ADMYRA: Clinical Trial to Compare Treatment With GP2017 and Humira® in Patients With Rheumatoid Arthritis

• Sponsor: Sandoz (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02744755
• Collaborator: Hexal AG (Industry)
• Enrollment: 353
• Locations: 83
• Arms: 2
• Actual Duration (Months): 17.9
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Clinical trial to compare treatment with GP2017 and Humira® in patients with Rheumatoid Arthritis

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Biological: Adalimumab - GP2017; Biological: Adalimumab - US licensed Humira	Phase 3

Detailed Description

The purpose of this study is to demonstrate similar efficacy and safety of GP2017 and US-licensed Humira® in patients with moderate to severe rheumatoid arthritis (RA) with inadequate response to Disease modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX).

Study Design

• Study Type: Interventional
• Actual Enrollment: 353 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Multicenter Study to Demonstrate Similar Efficacy and to Compare Safety and Immunogenicity of GP2017 and Humira® in Patients With Moderate to Severe Active Rheumatoid Arthritis
• Actual Study Start Date: Mar 31, 2016
• Actual Primary Completion Date: Jan 31, 2017
• Actual Study Completion Date: Sep 26, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GP2017 Group 1 will receive treatment with 40mg GP2017 (Adalimumab - GP2017) by subcutaneous injection every other week up to 24 weeks (Study Period 1) at which patients achieving at least a moderate clinical response continue treatment with 40mg GP2017 subcutaneous injection every other week up to 48 weeks (Study Period 2).	Biological: Adalimumab - GP2017; Adalimumab - GP2017; Other Names: GP2017
Active Comparator: US Licensed Humira Group 2 will receive treatment with 40mg Humira® (Adalimumab - US licensed Humira®) by subcutaneous injection every other week up to 24 weeks (Study Period 1) at which patients achieving at least a moderate clinical response will be switched to treatment with 40mg GP2017 subcutaneous injection every other week up to 48 weeks (Study Period 2).	Biological: Adalimumab - US licensed Humira; Adalimumab - US licensed Humira; Other Names: Humira - Comparator

Outcome Measures

Primary Outcome Measures

1. Study Period 1: Change in DAS28-CRP Score From Baseline at Week 12 in Patients Treated With GP2017 and Patients Treated With Humira [Study period 1: week 12]

   Disease activity score (DAS) 28-CRP is based on 28-joint count (tender and swollen joints), C-reactive protein and patient's assessment of global disease activity (GDA) or general health (GH), values range from 0.96 to 10.0 while higher values mean a higher disease activity. • A DAS28-CRP value >5.1 corresponds to a high disease activity • A DAS28-CRP value between 3.2 and 5.1 corresponds to a moderate disease activity • A DAS28-CRP value between 2.6 and 3.2 corresponds to a low disease activity • A DAS28-CRP value < 2.6 corresponds to remission DAS28-CRP = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GDA or GH + 0.96 where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm

Secondary Outcome Measures

1. Study Period 1: Time-weighted Averaged Change From Baseline in DAS28-CRP Until Week 24 in Patients Treated With GP2017 and With Humira [Study period 1: week 24]

   Disease activity score (DAS) 28-CRP is based on 28-joint count (tender and swollen joints), C-reactive protein and patient's assessment of global disease activity (GDA) or general health (GH), values range from 0.96 to 10.0 while higher values mean a higher disease activity. • A DAS28-CRP value >5.1 corresponds to a high disease activity • A DAS28-CRP value between 3.2 and 5.1 corresponds to a moderate disease activity • A DAS28-CRP value between 2.6 and 3.2 corresponds to a low disease activity • A DAS28-CRP value < 2.6 corresponds to remission DAS28-CRP = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GDA or GH + 0.96 where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm

2. Study Period 1- Proportion of Patients Achieving EULAR Criterion for Remission [week 4, week 12 and week 24]

   Proportion of patients achieving European League against Rheumatism (EULAR) remission (defined as DAS28 CRP < 2.6 )

3. Study Period 1- Proportion of Patients Achieving EULAR Criterion for Good Response [week 4, week 12 and week 24]

   Proportion of patients achieving European League against Rheumatism (EULAR) good response (defined as DAS28<=3.2 at post-baseline assessment timepoint(s) with an improvement of >1.2 in DAS28 from baseline.)

4. Study Period 1- Proportion of Patients Achieving EULAR Criterion for Moderate Response [week 4, week 12 and week 24]

   Proportion of patients achieving European League against Rheumatism (EULAR) moderate response (defined as DAS28<=3.2 at post-baseline assessment timepoint(s) with an improvement of >0.6 to <=1.2 from baseline or DAS28 >3.2 to <=5.1 with an improvement of >0.6 to <=1.2 or of >1.2 from baseline or DAS28 >5.1 with an improvement of >1.2 from baseline) ;

5. Study Period 1- Proportion of Patients Achieving EULAR/ACR Boolean Remission Criteria [week 4, week 12, week 24]

   Proportion of patients achieving EULAR/American College of Rheumatology (EULAR/ACR) Boolean remission criteria (defined as number of tender joint count 28 <=1 and swollen joint count 28 <=1, CRP level (mg/dL) <=1 and patient's global assessment <=1 on a scale of 1-10 (corresponding to <=10 on a scale of 1-100).

6. Study Period 1: Change in DAS28-CRP and DAS28-ESR Scores From Baseline to Week 24 in Patients Treated With GP2017 and Patients Treated With Humira [study period 1: week 2, 4, 24]

   DAS28-CRP is a disease activity score and defined in primary outcome measure. DAS28-ESR is the DAS28 erythrocyte sedimentation rate score. DAS28-CRP and DAS28-ESR: best is 0, < 2.6 - remission, ≥ 2.6 to ≤ 3.2 - low disease activity > 3.2 to ≤ 5.1 - moderate disease activity > 5.1 - high disease activity DAS28-ESR = 0.56 * sqrt(tender28) + 0.28*sqrt(swollen28) + 0.7 * ln(ESR) + 0.014 * GDA where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • ESR is erythrocyte sedimentation rate (mm/h) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm.Values range from 0 to 10. Higher values mean a higher disease activity.

