Biologics for chronic rhinosinusitis

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

Main objective

To assess the effects of biologics for the treatment of chronic rhinosinusitis.

Secondary objective

To maintain the currency of the evidence, using a living systematic review approach.

Background

This review is one of a suite of Cochrane Reviews looking at common management options for patients with chronic rhinosinusitis (Chong 2016a; Chong 2016b; Chong 2016c; Head 2016a; Head 2016b; Head 2016c; Head 2016d).

Description of the condition

Chronic rhinosinusitis represents a common source of ill health; 11% of UK adults reported chronic rhinosinusitis symptoms in a worldwide population study (Hastan 2011). Symptoms including nasal obstruction, nasal discharge, facial pain, anosmia and sleep disturbance have a major impact on quality of life, reportedly greater in several domains of the SF‐36 than angina or chronic respiratory disease (Gliklich 1995). Acute exacerbations, inadequate symptom control and respiratory disease exacerbation are common. Complications are rare, but may include visual impairment and intracranial infection.

Two major phenotypes of chronic rhinosinusitis have been described based on the presence or absence of nasal polyps on examination. Nasal polyps are tumour‐like hyperplastic swellings of the nasal mucosa, most commonly originating from within the ostiomeatal complex (Larsen 2004). Chronic rhinosinusitis with nasal polyps (CRSwNP) is diagnosed when polyps are seen (on direct or endoscopic examination) in the middle meatus or nasal cavity. Chronic rhinosinusitis without nasal polyps (CRSsNP) is diagnosed when no polyps are observed on examination.

Although the aetiology of chronic rhinosinusitis is not fully understood, it may involve abnormalities in the host response to irritants, commensal and pathogenic organisms and allergens, obstruction of sinus drainage pathways, abnormalities of normal mucociliary function, loss of the normal mucosal barrier or infection. Chronic rhinosinusitis is a heterogenous group of diseases, but three main patterns of inflammation have been identified: T_h1 driven, usually associated with chronic rhinosinusitis without nasal polyps; T_h2 driven, usually associated with chronic rhinosinusitis with nasal polyps in Caucasian patients; and T_h17 driven, associated typically with chronic rhinosinusitis with nasal polyps in Asian patients (Smith 2018). There is some overlap between phenotypes and inflammatory patterns and the current division of chronic rhinosinusitis into two main phenotypes, with and without polyps, is therefore likely to be inadequate for defining patient subgroups. Endotyping, using measurable biomarkers, is increasingly being performed but is not yet routinely incorporated into clinical practice.

Despite the differences in aetiology and phenotype, in clinical practice many treatments for chronic rhinosinusitis are initiated without knowledge of a patient's 'polyp status'. Even when it is known whether or not a patient with chronic rhinosinusitis has polyps, this knowledge does not always suggest adjustments to treatment. This review (and most of its companion reviews) will consider patients with and without polyps together in the initial evaluation of treatment effects. However, as biologics are primarily used in hospital settings and in well‐defined patient populations, subgroup analyses will explore potential differences between them (see below).

Description of the intervention

The term 'biologics' refers to medicinal products produced by a biological process. Monoclonal antibodies are one type of biologic. They target specific inflammatory mediators or immune cells in the pathophysiological pathways that produce chronic inflammatory diseases. Trials have evaluated these agents in conditions such as asthma and atopic dermatitis leading to growing interest in the possibility of using them to treat patients with chronic rhinosinusitis.

How the intervention might work

Monoclonal antibodies work on different target substances or receptors in the inflammatory pathway. The more we understand about the inflammatory pathways involved in chronic rhinosinusitis, the more we may be able to affect those pathways with biologics. Different biologics are likely to have very different efficacy in different patient populations depending on the pattern of inflammation in those patients. Recent trials in patients with chronic rhinosinusitis with nasal polyps have focused on biologics directed at the inflammatory mediators and receptors involved in T_h2 pathways. As yet none have investigated the effectiveness of biologics in T_h1 or T_h17 driven inflammation.

Currently, biologics are mainly used in patients with severe chronic rhinosinusitis where pharmacological therapy does not provide adequate symptom control, with the aim of reducing those symptoms and leading to an improvement in their quality of life. Some patients with severe chronic rhinosinusitis undergo surgical treatment aimed at achieving these goals. If patients respond well to biologics, surgical intervention may be avoided. If biologics are successful in reducing inflammation and reducing the size of nasal polyps, this should also be visible using endoscopy and computerised tomography (CT) scans. These changes can be documented and quantified using the relevant scoring system.

Biologics are, however, associated with adverse reactions that may be immune‐related and can be serious ‐ such as anaphylaxis. Biologics are widely used in rheumatology and some of the serious adverse events documented in those patients include tuberculosis reactivation, lymphoma and severe infections (Singh 2011; Tarp 2017). Another adverse reaction is pharyngitis, which may be serious enough for patients to discontinue treatment.

The following are descriptions of a number of classes and mechanisms of actions of monoclonal antibodies (mAb) with some specific named biologics. This is not an exhaustive list. The field is growing and our understanding of the mechanisms of action may change over time. Biologics not listed here may be evaluated in this review.

Anti‐IL‐4α mAb and anti‐IL‐13 mAb

Dupilumab, delivered by subcutaneous injection, is a human monoclonal antibody of the IgG4 subclass that targets the IL‐4Rα subunit and disrupts IL‐4 and IL‐13 signalling. This is involved in the T_h2 inflammatory pathway most typically seen in patients with chronic rhinosinusitis with nasal polyps. Trials of dupilumab in asthma have also shown improvement in the symptoms of coexisting chronic rhinosinusitis (Wenzel 2016). Lebrikizumab and tralokinumab are anti‐IL‐13 monoclonal antibodies.

Anti‐IL‐5 mAb

Mepolizumab, reslizumab and benralizumab are delivered subcutaneously or intravenously, and are human monoclonal (IgG₁) antibodies targeting interleukin 5 (IL‐5) or the IL‐5 receptor α subunit on the surface of eosinophil white blood cells. IL‐5 promotes eosinophil development survival, so targeting IL‐5 reduces blood and tissue eosinophil counts. Mepolizumab is currently approved by the UK's National Institute for Health and Care Excellence (NICE) for the treatment of severe eosinophilic asthma and as IL‐5 has been suggested as a parallel marker for the severity of both asthma and chronic rhinosinusitis with nasal polyps, it has the potential to treat both simultaneously (Chupp 2017; Dasgupta 2017; Pavord 2012). Reslizumab and benralizumab have had early success in patients with poorly controlled asthma (DuBuske 2018; Máspero 2017).

Anti‐IgE mAb

Omalizumab, also delivered subcutaneously, is a recombinant DNA‐derived humanised (IgG_1k) monoclonal antibody that specifically binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid, and to the membrane‐bound form of IgE (mIgE) on the surface of mIgE‐expressing B‐lymphocytes. It therefore has the effect of reducing the levels of IgE in the serum and tissues, with a subsequent blocking of the IgE‐mediated inflammatory cascade. This anti‐IgE treatment has to date been shown to be effective in allergic rhinitis and asthma (Casale 2001; Hanania 2011).

The anti‐IL monoclonal antibodies described above (anti‐IL‐4α, anti‐IL‐13, anti‐IL‐5) target a different phenotype of chronic rhinosinusitis than the anti‐IgE monoclonal antibodies and this difference will inform data analysis.

Further information about the mechanisms of action of biologics in this field can be found in Kariyawasam 2019.

