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Clinical Trial Results:
SWITCH: Randomised-controlled trial of switching to alternative tumour-necrosis factor (TNF)-blocking drugs or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-blocking drug.

Summary
EudraCT number	2010-023880-17
Trial protocol	GB
Global end of trial date	23 Nov 2015

Results information
Results version number	v1(current)
This version publication date	07 Jul 2018
First version publication date	07 Jul 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

RR10/9589

ISRCTN number

ISRCTN89222125

US NCT number

NCT01295151

WHO universal trial number (UTN)

Sponsor organisation name

University of Leeds

Sponsor organisation address

Hyde Terrace, Leeds, United Kingdom, LS2 9LN

Public contact

Regulatory Affairs and Governance Manager, CTRU QA Department, Leeds Institute of Clinical Trials Research, ctruq@leeds.ac.uk

Scientific contact

Regulatory Affairs and Governance Manager, CTRU QA Department, Leeds Institute of Clinical Trials Research, ctruq@leeds.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Dec 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Nov 2015

Global end of trial reached?

Yes

Global end of trial date

23 Nov 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

To compare alternative-mechanism-TNF-inhibitor and abatacept to rituximab in terms of disease response, quality of life, cost-effectiveness, and toxicity and safety over a 12 month period.

Protection of trial subjects

The randomised treatments in the study are all licensed having demonstrated health benefits with well characterised safety profiles. In addition, in order to be eligible for the trial patients must have already have been established on a biological therapy. Patients were monitored closely throughout the trial and were asked to attend regular outpatient appointments. CTRU prepared annual safety reports containing anonymised data to the MHRA, main REC and sponsor. The Data Monitoring and Ethics Committee reviewed un-blinded periodic safety data to determine patterns and trends of events or to identify safety issues which would not be apparent on an individual case basis. Trial data was collected on paper CRFs and was sent to CTRU where it was entered into a trial database application - MACRO. The database is stored on a private network protected by a firewall. Access is restricted to staff working on the trial by login and password. The trial data was then filed in locked filing cabinets. CTRU comply with all aspects of the Data Protection Act 1998. All information collected during the trial has been kept strictly confidential. Patient names were collected on the Consent Form and sent to CTRU and patients were informed in the Patient Information Sheet that their names were processed this way. For all other data collection forms that were transferred to or from CTRU, the data was coded with a trial number, the patients initials and date of birth.

Background therapy

All participants were required to be on a stable dose of methotrexate for 4 weeks prior to the screening visit and were expected to continue on this therapy for the duration of the study. Interruption of dose was permitted however. The protocol indicated participants would receive standard folic acid as per local policy. In addition, methylprednisolone was administered intravenously at a dose of 100mg prior to each rituximab infusion.

Evidence for comparator

Actual start date of recruitment

31 Jul 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 122

Worldwide total number of subjects

122

EEA total number of subjects

122

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Between July 2012 and December 2014, 678 patients were pre-screened for the trial across 35 centres. Of these, 149/678 patients appeared suitable for and consented to pre-randomisation tests to confirm eligibility. Of these, 122/149 patients were confirmed eligible, maintained their consent, and proceeded to randomisation.

Screening details

Of the 678 patients screened 529 patients were excluded pre-registration. 417 failed to meet the eligibility criteria. The main reasons were: had not failed an initial TNFi agent (95 patients), were not on a stable dose of methotrexate over the over the previous 28 days (92) and had received more than one TNFi drug or other biological agent (72)

Number of subjects started

678 ^[1]

Number of subjects completed

122

Reason: Number of subjects

Declined to consent (pre-consent): 90

Reason: Number of subjects

Other reason for non-registration (pre-consent): 22

Reason: Number of subjects

Ineligible to be randomised (pre-consent): 417

Reason: Number of subjects

Ineligible to be randomised (post-consent): 19

Reason: Number of subjects

Other reason for non-randomisation (post consent): 6

Reason: Number of subjects

Withdrew consent (post-consent): 2

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: "Numbers started pre-assignment period" is the total number considered for enrolment, including those that were not approached due to being clearly ineligible, those that did not consent to trial specific tests, those that consented to tests, but were not randomised, and those that were randomised. "Worldwide number enrolled" is the number of patients randomised and took part in the SWITCH trial.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