7. Study Period 1- Proportion of Patients Achieving ACR20/50/70 Response at Weeks 4, 12 and 24 [Week 4, week 12 and week 24]

   ACR20 response was defined if a patient fulfilled all 3 criteria below: -at least 20% improvement in tender 68 joint count -at least 20% improvement in swollen 66 joint-count; And at least 20% improvement in at least 3 of the following 5 measures: - Patient's assessment of RA pain (visual analogue scale (VAS) 100 mm), -Patient's global assessment of disease activity (VAS 100 mm), -Physician's global assessment of disease activity (VAS 100 mm), -Patient self-assessed disability index(HAQ-DI© score), -Acute phase reactant (CRP or ESR). ACR50 and ACR70 responses were defined as ACR20 response replacing "20% improvement" by "50% improvement" and "70% improvement", respectively.

8. Study Period 1 - Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI©) at Weeks 4, 12 and 24; [Weeks 4, 12 and 24;]

   Health assessment questionnaire (HAQ-DI) disability index ranges from 0 (best) to 3 (worst).The HAQ© was scored in accordance with the recommendation from the developers outlined in the "HAQ PACK" from Stanford University, California. Ramey Dr, Fries JF, Singh G. in B. Spilker Quality of Life and Pharmacoleconomics in Clinical Trials, 2nd ed, The Health Assessment Questionnaire 1995 -- Status and Review. Philadelphia: Lippincott-Raven Pub., 1996, p 227 - 237. Fries JF, Spitz P, Kraines G, Holman H. Measurement of Patient Outcome in Arthritis, Arthritis and Rheumatism, 1980, 23:137-145.

9. Study Period 1- Proportion of Patients Achieving HAQ-DI© in Normal Range (≤ 0.5) at Weeks 4, 12 and 24; [Weeks 4, 12 and 24;]

   Health assessment questionnaire disability index (HAQ-DI©) ranges from 0 (best) to 3 (worst)

10. Study Period 1- Proportion of Patients Achieving HAQ-DI© Score Improvement >0.3 at Weeks 4, 12 and 24 [Weeks 4, 12 and 24;]

    Health assessment questionnaire (HAQ-DI©) disability index ranges from 0 (best) to 3 (worst)

11. Study Period 1 - Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue Scale Relative to Baseline at Weeks 4, 12 and 24 (Change From Baseline) [Weeks 4, 12 and 24;]

    FACIT© fatigue scale is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function, ranging from 0 (worst) to 52 (best).

12. Study Period 1 - CRP (C-reactive Protein) Changes From Baseline in GP2017 and US-licensed Humira Treated at Weeks 4, 12 and 24 [Week 4, week 12, week 24]

    Outcome measure 13 presents changes in CRP measures in blood while Outome measure 7 presents changes in DAS28-CRP scores (calculated composite score to measure the disease activity)

13. Study Period 1 -ESR (Erythrocyte Sedimentation Rate) Changes From Baseline in GP2017 and US-licensed Humira Treated at Weeks 4, 12 and 24 [Week 4, week 12, week 24]

    Outcome measure 13 presents changes in ESR measures in blood while outcome measure 7 presents changes in DAS28-ESR scores (calculated composite score to measure the disease activity)

14. Study Period 1: Incidence and Severity of Injection Site Reactions in GP2017 and Humira [Treatment Period 1, 24 weeks]

    Incidence of injection site reactions in GP2017 and Humira

15. Study Period 1 - Immunogenicity by Measuring the Rate of Anti-drug Antibody (ADA) Formation Against Adalimumab in Patients Treated With GP2017 or Humira (Positive Patients) [baseline, week 2, week 4, week 12, week 24]

    Frequency of patients having anti-drug antibody (ADA) during 24 weeks

16. Study Period 2 - Immunogenicity by Measuring the Rate of Anti-drug Antibody (ADA) Formation Against Adalimumab in Patients Treated With GP2017 Who Continued GP2017 or Switched to GP2017 From Humira (Positive Patients) [week 24, week 36, week 48]

    Frequency of patients having anti-drug antibody (ADA) during 24 weeks

17. Study Period 2 : Proportion of Patients Achieving ACR20/50/70 Response at Week 48, in Patients Treated With GP2017 Who Continued GP2017 or Switched to GP2017 From Humira [week 48]

18. Study Period 2 - Health Assessment Questionnaire-Disability Index (HAQ-DI©) Changes From Week 24 at Week 48 in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira [Weeks 48]

    Health assessment questionnaire (HAQ-DI) disability index ranges from 0 (best) to 3 (worst)

19. Study Period 2 :Proportion of Patients Treated Continuously With GP2017 and Patients Treated With GP2017 After Switch From Humira Achieving HAQ-DI© Score in Normal Range ≤0.5 at Week 48 [week 48]

20. Study Period 2 : Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue Scale Changes From Week 24 at Week 48 in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira [week 48]

    FACIT©: from 0 (worst) to 52 (best), a score of less than 30 indicates severe fatigue

21. Study Period 2: Changes From Week 24 at Week 48 in DAS28-CRP and DAS28-ESR Scores in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira [week 48]

    DAS28-CRP is a disease activity score and defined in primary outcome measure. DAS28-ESR is the DAS28 erythrocyte sedimentation rate score. DAS28-CRP and DAS28-ESR: best is 0, < 2.6 - remission, ≥ 2.6 to ≤ 3.2 - low disease activity > 3.2 to ≤ 5.1 - moderate disease activity > 5.1 - high disease activity DAS28-ESR = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.7 * ln(ESR) + 0.014 * GDA where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • ESR is erythrocyte sedimentation rate (mm/h) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm.Values range from 0 to 10. Higher values mean a higher disease activity.

22. Study Period 2: Incidence of Injection Site Reactions in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira [up to 48 weeks]

    Incidence of injection site reactions

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have been diagnosed with RA ≥ 6 months prior to screening

2. Patients must have active disease, defined as DAS28-CRP ≥ 3.2 at the time of screening

3. Patients must have CRP levels above 5mg/l or ESR levels above the upper limits of normal

4. Patients must have had inadequate clinical response to MTX 10 - 25 mg/week

Exclusion Criteria:

1. Previous treatment with adalimumab, other anti-TNFα therapies or cell depleting agents, e.g. anti-CD20 therapy

2. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during treatment

3. Nursing (lactating) or pregnant women

4. History of or ongoing inflammatory or autoimmune diseases other than RA, e.g. mixed connective tissue disease, systemic lupus erythematosus etc.

