A Study of Tocilizumab + DMARDs in Patients With Moderate to Severe Active Rheumatoid Arthritis

A Single Arm, Open-label Study of Early Improvement of Anemia and Fatigue During Treatment With Tocilizumab (TCZ) in Combination With DMARDs, in Adult Patients With Moderate to Severe Active Rheumatoid Arthritis.

This single arm study will assess the effect of tocilizumab + DMARDs (Disease Modifying Anti-Rheumatic Drugs)on improvement of anemia and fatigue in patients with moderate to severe active rheumatoid arthritis. Eligible patients who have had an inadequate response to DMARDs will receive tocilizumab 8mg/kg iv every 4 weeks in combination with standard DMARDs, for 6 months. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: tocilizumab [RoActemra/Actemra]; Drug: Standard DMARDs (Disease Modifying Anti Rheumatic Drugs)

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Campania
    • Benevento, Campania, Italy, 82100
      • Azienda Ospedaliera Rummo; Divisione Di Reumatologia
    • Napoli, Campania, Italy, 80131
      • Azienda Ospedaliera A. Cardarelli; Medicina III - Divisione di Reumatologia
    • Napoli, Campania, Italy, 80131
      • UNIVERSITÀ DI NAPOLI FEDERICO II; Dipartimento di Immunologia Clinica ed Allergologia
    • Scafati, Campania, Italy, 84018
      • Ospedale M. Scarlato - Asl Sa1; U.O. Di Reumatologia
    • Telese Terme, Campania, Italy, 82037
      • Irccs Fondazione Salvatore Maugeri-Istituto Scientifico Di Telese;U.O. Riabilitazione Reumatologica
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2
    • Parma, Emilia-Romagna, Italy, 43100
      • Az. Ospedaliera Univ. di Parma; Medicina Interna e Reumatologia
    • Piacenza, Emilia-Romagna, Italy, 29100
      • Ospedale Guglielmo Da Saliceto Unità Operativa Semplice di Reumatologia e Immunologia
  • Lazio
    • Roma, Lazio, Italy, 00133
      • Policlinico Tor Vergata; Divisione Di Reumatologia
    • Roma, Lazio, Italy, 00189
      • Ospedale S.Pietro Fatebenefratelli; Divisione di Reumatologia
    • Roma, Lazio, Italy, 00153
      • Ospedale Nuovo Regina Margherita; Divisione di Medicina Interna Reumatologia
    • Viterbo, Lazio, Italy, 01100
      • Ospedale Belcolle; Divisione Di Reumatologia
  • Liguria
    • Savona, Liguria, Italy, 17100
      • Ospedale San Paolo; Divisione di Reumatologia
  • Lombardia
    • Bergamo, Lombardia, Italy, 24127
      • ASST PAPA GIOVANNI XXIII; Reumatologia Day Hospital-Torre 2 terzo piano
    • Monza, Lombardia, Italy, 20052
      • ASST DI MONZA; Reumatologia (Medicina I)
    • Rozzano, Lombardia, Italy, 20089
      • IRCCS Istituto Clinico Humanitas; Immunologia Clinica E Reumatologia
  • Piemonte
    • Torino, Piemonte, Italy, 10154
      • Ospedale S. Giovanni Bosco; S.C. A Direzione Uni Ria Di Immunologia Clinica
  • Puglia
    • Brindisi, Puglia, Italy, 72100
      • Ospedale Perrino; Medicina Interna - Divisione di Reumatologia
    • Martina Franca, Puglia, Italy, 74015
      • Presidio Ospedaliero Valle D'itria; Divisione Di Nefrologia
    • San Cesario Di Lecce, Puglia, Italy, 73016
      • Ospedale Galateo; U.O. Di Reumatologia
  • Sicilia
    • Catania, Sicilia, Italy, 95124
      • Ospedale Vittorio Emanuele Ii; U.O. Reumatologia Clinica Medica Condorelli
    • Gazzi, Sicilia, Italy, 98125
      • A.U.O. G. Martino- Policlinico Univ. Gazzi; Dept. Di Medicina Interna, Divisione Di Reumatologia
    • Palermo, Sicilia, Italy, 90127
      • Arnas Ospedale Civico; Medicina Interna II
    • Palermo, Sicilia, Italy, 90146
      • Az. Osp. Villa Sofia; Unità Operativa Reumatologia
    • Palermo, Sicilia, Italy, 90146
      • Ospedali Riuniti Villa Sofia- Cervello X; Divisione Medicina I
  • Toscana
    • Massa, Toscana, Italy, 54100
      • Ospedale Di Massa; Divisione Di Reumatologia
  • Veneto
    • Venezia, Veneto, Italy, 30127
      • Ospedale SS Giovanni e Paolo; Divisione Di Reumatologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients, >=18 years of age;
• rheumatoid arthritis >=6 months duration;
• DAS28>=3.2;
• inadequate response to prior treatment with a stable dose (>=8 weeks) of DMARD therapy.