N/A

Are arms mutually exclusive

Yes

Alternative mechanism TNFi

Arm description

a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion)

Arm type

Experimental

Investigational medicinal product name

Etanercept

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen, Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Etanercept was administered at either a dose of 50mg by subcutaneous injection per week or as two 25mg injections per week for a minimum of 24 weeks (unless not tolerated). For participants who were responding to treatment at week 24, treatment was continued following the same regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

Investigational medicinal product name

Adalimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen, Solution for injection/infusion, Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Adalimumab was given at a dose of 40mg by subcutaneous injection every 2 weeks for a minimum of 24 weeks (unless not tolerated). For participants who were responding to treatment at week 24 treatment was continued following the same regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

Investigational medicinal product name

Certolizumab Pegol

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen, Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Certolizumab pegol was given at a dose of 400mg by subcutaneous injection at weeks 0, 2, 4 and then at a dose of 200mg every 2 weeks thereafter for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued at the same 200mg every 2 weeks regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

Investigational medicinal product name

Golimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Golimumab will be given at a dose of 50mg by subcutaneous injection every 4 weeks for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued following the same regimen until week 48. Following week 48 treatment is at the discretion of the treating clinician.

Investigational medicinal product name

Infliximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Infliximab was given at a dose of 3mg/kg per intravenous infusion. The intravenous infusions were administered at week 0, 2 (+/- 2 days), 6 (+/- 2 days) and then 8-weekly thereafter (+/- 7 days) for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued at the same 8-weekly regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

Abatacept

Arm description

Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb.

Arm type

Experimental

Investigational medicinal product name

abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Abatacept was given at a dose of 125 mg by subcutaneous injection at week 0 and once weekly thereafter for a minimum of 24 weeks. For participants who are responding to treatment at week 24 treatment will continue following the same regimen until week 48. Following week 48 treatment is at the discretion of the treating clinician.

Rituximab

Arm description

Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary.

Arm type

Active comparator

Investigational medicinal product name

rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab will be given at a dose of 1g; 2 intravenous infusions will be administered at days 0 (week 0) and 15 (week 2; +5 days). In line with standard practice, a participant who loses an initial 6 month (week 24) response as per NICE guidance may receive a further cycle of rituximab after a minimum of 6 months following the first dose. The second cycle of rituximab will be given at a dose of 1g; 2 intravenous infusions will be administered at a 2 week interval (+5 days) e.g. week 24 and 26 (+5 days). Subsequent treatment following week 48 will be at the discretion of the treating clinician. Prior to receiving rituximab, intravenous methylprednisolone 100mg will also be given.

Number of subjects in period 1	Alternative mechanism TNFi	Abatacept	Rituximab
Started	41	41	40
Completed	31	34	31
Not completed	10	7	9
Consent withdrawn by subject	2	1	-
Physician decision	2	1	3
Death	-	1	1
Lost to follow-up	2	1	1
Trial termination	4	3	4

Baseline characteristics

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Reporting group title

Alternative mechanism TNFi

Reporting group description

Reporting group title

Abatacept

Reporting group description

Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb.

Reporting group title

Rituximab

Reporting group description

Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary.