5. Systemic corticosteroids > 7.5mg/day within 4 weeks prior to baseline

6. History or presence of cancer or lymphoproliferative disease other than a successfully and completely treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix and/or removed non-invasive colon polyps, with no evidence of recurrence

7. History of uncontrolled diabetes, unstable ischemic heart disease, congestive heart failure (New York Heart Association III-IV), active peptic ulcer disease, recent stroke (within 3 months)

8. Subject known to have immune deficiency, history of positive human immunodeficiency virus (HIV) status or immunocompromised for other reasons

9. History of clinically significant hematologic (e.g. severe anemia, leucopenia, thrombocytopenia), renal or liver disease (e.g. glomerulonephritis, fibrosis, cirrhosis, hepatitis)

10. History of persistent chronic infection; recurrent infection or active infections

11. History of tuberculosis, presence of active tuberculosis, latent tuberculosis as detected by imaging (e.g. chest X-ray, chest Computerized Tomography(CT) scan, Magnetic Resonance Imaging (MRI)) and/ or positive QuantiFERON-TB Gold test (QFT)

12. History or evidence of opportunistic infections, e.g. histoplasmosis, listeriosis, legionellosis

13. Positive serology Hepatitis B (either HBsAg or anti-HBc) or Hepatitis C (positive HCV-Ab or HCV-RNA) indicative of previous or current infections

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Arthritis & Rheumatology	Mesa	Arizona	United States	85032
2	Sun Valley Arthritis Center Ltd.	Peoria	Arizona	United States	85381
3	Medvin Clinical Research	Covina	California	United States	91723
4	MD Med Corp	Hemet	California	United States	92543
5	Talbert Medical Group	Huntington Beach	California	United States	92646
6	Denver Arthritis Clinic	Denver	Colorado	United States	80230
7	Joao Nascimento (Private Practice)	Bridgeport	Connecticut	United States	06606
8	Arthritis & Rheumatic Disease Specialties	Aventura	Florida	United States	33180
9	RASF - Clinical Research Center	Boca Raton	Florida	United States	33486
10	QPS MRA (Miami Research Associates)	Miami	Florida	United States	33143
11	Omega Research Consultants Orlando	Orlando	Florida	United States	32804
12	Family Clinical Trials, LLC.	Pembroke Pines	Florida	United States	33026
13	West Broward Rheumatology Associates, Inc.	Tamarac	Florida	United States	33321
14	McIlwain Medical Group, PA	Tampa	Florida	United States	33613
15	BayCare Medical Group, Inc	Tampa	Florida	United States	33614
16	Lovelace Scientific Resources, Inc.	Venice	Florida	United States	34292
17	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
18	Marietta Rheumatology Associates, PC	Marietta	Georgia	United States	30060
19	Center for Arthritis & Osteoporosis	Elizabethtown	Kentucky	United States	42701
20	Arthritis and Rheumatology Consultants	Edina	Minnesota	United States	55435
21	Physician Research Collaboration	Lincoln	Nebraska	United States	68516
22	Albuquerque Clinical Trials, Inc.	Albuquerque	New Mexico	United States	87102
23	Montefiore Medical Center PRIME	Lake Success	New York	United States	10467
24	Medication Management, LLC	Greensboro	North Carolina	United States	27410
25	PMG Research of Wilmington, LLC	Wilmington	North Carolina	United States	28401
26	Low Country Rheumatology, PA	North Charleston	South Carolina	United States	29406
27	Ramesh C Gupta, MD	Memphis	Tennessee	United States	38119
28	Austin Regional Clinic, P.A.	Austin	Texas	United States	78731
29	Tekton Research, Inc.	Austin	Texas	United States	78745
30	Sentara Medical Group Clinical Research	Norfolk	Virginia	United States	23502
31	IMEDICA s.r.o.	Brno		Czechia	602 00
32	Revmatologicka a interni ambulance	Kladno		Czechia	272 01
33	Revmatologicky Ustav	Praha 2		Czechia	12850
34	MEDICAL PLUS s.r.o.	Uherske Hradiste		Czechia	686 01
35	Revmacentrum MUDr. Mostera s.r.o.	Zidenice		Czechia	615 00
36	Praxis Dr. Walter	Rendsburg	Schleswig Holstein	Germany	24768
37	Rheumatologische Schwerpunktpraxis Steglitz	Berlin		Germany	12161
38	HRF Hamburger Rheuma Forschungszentrum	Hamburg		Germany	20095
39	Bekes Megyei Kozponti Korhaz Dr. Rethy Pal Tagkorhaz	Bekescsaba		Hungary	5600
40	Sopron Medical Egeszsegugyi Szolgaltato Kft.	Budapest		Hungary	1039
41	Hevizgyogyfurdo es Szent Andras Reumakorhaz Reumatologia III	Heviz		Hungary	8380
42	SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz Reumatologiai Osztaly	Nyiregyhaza		Hungary	4400
43	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged		Hungary	6725
44	Vital Medical Center	Veszprem		Hungary	8200
45	Azienda Socio Sanitaria Territoriale Fatebenefratelli (Presidio Ospedale Sacco)	Milano		Italy	20157
46	A.O.U. Senese Policlinico Santa Maria alle Scotte UOC Reumatologia	Siena		Italy	53100
47	Hospital Raja Perempuan Zainab II	Kota Bahru	Kelantan	Malaysia	15586
48	Hospital Raja Permaisuri Bainun	Ipoh	Perak	Malaysia	30990
49	Hospital Pulau Pinang	George Town	Pulau Pinang	Malaysia	10990
50	Hospital Sibu	Sibu	Sarawak	Malaysia	96000
51	Hospital Selayang	Batu Caves	Selangor	Malaysia	68100
52	Centro Investigacion en Artritis y Osteoporosis S.C.	Mexicali	Baja California Norte	Mexico	21200
53	Clinical Research Institute S.C.	Tlalnepantla	Estado De Mexico	Mexico	54055
54	Centro de Alta Especialidad en Reumatología e Investigación del Potosí, S.C.	San Luis Potosi	San Luis Potos	Mexico	78213
55	Investigacion y Biomedicina de Chihuahua, S.C.	Chihuahua		Mexico	31000
56	Instituto de Investigaciones Aplicadas a la Neurociencia A.C.	Durango		Mexico	34000
57	RM Pharma Specialists SA de CV	Mexico		Mexico	03100
58	Szpital Uniwersytecki nr 2 im.dr J. Biziela Dept of Clinical Reumatology	Bydgoszcz		Poland	85-168
59	Centrum Kliniczno - Badawcze J. Brzezicki, B. Górnikiewicz-Brzezicka Lekarze Spółka Partnerska	Elblag		Poland	82-300
60	Centrum Medyczne Pratia Gdynia ProFamilia Spolka Akcyjna, Oddzial w Gdyni	Gdynia		Poland	81-338
61	Centrum Terapii Wspolczesnej J.M. Jasnorzewska sp. komandytowo-akcyjna	Lodz		Poland	90-242
62	Ai Centrum Medyczne Sp. Z O.O. Sp.K.	Poznan		Poland	61-113
63	RCMed	Sochaczew		Poland	96-500
64	Slaskie Centrum Reumatologii,Rehabilitacji i Zapobiegania Niepelnosprawnosci im. Gen. Jerzego Zietka	Ustron		Poland	43-450
65	Niepubliczny Zakład Opieki Zdrowotnej "Biogenes" Sp. z o.o.	Wroclaw		Poland	53-224
66	Spitalul Clinic Judetean de Urgenta Brasov Sectia Reumatologie	Brasov		Romania	500365
67	Spitalul Clinic Judetean de Urgenta Cluj Napoca Sectia Reumatologie	Cluj-napoca		Romania	400006
68	Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei" Galati Sectia Reumatologie	Galati		Romania	800578
69	RK Medcenter SRL	Iasi		Romania	707027
70	Spitalul Municipal Ploiesti Sectia Reumatologie	Ploiesti		Romania	100337
71	SBIH of Nizhniy Novgorod region " City Clinical Hospital # 5"	Nizhny Novgorod		Russian Federation	603005
72	SPb SBIH "Clinical Rheumatological Hospital # 25"	Saint Petersburg		Russian Federation	190068
73	Research Institute of Emergency Medical Care	Saint Petersburg		Russian Federation	192242
74	SHI Ulyanovsk Reg Clinical Hospital	Ul'yanovsk		Russian Federation	432063
75	SBHI of Yaroslavl Region "Clinical Hospital #3"	Yaroslavl		Russian Federation	150007
76	Institute of Rheumatology	Belgrade		Serbia	11000
77	Special Hospital for Rheumatic Diseases	Novi Sad		Serbia	21112
78	Hospital de Cruces	Baracaldo		Spain	48903
79	Hospital Universitario de Fuenlabrada	Fuenlabrada		Spain	28942
80	Corporacio Sanitaria Parc Tauli	Sabadell		Spain	08201
81	Hospital Infanta Luisa	Sevilla		Spain	41010
82	Princess Alexandra Hospital; Dept of Rheumatology; Williams Day Unit	Harlow	Essex	United Kingdom	CM201QX
83	Royal Free Hospital	London		United Kingdom	NW3 2QG

