to Part of Dossier: Name of Active Ingredient: Title of Study: Quality of life study with adalimumab in rheumatoid arthritis. ESCALAR.

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1 2.0 Synopsis Abbott Laboratories Name of Study Drug: Individual Study Table Referring to Part of Dossier: Adalimumab (HUMIRA) (For National Authority Use Only) Name of Active Ingredient: Adalimumab Title of Study: Quality of life study with adalimumab in rheumatoid arthritis. ESCALAR. Investigator: Dra. Leonor Barile Fabris Study Site(s): 14 sites. Centro Medico Nacional Siglo XXI, Mexico City. Centro Medico Nacional La Raza, México City. Instituto Nacional de Rehabilitación, Mexico City. Hospital General Regional ISSSTE, Tijuana BC, Mexico Hospital Universitario UANL, Monterrey NL, Mexico. Hospital Miguel Hidalgo, Aguascalientes México. Hospital de Especialidades # 1 IMSS, Cd. Obregón, Sonora, Mexico. Hospital de Especialidades #25 IMSS, Monterrey NL, Mexico. Hospital General de Zona, SSA. Hermosillo, Sonora, Mexico Centro Médico Nacional # 1 IMSS, Mérida, Yucatán, Mexico. Hospital Central. San Luis Potosí, Mexico. Centro Médico Nacional de Occidente. Guadalajara, Jal. Mexico. Hospital General Regional # 1 IMSS. Querétaro, Mexico. Hospital General de Zona # 1 IMSS. Oaxaca, Mexico Publications: TBD Studied Period (Years): 1 year First Subject First Visit: 18 Dec 2003 Last Subject Last Visit: 23 Oct 2005 Objective(s): To evaluate efficacy, safety and quality of life of patients with RA treated with adalimumab plus methotrexate or adalimumab plus methotrexate plus any other DMARD 1

2 Methodology : Design: This was a 52 week long, open label, multicentric and randomized clinical trial of Adalimumab plus MTX and others non-biologic DMARDs, performed in 14 sites throughout Mexico. All patients gave written informed consent, and the Institutional Review Board at each study site approved the trial. After screening and baseline assessment, study visits were conducted at weeks 0, 2, 6, 12, 24 and thereafter each 8 weeks, up to 52 weeks. Patients were randomized to one of the following groups: G1) Adalimumab 40 mg subcutaneously (SC) every other week. This group also took MTX at previously used doses during the 4 weeks preceding the study. G2) Adalimumab plus MTX as indicated in group 1, plus another non biologic DMARD at previously used doses or as indicated by the local clinical researcher (except Cyclosporine and Azatioprine). In addition to the treatments under study, certain concomitant RA therapies were permitted during the study for both groups, salicylates, nonsteroidal anti-inflammatory drugs, and corticosteroids at maximum doses equivalent to 10 mgs of oral prednisone. Analgesics were suspended 24 hours before the study visits. Efficacy assessment: Our primary measure of efficacy was improvement in DAS 28 and HAQ. Secondary measures of efficacy included improvement in tender joint count (TJC), swollen joint count (SJC), and serum levels of Eritro Sedimentation Rate (ESR). Safety assessments: Adverse events were evaluated throughout the study. Events were noted due to both patient reporting and findings from the physical examinations and laboratory evaluations. Exclusion of an enrolled patient was considered if the local researcher thought that the patient had suffered a relevant adverse event or clinical deterioration. After stopping the drug treatment, patients were treated as their doctor considered necessary. Sample size estimation: Sample size was estimated by considering the previous DAS28 <2.6 reported for the combination of a Adalimumab plus MTX which goes from 12 to 34%. So we consider the mean value for G1 23%, with an increase to 40% in G2, using an alpha of 0.10, and a power of 80%. The number of patients resulted was 90 for each group, however, considering possible withdrew patients 10% more were added. Statistical analysis: In basal state, mean age, disease duration, TJC, SJC, serum levels of ESR, DAS 28 and HAQ were compared between groups through a t test, while sex, number of patients using steroids, number of patients suffering from hypertension, Diabetes Mellitus 2 (DM2), lipid disease or obesity were compared with the chi square test. Clinical response rates were evaluated at 24 and 52 weeks; the number of patients with DAS28 <2.6 were compared through a chi squared test, while the mean value of TJC, SJC, ESR, DAS 28 and HAQ were compared between groups through a t test. Percentage of improvement of each parameter was estimated. A chi square test was used to compare adverse events between both groups. In all cases a p value of 0.05 was considered significant. 2

3 Number of Subjects (Planned and Analyzed): Planned: 200 Analyzed: 200 patients included, 187 completed 52 weeks Diagnosis and Main Criteria for Inclusion: Active Rheumatoid Arthritis defined as the presence of at least 8 swollen joints and/or 9 tender joints, with more than 6 months of evolution. Test Product, Dose/Strength/Concentration, Mode of Administration and Lot Number: Adalimumab (HUMIRA) 40mg/0.8ml SC eow Duration of Treatment: 52 weeks Reference Therapy, Dose/Strength/Concentration and Mode of Administration and Lot Number: We studied combination of adalimumab plus MTX mg PO Weekly VS adalimumab plus MTX mg PO weekly plus any other non-biologic DMARD at any dose Criteria for Evaluation Efficacy: Our primary measure of efficacy was DAS 28 (decrease in DAS28 score and % of patients with DAS28 score equal or lower than 2.6). Secondary measures of efficacy included improvement in tender joint count (TJC), swollen joint count (SJC), and serum levels of Eritro Sedimentation Rate (ESR), Pain in a VAS 100mm, and HAQ. Pharmacokinetic: NA Safety: Adverse events were evaluated throughout the study. Events were noted due to both patient reporting and findings from the physical examinations and laboratory evaluations. 3