Reporting group values	Alternative mechanism TNFi	Abatacept	Rituximab	Total
Number of subjects	41	41	40	122
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	36	27	27	90
From 65-84 years	5	14	13	32
85 years and over	0	0	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	56.9 (45.5 to 59.8)	60.5 (45.2 to 66.9)	57 (52.4 to 67.4)	-
Gender categorical
Units: Subjects
Female	33	39	30	102
Male	8	2	10	20
Disease Duration Category
Units: Subjects
< 5 years	16	15	14	45
≥5 years	25	26	26	77
Rheumatoid Factor / Anti-citrullinated protein antibody status
Units: Subjects
RF seropositive or ACPA positive	36	31	33	100
Both RF seronegative and ACPA negative	5	10	7	22
Non-Response category
Units: Subjects
Primary	15	15	15	45
Secondary	26	26	25	77
Smoking status
Units: Subjects
Non-smoking (Never smoked)	12	17	21	50
Past smoker	18	13	11	42
Current smoker	11	11	8	30
Previous TNFi agent
Units: Subjects
Adalimumab	10	10	8	28
Certolizumab pegol	11	9	5	25
Etanercept	16	18	18	52
Golimumab	2	0	4	6
Infliximab	2	4	5	11
Disease Duration
Years between Rheumatoid Arthritis diagnosis and randomisation.
Units: Years
median (inter-quartile range (Q1-Q3))	5.9 (3.9 to 12.3)	6.9 (4 to 15.4)	7 (3.9 to 15.6)	-
Body Mass Index
Units: Kg/m2
median (inter-quartile range (Q1-Q3))	28.7 (25 to 34)	28.4 (24.3 to 34.5)	29 (25.4 to 33.5)	-

Subject analysis set title

Intention-to-treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients randomised

Subject analysis set title

Per-protocol population

Subject analysis set type

Per protocol

Subject analysis set description

Patients who deviated from the protocol or failed to comply with the required treatment regimen were excluded from the per-protocol population. Analysis was conducted by treatment received

Subject analysis sets values	Intention-to-treat	Per-protocol population
Number of subjects	122	41
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	90	31
From 65-84 years	32	10
85 years and over	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	57.3 (46.7 to 65.4)	57.7 (45.6 to 64.7)
Gender categorical
Units: Subjects
Female	20	30
Male	102	11
Disease Duration Category
Units: Subjects
< 5 years	45	11
≥5 years	77	30
Rheumatoid Factor / Anti-citrullinated protein antibody status
Units: Subjects
RF seropositive or ACPA positive	100	33
Both RF seronegative and ACPA negative	22	8
Non-Response category
Units: Subjects
Primary	45	18
Secondary	77	23
Smoking status
Units: Subjects
Non-smoking (Never smoked)	50	16
Past smoker	42	15
Current smoker	30	10
Previous TNFi agent
Units: Subjects
Adalimumab	28	9
Certolizumab pegol	25	9
Etanercept	52	16
Golimumab	6	2
Infliximab	11	5
Disease Duration
Years between Rheumatoid Arthritis diagnosis and randomisation.
Units: Years
median (inter-quartile range (Q1-Q3))	6.7 (3.9 to 14.2)	8 (4.4 to 14.3)
Body Mass Index
Units: Kg/m2
median (inter-quartile range (Q1-Q3))	29 (24.9 to 34.1)	29 (25.3 to 34.9)

End points

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Reporting group title

Alternative mechanism TNFi

Reporting group description

Reporting group title

Abatacept

Reporting group description

Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb.

Reporting group title

Rituximab

Reporting group description

Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary.

Subject analysis set title

Intention-to-treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients randomised

Subject analysis set title

Per-protocol population

Subject analysis set type

Per protocol

Subject analysis set description

Patients who deviated from the protocol or failed to comply with the required treatment regimen were excluded from the per-protocol population. Analysis was conducted by treatment received

Primary: Absolute reduction in DAS28 at 24 weeks post randomisation

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End point title

Absolute reduction in DAS28 at 24 weeks post randomisation

End point description

Endpoint description: DAS28 is a measure of disease activity in RA. The composite score is calculated as a function of the number of tender and swollen joints (total 28 joints), the erythrocyte sedimentation rate (ESR) and the patient’s global assessment of their arthritis measured - Tender Joint Count (TJC: Range 0-28) - Swollen Joint Count (SJC: Range 0-28) - Erythrocyte Sedimentation Rate (ESR: Range 0-99) - Patient-completed Visual Analogue Scale of Global Assessment of Arthritis With these four items, the DAS28 score is calculated in the following manner: DAS28=(0.56×√TJC)+(0.28×√SJC)+(0.7×log[e] ESR)+(0.014×VAS(mm)) Where log[e] is the natural logarithm function.