Sponsors and Collaborators

• Sandoz
• Hexal AG

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 1, 2017
• Statistical Analysis Plan - Mar 19, 2018

More Information

Publications

None provided.

• Responsible Party: Sandoz
• ClinicalTrials.gov Identifier: NCT02744755
• Other Study ID Numbers: GP17-302; 2015-003433-10
• First Posted: Apr 20, 2016
• Last Update Posted: Dec 19, 2018
• Last Verified: Nov 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Adalimumab

Study Results

Participant Flow

Recruitment Details	353 patients were randomized (1:1)and received at least one dose of study drug; 303 patients completed the study.Eligible patients in the Humira group who completed Study Period 1 (baseline to week 24) with an at least moderate response by DAS28-CRP score were switched to GP2017 treatment during Study Period 2 (Week 24 to week 48).
Pre-assignment Detail	Full analysis set: randomized patients (study drug assigned) Per protocol set study period 1 (SP1) / study period 2(SP2): patients who completed Week 12 (SP1) / Week 48 (SP2) without major protocol deviations and received at least 5 doses of study drug up to Week 10 (SP1) / 10 doses of IMP from Week 24 to Week 46 (SP2)

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Period Title: Study Period 1
STARTED	177	176
COMPLETED	163	168
NOT COMPLETED	14	8
Period Title: Study Period 1
STARTED	159	166
COMPLETED	145	158
NOT COMPLETED	14	8

Baseline Characteristics

Arm/Group Title	GP2017	Humira / Switched GP2017	Total
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Total of all reporting groups
Overall Participants	177	176	353
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.8 (12.81)	53.8 (12.22)	53.3 (12.51)
Sex: Female, Male (Count of Participants)
Female	153 86.4%	142 80.7%	295 83.6%
Male	24 13.6%	34 19.3%	58 16.4%
Race/Ethnicity, Customized (Count of Participants)
White	152 85.9%	152 86.4%	304 86.1%
American Indian or Alaska Native	14 7.9%	15 8.5%	29 8.2%
Black or African American	6 3.4%	3 1.7%	9 2.5%
Asian	1 0.6%	3 1.7%	4 1.1%
Other	4 2.3%	3 1.7%	7 2%

Outcome Measures

1. Primary Outcome

Title	Study Period 1: Change in DAS28-CRP Score From Baseline at Week 12 in Patients Treated With GP2017 and Patients Treated With Humira
Description	Disease activity score (DAS) 28-CRP is based on 28-joint count (tender and swollen joints), C-reactive protein and patient's assessment of global disease activity (GDA) or general health (GH), values range from 0.96 to 10.0 while higher values mean a higher disease activity. • A DAS28-CRP value >5.1 corresponds to a high disease activity • A DAS28-CRP value between 3.2 and 5.1 corresponds to a moderate disease activity • A DAS28-CRP value between 2.6 and 3.2 corresponds to a low disease activity • A DAS28-CRP value < 2.6 corresponds to remission DAS28-CRP = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GDA or GH + 0.96 where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm
Time Frame	Study period 1: week 12