Exclusion Criteria:

• rheumatic autoimmune disease other than rheumatoid arthritis;
• history of or current inflammatory joint disease other than rheumatoid arthritis;
• unsuccessful treatment with an anti-TNF agent;
• previous/concurrent treatment with any cell-depleting therapies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: tocilizumab [RoActemra/Actemra]; 8mg/kg iv every 4 weeks for 6 months; Drug: Standard DMARDs (Disease Modifying Anti Rheumatic Drugs); As prescribed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of Anemia at Week 4 Assessed as Change From Baseline in Hemoglobin	Hemoglobin levels were measured as grams/deciliter (g/dL).	Week 4
Improvement in Fatigue at Week 4 Assessed as Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scores	The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participants fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). Clinically relevant improvement is defined as a greater than or equal to (≥)5-point change from Baseline.	Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Hemoglobin Levels During the Study		Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
Improvement of Anemia Assessed as Change From Baseline in Hemoglobin	Improvement of anemia was evaluated as change in hemoglobin levels from baseline.	Weeks 2, 4, 8, 12, 16, 20, and 24
FACIT-F Scores	The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participants fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). Clinically relevant improvement is defined as a ≥5-point change from Baseline.	Baseline, Weeks 2, 4, 8,12, 16, 20 and 24
Improvement of Fatigue Assessed as Change From Baseline in FACIT-F Scores	The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participants fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). Clinically relevant improvement is defined as a ≥5-point change from Baseline.	Weeks 2, 4, 8, 12, 16, 20 and 24
Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Percent (%), 50% or 70% Improvement	The ACR response rates ACR20, ACR50, and ACR70 were defined as ≥20%, ≥50% and ≥ 70% improvement, respectively, in: swollen joint count (SJC) (66 joints) and tender joint count (TJC) (68 joints) and 3 of the 5 remaining ACR parameters: Patient assessment of pain; Patient Global Assessment of Disease Activity; Investigator Global Assessment of Disease Activity; participant self-rated assessment of disability measured by the Health Assessment Questionnaire Disability Index (HAQ-DI); and acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]).	Week 24
Percent Change From Baseline to Week 24 in TJC	Sixty-eight (68) joints were assessed at each visit for tenderness; joints were assessed and classified as tender/not tender. Tender joint count 68 (TJC-68) was calculated as the number of tender joints from 68 joints; the number of tender joints was summed (maximum score 68). Calculated values were used for the analysis. A negative score indicated improvement.	Week 24
Percent Change From Baseline to Week 24 in SJC	Sixty-six (66) joints were assessed at each visit for swelling; joints were assessed and classified as swollen/not swollen. Swollen joint count 66 (SJC-66) was calculated as the number of swollen joints from 66 joints; the number of swollen joints was summed (maximum score 66). Calculated values were used for the analysis. A negative score indicated improvement.	Week 24
Percent Change From Baseline to Week 24 in Patient Global Assessment of Pain	The participant's assessment of their current level of pain was displayed on a 100-millimeter (mm) horizontal visual analog scale (VAS). The left-hand extreme of the line was described as "no pain" and the right-hand as "unbearable pain". The participant was asked to mark the line that corresponded to their current level of pain; the distance from the left edge was recorded.	Week 24
Percent Change From Baseline to Week 24 in Patient's Global Assessment of Disease Activity	The participant's overall assessment of their current disease activity was displayed on a 100-mm horizontal VAS. The left-hand extreme of the line was described as "no disease activity" (symptom free and no arthritis symptoms) and the right-hand extreme as "maximum disease activity" (maximum arthritis disease activity). Participants were asked to assess their current level of disease activity and mark the line; the distance from the left edge was recorded.	Week 24