End point type

Primary

End point timeframe

Baseline to 24 weeks post randomisation

End point values	Alternative mechanism TNFi	Abatacept	Rituximab
Number of subjects analysed	41 ^[1]	41 ^[2]	40 ^[3]
Units: units
arithmetic mean (standard deviation)	1.4 ( 1.28 )	1.2 ( 1.72 )	1.3 ( 1.94 )

Notes
[1] - Prior to multiple imputation of missing values, 36/41 patients had complete data at weeks 0 and 24.
[2] - Prior to multiple imputation of missing values, 34/41 patients had complete data at weeks 0 and 24.
[3] - Prior to multiple imputation of missing values, 32/40 patients had complete data at weeks 0 and 24.

Primary endpoint analysis (ITT - TNFi vs RTX)

Statistical analysis description

Mixed-effects linear regression model. Outcome: Reduction in DAS28 between Weeks 0 and 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects) and randomising centre (random effect). Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. Non-Inferiority concluded if 95% CI lies wholly above NI margin of -0.6.

Comparison groups

Alternative mechanism TNFi v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

= 0.0094 ^[5]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

1.05

Notes
[4] - Non-inferiority margin: -0.6 units of DAS28 score. Position of 2-sided 95% confidence interval judged in relation to margin. If 2-sided interval lies wholly above -0.6, NI conclusion reached in ITT population (must be matched by similar conclusion in Per-protocol population). If 2-sided interval lies wholly above 0, superiority conclusion reached in ITT population.
[5] - One-sided P-Value, corresponding to a one-sided 97.5% test, using non-inferiority margin of -0.6. Must be less than 0.025 to conclude non-inferiority to rituximab. Per-Protocol population P-value=0.489; non-inferiority to rituximab not demonstrated

Primary endpoint analysis (ITT - ABT vs RTX)

Statistical analysis description

Comparison groups

Abatacept v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

P-value

= 0.0493 ^[7]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.79

Notes
[6] - Non-inferiority margin: -0.6 units of DAS28 score. Position of 2-sided 95% confidence interval for (abatacept - rituximab) judged in relation to margin. If 2-sided interval lies wholly above -0.6, Non-inferiority conclusion reached in ITT population (must be matched by similar conclusion in Per-protocol population). If 2-sided interval lies wholly above 0, superiority conclusion reached in ITT population.
[7] - One-sided P-Value, corresponding to a one-sided 97.5% test, using non-inferiority margin of -0.6. Must be less than 0.025 to conclude non-inferiority to rituximab. Per-Protocol Population P-value=0.216; non-inferiority to rituximab not demonstrated.

Secondary: ACR20 Response at 24 weeks

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End point title

ACR20 Response at 24 weeks

End point description

The ACR20 (American College of Rheumatology) response criterion is a composite endpoint. To achieve response, a patient must achieve between baseline and 24 weeks: 20% reduction in Tender Joint Counts and 20% reduction in Swollen Joint Counts and 20% reduction in 3 of the following 5 criteria: Patient-completed Pain VAS (Range 0-100mm) Patient-completed general health VAS (Range 0-100mm) Patient-completed assessment of disability (HAQ-DI, Range 0-3) Physician-completed assessment of disease activity (Range 0-100mm) Either C-reactive Protein or Erythrocyte Sedimentation Rate measure.

End point type

Secondary

End point timeframe

From baseline to 24 weeks.

End point values	Alternative mechanism TNFi	Abatacept	Rituximab
Number of subjects analysed	41 ^[8]	41 ^[9]	40 ^[10]
Units: Number of patients responding
Achieved ACR20 Response	16	11	10
Non-Response	20	24	27

Notes
[8] - Prior to multiple imputation of missing values, 36/41 patients had complete data for ACR Response.
[9] - Prior to multiple imputation of missing data, 35/41 patients had complete data for ACR20 Response.
[10] - Prior to multiple imputation of missing data, 37/40 patients had complete data for ACR20 Response.

ACR20 Response at 24 weeks (ITT - TNFi v RTX)

Statistical analysis description

Fixed-effects logistic regression model. Outcome: ACR20 Response at week 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects). Randomising centre not fitted due to non-convergence. Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. ITT analysis population.

