THE SAFETY PROFILE OF RITUXIMAB IN RHEUMATOID … · 1 Dr. Reddy’s Laboratories SA, Biologics,...

THE SAFETY PROFILE OF RITUXIMAB IN RHEUMATOID ARTHRITIS:

PROTOCOL FOR A SYSTEMATIC REVIEW AND PLANNED META-ANALYSIS OF RANDOMISED

CLINICAL TRIALS (VERSION 2 FINAL)

Date: 14-January-2015 (Version 2 Final)

Authors: Luis Velez-Nandayapa, MD*1,3,4

Aniruddha Bhattacharya, MD2

Chahna Parikh2

*Corresponding Author e-mail: [email protected] and [email protected] Address: Burstwiesenstrasse 17 8055, Zürich Switzerland 1 Dr. Reddy’s Laboratories SA, Biologics, Basel, Switzerland 2 Dr. Reddy’s Laboratories Ltd, Biologics Development Centre, Hyderabad, India 3 Candidate MSc in Pharmacovigilance, Drug Safety Research Unit and the University of Portsmouth 4 Candidate MSc in Epidemiology, London School of Hygiene and Tropical Medicine and the University of London

Page | 1 Protocol – Systematic Review & Meta-analysis Rituximab in Rheumatoid Arthritis

Version 2 Final – 14Jan2015

mailto:[email protected]

mailto:[email protected]

Table of content

Section Item Page

List of abbreviations 5

Research question 7

1. Introduction 8

2. Study Rationale 11

3. Objective 12

4. Protocol 13

5 Eligibility criteria 14

5.1. Inclusion criteria 14

5.2. Exclusion criteria 15

6 Search Strategy for Identification of Studies 16

6.1. Electronic Searching 16

6.2. PubMed, EMBASE and CENTRAL search terms 16

6.2.1. PubMed search 16

6.2.2. EMBASE search 17

6.2.3. CENTRAL search 17

6.3. Additional searching 17

7. Data extraction/collection and analysis 17

7.1. Study Selection process 17

7.2. Data extraction/collection and management 18

7.3. Information about site and publication 18

7.4. Information about type of study 19

7.5. Information about the sample 19

7.6. Information about safety reporting 19

7.7. Type of intervention 19



7.8. Type of studies 19

8. Methodology 20

8.1. Methodology quality/risk of bias assessment/appraisal 20

8.2. Terminology 20

8.3. Reviewers 20

9. Analysis outline 21

9.1. Case definition 21

9.2. Statistical analysis 21

9.3. Heterogeneity 22

9.4. Fixed and random effects 22

10. Statistical software 22

11. Primary analysis 23

11.1. Analysis of TEAEs, SAEs and withdrawals rate due to AEs 23

12. Secondary Analysis 23

12.1. Analysis of TEAEs rate (by PT) 23

12.2. Analysis of TEAEs rate (by PT) by dose 23

13. Sub-analysis 24

14. Prioritisation of outcomes 24

15. Sensitivity analysis 24

16. Ethics considerations 25

17. Contribution of authors 25

18. Support and funding 25

19. Protocol history and amendments 26

20. The PRISMA-P statement checklist 27

References 29

Appendix 1 33



Appendix 2 36



List of Abbreviations

AE Adverse event

ACR American College of Rheumatology

ADR Adverse Drug Reaction

ANA Anti-nuclear antibody

CI Confidence interval

DMARDs Disease Modifying Anti-rheumatic Drugs

EMBASE Excerpta Medica dataBASE

EULAR European League Against Rheumatism

FDA Food and Drug Administration

GRADE Grading of Recommendations Assessment, Development and Evaluation

HACA Human anti-chimeric antibody

MedDRA Medical Dictionary for Regulatory Activities

MTX Methotrexate

NNTH Number Needed to Treat for an Additional Harmful Outcome

OR Odds Ratio

OR-Peto Odds Ratio by Peto Method

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses

PROSPERO Prospective Register of Systematic Reviews

RR Risk Ratio

RTX Rituximab

SAE Serious adverse event

TNF Tumour necrosis factor

TEAE Treatment emergent adverse event

US United States



WHO World Health Organisation



Research Question

What is the safety profile (unintended effects and risks) with the use of rituximab (RTX) in

patients with rheumatoid arthritis (RA)?

According to the Cochrane Handbook for Systematic Reviews of Interventions1, in

systematic reviews and meta-analysis questions are stated broadly as review “Objectives”,

and specified in detail as “Criteria for considering studies for this review”. This protocol will

provide both the objective of this systematic review and meta-analysis as well as the criteria

selected for considering studies for this review; and the subsequent research will answer the

question posed.