Percent Change From Baseline to Week 24 in Investigator's Global Assessment of Disease Activity	The physician's assessment of the participant's current disease activity was displayed on a 100-mm horizontal VAS. The left-hand extreme of the line was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme was considered "maximum disease activity". The physician's global assessment of disease activity was completed by the Efficacy Assessor who could or could not be a physician. The assessor was asked to mark the line corresponding to their assessment of the participant's present level of disease activity; the distance from the left edge was recorded.	Week 24
Percent Change From Baseline to Week 24 in HAQ-DI	HAQ-DI includes 20 questions concerning participant's activities of daily life, grouped in 8 scales of 2 to 3 questions for each activity. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Overall score was computed as the sum of the domain scores and divided by the number of domains answered. Total possible score range was 0-3 where 0 (equals)=without difficulties; 1= with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all.	Week 24
Percent Change From Baseline to Week 24 in High-Sensitivity CRP (Hs-CRP)	hs-CRP is an acute phase reactant protein that is a clinical marker for Rheumatoid Arthritis (RA). hsCRP is measured in milligrams per liter (mg/L).	Week 24
Percent Change From Baseline to Week 24 in ESR	ESR is a blood test used to monitor therapy in inflammatory diseases such as RA and reflects acute phase reactant levels. ESR is measured in mm per hour (mm/hr); active disease in RA is defined by an ESR greater than 30 mm/hr.	Week 24
Percentage of Participants With a Response at Week 24 by European League Against Rheumatism (EULAR) Category	Disease response was assessed using EULAR Disease Activity Score Based on 28-Joint Count (DAS28) categories of Good, Moderate, or No Response. Good response was defined as a DAS28 score of less than (<)3.2 and improvement from baseline of >1.2; Moderate response was defined as a DAS28 score of 3.2-5.1 and improvement from baseline of 1.2-0.6 or a DAS28 score of >5.1 and improvement from baseline of >1.2; No response was defined as a DAS28 score of >5.1 and improvement from baseline of <1.2. Participants who discontinued prematurely were identified as non-responders.	Week 24
Percentage of Participants With a Response at Week 24 by DAS28 Category	DAS28 calculated from the number of swollen joints (SJC) and tender joints (TJC) using the 28 joints count, the ESR (mm/hr) and patient's global assessment of disease activity (participant rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2=low disease activity, DAS28 >5.1=high disease activity and DAS <2.6=remission.	Week 24
Percent Change From Baseline to Week 24 in DAS28 Score	DAS28 calculated from the number of swollen joints (SJC) and tender joints (TJC) using the 28 joints count, the ESR (mm/hr) and patient's global assessment of disease activity (participant rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2=low disease activity, DAS28 >5.1=high disease activity and DAS <2.6=remission.	Week 24
Percentage of Participants With an Improvement of ≥1 g/dL in Hemoglobin		Week 24
Number of Days as Assessed by Short Form-Health and Labour Questionnaire (SF-HLQ)	The SF-HLQ assessed productivity losses related to health problems in individuals with paid or unpaid work and consists of three modules (absenteeism from paid work, production losses without absenteeism from paid work and hindrance in the performance of paid and unpaid work). Any missed working days or number of worked days with reduced efficiency during the last month were reported.	Baseline
Change From Baseline to Weeks 12 and 24 in Number of Days as Assessed by SF-HLQ	The SF-HLQ assessed productivity losses related to health problems in individuals with paid or unpaid work and consists of three modules (absenteeism from paid work, production losses without absenteeism from paid work and hindrance in the performance of paid and unpaid work). Any missed working days or number of worked days with reduced efficiency during the last month were reported.	Weeks 12 and 24
Number of Hours as Assessed by SF-HLQ	Number of working hours lost, and number of hours of support in in taking over and performing usual household tasks in the last month: chores done by family members, chores done by other persons receiving no pay, home care, other paid care, total number of unpaid hours, and total number of hours during the last month were reported.	Baseline
