Trial Outcomes & Findings for Drug Concentration, Immunogenicity, and Efficacy Study in Patients With Rheumatoid Arthritis Currently Treated With Etanercept, Adalimumab, or Infliximab (NCT NCT01981473)

NCT ID: NCT01981473

Last Updated: 2016-01-12

Results Overview

Percentage of participants positive for antidrug antibodies among those treated with etanercept versus those treated with monoclonal antibodies (adalimumab or infliximab) was determined.

Recruitment status

COMPLETED

Target enrollment

605 participants

Primary outcome timeframe

1 day

Results posted on

2016-01-12

Participant Flow

This is a multicenter, non-interventional (NI) study conducted to evaluate data collected from a cross sectional population of participants with rheumatoid arthritis (RA) who received treatment with etanercept, adalimumab, or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.

Participants treated with one of the three targeted therapies were enrolled using interactive response technology to assure data for approximately 200 participants were included for each RA treatment.

Participant milestones

Participant milestones
Measure	Etanercept Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab Participants who had received treatment with Adalimumab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Overall Study STARTED	202	199	204
Overall Study COMPLETED	200	199	196
Overall Study NOT COMPLETED	2	0	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Etanercept Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Overall Study Incorrect diagnosis of RA	0	1
Overall Study Received treatment for < 6 months	0	1
Overall Study Received treatment for >24 months	2	6

Baseline Characteristics

Drug Concentration, Immunogenicity, and Efficacy Study in Patients With Rheumatoid Arthritis Currently Treated With Etanercept, Adalimumab, or Infliximab

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab n=199 Participants Participants who had received treatment with adalimumab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=196 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Total n=595 Participants Total of all reporting groups
Age, Continuous	56.5 years STANDARD_DEVIATION 13.37 • n=5 Participants	54.3 years STANDARD_DEVIATION 12.95 • n=7 Participants	60.7 years STANDARD_DEVIATION 13.01 • n=5 Participants	57.1 years STANDARD_DEVIATION 13.36 • n=4 Participants
Sex: Female, Male Female	155 Participants n=5 Participants	162 Participants n=7 Participants	157 Participants n=5 Participants	474 Participants n=4 Participants
Sex: Female, Male Male	45 Participants n=5 Participants	37 Participants n=7 Participants	39 Participants n=5 Participants	121 Participants n=4 Participants

PRIMARY outcome

Timeframe: 1 day

Percentage of participants positive for antidrug antibodies among those treated with etanercept versus those treated with monoclonal antibodies (adalimumab or infliximab) was determined.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=394 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Percentage of Participants Positive for Antidrug Antibodies Among Those Treated With Etanercept Versus Those Treated With Monoclonal Antibodies (Adalimumab or Infliximab).	0 Percentage of participants	24.4 Percentage of participants	—

SECONDARY outcome

Timeframe: 1 day

Percentage of participants with Low Disease Activity (LDA) (Disease Activity Score based on a 28-joint count \[DAS28\] Erythrocyte sedimentation rate \[ESR\] score ≤3.2) among those who are antidrug antibody positive versus negative (all participants receiving etanercept, adalimumab, or infliximab combined).

Outcome measures

Outcome measures
Measure	Etanercept n=94 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=484 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Percentage of Participants With Low Disease Activity (LDA) (DAS28 ESR Score ≤ 3.2) Among Those Who Are Antidrug Antibody Positive Versus Negative (All Patients Receiving Etanercept, Adalimumab, or Infliximab Combined).	56.4 percentage of participants	62.0 percentage of participants	—