1. Introduction

Rheumatoid arthritis is a common autoimmune disease that is associated with progressive

disability, systemic complications, early death, and socioeconomic costs2-4. It is associated

to significant morbidity, deformity and joint destruction that can lead to loss of function5,6.

The incidence and prevalence of the disease vary depending of the country and study type

performed; the range found for prevalence is from 1.8 x 1,000 inhabitants in Yugoslavia to

10.7 x 1,000 in the USA, and the incidence is from 0.1 x 1,000 inhabitants in France to 0.5 x

1,000 in the USA7. The aim of early treatment is controlling joint pain, inflammation, and

reducing joint damage and the risk of disability. Disease modifying anti-rheumatic drugs

(DMARDs) remain the preferred initial treatment for RA; they have been shown to reduce

disease activity, retard joint erosions and improve quality of life of patients8,9. However,

treatment with DMARDs does not offer a high rate of improvement and many patients either

fail to respond adequately or need to stop treatment because of side effects10. Biologics

agents have been introduced to treat RA in the last two decades. They are immune targeted

therapies which have shown effectiveness in patients who do not respond to DMARDs11-15.

In recent years, targeted research has provided further insight into the role of B-cells in the

pathophysiology of rheumatoid arthritis16,17.

RTX is an anti-CD20 monoclonal antibody that induces lysis and apoptosis of normal and

malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of

chemotherapy. The antibody is now used for the treatment of various CD20-expressing

lymphomas or leukemias, as first-line, salvage or maintenance therapy, with or without the

concomitant use of chemotherapy18. RTX has also been found to provide significant

improvement in the clinical signs and symptoms of RA in combination with methotrexate

(MTX) in adult patients with moderate to severe active RA who have demonstrated

inadequate response to one or more tumour necrosis factor (TNF) antagonist therapies19-21.

RTX is also recommended for patients with moderate to severe RA following failure of non-

biologic-DMARD therapy, as per current American College of Rheumatology (ACR)

guidelines22. There is evidence that, when used in combination with MTX, RTX is effective

and well tolerated, in managing RA20,23.

While the efficacy of RTX has been very well reviewed/assessed in systematic reviews and

meta-analyses, there is still uncertainty regarding the complete safety profile of this

treatment. Previous systematic reviews and meta-analysis22,24 have not fully evaluated the

safety profile, including all unintended effects and risks, of RTX.

Pires de Lemos, et al.24 published a systematic review which assessed the efficacy and

safety of RTX in patients with active RA who have and have not been treated with anti-TNF



agents before. The authors compared RTX 1000 mg with placebo; MTX was used in both

arms. There were no differences between groups regarding safety outcomes, reported as

adverse events with the exception of acute injection reactions. Six sub-analysis with safety

outcomes were performed at 24, 48-52 and 104 weeks for: 1) Serious adverse events; RR of

0.98 CI 95% (0.70 – 1.38), RR 0.93 (0.57 – 1.52), and RR 0.78 (0.51 – 1.19) respectively.

2) Serious infections; RR 0.86 (0.36 – 2.04), RR 0.68 (0.30 – 1.57), and RR 0.63 (0.31 –

1.27) respectively. 3) Losses of follow up; RR 0.47 CI 95% (0.29 – 0.76), RR 0.54 (0.04 –

7.56) and RR 0.48 (0.28 – 0.82) respectively. 4) Losses due to lack of efficacy; RR 0.27 CI

95% (0.16 – 0.45), RR 0.19 (0.08 – 0.50) RR 0.24 (0.09 – 0.064) respectively. 5) Losses

due to adverse events; RR 1.47 CI 95% (0.53 – 4.09), RR 0.95 (0.17 – 5.34) RR 0.38 (0.17

– 0.85) respectively. 6) Infusion reactions; RR 1st infusion of 1.55 CI 95% (1.30 – 1.86), RR

2nd infusion of 0.79 (0.63 – 0.99).

Hernandez-Cruz, et al.22, published a systematic review which assessed the efficacy and

safety of RTX in patients with active RA, as a part of the Consensus on the use of RTX in

RA. Six sub-analysis with safety outcomes were performed at 24 weeks for: 1) Serious

adverse events, OR of 0.94 CI 95% (0.68 – 1.30); 2) Death, OR 0.33 (0.08 – 1.37); 3)

Infusion reactions to 1st infusion OR 1.70 CI 95% (1.31 – 2.22); 4) Serious infections, OR

0.93 CI 95% (0.45 – 2.05); 5) Withdrawals any cause, OR 0.6 CI 95% (0.44 – 0.81); and 6)

Withdrawals due to AEs OR 2.23 CI 95% (0.87 – 5.69).