Comparison groups

Alternative mechanism TNFi v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.15 ^[11]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

5.53

Notes
[11] - 2-sided P-Value for null hypothesis that ACR20 response rates at 24 weeks are equal.

ACR20 Response at 24 weeks (ITT - ABT v RTX)

Statistical analysis description

Comparison groups

Abatacept v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.736

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

3.21

Secondary: DAS28 Score

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End point title

DAS28 Score

End point description

For a description of the derivation of the DAS28 score, please refer to description given under Primary Endpoint. NB: Values of mean and Std dev given here are at Week 48.

End point type

Secondary

End point timeframe

Baseline to 48 weeks. Measured at baseline, weeks 12, 24, 36 and 48.

End point values	Alternative mechanism TNFi	Abatacept	Rituximab
Number of subjects analysed	41 ^[12]	41 ^[13]	40 ^[14]
Units: Units of DAS28
arithmetic mean (standard deviation)	4.1 ( 1.58 )	4.8 ( 1.24 )	4.8 ( 1.42 )

Notes
[12] - Prior to multiple imputation of missing data, 26/41 patients had complete data at all timepoints.
[13] - Prior to multiple imputation of missing data, 24/41 patients had complete data at all timepoints.
[14] - Prior to multiple imputation of missing data, 21/40 patients had complete data at all timepoints.

DAS28 Score (ITT TNFi vs RTX)

Statistical analysis description

Mixed-effects linear regression model. Outcome: DAS28 over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are differences at 48 weeks. P-Values for interaction between trt-time are P=0.338 (24weeks), P=0.071 (36 weeks), P=0.552 (48 weeks).

Comparison groups

Alternative mechanism TNFi v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.249

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.39

Confidence interval

level

95%

sides

2-sided

lower limit

-1.04

upper limit

0.27

DAS28 Score (ITT - ABT vs RTX)

Statistical analysis description

Mixed-effects linear regression model. Outcome: DAS28 over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are differences at 48 weeks. P-Values for interaction between trt-time are P=0.976 (24weeks), P=0.871 (36 weeks), P=0.755 (48 weeks).

Comparison groups

Abatacept v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.859

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

0.71

Secondary: DAS28 Response

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End point title

DAS28 Response

End point description

Response defined as the achievement of a reduction in DAS28 of 1.2 or more (ie a change of -1.2 or less) since baseline. NB: The reported number of patients responding given here are for Week 48.

End point type

Secondary

End point timeframe

Baseline to 48 weeks. DAS28 measured at baseline, 12, 24, 36 and 48 weeks.

End point values	Alternative mechanism TNFi	Abatacept	Rituximab
Number of subjects analysed	41 ^[15]	41 ^[16]	40 ^[17]
Units: Number of patients responding
Response (DAS28 reduced by 1.2 or more)	19	18	13
Non-Response	11	12	10

Notes
[15] - Prior to multiple imputation of missing data, 26/41 patients had complete data at all timepoints.
[16] - Prior to multiple imputation of missing data, 24/41 patients had complete data at all timepoints.
[17] - Prior to multiple imputation of missing data, 21/40 patients had complete data at all timepoints.

DAS28 Response over 48 weeks (ITT - TNFi vs RTX)

Statistical analysis description

Mixed-effects logistic regression model. Outcome: Response over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are ORs at 48 weeks. P-Values for interaction between trt-time are P=0.116 (24weeks), P=0.327 (36weeks), P=0.699 (48weeks).

Comparison groups

Alternative mechanism TNFi v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.543

Method

Mixed models analysis

Parameter type

Odds ratio (OR)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

4.19

DAS28 Response over 48 weeks (ITT - ABT vs RTX)

Statistical analysis description

Mixed-effects logistic regression model. Outcome: Response over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are ORs at 48 weeks. P-Values for interaction between trt-time are P=0.930 (24weeks), P=0.888 (36weeks), P=0.675 (48weeks).