SECONDARY outcome

Timeframe: 1 day

Serum trough drug concentrations for etanercept, adalimumab, and infliximab compared between participants who are antidrug antibody positive versus negative. Units of measurement for Serum trough drug concentration is µg/mL.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Serum Trough Drug Concentrations for Etanercept, Adalimumab, and Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA+	NA µg/mL Standard Deviation NA There were no participants in ETN arm tested positive for anti-etanercept antibody.	1.5 µg/mL Standard Deviation 2.24	0.2 µg/mL Standard Deviation 0.90
Serum Trough Drug Concentrations for Etanercept, Adalimumab, and Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA-	1.8 µg/mL Standard Deviation 1.03	7.7 µg/mL Standard Deviation 4.72	9.8 µg/mL Standard Deviation 15.25

SECONDARY outcome

Timeframe: 1 Day

Percentage of participants positive for antidrug antibodies among those treated with etanercept, adalimumab, or infliximab were determined.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Percentage of Participants Positive for Antidrug Antibodies Among Those Treated With Etanercept, Adalimumab, or Infliximab.	0 Percentage of participants	31.2 Percentage of participants	17.4 Percentage of participants

SECONDARY outcome

Timeframe: 1 Day

The CDAI total scores for etanercept, adalimumab, or infliximab compared between participants who are antidrug antibody positive versus negative. CDAI = Disease activity score (DAS) 28 prorated Swollen Joint Count (0-28) + DAS 28 prorated Tender Joint Count (0-28) + Physician's Global Assessment (0-10) + Subject's Global Assessment (0-10). The total score range is 0-76. Score interpretation: Remission ≤ 2.8; Low Disease Activity CDAI \> 2.8 and ≤ 10; Moderate Disease Activity CDAI \> 10 and ≤ 22; High Disease Activity CDAI \> 22.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=194 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
The Clinical Disease Activity Index (CDAI) Total Scores for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA+	NA units on a scale Standard Deviation NA There were no participants in ETN arm tested positive for anti-etanercept antibody.	17.3 units on a scale Standard Deviation 13.56	21.7 units on a scale Standard Deviation 16.12
The Clinical Disease Activity Index (CDAI) Total Scores for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA-	12.6 units on a scale Standard Deviation 10.62	16.3 units on a scale Standard Deviation 14.83	18.5 units on a scale Standard Deviation 13.84

SECONDARY outcome

Timeframe: 1 day

The SDAI Total Scores for etanercept, adalimumab, or infliximab compared between participants who are antidrug antibody positive versus negative. SDAI = DAS 28 prorated Swollen Joint Count (0-28) + DAS 28 prorated Tender Joint Count (0-28) + Physician's Global Assessment (0-10) + Subject's Global Assessment (0-10) + C-reactive protein (CRP) (in mg/dL). The total score range is 0-86. Score interpretation: Remission SDAI ≤ 3.3; Low Disease Activity SDAI \> 3.3 and ≤ 11; Moderate Disease Activity SDAI \> 11 and ≤ 26; High Disease Activity SDAI \> 26.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=193 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
The Simplified Disease Activity Index (SDAI) Total Scores for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA+	NA units on a scale Standard Deviation NA There were no participants in ETN arm tested positive for anti-etanercept antibody.	18.5 units on a scale Standard Deviation 14.52	23.1 units on a scale Standard Deviation 16.33
The Simplified Disease Activity Index (SDAI) Total Scores for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA-	13.5 units on a scale Standard Deviation 10.95	16.8 units on a scale Standard Deviation 14.91	19.2 units on a scale Standard Deviation 13.89

SECONDARY outcome

Timeframe: 1 day

The DAS28 assessment is a derived measurement with differential weight given to each component. DAS28 will be calculated twice, utilizing first ESR, and then CRP as the acute phase reactant: 1) DAS28-ESR = 0.56 sqrt (28 painful/tender joint count) + 0.28 sqrt (28 swollen joint count) + 0.70 (ln ESR) + 0.014 GH, where GH=subject general health VAS (0-100 mm). 2) DAS28-4 CRP = 0.56 sqrt (28 painful/tender joint count) + 0.28 sqrt (28 swollen count) + 0.36 (ln CRP+1) + 0.014 GH + 0.96, where GH=subject general health VAS (0- 100 mm), higher scores were indicative of a worse outcome. The specific components of the DAS28 assessment that were used in this study are: Tender/Painful Joint Count (28), Swollen Joint Count (28), ESR/CRP, and Subject's General Health VAS assessment.