Singh JA, et al.15, published a paper within the Cochrane Library, an ‘Overview of Reviews’

titled “Biologics for rheumatoid arthritis: an overview of Cochrane reviews”. The authors’ aim

was to compare the efficacy and safety of abatacept, adalimumab, anakinra, etanercept,

infliximab, and RTX in patients with RA. This ‘Overview of Reviews’ was done by including

all Cochrane Reviews on Biologics for RA available in The Cochrane Library. The authors

included only data on standard dosing regimens for those biologics studied in placebo-

controlled trials. Two sub-analysis with safety outcomes were performed for RTX: 1)

Withdrawals due to AEs, OR of 2.89 CI 95% (0.84 – 9.92); and 2) Withdrawals due to any

cause, OR 0.27 (0.20 – 0.37).

A second paper published by Singh JA, et al.25, a systematic review and meta-analysis titled

“Adverse effects of biologics: a network meta-analysis and Cochrane overview (Review)”.

The authors combined the results from biologics used in many conditions to obtain much

needed risk estimates. The aim of the work by Singh JA, et. al., was to compare the

potential adverse effects of tumor necrosis factor inhibitor (adalimumab, certolizumab,

etanercept, golimumab, infliximab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist

(tocilizumab), anti-CD28 (abatacept), and anti-B cell (RTX) therapy in patients with any



disease condition except human immunodeficiency disease (HIV/AIDS). Four sub-analysis

with safety outcomes were performed for RTX: 1) Total AEs, OR of 1.54 CI 95% (0.49 –

4.63); 2) Withdrawals due to AEs, OR 2.74 (0.43 – 28.5); 3) Serious Infections, OR of 0.26

CI 95% (0.03 – 2.16); and 4) SAEs, OR 1.71 (0.69 – 4.49).



2. Study Rationale

Placebo-controlled clinical trials, systematic reviews and meta-analyses have demonstrated

that biologics, especially RTX, are effective in decreasing joint and systemic inflammation,

delaying radiographic joint destruction and disability, and improving productivity in patients

with RA19-21.

Safety is an important matter and with a limited number of RCTs which examine RTX in RA

it is prudent to pool safety data across studies to provide a better understanding of its safety

profile (toxicity) in RA.

To our knowledge, a systematic review and meta-analysis contemplating a complete

assessment of the safety profile of all unintended effects (risks) reported, by preferred term

(PT) according to Medical Dictionary for Regulatory Activities (MedDRA), of RTX for the

treatment of RA has not been done.

This systematic review and meta-analysis of RTX in RA aims to assess the complete safety

profile of the drug by evaluating all adverse events reported in randomised controlled clinical

trials.

The importance of this systematic review and meta-analysis is because of the increased

availability in the market of new biosimilars of RTX in several countries. This meta-analysis

will show the quantification of each risk (unintended effect) reported in clinical trials and can

be used in the future to map the safety profile of the original compound of RTX vs different

biosimilars of RTX available in the market and future biosimilars of RTX yet to launch.



3. Objective: The aim of this systematic review and meta-analysis is to provide reliable assessment of all

unintended effects (risks) reported with the use of RTX (MabThera® and Rituxan®

exclusively) for the treatment of RA.



4. Protocol The following protocol was submitted for registration with the International Prospective

Register of Systematic Reviews, PROSPERO database on December 22, 2014 (registration

number CRD42014015655). The Preferred Reporting Items for Systematic Reviews and

Meta-analyses (The PRISMA Statement)26, the Cochrane Handbook27 and the Cochrane

Adverse Effects Methods Group28,29 were used to guide the development of this protocol.

Subsequent to submission, on January 1, 2015, The Preferred Reporting Items for

Systematic Reviews and Meta-analyses Protocols (PRISMA-Protocol) 2015 Statement30 was

published. This protocol has been amended to reflect the new PRISMA-Protocol Statement

guidelines. Section 20 contains a table with the PRISMA-Protocol Statement’s checklist

which includes 17 points and their location in this protocol.

Section 19, ‘Protocol history and amendments’, contains a table with the protocol’s history

including the list changes for the amendment.