Outcome Measure Data

Analysis Population Description

Treatment Period 1 Per-Protocol set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	140	144
Least Squares Mean (Standard Error) [scores on a scale]	-2.16 (0.114)	-2.18 (0.110)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2017, Humira / Switched GP2017
	Comments	Therapeutic equivalence in terms of change from baseline in DAS28-CRP at week 12 will be concluded if the 95% confidence interval for the LS mean difference between GP2017 and Humira is contained within the interval [-0.6; 0.6]. A mixed-model repeated measures analysis was performed for DAS28-CRP change from baseline including treatment, stratification factors, time, the interaction between time (visits) and treatment all as categorical variables, and baseline DAS28-CRP as a continuous variable.
	Type of Statistical Test	Equivalence
	Comments	A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.129
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GP2017, Humira / Switched GP2017
	Comments	Therapeutic equivalence in terms of change from baseline in DAS28-CRP at week 12 will be concluded if the 90% confidence interval for the LS mean difference between GP2017 and Humira is contained within the interval [-0.6; 0.6]. A mixed-model repeated measures analysis was performed for DAS28-CRP change from baseline including treatment, stratification factors, time, the interaction between time (visits) and treatment all as categorical variables, and baseline DAS28-CRP as a continuous variable.
	Type of Statistical Test	Equivalence
	Comments	A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 90%; -0.19 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.129
	Estimation Comments

2. Secondary Outcome

Title	Study Period 1: Time-weighted Averaged Change From Baseline in DAS28-CRP Until Week 24 in Patients Treated With GP2017 and With Humira
Description	Disease activity score (DAS) 28-CRP is based on 28-joint count (tender and swollen joints), C-reactive protein and patient's assessment of global disease activity (GDA) or general health (GH), values range from 0.96 to 10.0 while higher values mean a higher disease activity. • A DAS28-CRP value >5.1 corresponds to a high disease activity • A DAS28-CRP value between 3.2 and 5.1 corresponds to a moderate disease activity • A DAS28-CRP value between 2.6 and 3.2 corresponds to a low disease activity • A DAS28-CRP value < 2.6 corresponds to remission DAS28-CRP = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GDA or GH + 0.96 where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm
Time Frame	Study period 1: week 24

Outcome Measure Data

Analysis Population Description

Treatment Period 1 Per-Protocol set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Least Squares Mean (Standard Error) [scores on a scale]	-1.85 (0.098)	-1.93 (0.092)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2017, Humira / Switched GP2017
	Comments	ANCOVA model included treatment, body weight as per CRF, prior therapy as per CRF, region as per CRF as fixed effects and baseline DAS28-CRP values as covariate.
	Type of Statistical Test	Equivalence
	Comments	A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GP2017, Humira / Switched GP2017
	Comments	ANCOVA model included treatment, body weight as per CRF, prior therapy as per CRF, region as per CRF as fixed effects and baseline DAS28-CRP values as covariate.
	Type of Statistical Test	Equivalence
	Comments	A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; -0.08 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments

3. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving EULAR Criterion for Remission
Description	Proportion of patients achieving European League against Rheumatism (EULAR) remission (defined as DAS28 CRP < 2.6 )
Time Frame	week 4, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
EULAR remission week 4	15 8.5%	7 4%
EULAR remission week 12	32 18.1%	38 21.6%
EULAR remission week 24	49 27.7%	71 40.3%

4. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving EULAR Criterion for Good Response
Description	Proportion of patients achieving European League against Rheumatism (EULAR) good response (defined as DAS28<=3.2 at post-baseline assessment timepoint(s) with an improvement of >1.2 in DAS28 from baseline.)
Time Frame	week 4, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Good response week 4	22 12.4%	25 14.2%
Good response week 12	51 28.8%	63 35.8%
Good response week 24	76 42.9%	93 52.8%

5. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving EULAR Criterion for Moderate Response
Description	Proportion of patients achieving European League against Rheumatism (EULAR) moderate response (defined as DAS28<=3.2 at post-baseline assessment timepoint(s) with an improvement of >0.6 to <=1.2 from baseline or DAS28 >3.2 to <=5.1 with an improvement of >0.6 to <=1.2 or of >1.2 from baseline or DAS28 >5.1 with an improvement of >1.2 from baseline) ;
Time Frame	week 4, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Moderate response week 4	63 35.6%	78 44.3%
Moderate response week 12	64 36.2%	62 35.2%
Moderate response week 24	42 23.7%	42 23.9%

6. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving EULAR/ACR Boolean Remission Criteria
Description	Proportion of patients achieving EULAR/American College of Rheumatology (EULAR/ACR) Boolean remission criteria (defined as number of tender joint count 28 <=1 and swollen joint count 28 <=1, CRP level (mg/dL) <=1 and patient's global assessment <=1 on a scale of 1-10 (corresponding to <=10 on a scale of 1-100).
Time Frame	week 4, week 12, week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
week 4	4 2.3%	0 0%
week 12	8 4.5%	12 6.8%
week 24	19 10.7%	26 14.8%

7. Secondary Outcome

Title	Study Period 1: Change in DAS28-CRP and DAS28-ESR Scores From Baseline to Week 24 in Patients Treated With GP2017 and Patients Treated With Humira
Description	DAS28-CRP is a disease activity score and defined in primary outcome measure. DAS28-ESR is the DAS28 erythrocyte sedimentation rate score. DAS28-CRP and DAS28-ESR: best is 0, < 2.6 - remission, ≥ 2.6 to ≤ 3.2 - low disease activity > 3.2 to ≤ 5.1 - moderate disease activity > 5.1 - high disease activity DAS28-ESR = 0.56 * sqrt(tender28) + 0.28*sqrt(swollen28) + 0.7 * ln(ESR) + 0.014 * GDA where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • ESR is erythrocyte sedimentation rate (mm/h) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm.Values range from 0 to 10. Higher values mean a higher disease activity.
Time Frame	study period 1: week 2, 4, 24

Outcome Measure Data

Analysis Population Description

Treatment Period 1 Per-Protocol set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
DAS28 CRP week 2	-0.86 (0.107)	-0.92 (0.101)
DAS28 CRP week 4	-1.31 (0.112)	-1.36 (0.105)
DAS28 CRP week 24	-2.61 (0.109)	-2.83 (0.103)
DAS28 ESR week 2	-0.94 (0.115)	-0.98 (0.109)
DAS28 ESR week 4	-1.51 (0.124)	-1.51 (0.117)
DAS28 ESR week 24	-2.97 (0.127)	-3.16 (0.120)

8. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving ACR20/50/70 Response at Weeks 4, 12 and 24
Description	ACR20 response was defined if a patient fulfilled all 3 criteria below: -at least 20% improvement in tender 68 joint count -at least 20% improvement in swollen 66 joint-count; And at least 20% improvement in at least 3 of the following 5 measures: - Patient's assessment of RA pain (visual analogue scale (VAS) 100 mm), -Patient's global assessment of disease activity (VAS 100 mm), -Physician's global assessment of disease activity (VAS 100 mm), -Patient self-assessed disability index(HAQ-DI© score), -Acute phase reactant (CRP or ESR). ACR50 and ACR70 responses were defined as ACR20 response replacing "20% improvement" by "50% improvement" and "70% improvement", respectively.
Time Frame	Week 4, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
ACR20 response Week 4	64 36.2%	71 40.3%
ACR20 response Week 12	100 56.5%	106 60.2%
ACR20 response Week 24	111 62.7%	130 73.9%
ACR50 response Week 4	25 14.1%	25 14.2%
ACR50 response Week 12	53 29.9%	67 38.1%
ACR50 response Week 24	78 44.1%	98 55.7%
ACR70 response Week 4	7 4%	9 5.1%
ACR70 response Week 12	24 13.6%	35 19.9%
ACR70 response Week 24	48 27.1%	53 30.1%

9. Secondary Outcome

Title	Study Period 1 - Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI©) at Weeks 4, 12 and 24;
Description	Health assessment questionnaire (HAQ-DI) disability index ranges from 0 (best) to 3 (worst).The HAQ© was scored in accordance with the recommendation from the developers outlined in the "HAQ PACK" from Stanford University, California. Ramey Dr, Fries JF, Singh G. in B. Spilker Quality of Life and Pharmacoleconomics in Clinical Trials, 2nd ed, The Health Assessment Questionnaire 1995 -- Status and Review. Philadelphia: Lippincott-Raven Pub., 1996, p 227 - 237. Fries JF, Spitz P, Kraines G, Holman H. Measurement of Patient Outcome in Arthritis, Arthritis and Rheumatism, 1980, 23:137-145.
Time Frame	Weeks 4, 12 and 24;

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Week 4	-0.32 (0.519)	-0.32 (0.449)
Week 12	-0.50 (0.576)	-0.47 (0.501)
Week 24	-0.63 (0.610)	-0.59 (0.543)

10. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving HAQ-DI© in Normal Range (≤ 0.5) at Weeks 4, 12 and 24;
Description	Health assessment questionnaire disability index (HAQ-DI©) ranges from 0 (best) to 3 (worst)
Time Frame	Weeks 4, 12 and 24;

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Week 4	27 15.3%	33 18.8%
Week 12	38 21.5%	40 22.7%
Week 24	46 26%	50 28.4%

11. Secondary Outcome

Title	Study Period 1- Proportion of Patients Achieving HAQ-DI© Score Improvement >0.3 at Weeks 4, 12 and 24
Description	Health assessment questionnaire (HAQ-DI©) disability index ranges from 0 (best) to 3 (worst)
Time Frame	Weeks 4, 12 and 24;

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Week 4	106 59.9%	117 66.5%
Week 12	102 57.6%	109 61.9%
Week 24	91 51.4%	106 60.2%

12. Secondary Outcome

Title	Study Period 1 - Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue Scale Relative to Baseline at Weeks 4, 12 and 24 (Change From Baseline)
Description	FACIT© fatigue scale is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function, ranging from 0 (worst) to 52 (best).
Time Frame	Weeks 4, 12 and 24;

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
Week 4	6.59 (7.949)	7.25 (8.591)
Week 12	10.49 (9.218)	10.62 (9.134)
Week 24	12.57 (10.760)	12.72 (9.451)

13. Secondary Outcome

Title	Study Period 1 - CRP (C-reactive Protein) Changes From Baseline in GP2017 and US-licensed Humira Treated at Weeks 4, 12 and 24
Description	Outcome measure 13 presents changes in CRP measures in blood while Outome measure 7 presents changes in DAS28-CRP scores (calculated composite score to measure the disease activity)
Time Frame	Week 4, week 12, week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
CRP change from baseline week 4	-4.79 (8.728)	-4.93 (12.128)
CRP change from baseline week 12	-5.98 (11.270)	-5.07 (11.791)
CRP change from baseline week 24	-2.51 (19.176)	-5.30 (13.726)

14. Secondary Outcome

Title	Study Period 1 -ESR (Erythrocyte Sedimentation Rate) Changes From Baseline in GP2017 and US-licensed Humira Treated at Weeks 4, 12 and 24
Description	Outcome measure 13 presents changes in ESR measures in blood while outcome measure 7 presents changes in DAS28-ESR scores (calculated composite score to measure the disease activity)
Time Frame	Week 4, week 12, week 24

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	127	138
ESR change from baseline week 4	-16.17 (14.693)	-13.98 (15.823)
ESR change from baseline week 12	-17.33 (16.214)	-15.08 (31.150)
ESR change from baseline week 24	-19.60 (20.494)	-20.49 (18.255)

15. Secondary Outcome

Title	Study Period 1: Incidence and Severity of Injection Site Reactions in GP2017 and Humira
Description	Incidence of injection site reactions in GP2017 and Humira
Time Frame	Treatment Period 1, 24 weeks

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	177	176
incidence of injection site reactions	7 4%	11 6.3%
injection site reactions MILD	7 4%	7 4%
injection site reactions MODERATE	0 0%	4 2.3%
injection site reactions SEVERE	0 0%	0 0%
Injection site erythema	2 1.1%	6 3.4%
Injection site pruritus	2 1.1%	3 1.7%
Injection site pain	2 1.1%	1 0.6%
Injection site inflammation	2 1.1%	0 0%
Injection site rash	0 0%	2 1.1%
Injection site discolouration	0 0%	1 0.6%

16. Secondary Outcome

Title	Study Period 1 - Immunogenicity by Measuring the Rate of Anti-drug Antibody (ADA) Formation Against Adalimumab in Patients Treated With GP2017 or Humira (Positive Patients)
Description	Frequency of patients having anti-drug antibody (ADA) during 24 weeks
Time Frame	baseline, week 2, week 4, week 12, week 24

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	177	176
Baseline	10 5.6%	6 3.4%
Week 2	12 6.8%	10 5.7%
Week 4	14 7.9%	22 12.5%
Week 12	16 9%	23 13.1%
Week 24	23 13%	25 14.2%

17. Secondary Outcome

Title	Study Period 2 - Immunogenicity by Measuring the Rate of Anti-drug Antibody (ADA) Formation Against Adalimumab in Patients Treated With GP2017 Who Continued GP2017 or Switched to GP2017 From Humira (Positive Patients)
Description	Frequency of patients having anti-drug antibody (ADA) during 24 weeks
Time Frame	week 24, week 36, week 48

