The study drug dose levels were 25mg, 75mg, 150mg and 300mg and was administered subcutaneously.
• Placebo
Secukinumab placebo was supplied as a 150mg lyophiized cake in individual glass vials each. The placebo dose levels were 25mg, 75mg, 150mg and 300mg and was administered subcutaneously.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Bruxelles
Czech Republic	Novartis Investigative Site	Ostrava
Czech Republic	Novartis Investigative Site	Pardubice
Czech Republic	Novartis Investigative Site	Praha 2
Czech Republic	Novartis Investigative Site	Uherske Hradiste
Germany	Novartis Investigative Site	Bayreuth
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hildesheim
Germany	Novartis Investigative Site	Muenchen
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Gyula
Japan	Novartis Investigative Site	Iizuka-city	Fukuoka
Japan	Novartis Investigative Site	Kawagoe	Saitama
Japan	Novartis Investigative Site	Kobe	Hyogo
Japan	Novartis Investigative Site	Kobe	Hyogo
Japan	Novartis Investigative Site	Kurashiki	Okayama
Japan	Novartis Investigative Site	Sagamihara-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Anyang-si	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Busan
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Lublin
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St-Petersburg
Russian Federation	Novartis Investigative Site	St-Petersburg
Russian Federation	Novartis Investigative Site	St.Petersburg
Russian Federation	Novartis Investigative Site	Tula
Russian Federation	Novartis Investigative Site	Tver
Russian Federation	Novartis Investigative Site	Yaroslavl
Slovakia	Novartis Investigative Site	Banska Bystrica
Slovakia	Novartis Investigative Site	Kosice	Slovak Republic
Slovakia	Novartis Investigative Site	Piestany	Slovak Republic
Taiwan	Novartis Investigative Site	Changhua
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Niaosong Township
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taichung	Taiwan ROC
United States	Novartis Investigative Site	Coeur d'Alene	Idaho
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Jackson	Tennessee
United States	Novartis Investigative Site	Kalamazoo	Michigan
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Little Rock	Arkansas
United States	Novartis Investigative Site	Mesa	Arizona
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Peoria	Arizona
United States	Novartis Investigative Site	Rochester	New York
United States	Novartis Investigative Site	Santa Monica	California
United States	Novartis Investigative Site	Springfield	Illinois
United States	Novartis Investigative Site	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Czech Republic,  Germany,  Hungary,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Slovakia,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With American College of Rheumatology Response of 20 (ACR20) at 16 Weeks	A participant was considered to have achieved the incidence of response (ACR20 criteria) if he/she had at least a 20% improvement in both the tender and swollen 28-joint counts and had at least 20% improvement in at least 3 of the following 5 measures: patient's assessment of rheumatoid athritis (RA) pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's self-assesseddisability (Health Assessment Questionnaire [HAQ©] score)and acute phase rectant (C-reactive protein [hsCRP]/ESR).	16cweeks	No
Secondary	Number of Participants Who Achieved an ACR50 or ACR70 Response at Week 16	A participant was considered as improved according to the ACR50 or ACR70 criteria if he/she had at least a 50% or 70% improvement, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: patient's assessment of rheumatoid athritis (RA) pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient self-assessed disability (Health Assessment Questionnaire [HAQ©] score) and Acute phase reactant (C-reactive protein [hsCRP]/ESR). Participants were defined as ACR50/70 responders at a given post-randomization visit if they satisfied the ACR50/70 criteria, respectively. Participants were considered ACR50/70 nonresponders if they failed the ACR50/70 criteria respectively. Participants who prematurely discontinued from study due to insufficient therapeutic effect were also considered nonresponders.	Week 16	No
Secondary	Number of Participants Who Achieved an ACR20, ACR50 or ACR70 Response up to Week 16	A participant was considered as improved according to the ACR20, ACR50 or ACR70 criteria if he/she had as least a 20%, 50% or 70% improvement, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: patient's assessment of rheumatoid athritis (RA) pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's self-assessed disability and acute phase rectant or Erythrocyte sedimentation rate (ESR).	at Weeks2, 4, 8, 12, 16	No
Secondary	Change From Baseline in Disease Activity Score 28 Using CRP (DAS28-CRP)	The DAS28 is a measure of disease activity in Rheumatoid Arthritis (RA). The score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (ESR) or hsCRP, and the patient's 'global assessment of global health (indicated by marking a 100 mm line between very good and very bad). A DAS28 score greater than 5.1 implies active disease, less than 3.2 well controlled disease, and less than 2.6 remission. The DAS28-CRP was derived from swollen joint count, tender joint count, hsCRP and patient's global assessment of disease activity.	Baseline, week 16	No
Secondary	Change From Baseline in Medical Outcome Short Form (36) Health Survey (SF-36® v2)	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health) which can be aggregated to derive a physical-component summary score and a mental-component score. Scores are normally determined with the use of norm-based methods which standardize scores based on an assessment of the general U.S. population free of chronic conditions. The scores range for each subscale from 0 to 10, and the composite score ranges from 0 to 100, with the higher scores indicative of better health.	Baseline, week 16	No
Secondary	Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 16	The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue©) is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants responded to each item on a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much) based on their experience of fatigue during the past 2 weeThe scale score was computed by summing the item scores, after reversing those items that were worded in the negative direction. When there were missing item scores, the subscale score was computed by summing the non-missing item scores, multiplying by 13 (the total number of items in the scale) and dividing by the number of non-missing items. The latter rule applied only when at least half of the items (seven or more) were non-missing. FACIT-Fatigue subscale scores range from 0 to 52, where higher scores represent less fatigue.	Baseline, Week 16	No