Comparison groups

Abatacept v Rituximab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.869

Method

Mixed models analysis

Parameter type

Odds ratio (OR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

2.73

Secondary: HAQ-DI

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End point title

HAQ-DI

End point description

HAQ-DI questionnaire (See: Pincus T, Summey JA, Soraci SA, et al. Assessment of patient satisfaction in activities of daily living using a modified stanford health assessment questionnaire. Arthritis & Rheumatism. 1983;26(11):1346-53.). Patients respond to 20 questions across 8 domains relating to physical function, and the need for any help or aids to undertake daily activities. The extent of disability is scored from 0 (no disability) to 3 (severe disability) for each item relating to rising, dressing, walking and other activities. The use of help or aids increases the category score from 0 or 1 to a 2. If the category score is already a 2 or 3, no adjustment is made. The total score is derived by taking the maximum score across all domains and dividing by 8 to provide an average score in the range 0-3. NB: the median and IQR given here corresponds to Week 48

End point type

Secondary

End point timeframe

HAQ-DI questionnaire completed by the patient at baseline and weeks 12, 24, 36, 48.

End point values	Alternative mechanism TNFi	Abatacept	Rituximab
Number of subjects analysed	30	34	30
Units: Units of HAQDI
median (inter-quartile range (Q1-Q3))	1.5 (1.1 to 1.9)	1.6 (1 to 2.1)	1.7 (1.1 to 2.1)

No statistical analyses for this end point

Secondary: RAQOL

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End point title

RAQOL

End point description

See de Jong Z, van der Heijde D, McKenna SP, Whalley D. The reliability and construct validity of the RAQoL: a rheumatoid arthritis-specific quality of life instrument. Rheumatology. 1997 August 1, 1997;36(8):878-83. Thirty item questionnaire, each item having a Yes (score as 1) / No (score as 0) response to ascertain the extent of rheumatoid arthritis symptoms experienced, maximum score 30. NB: the median and IQR given here corresponds to Week 48

End point type

Secondary

End point timeframe

Baseline and weeks 12, 24, 36, 48.

End point values	Alternative mechanism TNFi	Abatacept	Rituximab
Number of subjects analysed	30	34	30
Units: Units of RAQoL
median (inter-quartile range (Q1-Q3))	19 (9 to 23)	17.5 (11.4 to 24)	19.5 (12 to 25)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All AEs/ARs and SAEs were monitored from randomisation until a minimum of 30 days* post last dose of randomised treatment during the interventional phase (week 48 max). Monitoring for SARs and SUSARs continued during the observational phase (week 96 max).

Adverse event reporting additional description

At each clinical assessment visit (weeks 12, 24, 36, 48) patients were asked to reported adverse events. Serious Adverse Events, Serious Adverse Reactions and Suspected Unexpected Serious Adverse Reactions were subject to expedited reporting.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Alternative TNFi

Reporting group description

All participants randomised to receive alternative TNFi. One participant was withdrawn prior to receiving any IMP due to eligibility randomisation, this patient reported no Adverse Events.

Reporting group title

Abatacept

Reporting group description

All participants randomised to abatacept. All participants received at least one injection of abatacept.

Reporting group title

Rituximab

Reporting group description

All patients randomised to receive rituximab. All participants received at least one infusion of rituximab.

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories cannot be completed.

Serious adverse events	Alternative TNFi	Abatacept	Rituximab
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 40 (2.50%)	4 / 41 (9.76%)	4 / 40 (10.00%)
number of deaths (all causes)	0	1	1
number of deaths resulting from adverse events	0	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Melanoma
subjects affected / exposed	0 / 40 (0.00%)	0 / 41 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Gastrointestinal disorders
Epigastric chest pain
subjects affected / exposed	0 / 40 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	0 / 40 (0.00%)	0 / 41 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 40 (2.50%)	0 / 41 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Left Basal Pneumonia
subjects affected / exposed	0 / 40 (0.00%)	0 / 41 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 40 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Flare of Rheumatoid Arthritis
subjects affected / exposed	0 / 40 (0.00%)	0 / 41 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Collapse, broken coccyx
subjects affected / exposed	0 / 40 (0.00%)	0 / 41 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 40 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Chest Infection
subjects affected / exposed	0 / 40 (0.00%)	1 / 41 (2.44%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Alternative TNFi	Abatacept	Rituximab
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 40 (0.00%)	0 / 41 (0.00%)	0 / 40 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

01 Mar 2012

Inclusion of the option for subcutaneous IMPs to be sourced and delivered to participants homes by a third party home healthcare providers as per local hospital practice.