Why it is important to do this review

To date much of the literature around the role of these new drugs has been focused on the allergy, asthma and immunology subspecialties. As the role for biologic therapies in chronic rhinosinusitis continues to be defined and pharmaceutical companies are now targeting this condition, it is increasingly important for practising otorhinolaryngologists, especially sub‐specialist rhinologists, to determine the place of biologics in the treatment cascade by keeping up‐to‐date on their progression. NICE is currently conducting a health technology appraisal of the clinical and cost‐effectiveness of dupilumab for chronic rhinosinusitis with nasal polyps (NICE 2019). This Cochrane Review will aim to look at the balance of benefits and harms for biologic drugs in the treatment of patients with chronic rhinosinusitis. It will also serve to identify areas for future research, especially as the knowledge of specific chronic rhinosinusitis endotypes increases.

This review will be a living systematic review, whereby we will search key databases monthly and update the review as and when new important evidence is found. A living systematic review approach is appropriate for this review because: 1) the topic is important for health care decision‐making; 2) there is uncertainty about the existing evidence; and 3) this is a rapidly developing field where new trials are being actively planned and completed. We will revisit the scope (population, intervention, comparison, outcomes) of the review yearly, or more frequently as appropriate, to ensure that new agents or uses are included as this field develops. In addition to having more data on safety and efficacy, our understanding of how biologics work, the best way to measure outcomes and how outcomes are interpreted will very likely change as more research is completed. Therefore, we will adapt our definition of what outcomes to measure and how outcomes should be measured and interpreted over time.

Objectives

Main objective

To assess the effects of biologics for the treatment of chronic rhinosinusitis.

Secondary objective

To maintain the currency of the evidence, using a living systematic review approach.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials and quasi‐randomised trials.

We will consider cross‐over trials if there is sufficient evidence to suggest that the condition of patients was stable and the washout period was adequate. Otherwise, we will only use the first phase of cross‐over trials.

We will only include studies where patients were followed up for at least three months, to reflect the importance of focusing on long‐term outcomes for a chronic condition.

Types of participants

Patients with chronic rhinosinusitis, whether with polyps (CRSwNP) or without polyps (CRSsNP).

We will exclude studies that have included a majority of patients with:

• cystic fibrosis;

• allergic fungal sinusitis/eosinophilic fungal/mucinous rhinosinusitis;

• antrochoanal polyps (benign polyps originating from the mucosa of the maxillary sinus);

• malignant polyps;

• primary ciliary dyskinesia;

• a history of surgery for nasal polyps within three months of entry to the study.

Types of interventions

Intervention

All monoclonal antibodies used for the treatment of chronic rhinosinusitis. This includes but is not limited to the following:

• anti‐IL‐4α mAb (dupilumab);

• anti‐IL‐13 (lebrikizumab, tralokinumab);

• anti‐IL‐5 mAb (reslizumab, benralizumab, mepolizumab);

• anti‐IgE mAb (omalizumab).

These are the biologics identified in November 2019 as most likely to be used in patients with chronic rhinosinusitis. Additional monoclonal antibodies and other classes of biologics will also be included in this review when they are evaluated in patients with chronic rhinosinusitis.

All routes of administration, doses and duration of treatment will be included. However, studies should follow up participants for three months or more.

Comparison

Placebo or no treatment. Surgery will be an alternative treatment (comparison) when trials in the area become available.

Concurrent treatments

It is expected that most studies will have used intranasal steroids as a concurrent treatment. There will be no limitation on the type of pharmacological concurrent treatments used.

Comparison pairs

The main comparison pairs will be:

• anti‐IL‐4α mAb plus intranasal steroids versus placebo/no treatment plus intranasal steroids;

• anti‐IL‐13 plus intranasal steroids versus placebo/no treatment plus intranasal steroids;

• anti‐IL‐5 mAb plus intranasal steroids versus placebo/no treatment plus intranasal steroids;

• anti‐IgE mAb plus intranasal steroids versus placebo/no treatment plus intranasal steroids.

Types of outcome measures

We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies.

Our primary intention will be to assess the effects of assignment, rather than adherence to treatment.

Primary outcomes

• Health‐related quality of life, using validated disease‐specific health‐related quality of life scores, such as the Sino‐Nasal Outcome Test‐22 (SNOT‐22), Rhinosinusitis Outcome Measures‐31 (RSOM‐31) and SNOT‐20.

• Disease severity, as measured by validated patient‐reported symptom score (such as the Chronic Sinusitis Survey (CSS) questionnaire and visual analogue scales). Where this is unavailable, we will consider including data measuring the severity of individual symptoms (see below).

• Serious adverse events (SAEs), measured by the number of participants affected. A SAE is defined as "Death, a life‐threatening adverse event, inpatient hospitalisation or prolongation of existing hospitalisation, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition" (FDA 2018).

Many studies within this suite of reviews (Chong 2016a; Chong 2016b; Chong 2016c; Head 2016a; Head 2016b; Head 2016c; Head 2016d) did not use/present data using instruments that were either validated or evaluated all four types of symptoms meeting the EPOS 2012 diagnostic criteria in a composite score. If data from a validated score are unavailable, we will analyse data related to each of these individual symptoms, if presented.

Secondary outcomes

• Avoidance of surgery, measured by numbers (proportions) of participants who had, or did not have, surgery for chronic rhinosinusitis symptoms, or who no longer fulfilled the eligibility criteria for surgery*. (See comments in Assessment of risk of bias in included studies).

• Extent of disease as measured by either:

  • endoscopic score (depending on population, either nasal polyps size score or other such as Lund‐Kennedy); and/or

  • computerised tomography (CT) scan score (e.g. Lund‐Mackay with a range of 0 to 24, higher = worse).

• Health‐related quality of life, using generic quality of life scores, such as the SF‐36, EQ‐5D and other well‐validated instruments.

• Adverse effects: nasopharyngitis, including sore throat.

Outcomes will be measured at 3 to 6 months, 6 to 12 months and more than 12 months. For adverse events, we will analyse data from the longest time periods.

*We will record and tabulate the eligibility criteria for surgery used in the included studies.

Search methods for identification of studies

The Cochrane ENT Information Specialist will conduct systematic searches for randomised controlled trials and controlled clinical trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary. We will identify completed trials that have not been published, and contact the principal investigator or pharmaceutical company to obtain original data or clinical study reports.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:

• the Cochrane ENT Trials Register (search via the Cochrane Register of Studies to date);

• the Cochrane Central Register of Controlled Trials (CENTRAL) (search via the Cochrane Register of Studies to date);

• Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to date);

• Ovid Embase (1974 to date);

• Web of Knowledge, Web of Science (1945 to date);

• ClinicalTrials.gov, www.clinicaltrials.gov (search via the Cochrane Register of Studies to date);

• ClinicalTrials.gov, www.clinicaltrials.gov (search via www.clinicaltrials.gov to date);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (search to date);

• European Union Clinical Trials Register (EUCTR), https://www.clinicaltrialsregister.eu/ (search to date).

The subject strategies for databases will be modelled on the search strategy designed for CENTRAL (Appendix 1). Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions version 5) (Handbook 2011).

Living systematic review considerations

As a living systematic review, the Information Specialist will conduct monthly searches of:

• the Cochrane ENT Trials Register (search via the Cochrane Register of Studies to date);

• the Cochrane Central Register of Controlled Trials (CENTRAL) (search via the Cochrane Register of Studies to date);

• Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to date);

• Ovid Embase (1974 to date);

• Web of Knowledge, Web of Science (1945 to date);

• ClinicalTrials.gov, www.clinicaltrials.gov (search via the Cochrane Register of Studies to date).

To facilitate these searches the Information Specialist will set up monthly auto‐alerts where available.

The Information Specialist will also conduct quarterly searches of the following sources, and prior to publication of any update:

• ClinicalTrials.gov (search via www.clinicaltrials.gov to date);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (search to date);

• European Union Clinical Trials Register (EUCTR), https://www.clinicaltrialsregister.eu/ (search to date).

A summary of trials identified versus reports obtained will be published in the review.

