Supplementary appendix A.
Inclusion Criteria
(1) Patients who underwentthe last observation after 54weeksof treatment and were clinically stable at the last visit of the phase I/II study
(2)Patients whowerejudged to be suitable by the investigators for treatment with CT-P13 at the time of completion of the last observation after 54weeks of treatment in the phase I/II study
(3)Patients who wereable to comply with the extension study protocol
(4)Patients whosigned and dated the written informed consent form for participation inthe extension study
(5)Femaleswho experienced their last period more than one year priorto study entry. Both male and female patients and their partners of childbearing potential who hadagreed to use more than 2 methods of contraception,as described below, from study entry to 6 months after discontinuation of study treatments
1)Barrier contraceptives (male condom, female condom, or diaphragm with spermicidal gel)
2)Hormonalcontraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings)
3)Intrauterine devices
(6)Male or female patients and their partners who had been surgically sterilized for less than6 months prior to study entry had agreed to use 2 medically accepted methods ofcontraception as per inclusion criterion 5
(7)Patients who met the following criteria viathe screening laboratory tests
1)Serum creatinine <1.7 × upper limit of normal (ULN)
2)Serum alanine aminotransferase (ALT) and Serum aspartate aminotransferase (AST) <2 × ULN
3)Hemoglobin ≥8.0 g/dL
4)White blood cell count ≥4.0 × 103 cells/μL
5)Neutrophil count ≥1.5 × 103 cells/μL
6)Lymphocyte count≥1.0 × 103 cells/μL
7)Platelet count ≥100 × 103 cells/μL
8)Blood β-D-glucan negative
(8)Patients who werereceiving oral glucocorticoids less than or equivalent to ≤10 mg dailyof Prednisolone at the time of study entry. However, patients were permitted to receive topical, otological, and ophthalmic glucocorticoid preparations.
Exclusion criteria
(1)Patients who had clinical indications ofa deterioration of RA disease as compared with the disease status at the study entry of Phase I/II study
(2)Patients who received a live or live-attenuated vaccination during Phase I/II study or who werescheduled to receive a live or live-attenuated vaccination during the period of this study
(3)Patients who had a current infection with hepatitis B, hepatitis C or HIV at the time of study entry.
(4)Patients who had a positive result to the screening test for HIV antibody, HBs antigen, HBc antibody or HCV antibody
(5)Patients who had a current diagnosis of TB or nontuberculousmycobacterial infection at the time of study entry
(6)Patients who had a current diagnosis of serious infection (such as sepsis,abscess or opportunistic infections, or invasive fungal infection such as histoplasmosis) at the time of study entry
(7)Patients who had recent exposure to persons with active TB at the time of study entry, or whohad a positive result to thescreening test for latent TB defined as a positive result of interferon-γ release assay and who was not enable to receive Isoniazid therapy
(8)Patients who had a current diagnosis of drug or alcohol abuse
(9)Patients who had a medical condition including one or more of the following:
1)Bone marrow hypoplasia
2)Severe or uncontrolled diabetes mellitus
3)Any other inflammatory or rheumatic diseases, including but not limited to psoriatic arthritis, AS, spondyloarthritis, systemic lupus erythematosus, Lyme disease, or fibromyalgia, that could confound the evaluation of the effect of study treatment
4)Malignancy
5)Congestive heart failure (New York Heart Association class III/IV) or angina (Canadian Cardiovascular Society class III/IV)
6)Organ transplantation
7)Class IV of Steinbrocker classification at the time of study entry
8)Any clinically significant respiratory disease, including but not limited to chronic obstructive pulmonary disease, asthma, bronchiectasis, or pleural effusion, and deteriorated during Phase I/II study
9)New diagnosis or exacerbation of interstitial pneumonitis during phase I/II study
10)Diagnosis or symptoms suggestive of demyelinating disorders, includingmultiple sclerosis and Guillain-Barré syndrome
11)Nervous system damage, if it might interfere with the investigator’s assessment
(10)Female patients who were currently pregnant or breastfeeding
(11)Patients who, in the opinion of principal- or sub-investigator, should notparticipate in the study.
Supplementary appendix B.
Table S1 Changes in ADA status at each study point
Week 62(0x) / Week 86
(24x) / Week 110
(48x) / Week 134
(72x)
CT-P13 throughout study / ADA (+)
12 / ADA (+) / Dosage Escalated / 5 / 3 / 3
Dosage Unchanged / 1 / 1 / 1
ADA (-) / Dosage Escalated / 5 / 5 / 5
Dosage Unchanged / 0 / 0 / 0
ADA (-)
26 / ADA (+) / Dosage Escalated / 0 / 0 / 0
Dosage Unchanged / 0 / 0 / 1
ADA (-) / Dosage Escalated / 11 / 11 / 10
Dosage Unchanged / 15 / 14 / 12
Switched from IFX to CT-P13 / ADA (+)
16 / ADA (+) / Dosage Escalated / 3 / 2 / 3
Dosage Unchanged / 4 / 2 / 1
ADA (-) / Dosage Escalated / 2 / 2 / 2
Dosage Unchanged / 2 / 2 / 2
ADA (-)
17 / ADA (+) / Dosage Escalated / 0 / 0 / 0
Dosage Unchanged / 1 / 1 / 0
ADA (-) / Dosage Escalated / 4 / 5 / 5
Dosage Unchanged / 12 / 9 / 10
Supplementary appendix C.