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	159	166
Week 24	22 12.4%	25 14.2%
Week 36	21 11.9%	22 12.5%
Week 48	12 6.8%	12 6.8%

18. Secondary Outcome

Title	Study Period 2 : Proportion of Patients Achieving ACR20/50/70 Response at Week 48, in Patients Treated With GP2017 Who Continued GP2017 or Switched to GP2017 From Humira
Time Frame	week 48

Outcome Measure Data

Analysis Population Description

Treatment period 2 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	108	126
ACR20 response Week 48	93 52.5%	111 63.1%
ACR50 response Week 48	72 40.7%	81 46%
ACR70 response Week 48	49 27.7%	55 31.3%

19. Secondary Outcome

Title	Study Period 2 - Health Assessment Questionnaire-Disability Index (HAQ-DI©) Changes From Week 24 at Week 48 in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira
Description	Health assessment questionnaire (HAQ-DI) disability index ranges from 0 (best) to 3 (worst)
Time Frame	Weeks 48

Outcome Measure Data

Analysis Population Description

Treatment period 1 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	108	126
Mean (Standard Deviation) [score on a scale]	0.01 (0.358)	-0.03 (0.427)

20. Secondary Outcome

Title	Study Period 2 :Proportion of Patients Treated Continuously With GP2017 and Patients Treated With GP2017 After Switch From Humira Achieving HAQ-DI© Score in Normal Range ≤0.5 at Week 48
Time Frame	week 48

Outcome Measure Data

Analysis Population Description

Treatment period 2 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	108	126
Count of Participants [Participants]	45 25.4%	52 29.5%

21. Secondary Outcome

Title	Study Period 2 : Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue Scale Changes From Week 24 at Week 48 in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira
Description	FACIT©: from 0 (worst) to 52 (best), a score of less than 30 indicates severe fatigue
Time Frame	week 48

Outcome Measure Data

Analysis Population Description

Treatment period 2 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	108	126
Mean (Standard Deviation) [score on a scale]	-0.65 (7.421)	-0.85 (7.476)

22. Secondary Outcome

Title	Study Period 2: Changes From Week 24 at Week 48 in DAS28-CRP and DAS28-ESR Scores in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira
Description	DAS28-CRP is a disease activity score and defined in primary outcome measure. DAS28-ESR is the DAS28 erythrocyte sedimentation rate score. DAS28-CRP and DAS28-ESR: best is 0, < 2.6 - remission, ≥ 2.6 to ≤ 3.2 - low disease activity > 3.2 to ≤ 5.1 - moderate disease activity > 5.1 - high disease activity DAS28-ESR = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.7 * ln(ESR) + 0.014 * GDA where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • ESR is erythrocyte sedimentation rate (mm/h) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm.Values range from 0 to 10. Higher values mean a higher disease activity.
Time Frame	week 48

Outcome Measure Data

Analysis Population Description

Treatment period 2 per protocol set. Patients with data available

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	108	126
DAS28-CRP Week 48, change from week 24	-0.10 (0.893)	0.00 (0.941)
DAS28-ESR Week 48, change from week 24	-0.04 (1.015)	0.00 (1.025)

23. Secondary Outcome

Title	Study Period 2: Incidence of Injection Site Reactions in Patients Treated Continuously With GP2017 and in Patients Treated With GP2017 After Switch From Humira
Description	Incidence of injection site reactions
Time Frame	up to 48 weeks

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	GP2017	Humira / Switched GP2017
Arm/Group Description	Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).	Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
Measure Participants	159	166
Number of patients with ISRs	1 0.6%	2 1.1%
Injection site erythema	1 0.6%	2 1.1%
Injection site pruritus	0 0%	1 0.6%
injection site reactions MILD	1 0.6%	1 0.6%
injection site reactions MODERATE	0 0%	1 0.6%
injection site reactions SEVERE	0 0%	0 0%