5. Eligibility Criteria Studies fulfilling the eligibility criteria will be included, the list of Inclusion Criteria and

Exclusion Criteria are shown below following the PICO strategy31, criteria which is outlined in

the Preferred Reporting Items for Systematic Reviews and Meta-analyses, the PRISMA

Statement27 as the five PICOS:

5.1. Inclusion Criteria Population (P)

• Human subjects

• Adults (≥ 18 years old) subjects participating in randomised clinical trials with RTX in RA

Intervention/exposure of interest (I)

• Studies with RTX (MabThera® and Rituxan® exclusively) in the following indication:

o treatment of RA

• Treatment with RTX alone or in combination with MTX vs active comparator, control

and/or placebo

• Studies with different doses and combinations of RTX will be included

Comparator (C)

• RTX against active comparators and/or control

• Placebo/no treatment and/or standard of care

Outcomes (O)

• Contains a comprehensive safety reporting of number of events as outcomes of interest:

• at least one type of AE/TEAE/SAE/ADR information reported for RTX, active

comparator and/or placebo

• or, in case of no reports of AEs/TEAEs/SAEs/ADRs, the paper must state that a

review was done and no AEs/TEAEs/SAEs/ADRs were found

• Safety data reported as number of events by preferred term (PT) using MedDRA

coding

• Withdrawals due to AEs/TEAEs/SAEs/ADRs

Study (S) Design

• Randomised/randomized controlled clinical trials

• Comparative at least with two arms



• Double-blind studies

5.2. Exclusion Criteria Language

• There is no language limitation.

Population (P)

• Animal studies and/or in vitro studies

• Studies in which subjects of study were not humans

Intervention/exposure of interest (I)

• Other biologics different from RTX

• Other RTX biosimilars

Comparator (C)

• No exclusion criteria

Outcomes (O)

• Contains no comprehensive safety reporting and no reports of any AE/TEAE/SAE/ADR

by number of subjects and/or percentages.

Study (S) Design

• Cohort studies (including prospective and retrospective studies)

• Case-control studies

• Clinical trials with single arm

• Clinical trials in which randomisation was not performed to allocate the intervention

• Open clinical trials

• Drug utilisation studies

• Case reports, case series, and case studies, and

• Reviews, including systematic reviews and meta-analyses

Other limitations

Limitations will be imposed on publication status; only published clinical trials will be

considered and grey literature searching will not be feasible/performed. No limitations will be

imposed in regards to languages and duration of study follow-up or period of study conduct.



6. Search Strategy for Identification of Studies 6.1. Electronic Searching

A validated process for evaluating the quality and completeness of the electronic search

strategy has been performed. The searches have been subject to a peer review and piloted

in order to evaluate the grade/level of recall (sensitivity) and precision (positive predictive

value) following the guidance established by Sampson M, et al.32, Wong SS, et al.33 and the

Cochrane Handbook for Systematic Reviews of Interventions (Chapter 6: Searching for

studies)34 with the exception that the search strategy will not be conducted by librarians, but

by the authors.

A systematic search of the following databases will be performed: PubMed, Excerpta Medica

dataBASE (EMBASE), and the Cochrane Central Register of Controlled Trials (CENTRAL).

Accumulative literature search for the period between 01-January-1980 to current date will

be performed.

The keyword strategy is outlined below:

6.2. PubMed, EMBASE and CENTRAL search terms

Both the terms “randomized” and “randomised” will be included in the search terms in each

database; PubMed, EMBASE and CENTRAL.

6.2.1. PubMed search

(rituximab) OR (rituximab.tw.) OR (rituximab mesh terms)

AND

(randomised) OR (randomised mesh terms) OR (randomised.ab.) OR (randomized) OR

(randomized mesh terms) OR (randomized.ab.)

AND

(clinical trial) OR (clinical trial.pt.) OR (clinical trial mesh terms)

AND

(rheumatoid arthritis) OR (rheumatoid arthritis mesh terms)



6.2.2. EMBASE search

(rituximab) OR (rituximab mesh terms)

AND

(randomised) OR (randomised mesh terms) OR (randomized) OR (randomized mesh terms)

AND

(clinical trial) OR (clinical trial mesh terms)

AND

(rheumatoid arthritis) OR (rheumatoid arthritis mesh terms)

6.2.3. CENTRAL search

(rituximab)

AND

(randomised) OR (randomized)

AND

(clinical trial)

AND

(rheumatoid arthritis)

6.3. Additional searching

A manual search for other published studies will be performed using any references cited

from papers which are considered relevant.

Due to time constraints of this project, extensive grey literature searching will not be feasible.

The search strategy chosen will identify exclusively studies published in the literature.

7. Data extraction/collection and analysis 7.1. Study Selection process

Chapter 7 of the Cochrane Handbook35 will be used to guide the study selection process,

data extraction/collection and analysis.



Five steps will divide the study selection process: 1) Identification of records (number of

records identified through database searching and manual searching); 2) Deletion of

duplicates records; 3) Screening of records (identifying the number of records excluded); 4)

Eligibility of records (full-text articles assessed for eligibility, mentioning the reasons of

articles excluded); and 5) Inclusion of articles, mentioning the number of articles selected for

qualitative and quantitative analysis (meta-analysis). The outputs of the searches will be

imported using EndNote X7.2.1 as reference management software. A validated eligibility

form in a dataset in Excel (exported from EndNote) will be used for the study selection

process. Two reviewers (AB and CP) will review all identified records (tittles and abstracts)

from the databases search and manual search for their potential relevance; duplicated

records will be deleted. If there is any uncertainty at this stage, the article will remain

included until the full text is reviewed. The screening process will identify records to be

reviewed through the full-text article. Articles will be assessed for eligibility. Where papers

are determined to be ineligible, the reason of the exclusion will be recorded onto the dataset.