Biologics are a new class of intervention. The search strategy developed is highly sensitive, in order to try to capture new interventions as they are introduced. The Information Specialist will review the search methods (the sources and search frequency) and the search terms (index terms and free text terms) on an annual basis. The aim will be to include new terms for new interventions as they are introduced, and to increase precision as interventions are removed or withdrawn.

Searching other resources

We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, the Information Specialist will search Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. The Information Specialist will also run non‐systematic searches of Google Scholar to retrieve grey literature and other sources of potential trials.

We will not perform a separate search for adverse effects. We will consider adverse effects described in included studies only.

Clinical study reports and other sources of evidence

This review meets many of the 18 criteria for considering clinical study reports as a source of evidence (Jefferson 2018). In particular, there is a concern about publication bias with a new class of drugs for this current condition. Moreover, these are very costly agents that are already marketed for other conditions and there is a risk of off‐label use.

There are no established search procedures to identify clinical study reports at the time of publication of this protocol. We plan to identify unpublished studies and clinical study reports by searching and requesting data from various sources beyond those listed above under electronic searches. These include, but are not limited to:

1. Regulatory bodies: We will search the websites of the UK Medicine and Healthcare Regulatory Authority (UK MHRA), the US Food and Drug Administration (FDA) (http://www.fda.gov) and the European Medicines Agency (EMA) (https://www.ema.europa.eu/en). We would make a formal request for all relevant clinical study reports to the EMA under the Access to Documents Policy (0043).

2. Clinical trial data platforms/repositories shared by multiple funders or manufacturers:

   • Clinical Study Data Request (CSDR) (https://clinicalstudydatarequest.com);

   • AllTrials (http://www.alltrials.net);

   • TrialsTracker website (https://trialstracker.ebmdatalab.net).

3. Manufacturer‐specific clinical trial repositories and data sharing platforms:

   • Novartis Clinical Trial Results Database (https://www.novctrd.com);

   • GSK Study Register (https://www.gsk‐studyregister.com).

4. Direct requests to manufacturers: We will compile a list of all identified trials from registries and write to the manufacturers/sponsors of each trial individually to ask for additional data.

A summary of trials identified versus reports obtained will be published in the review.

Living systematic review considerations

As a living systematic review, the Information Specialist will conduct quarterly searches to retrieve existing systematic reviews relevant to this systematic review and monthly searches of the Web of Knowledge Science Citation Index for articles referencing the published review and its included studies. Google Scholar searches will be conducted on an annual basis. We will review on an ongoing basis (and at least every six months) the various sources used to search for clinical study reports, updating the list of sources searched and as and when required. We will make contact with the principal investigators of ongoing trials and ask them to advise us when results are available, or to share early or unpublished data.

Data collection and analysis

Selection of studies

We will consider using Cochrane's Screen4Me workflow to help assess the search results, depending on the number of results retrieved from the database searches. Screen4Me comprises three components: 1) known assessments – a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labelled as 'a RCT' or as 'not a RCT'. 2) The machine learning classifier (RCT model) (Wallace 2017), available in the Cochrane Register of Studies (CRS‐Web), assigns a probability of being a true RCT (from 0 to 100) to each citation. For citations that are assigned a probability score below the cut‐point at a recall of 99% we will assume these to be non‐RCTs. For those that score on or above the cut‐point we will either manually dual screen these results or send them to 3) Cochrane Crowd for screening (Cochrane's citizen science platform where the Crowd help to identify and describe health evidence). For more information about Screen4Me and the evaluations that have been done, please go to the Screen4Me website on the Cochrane Information Specialist's portal and see Marshal 2018, McDonald 2017, Noel‐Storr 2018 and Thomas 2017.

At least two review authors will independently screen the remaining titles and abstracts to identify potentially relevant studies. At least two review authors will independently evaluate the full text of each potentially relevant study to determine whether it meets the inclusion/exclusion criteria for this review.

We will resolve any differences by discussion and consensus, with the involvement of a third author for clinical and/methodological input where necessary.

Living systematic review considerations

We will immediately collate and screen any new citations retrieved by the monthly searches using the approach outlined above including, as a first step in monthly screening, applying the Screen4Me workflow starting with the RCT model.

Data extraction and management

Two review authors will independently extract outcome data from each study using a standardised data collection form (see Appendix 2). Whenever a study has more than one publication, we will retrieve all publications to ensure complete extraction of data. Where there are discrepancies in the data extracted by different review authors, we will check these against the original reports and resolve differences by discussion and consensus, with the involvement of a third author or a methodologist where appropriate. We will contact the original study authors for clarification or for missing data whenever possible. If differences are found between publications of a study, we will contact the original authors for clarification. We will use data from the main paper(s) if no further information is found.

In addition, we will also compare trials identified through study registers with identified publications. Whenever an unpublished trial is identified (registered in trial registry, but more than 12 months since completion of recruitment and no data/incomplete data published), we will contact the contact person listed in the trial registry websites for information. Whenever clinical study reports or data from regulatory bodies are available, we will compare these against the journal reports and use them as the primary source of data if there is a discrepancy in the information. However, current experience with the use of clinical study reports suggests that there is often a considerable time lag between requesting these data and obtaining them. Therefore, we will make use of data from journal reports as the main source of evidence as a starting point and then check the data against the clinical study reports and regulatory data as and when these are available.

We will include key characteristics of the studies, such as study design, setting, sample size, population and how outcomes were defined or collected in the studies. In addition, we will also collect baseline information on prognostic factors or effect modifiers. For this review, this includes:

• presence or absence of nasal polyps;

• polyp score (where applicable);

• whether the patient has had previous sinus surgery.

The primary effect of interest is the effect of treatment assignment, which reflects the outcomes of treatment for people who were prescribed the intervention rather than per protocol analysis (the effect on people who completed the full course of treatment as planned). For the outcomes of interest to the review, we will extract the findings from the studies on an available case analysis basis, i.e. we will include available data from all participants at the time points based on the treatment randomised whenever possible, irrespective of compliance or whether patients had received the treatment as planned.

In addition to extracting pre‐specified information about study characteristics and aspects of methodology relevant to risk of bias, we will extract the following summary statistics for each trial and each outcome:

• For continuous data: the mean values, standard deviations and number of patients for each treatment group. Where endpoint data are not available, we will extract the values for change from baseline. We will analyse data from measurement scales such as SNOT‐22 and EQ‐5D as continuous data.

• For binary data: the number of participants experiencing an event and the number of patients assessed at the time point.

• For ordinal scale data: if the data appear to be approximately normally distributed or if the analysis that the investigators performed suggests parametric tests were appropriate, then we will treat the outcome measures as continuous data. Alternatively, if data are available, we may convert into binary data.

We have prespecified the time points of interest for the outcomes in this review. While studies may report data at multiple time points, we will only extract the longest available data within the time points of interest. For example, for 'short' follow‐up periods, our time point is defined as three to six months post‐randomisation. If a study has reported data at three, four and six months, we will only extract and analyse the data for the six‐month follow‐up.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias of each included study.

In the first version of the review, we will use the original version of the Cochrane 'Risk of bias' tool (ROB‐1) (Handbook 2011). Subsequently, we will use the Cochrane 'Risk of bias 2.0' tool (ROB‐2) (Sterne 2019), according to the guidance in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (version 6; Handbook 2019).

When using the ROB‐1, we will follow the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will assess the risk of bias as 'low', 'high' or 'unclear' for each of the following six domains:

• sequence generation;

• allocation concealment;

• blinding of participants, personnel and outcome assessment;

• incomplete outcome data;

• selective reporting;

• other sources of bias.

In future iterations of this living systematic review, we will apply the ROB‐2 tool according to the guidance in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2019). We will assess the risk of bias as 'low', 'high' or 'some concerns' for each of the following five domains:

• risk of bias arising from the randomisation process;

• risk of bias due to deviations from the intended interventions;

• risk of bias due to missing outcome data;

• risk of bias in measurement of outcome;

• risk of bias in selection of the reported result.