Change From Baseline to Weeks 12 and 24 in Number of Hours as Assessed by SF-HLQ	Number of working hours lost, and number of hours of support in in taking over and performing usual household tasks in the last month: chores done by family members, chores done by other persons receiving no pay, home care, other paid care, total number of unpaid hours, and total number of hours during the last month were reported. Changes from baseline were only calculated in participants who completed the questionnaire at all times (baseline, Week 12, and Week 24). Negative number indicates improvement.	Baseline
SF-HLQ Hindrance Score	Participants were asked if their health problems hindered their paid work on a scale of 1 to 3 (1=no, 2=yes, slightly, 3=yes, very much) and their unpaid work including household work, going shopping, odd jobs, specific activities sharing the household on a scale of 0 to 3 (0=performed without being bothered by healthy problems; 1=performed although bothered by health problems; 2=not performed because of health problems; 3=not performed for reasons other than health problems). The total hindrance score for unpaid work was derived by adding up the item scores. This hindrance score is a measure of the hindrance experienced as a result of health problems during the performance of unpaid work. The minimum score per item for hindrance score was 0, maximum score was 2 (Score of 3 was not considered since the reasons were "other than health problems"). Total score was calculated by adding all 4 items together and ranged from 0 (best possible score) to 8 (worst possible score).	Baseline
Change From Baseline to Weeks 12 and 24 SF-HLQ Hindrance Score	Participants were asked if health problems hindered their paid work on a scale of 1 to 3 (1=no, 2=yes, slightly, 3=yes, very much) and their unpaid work including household work, going shopping, odd jobs, specific activities sharing the household on a scale of 0 to 3 (0=performed without being bothered by healthy problems; 1=performed although bothered by health problems; 2=not performed because of health problems; 3=not performed for reasons other than health problems). Hindrance score is a measure of the hindrance experienced as a result of health problems during the performance of unpaid work. The minimum score per item for hindrance score was 0, maximum score was 2 (Score of 3 was not considered since the reasons were "other than health problems"). Total score was calculated by adding all 4 items together and ranged from 0 (best possible score) to 8 (worst possible score). A negative change from baseline indicates improvement.	Baseline
Efficiency as Assessed by SF-HLQ	Participants were ask to rate their efficiency in working on a scale of of 0 to 10 (0=very worse, 10=as usual). Overall efficiency score was based on the first 6 items of Question 6, which is a descriptive instrument comprised of 7 items designed to evaluate the specific problems affecting production. These 7 items relate to the effect of health problems on concentration, work pace, the need to be alone, making decisions, postponing and transferring work to others. The participant can choose from 4 possible answers: (almost) never, sometimes, often and (nearly) always. Efficiency score range=6 to 24; higher scores indicate higher impairment.	Baseline
Change From Baseline to Weeks 12 and 24 in Efficiency as Assessed by SF-HLQ	Participants were ask to rate their efficiency in working on a scale of of 0 to 10 (0=very worse, 10=as usual). Overall efficiency score was based on the first 6 items of Question 6, which is a descriptive instrument comprised of 7 items designed to evaluate the specific problems affecting production. These 7 items relate to the effect of health problems on concentration, work pace, the need to be alone, making decisions, postponing and transferring work to others. The participant can choose from 4 possible answers: (almost) never, sometimes, often and (nearly) always. Efficiency score range=6 to 24; higher scores indicate higher impairment. Change from baseline was only calculated for participants who completed the questionnaire at all times (baseline, Week 12 and Week 24). A negative change from baseline indicates improvement.	Baseline

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2009
• Primary Completion (Actual): July 22, 2011
• Study Completion (Actual): July 22, 2011

Study Registration Dates

• First Submitted: July 30, 2009
• First Submitted That Met QC Criteria: July 31, 2009
• First Posted (Estimate): August 4, 2009

Study Record Updates

• Last Update Posted (Actual): August 3, 2017
• Last Update Submitted That Met QC Criteria: June 28, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Antirheumatic Agents
• Other Study ID Numbers: ML22462; 2009-011105-17