A third reviewer (LVN) will review the outputs of the first and second reviewers in order to

assess integrity, consistency, and verification of the data. In the event of discrepancies and

disagreements found by the third reviewer, a consensus between the authors/reviewers will

be undertaken before an article is included or excluded. In the event information pertinent to

inclusion criteria is not contained within the article text, an effort will be made to contact the

listed corresponding author. If no reply is received, the article will be excluded. A PRISMA

flow chart of the study selection procedure will be prepared, and a log of rejected studies will

be maintained.

7.2. Data extraction/collection and management

Data items to be extracted are detailed below; data extraction/collection will be compiled in

the dataset in Excel.

7.3. Information about site and publication

First author, year of publication, and country of study or country of origin for first author in

case a multicentre/multinational study.



7.4. Information about type of study

Description of the randomisation and appropriateness of the randomisation; description of

the double-blind process; description of the design in regards to interventions/exposures,

multicentre, number and types of arms, parallel or cross-over, and length of the study.

7.5. Information about the sample

Total sample (N=) for the study, sample size for safety analysis in each arm (adults ≥18

years), description and quantification of withdrawals due to adverse events.

7.6. Information about safety reporting

Type of events reported as AEs, TEAEs, ADRs, SAEs, no report on safety; quantification of

events by AEs, TEAEs, ADRs, and SAEs; list of events by preferred term (MedDRA version

17). In case of percentages and no number of events reported, a calculation will be

performed if total number of subjects in each arm is clearly defined/reported). Number of

withdrawals due to AEs, TEAEs, ADRs, and SAEs.

7.7. Type of intervention

Specification for each medication used and/or placebo and/or no treatment the following:

dose (mg), freq. / day (Total Daily Dose), route of administration, treatment period (days).

7.8. Types of studies The types of studies to be included in this systematic review will be:

• Randomised/randomized controlled clinical trials

• Double-blind

Limitations will be imposed on publication status; only published clinical trials will be

considered and grey literature searching will not be feasible/performed. No limitations will be

imposed in regards to languages and duration of study follow-up or period of study conduct.



8. Methodology 8.1. Methodological quality/risk of bias assessment/appraisal The risk of bias and methodological quality for individual studies will be appraised using the

Cochrane Effective Practice and Organization of Care tool for assessing risk of bias36 see

Appendix 1. The following criteria will be considered assessing risk of bias in intervention

studies: selection bias, performance bias, detection bias, attrition bias, information bias,

reporting bias, and other bias will be evaluated. Appendix 2 shows the Quality Assessment

Form (for an individual study) which describes the level of risk as high, low or unknown.

The quality of evidence for all outcomes will be evaluated using the Grading of

Recommendations Assessment, Development and Evaluation (GRADE) working group

methodology37. The quality of evidence will be assessed across the domains of risk of bias,

consistency, directness, precision, and publication bias. Quality will be adjudicated as high

(further research is very unlikely to change our confidence in the estimate of effect),

moderate (further research is likely to have an important impact on our confidence in the

estimate of effect and may change the estimate), low (further research is very likely to have

an important impact on our confidence in the estimate of effect and is likely to change the

estimate), or very low (very uncertain about the estimate of effect).

Publication bias will be assessed using funnel plots38.

8.2. Terminology

For the purposes of analysis and consistency in the safety information of publications

selected, Treatment Emergent Adverse Events (TEAEs) represent any AE or ADR reported

after randomisation of the patient.

All AEs/SAEs/TEAEs reported by preferred term (PT) or reported by verbatim will be coded

to PT according with MedDRA version 17.

All AEs and ADRs reported will be grouped as TEAEs.

8.3. Reviewers

The extraction of data will be performed by two reviewers (AB and CP). The two reviewers

will extract, separately, the data in a dataset in Excel which will be validated. In case of

discrepancies in regards to the data extraction found between the first and second reviewer,

a third reviewer (LVN) will be involved and resolution of the discrepancy will be reached



through consensus. The third reviewer (LVN) will perform a second review of all data

extracted, aiming to assure integrity and consistency of the data.

When sufficient safety data cannot be identified, the authors will be contacted (with a

maximum of three emails attempts). In case there is no answer from the authors the paper

will be excluded.