Adverse Events

Time Frame	Each patient was followed up for safety during the whole study treatment duration ( approximately 24 months) , and Adverse Events were collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) for every single patient, + 30 day safety follow up period after study treatment discontinuation.
Adverse Event Reporting Description	AE additional description
Arm/Group Title	Study Period 1 SP1 SAF GP2017		Study Period 1 SP1 SAF Humira		Study Period 2 SP2 SAF Continued GP2017		Study Period 2 SP2 SAF Humira to GP2017		Entire Study SP1 SAF GP2017		Entire Study SP1 SAF Humira/Switched GP2017
Arm/Group Description	Study Period 1 SP1 SAF GP2017		Study Period 1 SP1 SAF Humira		Study Period 2 SP2 SAF Continued GP2017		Study Period 2 SP2 SAF Humira to GP2017		Entire study SP1 SAF GP2017		Entire study SP1 SAF Humira/Switched GP2017
All Cause Mortality
	Study Period 1 SP1 SAF GP2017		Study Period 1 SP1 SAF Humira		Study Period 2 SP2 SAF Continued GP2017		Study Period 2 SP2 SAF Humira to GP2017		Entire Study SP1 SAF GP2017		Entire Study SP1 SAF Humira/Switched GP2017
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/177 (0%)		0/176 (0%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		0/176 (0%)
Serious Adverse Events
	Study Period 1 SP1 SAF GP2017		Study Period 1 SP1 SAF Humira		Study Period 2 SP2 SAF Continued GP2017		Study Period 2 SP2 SAF Humira to GP2017		Entire Study SP1 SAF GP2017		Entire Study SP1 SAF Humira/Switched GP2017
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/177 (2.8%)		4/176 (2.3%)		4/159 (2.5%)		6/166 (3.6%)		7/177 (4%)		10/176 (5.7%)
Cardiac disorders
Angina pectoris	0/177 (0%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		1/176 (0.6%)
Gastrointestinal disorders
Constipation	1/177 (0.6%)		0/176 (0%)		1/159 (0.6%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Diarrhoea	0/177 (0%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		1/176 (0.6%)
Pancreatitis acute	0/177 (0%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		1/176 (0.6%)
Upper gastrointestinal haemorrhage	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Hepatobiliary disorders
Cholecystitis	1/177 (0.6%)		0/176 (0%)		0/159 (0%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Hepatitis	1/177 (0.6%)		0/176 (0%)		0/159 (0%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Infections and infestations
Bronchitis	0/177 (0%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		1/176 (0.6%)
Diverticulitis	0/177 (0%)		0/176 (0%)		1/159 (0.6%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Pneumonia	0/177 (0%)		0/176 (0%)		0/159 (0%)		2/166 (1.2%)		0/177 (0%)		2/176 (1.1%)
Pneumonia bacterial	1/177 (0.6%)		0/176 (0%)		0/159 (0%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Injury, poisoning and procedural complications
Humerus fracture	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Lumbar vertebral fracture	0/177 (0%)		0/176 (0%)		1/159 (0.6%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Metabolism and nutrition disorders
Hyponatraemia	0/177 (0%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		1/176 (0.6%)
Musculoskeletal and connective tissue disorders
Back pain	1/177 (0.6%)		0/176 (0%)		0/159 (0%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm benign	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Uterine leiomyoma	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Nervous system disorders
Encephalopathy	0/177 (0%)		0/176 (0%)		1/159 (0.6%)		0/166 (0%)		1/177 (0.6%)		0/176 (0%)
Epilepsy	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Hemianopia homonymous	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Intracranial pressure increased	0/177 (0%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		0/177 (0%)		1/176 (0.6%)
Reproductive system and breast disorders
Uterine prolapse	0/177 (0%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		1/176 (0.6%)
Other (Not Including Serious) Adverse Events
	Study Period 1 SP1 SAF GP2017		Study Period 1 SP1 SAF Humira		Study Period 2 SP2 SAF Continued GP2017		Study Period 2 SP2 SAF Humira to GP2017		Entire Study SP1 SAF GP2017		Entire Study SP1 SAF Humira/Switched GP2017
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/177 (46.9%)		74/176 (42%)		28/159 (17.6%)		26/166 (15.7%)		94/177 (53.1%)		80/176 (45.5%)
Blood and lymphatic system disorders
Leukopenia	2/177 (1.1%)		0/176 (0%)		2/159 (1.3%)		0/166 (0%)		4/177 (2.3%)		0/176 (0%)
Neutropenia	3/177 (1.7%)		0/176 (0%)		2/159 (1.3%)		0/166 (0%)		5/177 (2.8%)		0/176 (0%)
Gastrointestinal disorders
Diarrhoea	4/177 (2.3%)		7/176 (4%)		0/159 (0%)		0/166 (0%)		4/177 (2.3%)		7/176 (4%)
Nausea	5/177 (2.8%)		1/176 (0.6%)		0/159 (0%)		0/166 (0%)		5/177 (2.8%)		1/176 (0.6%)
General disorders
Fatigue	5/177 (2.8%)		0/176 (0%)		0/159 (0%)		1/166 (0.6%)		5/177 (2.8%)		1/176 (0.6%)
Injection site erythema	2/177 (1.1%)		6/176 (3.4%)		1/159 (0.6%)		2/166 (1.2%)		3/177 (1.7%)		6/176 (3.4%)
Infections and infestations
Bronchitis	4/177 (2.3%)		8/176 (4.5%)		1/159 (0.6%)		4/166 (2.4%)		4/177 (2.3%)		12/176 (6.8%)
Gastroenteritis	2/177 (1.1%)		4/176 (2.3%)		1/159 (0.6%)		0/166 (0%)		3/177 (1.7%)		4/176 (2.3%)
Influenza	3/177 (1.7%)		5/176 (2.8%)		1/159 (0.6%)		0/166 (0%)		4/177 (2.3%)		5/176 (2.8%)
Oral herpes	4/177 (2.3%)		3/176 (1.7%)		1/159 (0.6%)		0/166 (0%)		5/177 (2.8%)		3/176 (1.7%)
Pharyngitis	9/177 (5.1%)		10/176 (5.7%)		1/159 (0.6%)		3/166 (1.8%)		10/177 (5.6%)		10/176 (5.7%)
Sinusitis	5/177 (2.8%)		3/176 (1.7%)		0/159 (0%)		2/166 (1.2%)		5/177 (2.8%)		5/176 (2.8%)
Upper respiratory tract infection	12/177 (6.8%)		7/176 (4%)		4/159 (2.5%)		3/166 (1.8%)		14/177 (7.9%)		9/176 (5.1%)
Urinary tract infection	4/177 (2.3%)		6/176 (3.4%)		2/159 (1.3%)		3/166 (1.8%)		6/177 (3.4%)		8/176 (4.5%)
Viral upper respiratory tract infection	26/177 (14.7%)		16/176 (9.1%)		4/159 (2.5%)		4/166 (2.4%)		29/177 (16.4%)		19/176 (10.8%)
Injury, poisoning and procedural complications
Fall	2/177 (1.1%)		3/176 (1.7%)		0/159 (0%)		1/166 (0.6%)		2/177 (1.1%)		4/176 (2.3%)
Investigations
Transaminases increased	0/177 (0%)		3/176 (1.7%)		1/159 (0.6%)		1/166 (0.6%)		1/177 (0.6%)		4/176 (2.3%)
Metabolism and nutrition disorders
Hypercholesterolaemia	3/177 (1.7%)		3/176 (1.7%)		2/159 (1.3%)		0/166 (0%)		5/177 (2.8%)		3/176 (1.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/177 (4.5%)		0/176 (0%)		2/159 (1.3%)		0/166 (0%)		10/177 (5.6%)		0/176 (0%)
Rheumatoid arthritis	3/177 (1.7%)		1/176 (0.6%)		5/159 (3.1%)		2/166 (1.2%)		6/177 (3.4%)		3/176 (1.7%)
Nervous system disorders
Headache	7/177 (4%)		5/176 (2.8%)		2/159 (1.3%)		2/166 (1.2%)		8/177 (4.5%)		7/176 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	2/177 (1.1%)		1/176 (0.6%)		3/159 (1.9%)		0/166 (0%)		5/177 (2.8%)		1/176 (0.6%)
Skin and subcutaneous tissue disorders
Urticaria	0/177 (0%)		3/176 (1.7%)		0/159 (0%)		1/166 (0.6%)		0/177 (0%)		4/176 (2.3%)
Vascular disorders
Hypertension	5/177 (2.8%)		3/176 (1.7%)		2/159 (1.3%)		1/166 (0.6%)		6/177 (3.4%)		4/176 (2.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.