For ROB‐2, we will only assess the outcomes included in the 'Summary of findings' table.

For the outcome 'disease severity, as measured by validated patient‐reported symptom score' we will only conduct a ROB‐2 assessment if this is reported. If only the results from individual symptoms, or non‐validated scores, are reported we will not individually assess these, as the risk of bias is likely to be present due to the choice of outcome measure and selective reporting of only certain aspects of the condition.

There is a particular risk of bias in assessing the outcome 'avoidance of surgery', as there are no widely accepted criteria to determine when patients should or should not have surgery. Unless studies explicitly specify what criteria are used for making judgements and both the investigator (offering/deciding on the surgery) and participants were blinded, there are potential biases in the decision‐making process of the study personnel in determining whether or not a subject fulfils the criteria for surgery and/or whether they should be offered the option of surgery. This will be assessed in the 'Blinding, outcomes assessment' domain using the ROB‐1 tool and the 'Risk of bias in the measurement of outcome' domain when we are using the ROB‐2 tool.

Measures of treatment effect

We will summarise the effects of dichotomous outcomes (e.g. proportion of patients with symptom resolution) as risk ratios (RR) with 95% confidence intervals (CIs). For the key outcomes that we will present in the 'Summary of findings' tables, we will also express the results as absolute numbers based on the pooled results and compared to the assumed risk. We may also calculate the number needed to treat to benefit (NNTB) using the pooled results. The assumed baseline risk is typically either (a) the median of the risks of the control groups in the included studies, this being used to represent a 'medium‐risk population' or, alternatively, (b) the average risk of the control groups in the included studies is used as the 'study population' (Handbook 2019). If a large number of studies are available, and where appropriate, we may also present additional data based on the assumed baseline risk in (c) a low‐risk population and (d) a high‐risk population.

For continuous outcomes, we will express treatment effects as a mean difference (MD) with standard deviation (SD) or as a standardised mean difference (SMD) if different scales have been used to measure the same outcome. We will provide a clinical interpretation of the SMD values using either Cohen's d or by conversion to a recognised scale if possible.

Unit of analysis issues

Cross‐over trials and cluster‐randomised trials are unlikely for this review topic. This review will not use data from phase II of cross‐over studies (unless there is sufficient evidence to suggest that the condition of patients was stable and the washout period was adequate). If these trial designs are found and deemed suitable to use, we will seek advice from the Cochrane Bias Methods Group and use the latest version of the ROB‐2 tool for cross‐over and cluster‐randomised trials.

We foresee that trials will take multiple measurements or observations of a single outcome in the same patients (repeated measurements). In these situations, we will only extract and analyse the data point for the longest available follow‐up specified in this protocol.

Dealing with missing data

We will try to contact study authors via email whenever the outcome of interest is not reported, if the methods of the study suggest that the outcome had been measured. We will do the same if not all data required for meta‐analysis have been reported, unless the missing data are standard deviations. If standard deviation data are not available, we will approximate these using the standard estimation methods from P values, standard errors or 95% CIs if these are reported as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2019). If it is impossible to estimate these, we will contact the study authors.

Apart from imputations for missing standard deviations, we will conduct no other imputations. We will extract and analyse all data using the available case analysis method.

Assessment of heterogeneity

We will assess clinical heterogeneity (which may be present even in the absence of statistical heterogeneity) by examining the included trials for potential differences between studies in the types of participants recruited, interventions or controls used and the outcomes measured.

We will assess statistical heterogeneity by visually inspecting the forest plots and by considering the Chi² test (with a significance level set at P value < 0.10) and the I² statistic, which calculates the percentage of variability that is due to heterogeneity rather than chance (Handbook 2019).

Assessment of reporting biases

We will assess reporting bias as between‐study publication bias and within‐study outcome reporting bias.

Outcome reporting bias (within‐study reporting bias)

We will assess within‐study reporting bias by comparing the outcomes reported in the published report against the study protocol, whenever this can be obtained. If the protocol or trial registry entry is not available, we will compare the outcomes reported to those listed in the methods section. If results are mentioned but not reported adequately in a way that allows analysis (e.g. the report only mentions whether the results were statistically significant or not), bias in a meta‐analysis is likely to occur. We will seek further information from the study authors. If no further information can be found, we will note this as being a 'high' risk of bias when the ROB‐1 tool is used. If there is insufficient information to judge the risk of bias we will note this as an 'unclear' risk of bias (Handbook 2011). When the ROB‐2 tool is used, we will assess selective reporting bias in a similar way, according to the signalling questions in the 'risk of bias in selection of the reported result' domain (Handbook 2019). However, we will assess selective non‐reporting bias at the synthesis level, using the latest tools (e.g. ROB‐ME) if available.

Publication bias (between‐study reporting bias)

We will assess funnel plots if sufficient studies (more than 10) are available for an outcome. If we observe asymmetry of the funnel plot, we will conduct more formal investigation using the methods proposed by Egger 1997. We will also report on whether there were any studies identified through trial registries and other sources (Searching other resources), with unpublished reports.

Data synthesis

We will conduct all meta‐analyses using RevMan Web (RevMan Web 2019). For dichotomous data, we plan to analyse treatment differences as a risk ratio (RR) calculated using the Mantel‐Haenszel methods.

For continuous outcomes, if all the data are from the same scale, we may pool mean values obtained at follow‐up with change outcomes and report this as a MD. However, if the SMD has to be used as an effect measure, we will not pool change and endpoint data.

We propose using a random‐effects model since it is likely that there will be clinical heterogeneity in response to different types of biologics or different types of monoclonal antibodies. However, we will also undertake a sensitivity analysis to examine the effects of using the alternative fixed‐effect model.

Living systematic review considerations

When new evidence will be incorporated into the living systematic review

Whenever new evidence (meaning studies, data or information) relevant to the review is identified, we will extract the data and assess risk of bias, as appropriate. We will immediately incorporate any important new evidence into the review.

We will not adjust the meta‐analyses to account for multiple testing, given that the methods related to frequent updating of meta‐analyses are under development (Simmonds 2017). Sequential methods will not be used for updated meta‐analyses (Handbook 2019).

Subgroup analysis and investigation of heterogeneity

When studies have a mixed group of patients, we will analyse the study as one subgroup (rather than as a mixed group) if more than 80% of patients belong to one category. For example, if 81% of patients have chronic rhinosinusitis without nasal polyps, we will analyse the study as that subgroup.

We will conduct subgroup analyses based on the phenotypes of patients (whether patients have chronic rhinosinusitis with or without nasal polyps, are a mixed group or the status of polyps is not known or not reported) regardless of whether statistical heterogeneity is observed, as these are widely suspected to be potential effect modifiers. Although there appears to be a considerable overlap between the two forms of chronic rhinosinusitis with regards to inflammatory profile, clinical presentation and effect of treatment (Cho 2012; DeMarcantonio 2011; Ebbens 2010; Fokkens 2007; Ragab 2004; Ragab 2010; van Drunen 2009), there is some evidence pointing to differences in the respective inflammatory profiles (Kern 2008; Keswani 2012; Tan 2011; Tomassen 2011; Zhang 2008; Zhang 2009), and potentially even differences in treatment outcome (Ebbens 2011).

This will be presented as the main subgroup analysis for effectiveness outcomes in this review. We will present all other subgroup analysis results in tables.

In addition to subgrouping by phenotype, we will conduct the following subgroup analyses in the presence of statistical heterogeneity:

• Patients with asthma as a comorbidity. Patients with asthma may have different inflammatory markers and respond differently. In addition to chronic rhinosinusitis symptoms, they may also benefit from better control of asthma symptoms. However, there are no clear data to tell us which patients will benefit more or less from certain types of biologics, therefore the direction of effects is unclear.