Serious adverse events (SAEs) and TEAEs (AEs and ADRs) will be listed by Preferred Term

(PT) in accordance with MedDRA (version 17.0).

9. Analysis Outline

As the primary objective of this systematic review and meta-analysis is the quantification of

safety outcomes of events (preferred terms) in subjects with RA treated with RTX, active

comparator and/or placebo, a case definition is required.

9.1. Case definition

Any AE/SAE/TEAE reported by verbatim or preferred term (according to MedDRA) during

the participation of a randomised, controlled, double-blind, clinical trial in which subjects with

RA were allocated to the treatment of RTX, active comparator and/or placebo.

9.2. Statistical analysis

The measure of association selected for this meta-analysis will be the crude odds ratio (OR)

as a measure of relative effect39. The OR calculation by Peto method (Peto-OR) will be

used for rare events defined as ≤ 1% of the total sample40. The analysis of OR and Peto-OR

will include 95% Confidence Intervals and p values as generated from the chi-squared and

Fishers’ exact test; the latter will be performed in the event the number of events are ≤5,

reported in all studies with at least one arm treated with RTX. The number needed to treat

for an additional harmful outcome (NNTH) will be calculated as absolute effect measure41.

Forest plots will be performed for each pool. The forest plot provides context to the analysis

and serves to highlight the following points: a) The effect sizes are reasonably consistent

from study to study; most will fall in the range of 0.50 to 0.90, which will suggest that it would

be appropriate to compute a summary effect size; b) The summary effect size; and c) The



confidence interval that bounds each effect size indicates the precision in that study. If the

interval excludes 1.0, the p-value is less than 0.05 and the study is statistically significant42.

9.3. Heterogeneity

The proportion of variability that is due to heterogeneity rather than sampling error will also

be quantified using the I2 measure43,44. The statistical heterogeneity will be examined prior to

conducting the meta-analysis. Funnel plots will be drawn to explore asymmetry that might

be explained by considerable heterogeneity. If extensive statistical (for example, I2 ≥75%)

heterogeneity is observed, a meta-regression analysis will be conducted and the

appropriateness of pooling/excluding study results will be considered42.

9.4. Fixed and random effects

Both, fixed-effect and random-effects models will be performed; however, only one analysis

will be selected for the final results and final written paper. The first analysis performed will

be the fixed-effect analysis, with the assumption that the true effect size of each study is the

same (or very similar) in all studies, and the summary of the effect is our estimate of this

common effect size39,42. In case the effect size of each study is different, a random effect

model will be performed, with the assumption that the true effect size varies from one study

to the next. In the random effect model, the summary effect is our estimate of the mean of

these effects42.

10. Statistical software

For this meta-analysis, the Comprehensive Meta-Analysis (version 2, Professional),

developed by Borenstein et al.42 and the National Institutes of Health, was selected. It was

considered superior for this analysis because it offers an advantage in comparison to

RevMan, developed by The Cochrane Collaboration39, which is the ability to perform a meta-

regression analysis which has been considered in the statistical analysis of this protocol.



11. Primary analysis (primary outcomes) 11.1. Analysis of TEAEs, SAEs and withdrawals rate due to AEs

The primary analysis will provide with an estimate of the total TEAEs rate, SAEs rate and

withdrawals rate due to AEs with the use of RTX.

The following endpoints will be analysed:

o All TEAEs rate

o All SAEs rate

o Withdrawals rate due to AEs

The TEAEs, SAEs and withdrawals rate due to AEs, ORs values, and the associated 95%

Confidence intervals will be estimated. The ORs of the total TEAEs, SAEs and withdrawals

due to AEs reporting rate between RTX + MTX, RTX alone, and RTX + other therapy vs any

active comparator and/or placebo/standard of care will be computed, using fixed-effect and

random-effect models42.

Forest plots will be performed for each pool.

12. Secondary analysis (secondary outcomes) 12.1. Analysis of TEAEs rate by PT

An analysis of TEAEs rate by PT will be performed using OR (and OR Peto) calculations for

the following:

o Pool 1 – all TEAEs (by PT)

o Pool 1A all TEAEs (by PT) using RTX + MTX

o Pool 1B all TEAEs (by PT) using RTX alone

o Pool 1C all TEAEs (by PT) using RTX + other therapy

12.2. Analysis of TEAEs by dose

An analysis of TEAEs rate by PT and by dose will be performed using OR (and OR Peto)

calculations for the following:

o Pool 2 – analysis by dose used

o Pool 2A - Low dose 500 mg (and ≤1000 mg)

o Pool 2B - High dose ≥ 1000 mg




13. Sub-analysis (tertiary outcomes)

The following sub-analysis are planned: 1) serious infections; 2) infections; 3) infusion

reactions; 4) blood dyscrasias; 5) lack of efficacy; 6) immunogenicity; and 7) malignancies.