01 Mar 2012

Amendment from intravenous formulation of abatacept to subcutaneous formulation following agreement from manufacturers of abatacept to provide trial supplies. This also required changes to other documentation to i) include a further vendor responsible for packaging and labelling of the abatacept trial supplies and ii) amend wording on the labels for sub-cutaneous abatacept.

06 Mar 2012

Wording added to the label for subcutaneous abatacept as requested by Bristol Myers Squibb (the manufacturers of abatacept).

29 May 2012

Addition of Almac Limited as the responsible party for the packaging, labelling and batch release of abatacept. Also, addition of trial identifier (the word 'SWITCH') to the already approved label for abatacept.

15 May 2013

Clarification included in the proptocol that where local practice indicates the use of a home healthcare provider for the delivery of subcutaneous IMPs, the trial procedures will map onto the established, standard care practices in place at each individual site in terms of services and record keeping and retention requirements.

09 Oct 2013

Approval was obtained for a letter to provide to participants that explained a discrepancy between the expiry date given on the internal and external packaging of abatacept. Amendment was submitted to ethics committee only as competent authority

09 Oct 2013

Addition of a Patient Advert designed to advertise the trial directly to patients, with the intention that sites display the patient advert in patient waiting rooms etc. In addition, information contained within the advert was intended to be used via various means e.g. patient websites, e-bulletins, social media for the purpose of advertising the trial to the wider rheumatoid arthritis community. Submitted to Main Research Ethics Committee only as related only to information to be provided to the participant.

10 Dec 2013

Addition of golimumab to alternative mechanism TNFi arm following feedback from sites that use of golimumab was becoming more commonplace and therefore the ability to use this may expand the field of potential patients/increase pragmatism of study/would reflect standard practice more closely.

10 Dec 2013

Modification of the primary endpoint from a dichotomous endpoint (whether or not the patient achieved a reduction of greater than 1.2 units in DAS28 with no toxicity) to a continuous endpoint (change in DAS28 score).

02 May 2014

R&D form amended to enable the use of Participant Identification Centres in order to identify further participants. Submitted to Main Research Ethics Committee only.

16 May 2014

Corrections of errors noted in the Research Ethics Committee form and the Patient Information Sheet relating to the amount of radiation patients would be exposed to as part of the imaging aspects of the study. Submitted to Main Research Ethics Committee only as related to information provided on the Patient Information Sheet.

08 Aug 2014

A Participant Information Summary Sheet was created to summarise and complement the main Participant Information Sheet & Informed Consent Document before the patient reads the main Participant Information Sheet and Informed Consent Form following feedback from patient and public involvement representatives that the current Participant Information Sheet and Informed Consent Form was lengthy and a supplementary summary sheet would be beneficial. Submitted to Main Research Ethics Committee only as related to information provided on the Patient Information Sheet.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
02 Dec 2014	A temporary halt to recruitment was necessary following the withdrawal of funding by the NIHR Health Technologies Assessment programme. The halt was considered temporary at the time as the Chief Investigator sought alternative sources of funding. This was submitted as a Substantial Amendment to the Medicines and Healthcare Products Regulatory Authority and the Main Research Ethics Committee on 16th December 2014 and approvals received on 9th January 2015 and 30th December 2014 respectively. Unfortunately, discussions to secure an alternative funding source were not successful and the need for a permanent halt was conveyed to participating sites on 9th February 2015. This was followed by submission of a substantial amendment on 9th April 2015 to update the protocol accordingly .	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results: SWITCH: Randomised-controlled trial of switching to alternative tumour-necrosis factor (TNF)-blocking drugs or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-blocking drug.

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Primary: Absolute reduction in DAS28 at 24 weeks post randomisation

Primary: Absolute reduction in DAS28 at 24 weeks post randomisation

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SWITCH: Randomised-controlled trial of switching to alternative tumour-necrosis factor (TNF)-blocking drugs or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-blocking drug.