Secondary	Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 16	The distribution of EULAR response criteria was according to DAS28-CRP at Week 16. EULAR response criteria are based on DAS28-CRP status in combination with DAS28-CRP improvements. The EULAR response criteria are as follows: Week 16 DAS28-CRP <3.2 with DAS28-CRP improvement >1.2 corresponds to 'good response'; Week 16 DAS28-CRP <3.2 with DAS28-CRP improvement between 0.6 to 1.2, or Week 16 DAS28-CRP between 3.2 to 5.1 with DAS28-CRP improvement >1.2 or from 0.6 to 1.2, or WeeK 16 DAS28-CRP >5.1 with DAS28-CRP improvement >1.2 correspond to 'moderate response; Week 16 DAS28-CRP <3.2 with DAS28-CRP improvement <0.6, or Week 16 DAS28-CRP between 3.2 to 5.1 with DAS28-CRP improvement <0.6, or Week 16 DAS28-CRP >5.1 with DAS28-CRP improvement between 0.6 to 1.2 or <0.6 correspond to 'no response'.	Week 16	No
Secondary	Change From Baseline in Rheumatoid Factor (RF) Concentrations at Week 16	Only values that were above normal range (12 U/mL) were were included.	Baseline, Week 16	No
Secondary	Anti-CCP (Cyclic Citrulinated Peptide) Antibodies Concentrations at Baseline and at Week 16	Only values that were above normal range (20 units) were included.	Baseline, Week 16	No
Secondary	Change From Baseline in ACR Component: Adjusted Swollen 28-joint Count at Week 16	Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a positive result for swollen joint count. Joint counts were performed according to the visit schedule by the physician or by well trained personnel. Whenever possible, the same evaluator performed these assessments at all visits. The following 28 joints were assessed for tenderness and swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). If the number of joints for which data were available (e.g., S) was less than 28, the number of swollen joints (e.g., s) was scaled up proportionately (i.e., 28*(s/S)).	Baseline, week 16	No
Secondary	Change From Baseline in Disease Activity Score 28 Using ESR (DAS28-ESR) at Week 16	The DAS28 is a measure of disease activity in Rheumatoid Arthritis (RA). The score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (ESR) or hsCRP, and the patient's 'global assessment of global health (indicated by marking a 100 mm line between very good and very bad). A DAS28 score greater than 5.1 implies active disease, less than 3.2 well controlled disease, and less than 2.6 remission.The DAS28 was also derived using erythrocyte sedimentation rate (ESR) (referred to as DAS28-ESR).	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: Adjusted Tender 28-joint Count at Week 16	The ACR tender joint count (28 joints) was done by scoring several different aspects of tenderness as assessed by pressure and joint manipulation on physical examination. Joint counts were performed according to the visit schedule by the physician or by well trained personnel. The following 28 joints were assessed for tenderness and swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). If the number of joints for which data were available (e.g., T) was less than 28, the number of tender joints (e.g., t) was scaled up proportionately (i.e., 28*(t/T)).	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: Patient's Assessment of RA Pain at Week 16	The patient's assessment of pain was performed at all visits using 100 mm visual analog scale (VAS) ranging from "no pain" to "unbearable pain" after the question "Please indicate with a vertical mark ( | ) through the horizontal line the most pain you had from your rheumatoid arthritis over the last 24 hours.	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: Patient's Global Assessment of Disease Activity at Week 16	The patient's global assessment of disease activity was performed at the visits on a 100 mm non-anchored visual analog scale, from no arthritis (0) activity to maximal arthritis (100) activity, after the question, "Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing".	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: Physician's Global Assessment of Disease Activity at Week 16	The physician's global assessment of disease activity was performed at the visits usingon a 100 mm non-anchored visual analog scale, from no arthritis (0) activity to maximal arthritis (100) activity, after the question, "Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing".	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: Health Assessment Questionnaire (HAQ©) Score at Week 16	HAQ© was used to assess physical ability and functional status of patients as well as quality of life at the visits in these 8 categories assessed by the Disability Index: dressing & grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Patients report amount of difficulty they have in performing 2 or 3 specific activities. There are 4 possible responses (0, 1, 2, 3) for these questions which include types of assistance, if any; the participant uses for his/her usual activities: 0: without any difficulty- No assistance is needed; 1: with some difficulty - A special device is used by the patient in his/her usual activities; 2: with much difficulty - The patient usually needs help from another person. 3: Unable to do - the patient usually needs both a special device and help from another person. Scores of 0 - 1 are generally considered to represent mild to moderate difficulty, 1-2 moderate to severe disability, and 2 -3 severe to very severe disability.	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: High Sensitivity C-reactive Protein (hsCRP)	Blood for this assessment was obtained at the visits in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment.Since the results of this test may have unblinded study personnel, results from the central lab were provided for screening and baseline only. The hsCRP results from samples collected during the treatment period were revealed only after final database lock.	Baseline, week 16	No
Secondary	Change From Baseline in ACR Component: Erythrocyte Sedimentation Rate (ESR) at Week 16	Blood for ESR, which is helpful to diagnose inflammatory diseases and to monitor disease activity and response to therapy, was obtained at the visits.	Baseline, week 16	No