14. Prioritisation of outcomes

The priority of outcomes to analyse will be the following:

1) Primary outcomes (analysis of TEAEs, SAEs and withdrawals rate due to AEs)

2) Secondary outcomes (analysis of TEAEs rate by PT and by dose)

3) Tertiary outcomes (sub-analysis planned of: 1) serious infections; 2) infections; 3)

infusion reactions; 4) blood dyscrasias; 5) lack of efficacy; 6) immunogenicity; and 7)

malignancies)

15. Sensitivity analysis

Thresholds for the interpretation of I2 can be misleading; however, the recommendations of

the Cochrane Collaboration39 will be followed in regards to sensitivity analysis. A threshold

of ≥75% in heterogeneity (75% to 100%: considerable heterogeneity) using the I2 statistic

will be used and the appropriateness of excluding studies which exceed this threshold will be

considered as a first step in a sensitivity analysis to decrease heterogeneity. If, after

excluding studies, considerable heterogeneity persists, (≥75%) a second method of

sensitivity analysis will be performed. The ‘trim and fill’ method45-47 aims both to identify and

correct for funnel plot asymmetry arising from publication bias. The first step in this method

is to ‘trim’ (remove) the smaller studies causing funnel plot asymmetry; secondly, to use the

trimmed funnel plot to estimate the true ‘center’ of the funnel; finally, the third step is to

replace the omitted studies and their missing ‘counterparts’ around the center (filling). As

well as providing an estimate of the number of missing studies, an adjusted intervention

effect is derived by performing a meta-analysis including the filled studies.



16. Ethics considerations

This project will not handle primary patient data. All included data will be already in the public

domain, derived from publications. While the methods employed are scientifically sound, the

project is considered exempt from the need to seek ethics committee approval for its

conduct or reporting.

17. Contribution of Authors

Guarantor: LVN

Initiation and conceptualisation of the study, reviewed previous systematic reviews, wrote

the draft protocol and project management (LVN).

Final protocol (LVN, AB, and CP)

Search strategy (LVN, AB, and CP)

Search validation/evaluation – level of recall (sensitivity) and precision (positive predictive

value) (LVN)

Run searches (LVN)

Identify relevant titles and abstracts from searches (LVN, AB, and CP)

Obtain PDF files and copies of records (LVN, AB, and CP)

Selection of records (LVN, AB, CP)

Data extraction from records (LVN, AB, and CP)

Data entry into Comprehensive Meta-Analysis (version 2, Professional) software (LVN)

Carry out analysis (LVN)

Interpret data (LVN, AB, and CP)

Draft final protocol (LVN, with contributions from all)

18. Support and funding

This systematic review is supported by Dr. Reddy’s Laboratories by allocating resource time

of the authors for the development of this systematic review and meta-analysis and for the

provision of full articles. No other sources of funding have been received for this review. Page | 25

Protocol – Systematic Review & Meta-analysis Rituximab in Rheumatoid Arthritis Version 2 Final – 14Jan2015

19. Protocol history and amendments

The table below outlines the protocol’s history from its inception to the last amendment.

Ref. Item Date Comment 1 Finalisation Protocol

Version 1 21-Dec-2014 None

2 Submission/registration to PROSPERO database

22-Dec-2014 Registration no.: CRD42014015665

3 Publication PRISMA-P 2015 statement

01-Jan-2015 Reference number 30 – inclusion list of references

4 Amendment Protocol and Finalisation Protocol Version 2

13-Jan-2015 The protocol was amended to reflect the PRISMA-P 2015 statement. The following points were included/updated: • Item 1. Identification. The word ‘planned’

was included in the title of the protocol in regards to the planned meta-analysis.

• Item 3. Identification of the guarantor of the review and mailing address was included.

• Item 5. Description of the role of supporter and/or funder.

• Item 13. Prioritisation of outcomes • Item 17. Grading the quality of evidence

(GRADE working group) A change was performed during the amendment process. The primary and secondary analysis were switched to reflect the following order: • Primary analysis: Section 11.1. Analysis of TEAEs, SAEs and withdrawals rate due to AEs • Secondary analysis: Section 12.1. Analysis of TEAEs rate by PT Section 12.2. Analysis of TEAEs by dose



20. The PRISMA-P 2015 Statement’s checklist

The table below outline the PRISMA-P statement checklist and the localisation of the 17 items in the protocol.