• Patients with non‐steroidal anti‐inflammatory drug (NSAID)‐exacerbated respiratory disease (N‐ERD). The rationale is similar to that for patients with asthma as a comorbidity.

• Treatment regimens. For agents acting on the same target substance or receptor, treatment regimens such as dose and frequency of initial treatment and maintenance treatment are likely to be important. However, at the preparation of this protocol in 2019 there was not enough information to inform how these subgroups should be defined. We will revisit this question as part of our regular re‐evaluation of the review methods, as and when more data are available from trials.

Sensitivity analysis

We will carry out sensitivity analyses to determine whether the findings are robust to the decisions made in the course of identifying, screening and analysing the trials. We plan to conduct sensitivity analysis for the following factors, whenever possible:

• risk of bias of included studies: excluding studies with high risk of overall bias for the results, as assessed using the Cochrane ROB‐1 and ROB‐2 tools;

• impact of model chosen: fixed‐effect versus random‐effects model;

• how outcomes were measured: we will investigate the impact of including data where the validity of the measurement is unclear.

If any of these investigations finds a difference in the size of the effect or heterogeneity, we will mention this in the 'Effects of interventions' section.

Summary of findings and assessment of the certainty of the evidence

We will use the GRADE approach to rate the overall certainty of evidence for each outcome using the GDT tool (https://gradepro.org/) for the main comparison pairs listed in the Types of interventions section. The certainty of evidence reflects the extent to which we are confident that an estimate of effect is correct and we will apply this in the interpretation of results. There are four possible ratings: 'high', 'moderate', 'low' and 'very low'. A rating of 'high' certainty evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of 'very low' certainty implies that any estimate of effect obtained is very uncertain.

The GRADE approach rates evidence from RCTs that do not have serious limitations as high certainty. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:

• study limitations (risk of bias);

• inconsistency;

• indirectness of evidence;

• imprecision;

• publication bias.

The 'Summary of findings' tables will present only the seven top priority outcomes (disease‐specific health‐related quality of life, disease severity as measured by validated patient‐reported symptom score, serious adverse events (SAEs), avoidance of surgery, extent of disease as measured by endoscopic score or CT scan score, generic health‐related quality of life and other adverse effects).

Methods for future updates

We will review the scope and methods of this review approximately yearly (or more frequently if appropriate) in the light of potential changes in the topic area, or the evidence being included in the review (for example, additional comparisons, interventions or outcomes, or new review methods available).

Conditions under which the review will no longer be maintained as a living systematic review

The review will no longer be maintained as a living systematic review once there is high‐certainty evidence obtained for the primary effectiveness outcomes of the review; new studies are not expected to be conducted regularly for the interventions included in this review; or the review topic is no longer a priority for health care decision‐making.