Outcome measures

Outcome measures
Measure	Etanercept n=197 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=197 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=185 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Disease Activity Score Based on a 28-joint Count (DAS28), Calculated With Erythrocyte Sedimentation Rate for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA+	NA Units on a scale Standard Deviation NA There were no participants in ETN arm tested positive for anti-etanercept antibody.	3.1 Units on a scale Standard Deviation 1.22	3.5 Units on a scale Standard Deviation 1.33
Disease Activity Score Based on a 28-joint Count (DAS28), Calculated With Erythrocyte Sedimentation Rate for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA-	2.5 Units on a scale Standard Deviation 1.20	2.8 Units on a scale Standard Deviation 1.43	3.1 Units on a scale Standard Deviation 1.31

SECONDARY outcome

Timeframe: 1 day

The DAS28 assessment is a derived measurement with differential weight given to each component. DAS28 will be calculated twice, utilizing first ESR, and then CRP as the acute phase reactant: 1) DAS28-ESR = 0.56 sqrt (28 painful/tender joint count) + 0.28 sqrt (28 swollen joint count) + 0.70 (ln ESR) + 0.014 GH, where GH=subject general health VAS (0 100 mm). 2) DAS28-4 CRP = 0.56 sqrt (28 painful/tender joint count) + 0.28 sqrt (28 swollen count) + 0.36 (ln CRP+1) + 0.014 GH + 0.96, where GH=subject general health VAS (0-100 mm), higher scores were indicative of a worse outcome. The specific components of the DAS28 assessment that were used in this study are: Tender/Painful Joint Count (28), Swollen Joint Count (28), ESR/CRP, and Subject's General Health VAS assessment.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Disease Activity Score, 28 Joint Count, Calculated With C-reactive Protein (DAS28-CRP) for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA+	NA Units on a scale Standard Deviation NA There were no participants in ETN arm tested positive for anti-etanercept antibody.	3.4 Units on a scale Standard Deviation 1.22	3.7 Units on a scale Standard Deviation 1.30
Disease Activity Score, 28 Joint Count, Calculated With C-reactive Protein (DAS28-CRP) for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA-	2.9 Units on a scale Standard Deviation 1.18	3.1 Units on a scale Standard Deviation 1.36	3.4 Units on a scale Standard Deviation 1.26

SECONDARY outcome

Timeframe: 1 day

The HAQ-DI assesses the degree of difficulty a participant has experienced during the past week in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities. Each activity category consists of 2-3 items. For each question in the questionnaire, the level of difficulty is scored from 0 to 3 with 0 representing "no difficulty," 1 as "some difficulty," 2 as "much difficulty," and 3 as "unable to do." Any activity that requires assistance from another individual or requires the use of an assistive device adjusts to a minimum score of 2 to represent a more limited functional status. The total score range for the HAQ-DI scale, minimum score was 0 (best), maximum score was 3 (worst).

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Health Assessment Questionnaire-Disability Index (HAQ DI) Scores for for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA+	NA Units on a scale Standard Deviation NA There were no participants in ETN arm tested positive for anti-etanercept antibody.	1.0 Units on a scale Standard Deviation 0.75	1.2 Units on a scale Standard Deviation 0.69
Health Assessment Questionnaire-Disability Index (HAQ DI) Scores for for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. AA-	0.8 Units on a scale Standard Deviation 0.68	0.9 Units on a scale Standard Deviation 0.70	1.0 Units on a scale Standard Deviation 0.63

SECONDARY outcome

Timeframe: 1 day

HAQ DI (\<=0.5) scores for etanercept, adalimumab, or infliximab compared between participants who are antidrug antibody positive versus negative.