Table S2 Changes over time in disease activity, and physical performance assessment endpoints - FAS
Efficacy Parameter / Assessment point / CT-P13throughout study
(N= 37) / Switched from IFX
to CT-P13
(N= 32) / P value*
ACR20 response / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / 30 (81.1)
32 (86.5)
29 (78.4)
27 (73.0)
30 (81.1)
30 (81.1)
29 (78.4) / 28 (87.5)
26 (81.3)
21 (65.6)
20 (62.5)
26 (81.3)
19 (59.4)
20 (62.5) / p=0.527
p=0.743
p=0.286
p=0.440
p=1.000
p=0.064
p=0.187
ACR50 response / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / 21 (56.8)
23 (62.2)
23 (62.2)
22 (59.5)
26 (70.3)
25 (67.6)
26 (70.3) / 22 (68.8)
22 (68.8)
14 (43.8)
14 (43.8)
18 (56.3)
16 (50.0)
17 (53.1) / p=0.331
p=0.619
p=0.151
p=0.232
p=0.316
p=0.151
p=0.213
ACR70 response / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / 13 (35.1)
12 (32.4)
19 (51.4)
17 (45.9)
19 (51.4)
18 (48.6)
20 (54.1) / 11 (34.4)
13 (40.6)
7 (21.9)
8 (25.0)
11 (34.4)
12 (37.5)
13 (40.6) / p=1.000
p=0.616
p=0.014
p=0.084
p=0.224
p=0.466
p=0.336
EULAR responders (ESR), n (%) / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / 33 (89.2)
34 (91.9)
33 (89.2)
34 (91.9)
33 (89.2)
31 (83.8)
30 (81.1) / 30 (93.8)
31 (96.9)
27 (84.4)
23 (71.9)
27 (84.4)
21 (65.6)
21 (65.6) / p=0.679
p=0.618
p=0.723
p=0.053
p=0.723
p=0.099
p=0.176
EULAR responders (CRP), n (%) / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / 34 (91.9)
34 (91.9)
35 (94.6)
33 (89.2)
33 (89.2)
33 (89.2)
31 (83.8) / 30 (93.8)
31 (96.9)
25 (78.1)
25 (78.1)
27 (84.4)
22 (68.8)
22 (68.8) / p=1.000
p=0.618
p=0.071
p=0.324
p=0.723
p=0.069
p=0.163
Change from baseline in DAS28 (ESR), mean SD / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / -2.419 ±1.522
-2.387 ±1.331
-2.619 ±1.533
-2.707 ±1.589
-2.768 ±1.473
-2.747 ±1.727
-2.761 ±1.613 / -2.320 ±1.190
-2.579 ±1.033
-1.996 ±1.223
-2.036 ±1.305
-2.384 ±1.349
-1.940 ±1.664
-1.964 ±1.711 / p=0.767
p=0.509
p=0.069
p=0.062
p=0.266
p=0.053
p=0.051
Change from baseline in DAS28 (CRP), mean SD / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / -2.393 ±1.499
-2.350 ±1.324
-2.595 ±1.488
-2.664 ±1.570
-2.644 ±1.512
-2.804 ±1.646
-2.783 ±1.590 / -2.268 ±1.151
-2.560 ±1.070
-1.830 ±1.313
-2.013 ±1.333
-2.299 ±1.268
-1.923 ±1.618
-2.030 ±1.734 / p=0.702
p=0.475
p=0.028
p=0.070
p=0.314
p=0.029
p=0.064
Change from baseline in SDAI, mean SD / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / -21.28 ±14.91
-21.35 ±13.10
-22.58 ±14.91
-22.24 ±15.27
-21.60 ± 13.85
-22.49 ±15.16
-22.25 ± 14.23 / -21.61 ±12.34
-22.98 ± 11.55
-17.93 ± 10.87
-18.36 ±11.01
-19.72 ±11.58
-16.91 ±15.41
-17.71 ± 15.03 / p=0.919
p=0.588
p=0.148
p=0.237
p=0.545
p=0.135
p=0.202
Change from baseline in CDAI, mean SD / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / -19.95±13.82
-20.08 ±12.02
-21.32 ±13.94
-21.02 ±14.14
-20.19 ±12.73
-20.99 ±14.34
-20.73 ±13.39 / -20.41 ±11.70
-21.54 ± 11.09
-17.28 ± 10.12
-17.23 ± 10.40
-18.48 ±10.81
-15.68 ±14.37
-16.54 ±13.96 / p=0.881
p=0.602
p=0.178
p=0.215
p=0.552
p=0.130
p=0.209
Change from baseline in HAQ-DI,mean SD / 14W
30W
54W
62W (0xW)
86W (24xW)
110W (48xW)
134W (72xW) / -0.48 ±0.48
-0.62 ±0.51
-0.72 ±0.59
-0.70 ±0.58
-0.66 ±0.67
-0.66 ±0.58
-0.67 ±0.60 / -0.34 ±0.38
-0.46±0.47
-0.36 ±0.51
-0.37 ±0.54
-0.44 ±0.48
-0.38 ±0.52
-0.40 ±0.56 / p=0.202
p=0.179
p=0.009
p=0.018
p=0.137
p=0.044
p=0.060
*: Statistical comparison was made between groups by student’s t-test. CDAI, clinical disease activity index; CRP, C reactive protein; DAS28 (CRP), disease activity score using a 28-joint count and CRP level; DAS28 (ESR), disease activity score using a 28-joint count and ESR; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; FAS, full analysis set; HAQ-DI, Health Assessment Questionnaire disability index; IFX, innovator infliximab; SDAI, simplified disease activity index.