Item Checklist item description Localisation

1 Protocol title (identification) Front page 2 Protocol registration Section 4. Protocol 3 Author’s information Front page 4 Amendments Section 4. Protocol

Section 19. Protocol history and amendments

5 Support Section 17. Support and funding 6 Review rationale Section 2. Study rationale 7 Review objectives Section 3. Objective 8 Eligibility criteria Section 5. Eligibility criteria 9 Information sources Section 6. Search strategy for

identification of studies Section 6.1. Electronic searching Section 6.2. PubMed, EMBASE and CENTRAL searches Section 6.3. Additional searching Section 8.3. Reviewers

10 Search strategy Section 6. Search strategy for identification of studies

11 Study records • Data management • Selection process • Data collection process

Section 7. Data extraction/collection and analysis Section 7.1. Study selection process Section 7.2. Data extraction/collection and management

12 Data items Section 11. Primary analysis Section 12. Secondary analysis Section 13. Sub-analysis

13 Outcomes and prioritisation Section 11. Primary analysis Section 12. Secondary analysis Section 13. Sub-analysis Section 14. Prioritisation

14 Risk of bias in individual studies Section 8. Methodology Section 8.1. Methodological quality/risk of bias assessment/appraisal

15 Data synthesis Section 9. Analysis outline Section 9.1. Case definition Section 9.2. Statistical analysis Section 9.3. Heterogeneity Section 9.4. Fixed and random effects

16 Assessment of meta-bias Section 8.1. Methodological quality/risk



of bias assessment/appraisal 17 Confidence in cumulative evidence Section 8.1. Methodological quality/risk

of bias assessment/appraisal



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Appendix 1 - Items for consideration in risk of bias assessment Table 8.5.a: The Cochrane Collaboration’s tool for assessing risk of bias; Chapter 8: Assessing risk of bias in included studies35. Domain Support for judgement Review authors’ judgement

Selection bias.

Study participants

selection method

Describe the method used

to select participants in

sufficient detail to allow an

assessment of whether it should produce comparable

groups/representative population. Non response bias should be assessed.

Selection bias (biased

allocation to study groups)

due to inadequate participant selection?

Study group allocation

concealment (for RCTs

only)

Describe the method used

to conceal the allocation to

study groups in sufficient

detail to determine whether allocations could have been foreseen in advance of, or during, enrolment.

Selection bias (biased

allocation to study groups)

due to inadequate

concealment of allocations

prior to assignment?

Performance bias.

Blinding of participants

and personnel to

exposure (For RCTs

only, see information

bias for observational

studies) Assessments

should be made for each

main outcome (or class of

outcomes).

Describe all measures used, if any, to blind study participants and personnel

from knowledge of exposure group. Provide any information relating to whether the intended blinding was effective.

Performance bias due to

knowledge of the

exposure group by

participants and personnel

during the study?

Detection bias.

Blinding of outcome

assessment (For RCTs

Describe all measures used, if any, to blind outcome assessors from knowledge of

Detection bias due to

knowledge of the



only, see information

bias for observational

studies) Assessments

should be made for each

main outcome (or class of

outcomes).

participant exposure group. Provide any information relating to whether the intended blinding was effective.

exposure group by

outcome assessors?

Attrition bias.

Incomplete outcome

data Assessments should

be made for each main

outcome (or class of

outcomes).

Describe the completeness of outcome data for each main outcome, including attrition (loss to follow up) and exclusions from the analysis. Incomplete case ascertainment should be considered. State whether

attrition and exclusions were reported, the numbers in each exposure group (compared with total initial participants), reasons for attrition/exclusions where reported, and any reinclusions in analyses

performed by the review authors.

Attrition bias due to

amount, nature or

handling of incomplete

outcome data?

Information bias.

Missclassification of

exposure and/or

outcome

Describe the methods used to classify exposure and outcome data. State whether subjective or objective measures were used and whether misclassification is likely to be differential or nondifferential. Consider recall bias in case-control

studies and observer bias

(blinding to exposure/disease status).

Information bias due to

misclassification of

exposure and/or outcome?

Reporting bias.

Selective reporting. State how the possibility of Reporting bias due to



selective outcome reporting was examined by the review authors, and what was found.

selective outcome

reporting?

Other bias.

Other sources of bias. State any important concerns about bias not addressed in the other domains in the tool.

Residual confounding should be considered in observational studies.

Bias due to problems not

covered elsewhere in the

table?



Appendix 2 - Quality Assessment Form (for an individual study)

Entry Judgement Support for judgement Selection bias- randomisation, allocation concealment etc

Low risk, high risk or unknown risk

Performance bias- blinding of participants etc (if applicable)


Detection bias - blinding of outcome assessment etc (if applicable)


Attrition bias- incomplete outcome data etc


Information bias- misclassification of outcome and/or exposure


Reporting bias- selective reporting


Other bias Low risk, high risk or unknown risk



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