4 Statistical Methods Efficacy: In basal state, mean age, disease duration, TJC, SJC, serum levels of ESR, DAS 28 and HAQ were compared between groups through a t test, while sex, number of patients using steroids, number of patients suffering from hypertension, Diabetes Mellitus 2 (DM2), lipid disease or obesity were compared with the chi square test. Clinical response rates were evaluated at 24 and 52 weeks; the number of patients with DAS28 <2.6 were compared through a chi squared test, while the mean value of TJC, SJC, ESR, DAS 28 and HAQ were compared between groups through a t test. Percentage of improvement of each parameter was estimated. A chi square test was used to compare adverse events between both groups. In all cases a p value of 0.05 was considered significant. Pharmacokinetic: NA Safety: Descriptive statistics were used to analyze aedverse events reported. 4

5 Summary/Conclusions Efficacy Results: A total of 200 RA patients were included, 98 in G1 and 102 in G2. Table 1 shows both groups basal conditions, 94% of patients in G1 and 92% in G2 were female. Patients in G1 were older (47 years old ±10 years) than patients in G2 (43 yrs old ±10 years) (p=0.003), had a longer disease duration 18±14 years for G1 vs. 14±11 years for G2 (p=0.050), and used more corticosteroids, 62% in G1 vs. 46% in G2 (p=0.031). However, mean values of AR activity indicators were similar: TJC 18±6 in G1 and 18±16 in G2; SJC in G1 16±5 and in G2 16±6; DAS28 G1 6.24±0.80 and G2 6.05±0.95, HAQ G1 2.44±0.72 and G2 2.37±0.63, ESR using median and percentile because of its non Gaussian distribution, in G1was 28 (15-40) and G2 22 ( ); (all AR activity indicators with p values >0.05). There were also not significant differences between groups in co-morbidity: 16% of G1 and 11% of G2 were hypertensive; G1 3% and G2 5% had DM2 at the diagnoses; and 8% of G1 and 4% of G2 had lipid disease. There was a statistically significant different between the two groups in terms of obesity 27% of G1 and 14% of G2, p= Also, at basal state according to the DAS28 activity index, 26 (13%) of patients showed moderate AR activity, 10% of G1 and 16% of G2, and 174 (87%) showed severe AR activity, 90% of G1 and 84% of G2 (p=0.17). During the study, patients in group 2 used in 91% of cases 2 non-biological DMARs (including MTX), 8% used 3, and 1% used 4. Sulfasalazine was used in 33% of patients, and hydroxychloroquine in 29%. The following mean percentage of reductions were observed at week 24 and 52: DAS26, G1 46% at week 24, 50% at week 52, and G2 41%, 44% respectively (p value G1 vs G2 at 24 weeks 0.37, and at 52 weeks 0.27); TJC, G1 80%, 84%, and G2 70%, 75% (p=0.19, 0.14); SJC, G1 86%, 91%, and G2 79%, 80% (p=0.07, 0.004); HAQ, G1 28%, 28%, and G2 34%, 32% (p=0.07,0.27); ESR median, G1 26%, 32%, and G2 17%, 32% (p=0.96,0.32). DAS28 <2.6, G1 in 25/93 (26.9%) of patients at week 24, and 32/93 (34.4%) of patients at week 52 vs. G2 29/94 (30.9%), and 33/94 (35.1%) respectivelly (p=0.54, 0.92). Pharmacokinetic Results: NA 5

6 Safety Results: Thirteen patients withdrew from the study prematurely: 5 from G1 and 8 from G2. Six patients withdrew during the first 24 weeks and 7 between weeks 24 and 52. There were no statistical differences in kind and number of causes of withdrawal between groups: 7 patients suffered adverse events, 2 in G1 and 5 in G2; a total of 2 patients, one from each group, experienced lack of efficacy; 2 patients from G2 withdrew consent; 1 patient from G1 violated protocol, and 1 patient from G1 was lost to follow up. The adverse events detected were: 4 infections, 1 case of rhino-sino bronchial syndrome, 2 cases of tuberculosis (1 peritoneal and 1 ganglionar), 1 case of sinusitis, 1 case of cervico uterine cancer, 1 case of hyperprolactinemia, and 1 case of depression and abuse of benzodiazepines. There was not a clinical nor statistical significant difference between groups with the exception of diarrhea, observed in 2 patients (2.2%) from G1, and 9 (9.6%) from G2 (p=0.030). The most frequent adverse events were: upper respiratory tract infections in 18.7% of patients, Headache in 17.1% of patients, flu like syndrome in 13.9% of patients, injection site pain or reaction in 13.9% of patients and rash in 11.2% of patients. Conclusions: Combination of adalimumab with any other DMARDs is safe and generally well tolerated. Adding to adalimumab more than one DMARD does not increase remission rates in this study both groups resulted with similar percentage of patients with clinical remission evaluated with DAS28 < 2.6 as the previously reported, and confirms the clinical effectiveness of the combined therapy based on Adalimumab plus Mtx in early or late AR active patients. 6