Outcome measures

Outcome measures
Measure	Etanercept n=200 Participants Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Percentage of HAQ DI (<=0.5) Scores for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. % AA+	NA percentage of participants There were no participants in ETN arm tested positive for anti-etanercept antibody.	30.6 percentage of participants	20.6 percentage of participants
Percentage of HAQ DI (<=0.5) Scores for Etanercept, Adalimumab, or Infliximab Compared Between Participants Who Are Antidrug Antibody Positive Versus Negative. % AA-	42.5 percentage of participants	36.5 percentage of participants	26.1 percentage of participants

SECONDARY outcome

Timeframe: 1 day

Population: FAS included participants who were diagnosed of RA and who received continuous treatment with either etanercept, adalimumab, or infliximab for a minimum of 6 months to 24 months prior to study assessment visit. No participants for etanercept arm were antibody positive, therefore there is no correlation to report.

Correlation of antidrug antibody titers with efficacy measures analysed using Spearman correlation coefficient.

Outcome measures

Outcome measures
Measure	Etanercept Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Correlation of Antidrug Antibody Titers With Efficacy Measures. CDAI	—	0.07447 Correlation coefficient	0.05256 Correlation coefficient
Correlation of Antidrug Antibody Titers With Efficacy Measures. SDAI	—	0.08970 Correlation coefficient	0.06806 Correlation coefficient
Correlation of Antidrug Antibody Titers With Efficacy Measures. DAS28-ESR	—	0.12179 Correlation coefficient	0.08950 Correlation coefficient
Correlation of Antidrug Antibody Titers With Efficacy Measures. DAS28-CRP	—	0.12710 Correlation coefficient	0.08366 Correlation coefficient

SECONDARY outcome

Timeframe: 1 day

Correlation of antidrug antibody titers with trough drug concentration analysed using Spearman correlation coefficient.

Outcome measures

Outcome measures
Measure	Etanercept Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab/ Infliximab n=199 Participants Participants who had received treatment with adalimumab or infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=195 Participants Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Correlation of Antidrug Antibody Titers With Trough Drug Concentration.	—	-0.69017 Correlation coefficient	-0.60542 Correlation coefficient

Adverse Events

Etanercept

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Adalimumab

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Infliximab

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Etanercept n=200 participants at risk Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab n=199 participants at risk Participants who had received treatment with adalimumab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=196 participants at risk Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Renal and urinary disorders Renal Failure	0.50% 1/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Investigations Blood Count Abnormal	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Measure	Etanercept n=200 participants at risk Participants who had received treatment with etanercept for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Adalimumab n=199 participants at risk Participants who had received treatment with adalimumab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.	Infliximab n=196 participants at risk Participants who had received treatment with infliximab for a minimum of 6 months and maximum of 24 months prior to the study assessment visit.
Blood and lymphatic system disorders Neutropenia	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Cardiac disorders Atrial Fibrillation	0.50% 1/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
General disorders Fatigue	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.50% 1/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
General disorders Injection Site Reaction	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	1.0% 2/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Infections and infestations Clostridium Difficile Colitis	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Infections and infestations Nasopharyngitis	0.50% 1/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Infections and infestations Oesophageal Candidiasis	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Infections and infestations Respiratory Tract Infection	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.50% 1/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Infections and infestations Upper Respiratory Tract Infection	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Investigations Blood Alkaline Phosphatase Increased	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Investigations Blood Bilirubin Increased	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Investigations Blood Pressure Increased	0.50% 1/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	0.50% 1/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	1.0% 2/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Musculoskeletal and connective tissue disorders Rheumatoid Arthritis	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Musculoskeletal and connective tissue disorders Synovial Cyst	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Nervous system disorders Dizziness	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Respiratory, thoracic and mediastinal disorders Cough	0.50% 1/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/200 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.00% 0/199 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.	0.51% 1/196 • From the signing of the informed consent until the follow-up visit (+28 days) following the assessment visit.