Appendices

Appendix 1. Draft search strategies

CENTRAL	MEDLINE	Embase
1MESH DESCRIPTOR Sinusitis EXPLODE ALL AND CENTRAL:TARGET 2MESH DESCRIPTOR Rhinitis AND CENTRAL:TARGET 3MESH DESCRIPTOR Rhinitis, Atrophic AND CENTRAL:TARGET 4MESH DESCRIPTOR Rhinitis, Vasomotor AND CENTRAL:TARGET 5MESH DESCRIPTOR Paranasal Sinus Diseases AND CENTRAL:TARGET 6MESH DESCRIPTOR Paranasal Sinuses EXPLODE ALL AND CENTRAL:TARGET 7(rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 1238 8(kartagener* near syndrome*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 9(inflamm* near sinus*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 10((maxilla* or frontal*) near sinus*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 11#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 AND CENTRAL:TARGET 12MESH DESCRIPTOR Chronic Disease EXPLODE ALL AND CENTRAL:TARGET 12795 13MESH DESCRIPTOR Recurrence EXPLODE ALL AND CENTRAL:TARGET 11674 14(chronic or persis* or recur*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 15#12 or #13 or #14 AND CENTRAL:TARGET 16#11 and #15 AND CENTRAL:TARGET 17(CRSsNP):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 18((sinusitis or rhinitis) near (chronic or persis* or recur*)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 19#16 or #17 or #18 AND CENTRAL:TARGET 20MESH DESCRIPTOR Nasal Polyps EXPLODE ALL AND CENTRAL:TARGET 21MESH DESCRIPTOR Nose EXPLODE ALL AND CENTRAL:TARGET 22MESH DESCRIPTOR Nose Diseases EXPLODE ALL AND CENTRAL:TARGET 23#21 or #22 AND CENTRAL:TARGET 24MESH DESCRIPTOR Polyps EXPLODE ALL AND CENTRAL:TARGET 25#23 and #24 AND CENTRAL:TARGET 26((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) near (papilloma* or polyp*)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 27(rhinopolyp* or CRSwNP):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 28#19 or #20 or #25 or #26 or #27 AND CENTRAL:TARGET 29MESH DESCRIPTOR Antibodies, Monoclonal EXPLODE ALL AND CENTRAL:TARGET 30MESH DESCRIPTOR Antibodies, Anti‐Idiotypic EXPLODE ALL AND CENTRAL:TARGET 31MESH DESCRIPTOR Immunoglobulin E EXPLODE ALL AND CENTRAL:TARGET 32MESH DESCRIPTOR Interleukins EXPLODE ALL AND CENTRAL:TARGET 33MESH DESCRIPTOR Receptors, Interleukin EXPLODE ALL AND CENTRAL:TARGET 34MESH DESCRIPTOR Biological Therapy EXPLODE ALL AND CENTRAL:TARGET 35MESH DESCRIPTOR Granulocyte‐Macrophage Colony‐Stimulating Factor EXPLODE ALL AND CENTRAL:TARGET 36MESH DESCRIPTOR Cytokines EXPLODE ALL AND CENTRAL:TARGET 37MESH DESCRIPTOR Etanercept EXPLODE ALL AND CENTRAL:TARGET 38MESH DESCRIPTOR Immunoglobulin G EXPLODE ALL AND CENTRAL:TARGET 39(Antibod* adj3 monoclonal):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 40(Interleukin* or IgE or "immunoglobulin E" or Antiglobulin* or antiidiotyp*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 41(anti adj3 (globulin* or idiotyp* or immunoglobulin* or M1 or CCR4 or "LFA 1" or "GATA 3" or OX40L)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 42(ralokimumab or Adalimumab or Alemtuzumab or Bevacizumab or Certolizumab or Cetuximab or Denosumab or Ipilimumab or Natalizumab or Omalizumab or Palivizumab or Ranibizumab or Trastuzumab or stekinumab or mepolizumab or Nucala or SB240563 or "SB 240563" or dupilumab or REGN668 or AMG317 or "AMG 317" or AMG827 or "AMG 827" or DNAzyme or antiTSLP or CSL311 or "CSL 311" or "AMG 761" or AMG761 or "AMG 837" or KW0761 or "KW 0761" or "CSF 2" or "CSF GM"):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 43(siliq or D2E7 or humira or campath or Lemtrada or avastin or cimzia or CDP870 or "CDP 870" or Erbitux or C225 or Xgeva or prolia or "AMG 162" or AMG162 or Yervoy or Tysabri or Antegren or Xolair or Synagis or RhuFab or lucentis or Herceptin or stelara or CNTO or ASM8 or granulocyte‐macrophage or GM‐CSF or QGE031 or Raptiva or AK001 or "AK 001"):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 44((B‐cell or T‐cell or Eosinophil or "mast cell" or stimulating) adj3 factor):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 45(CD23 or CD2 or CD11a or CD20 or CD25 opr CD252 or (receptor* adj3 apsilon)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 1679 46(CD adj3 ("23" or antigen* or "2" or 11a or "20" or "25" or "252")):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 47((antigamma or "anti gamma") adj3 Antibod*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 48(IgEid or "55700" or SCH55700 or CEP38072 or "CEP 38072" or cinqair or DCP835 or "DCP 835" or GM‐CSF or TNF or TSLP or OX40L):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 12035 49(IL adj3 ("5" or five or "4" or four or "13" or thirteen or "1" or one or "10" or ten or "11" or eleven or "12" or twelve or "15" or fifteen or "16" or sixteen or "17" or seventeen or "18" or eighteen or "2" or two or "23" or "twenty three" or "12" or twelve or "27" or "twenty seven" or "3" or three or "33" or "thirty three" or "6" or six or "7" or seven or "8" or eight or "9" or nine or 5R* or 1R1 or 4R* or 12p40 or IL‐23p40 or 17A or 17RA or "22" or "twenty two" or "31" or "thirty one" or 31R)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 50(biologic or biologics or biotherap*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 51biologic* adj3 therap* AND CENTRAL:TARGET 52(mAB or mepo or MDX or MEDI or siglec* or "lectin 8"):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 53SAR231893 or reslizumab or siglec8 or benralizumab or lebrikizumab or brodalumab or Tralokinumab or Quilizumab or Ligelizumab or Mogamulizumab or Efalizumab or Pitrakinra or Odulimomab or Mogamulizumabor or BCGF or binetrakin or "anti antibod*" AND CENTRAL:TARGET 54(Canakinumab or Ilaris or Rilonacept or Arcalyst or Anakinra or Kineret or Antril or Altrakincept or Nuvance or Pascolizumab or SB 240683 or VAK694 or QBX258 or VAK 694 or VAK‐694 or dectrekumab QAX‐576 or QAX576 or QAX 576 or aerovant or AER‐001 or AER001 or "AER 001" or BAY‐16‐9996 or BAY 16‐9996 or Bosatria or Nucala or CDP 835 or CDP835 or CDP‐835 or CINQAIR or CTx55700 or CTx 55700 or CTx‐55700 or DCP 835 or DCP‐835 or DCP835 or SCH5570 or SCH 5570 SCH‐5570 or TRFK‐5 or TRFK 5 or TRFK5 or BIW‐8405* or BIW8405* or BIW 8405* or KHK 4563 or KHK‐4563 or KHK4563 or Enokizumab or 7F3com‐2H2 or Ustekinumab or Stelara or CNTO‐1275 or CNTO1275 or CNTO 1275 or Anrukinzuma* or IMA‐638 or PF‐05230917 or GSK679586 or GSK‐679586 or GDK 679586 or IMA026 or IMA‐026 or "IMA 026" or IMA638 or IMA 638 MILR1444A or MILR 1444A or MILR‐1444A or PRO‐301444 or PRO301444 or PRO 301444 or RG‐3637 or RG3637 or RG 3637 or RO‐5490255 or RO5490255 or RO 5490255 or TNX‐650 or TNX650 or TNX 650 or RPC‐4046 or ABT‐308 or RPC4046 or ABT308 or RPC 4046 or ABT 308 or CAT‐354 or CAT354 or CAT 354 or Secukinumab or Cosentyx or AIN‐457 or KB‐03303A or NVP‐AIN 457 or AIN457 or KB03303A or NVP‐AIN457 or AIN 457 or KB 03303A or NVP‐AIN‐457 or KHK‐4827 or KHK4827 or KHK 4827 or fezakinumab * or ILV‐094 or PF‐5212367 or ILV094 or PF5212367 or "ILV 094" or PF 5212367 or BMS‐981164 or BMS981164 or BMS 981164 or Nemolizumab or CIM331 or CIM 331 or CIM‐331 or Lenzilumab or KB003 or "KB 003" or KB‐003 or ABT‐D2E7 or D2E7 or LU 200134 or ABTD2E7 or LU200134 or ABT D2E7 or LU 200134 or Golimumab or Simponi or CNTO‐148 or CNTO148 or CNTO 148 or Inflixima or cA2 or CenTNF or Remicade or TA‐650 or TA650 or TA 650 or Etanercept or Enbrel or p75TNFR‐Ig or rhu TNFR‐Fc or TNFR‐Fc‐p75 or TNR‐001 or TNR001 or "TNR 001" or AMG‐157 or MEDI‐9929 or AMG157 or AMG 157 MEDI4212 or MEMP1972A or RG7449 or MEMP 1972A or RG 7449 or MEMP‐1972A or RG‐7449 or Mogamulizumab or KM8761 or Poteligeo or KM‐8761 or KM 8761 or Alefacept or Amevive or "ASP 0485" or BG 9273 or BG 9712 or ASP0485 or BG9273 or BG9712 or ASP‐0485 or BG‐9273 or BG‐9712 or Xanelim or Rituximab or Rituxan or Daclizumab or Zenapax or Oxeluma* or huMAb or OX40L or RG 4930 or RO4989991 or RG4930 or RG‐4930 or RO 4989991 or RO‐4989991 or Bertilimumab or Tezepeluma or Isunakinra or "Fusion Protein*" or cytokine*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 55#54 OR #53 OR #52 OR #51 OR #50 OR #49 OR #48 OR #47 OR #46 OR #45 OR #44 OR #43 OR #42 OR #41 OR #40 OR #39 OR #38 OR #37 OR #36 OR #35 OR #34 OR #33 OR #32 OR #30 OR #31 OR #29 56#55 AND #28	1. exp Sinusitis/ 2. paranasal sinus diseases/ or rhinitis/ or rhinitis, atrophic/ or rhinitis, vasomotor/ 3. exp Paranasal Sinuses/ 4. (rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis).ab,ti. 5. (kartagener* adj3 syndrome*).ab,ti. 6. (inflamm* adj5 sinus*).ab,ti. 7. ((maxilla* or frontal*) adj3 sinus*).ab,ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. exp chronic disease/ 10. exp Recurrence/ 11. (chronic or persis* or recur*).ab,ti. 12. 9 or 10 or 11 13. 8 and 12 14. CRSsNP.ab,ti. 15. ((sinusitis or rhinitis) adj3 (chronic or persis* or recur*)).ab,ti. 16. 13 or 14 or 15 17. exp Nasal Polyps/ 18. exp Nose/ or exp Nose Diseases/ 19. exp Polyps/ 20. 18 and 19 21. ((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) adj3 (papilloma* or polyp*)).ab,ti. 22. (rhinopolyp* or CRSwNP).ab,ti. 23. 16 or 17 or 20 or 21 or 22 24. exp Antibodies, Monoclonal/ 25. exp Antibodies, Anti‐Idiotypic/ 26. exp Immunoglobulin E/ 27. exp INTERLEUKINS/ 28. exp Receptors, Interleukin/ 29. exp Biological Therapy/ 30. exp Granulocyte‐Macrophage Colony‐Stimulating Factor/ 31. exp Cytokines/ 32. exp Etanercept/ or exp Alefacept/ 33. (Antibod* adj3 monoclonal).ab,ti. 34. (Interleukin* or IgE or "immunoglobulin E" or Antiglobulin* or antiidiotyp*).ab,ti. 35. (anti adj3 (globulin* or idiotyp* or immunoglobulin* or M1 or CCR4 or "LFA 1" or "GATA 3" or OX40L)).ab,ti. 36. (ralokimumab or Adalimumab or Alemtuzumab or Bevacizumab or Certolizumab or Cetuximab or Denosumab or Ipilimumab or Natalizumab or Omalizumab or Palivizumab or Ranibizumab or Trastuzumab or stekinumab or mepolizumab or Nucala or SB240563 or "SB 240563" or dupilumab or REGN668 or AMG317 or "AMG 317" or AMG827 or "AMG 827" or DNAzyme or antiTSLP or CSL311 or "CSL 311" or "AMG 761" or AMG761 or "AMG 837" or KW0761 or "KW 0761" or "CSF 2" or "CSF GM").ab,ti. 37. (siliq or D2E7 or humira or campath or Lemtrada or avastin or cimzia or CDP870 or "CDP 870" or Erbitux or C225 or Xgeva or prolia or "AMG 162" or AMG162 or Yervoy or Tysabri or Antegren or Xolair or Synagis or RhuFab or lucentis or Herceptin or stelara or CNTO or ASM8 or granulocyte‐macrophage or GM‐CSF or QGE031 or Raptiva or AK001 or "AK 001").ab,ti. 38. ((B‐cell or T‐cell or Eosinophil or "mast cell" or stimulating) adj3 factor).ab,ti. 39. (CD23 or CD2 or CD11a or CD20 or CD25 opr CD252 or (receptor* adj3 apsilon)).ab,ti. 40. (CD adj3 ("23" or antigen* or "2" or 11a or "20" or "25" or "252")).ab,ti. 41. ((antigamma or "anti gamma") adj3 Antibod*).ab,ti. 42. (IgEid or "55700" or SCH55700 or CEP38072 or "CEP 38072" or cinqair or DCP835 or "DCP 835" or GM‐CSF or TNF or TSLP or OX40L).ab,ti. 43. (IL adj3 ("5" or five or "4" or four or "13" or thirteen or "1" or one or "10" or ten or "11" or eleven or "12" or twelve or "15" or fifteen or "16" or sixteen or "17" or seventeen or "18" or eighteen or "2" or two or "23" or "twenty three" or "12" or twelve or "27" or "twenty seven" or "3" or three or "33" or "thirty three" or "6" or six or "7" or seven or "8" or eight or "9" or nine or 5R* or 1R1 or 4R* or 12p40 or IL‐23p40 or 17A or 17RA or "22" or "twenty two" or "31" or "thirty one" or 31R)).ab,ti. 44. (IL5 or IL4 or IL13 or IL1 or IL10 or IL11 or IL12 or IL15 or IL15 or IL16 or IL17 or IL18 or IL2 or IL23 or IL12 or IL27 or IL3 or IL33 or IL6 or IL7 or IL8 or IL9 or IL22 or IL31).ab,ti. 45. (biologic or biologics or biotherap*).ab,ti. 46. (biologic* adj3 therap*).ab,ti. 47. (mAB or mepo or MDX or MEDI or siglec* or "lectin 8").ab,ti. 48. (SAR231893 or reslizumab or siglec8 or benralizumab or lebrikizumab or brodalumab or Tralokinumab or Quilizumab or Ligelizumab or Mogamulizumab or Efalizumab or Pitrakinra or Odulimomab or Mogamulizumabor or BCGF or binetrakin or "anti antibod*").ab,ti. 49. (siglec8 or TPI ASM8 or Rilonacept).rn. 50. (Canakinumab or Ilaris or Rilonacept or Arcalyst or Anakinra or Kineret or Antril or Altrakincept or Nuvance or Pascolizumab or SB 240683 or VAK694 or QBX258 or VAK 694 or VAK‐694 or dectrekumab QAX‐576 or QAX576 or QAX 576 or aerovant or AER‐001 or AER001 or "AER 001" or BAY‐16‐9996 or BAY 16‐9996 or Bosatria or Nucala or CDP 835 or CDP835 or CDP‐835 or CINQAIR or CTx55700 or CTx 55700 or CTx‐55700 or DCP 835 or DCP‐835 or DCP835 or SCH5570 or SCH 5570 SCH‐5570 or TRFK‐5 or TRFK 5 or TRFK5 or BIW‐8405* or BIW8405* or BIW 8405* or KHK 4563 or KHK‐4563 or KHK4563 or Enokizumab or 7F3com‐2H2 or Ustekinumab or Stelara or CNTO‐1275 or CNTO1275 or CNTO 1275 or Anrukinzuma* or IMA‐638 or PF‐05230917 or GSK679586 or GSK‐679586 or GDK 679586 or IMA026 or IMA‐026 or "IMA 026" or IMA638 or IMA 638 MILR1444A or MILR 1444A or MILR‐1444A or PRO‐301444 or PRO301444 or PRO 301444 or RG‐3637 or RG3637 or RG 3637 or RO‐5490255 or RO5490255 or RO 5490255 or TNX‐650 or TNX650 or TNX 650 or RPC‐4046 or ABT‐308 or RPC4046 or ABT308 or RPC 4046 or ABT 308 or CAT‐354 or CAT354 or CAT 354 or Secukinumab or Cosentyx or AIN‐457 or KB‐03303A or NVP‐AIN 457 or AIN457 or KB03303A or NVP‐AIN457 or AIN 457 or KB 03303A or NVP‐AIN‐457 or KHK‐4827 or KHK4827 or KHK 4827 or fezakinumab * or ILV‐094 or PF‐5212367 or ILV094 or PF5212367 or "ILV 094" or PF 5212367 or BMS‐981164 or BMS981164 or BMS 981164 or Nemolizumab or CIM331 or CIM 331 or CIM‐331 or Lenzilumab or KB003 or "KB 003" or KB‐003 or ABT‐D2E7 or D2E7 or LU 200134 or ABTD2E7 or LU200134 or ABT D2E7 or LU 200134 or Golimumab or Simponi or CNTO‐148 or CNTO148 or CNTO 148 or Inflixima or cA2 or CenTNF or Remicade or TA‐650 or TA650 or TA 650 or Etanercept or Enbrel or p75TNFR‐Ig or rhu TNFR‐Fc or TNFR‐Fc‐p75 or TNR‐001 or TNR001 or "TNR 001" or AMG‐157 or MEDI‐9929 or AMG157 or AMG 157 MEDI4212 or MEMP1972A or RG7449 or MEMP 1972A or RG 7449 or MEMP‐1972A or RG‐7449 or Mogamulizumab or KM8761 or Poteligeo or KM‐8761 or KM 8761 or Alefacept or Amevive or "ASP 0485" or BG 9273 or BG 9712 or ASP0485 or BG9273 or BG9712 or ASP‐0485 or BG‐9273 or BG‐9712 or Xanelim or Rituximab or Rituxan or Daclizumab or Zenapax or Oxeluma* or huMAb or OX40L or RG 4930 or RO4989991 or RG4930 or RG‐4930 or RO 4989991 or RO‐4989991 or Bertilimumab or Tezepeluma or Isunakinra or "Fusion Protein*" or cytokine*).ab,ti. 51. or/24‐50 52. 23 and 51 53. randomized controlled trial.pt. 54. controlled clinical trial.pt. 55. randomized.ab. 56. placebo.ab. 57. drug therapy.fs. 58. randomly.ab. 59. trial.ab. 60. groups.ab. 61. 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 62. exp animals/ not humans.sh. 63. 61 not 62	1. exp Sinusitis/ 2. paranasal sinus diseases/ or rhinitis/ or rhinitis, atrophic/ or rhinitis, vasomotor/ 3. exp Paranasal Sinuses/ 4. (rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis).ab,ti. 5. (kartagener* adj3 syndrome*).ab,ti. 6. (inflamm* adj5 sinus*).ab,ti. 7. ((maxilla* or frontal*) adj3 sinus*).ab,ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. exp chronic disease/ 10. exp Recurrence/ 11. (chronic or persis* or recur*).ab,ti. 12. 9 or 10 or 11 13. 8 and 12 14. CRSsNP.ab,ti. 15. ((sinusitis or rhinitis) adj3 (chronic or persis* or recur*)).ab,ti. 16. 13 or 14 or 15 17. exp Nasal Polyps/ 18. exp Nose/ or exp Nose Diseases/ 19. exp Polyps/ 20. 18 and 19 21. ((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) adj3 (papilloma* or polyp*)).ab,ti. 22. (rhinopolyp* or CRSwNP).ab,ti. 23. 16 or 17 or 20 or 21 or 22 24. exp Antibodies, Monoclonal/ 25. exp Antibodies, Anti‐Idiotypic/ 26. exp Immunoglobulin E/ 27. exp INTERLEUKINS/ 28. exp Receptors, Interleukin/ 29. exp Biological Therapy/ 30. exp Granulocyte‐Macrophage Colony‐Stimulating Factor/ 31. exp Cytokines/ 32. exp Etanercept/ or exp Alefacept/ 33. (Antibod* adj3 monoclonal).ab,ti. 34. (Interleukin* or IgE or "immunoglobulin E" or Antiglobulin* or antiidiotyp*).ab,ti. 35. (anti adj3 (globulin* or idiotyp* or immunoglobulin* or M1 or CCR4 or "LFA 1" or "GATA 3" or OX40L)).ab,ti. 36. (ralokimumab or Adalimumab or Alemtuzumab or Bevacizumab or Certolizumab or Cetuximab or Denosumab or Ipilimumab or Natalizumab or Omalizumab or Palivizumab or Ranibizumab or Trastuzumab or stekinumab or mepolizumab or Nucala or SB240563 or "SB 240563" or dupilumab or REGN668 or AMG317 or "AMG 317" or AMG827 or "AMG 827" or DNAzyme or antiTSLP or CSL311 or "CSL 311" or "AMG 761" or AMG761 or "AMG 837" or KW0761 or "KW 0761" or "CSF 2" or "CSF GM").ab,ti. 37. (siliq or D2E7 or humira or campath or Lemtrada or avastin or cimzia or CDP870 or "CDP 870" or Erbitux or C225 or Xgeva or prolia or "AMG 162" or AMG162 or Yervoy or Tysabri or Antegren or Xolair or Synagis or RhuFab or lucentis or Herceptin or stelara or CNTO or ASM8 or granulocyte‐macrophage or GM‐CSF or QGE031 or Raptiva or AK001 or "AK 001").ab,ti. 38. ((B‐cell or T‐cell or Eosinophil or "mast cell" or stimulating) adj3 factor).ab,ti. 39. (CD23 or CD2 or CD11a or CD20 or CD25 opr CD252 or (receptor* adj3 apsilon)).ab,ti. 40. (CD adj3 ("23" or antigen* or "2" or 11a or "20" or "25" or "252")).ab,ti. 41. ((antigamma or "anti gamma") adj3 Antibod*).ab,ti. 42. (IgEid or "55700" or SCH55700 or CEP38072 or "CEP 38072" or cinqair or DCP835 or "DCP 835" or GM‐CSF or TNF or TSLP or OX40L).ab,ti. 43. (IL adj3 ("5" or five or "4" or four or "13" or thirteen or "1" or one or "10" or ten or "11" or eleven or "12" or twelve or "15" or fifteen or "16" or sixteen or "17" or seventeen or "18" or eighteen or "2" or two or "23" or "twenty three" or "12" or twelve or "27" or "twenty seven" or "3" or three or "33" or "thirty three" or "6" or six or "7" or seven or "8" or eight or "9" or nine or 5R* or 1R1 or 4R* or 12p40 or IL‐23p40 or 17A or 17RA or "22" or "twenty two" or "31" or "thirty one" or 31R)).ab,ti. 44. (IL5 or IL4 or IL13 or IL1 or IL10 or IL11 or IL12 or IL15 or IL15 or IL16 or IL17 or IL18 or IL2 or IL23 or IL12 or IL27 or IL3 or IL33 or IL6 or IL7 or IL8 or IL9 or IL22 or IL31).ab,ti. 45. (biologic or biologics or biotherap*).ab,ti. 46. (biologic* adj3 therap*).ab,ti. 47. (mAB or mepo or MDX or MEDI or siglec* or "lectin 8").ab,ti. 48. (SAR231893 or reslizumab or siglec8 or benralizumab or lebrikizumab or brodalumab or Tralokinumab or Quilizumab or Ligelizumab or Mogamulizumab or Efalizumab or Pitrakinra or Odulimomab or Mogamulizumabor or BCGF or binetrakin or "anti antibod*").ab,ti. 49. (siglec8 or TPI ASM8 or Rilonacept).rn. 50. (Canakinumab or Ilaris or Rilonacept or Arcalyst or Anakinra or Kineret or Antril or Altrakincept or Nuvance or Pascolizumab or SB 240683 or VAK694 or QBX258 or VAK 694 or VAK‐694 or dectrekumab QAX‐576 or QAX576 or QAX 576 or aerovant or AER‐001 or AER001 or "AER 001" or BAY‐16‐9996 or BAY 16‐9996 or Bosatria or Nucala or CDP 835 or CDP835 or CDP‐835 or CINQAIR or CTx55700 or CTx 55700 or CTx‐55700 or DCP 835 or DCP‐835 or DCP835 or SCH5570 or SCH 5570 SCH‐5570 or TRFK‐5 or TRFK 5 or TRFK5 or BIW‐8405* or BIW8405* or BIW 8405* or KHK 4563 or KHK‐4563 or KHK4563 or Enokizumab or 7F3com‐2H2 or Ustekinumab or Stelara or CNTO‐1275 or CNTO1275 or CNTO 1275 or Anrukinzuma* or IMA‐638 or PF‐05230917 or GSK679586 or GSK‐679586 or GDK 679586 or IMA026 or IMA‐026 or "IMA 026" or IMA638 or IMA 638 MILR1444A or MILR 1444A or MILR‐1444A or PRO‐301444 or PRO301444 or PRO 301444 or RG‐3637 or RG3637 or RG 3637 or RO‐5490255 or RO5490255 or RO 5490255 or TNX‐650 or TNX650 or TNX 650 or RPC‐4046 or ABT‐308 or RPC4046 or ABT308 or RPC 4046 or ABT 308 or CAT‐354 or CAT354 or CAT 354 or Secukinumab or Cosentyx or AIN‐457 or KB‐03303A or NVP‐AIN 457 or AIN457 or KB03303A or NVP‐AIN457 or AIN 457 or KB 03303A or NVP‐AIN‐457 or KHK‐4827 or KHK4827 or KHK 4827 or fezakinumab * or ILV‐094 or PF‐5212367 or ILV094 or PF5212367 or "ILV 094" or PF 5212367 or BMS‐981164 or BMS981164 or BMS 981164 or Nemolizumab or CIM331 or CIM 331 or CIM‐331 or Lenzilumab or KB003 or "KB 003" or KB‐003 or ABT‐D2E7 or D2E7 or LU 200134 or ABTD2E7 or LU200134 or ABT D2E7 or LU 200134 or Golimumab or Simponi or CNTO‐148 or CNTO148 or CNTO 148 or Inflixima or cA2 or CenTNF or Remicade or TA‐650 or TA650 or TA 650 or Etanercept or Enbrel or p75TNFR‐Ig or rhu TNFR‐Fc or TNFR‐Fc‐p75 or TNR‐001 or TNR001 or "TNR 001" or AMG‐157 or MEDI‐9929 or AMG157 or AMG 157 MEDI4212 or MEMP1972A or RG7449 or MEMP 1972A or RG 7449 or MEMP‐1972A or RG‐7449 or Mogamulizumab or KM8761 or Poteligeo or KM‐8761 or KM 8761 or Alefacept or Amevive or "ASP 0485" or BG 9273 or BG 9712 or ASP0485 or BG9273 or BG9712 or ASP‐0485 or BG‐9273 or BG‐9712 or Xanelim or Rituximab or Rituxan or Daclizumab or Zenapax or Oxeluma* or huMAb or OX40L or RG 4930 or RO4989991 or RG4930 or RG‐4930 or RO 4989991 or RO‐4989991 or Bertilimumab or Tezepeluma or Isunakinra or "Fusion Protein*" or cytokine*).ab,ti. 51. or/24‐50 52. 23 and 51 53. randomized controlled trial.pt. 54. controlled clinical trial.pt. 55. randomized.ab. 56. placebo.ab. 57. drug therapy.fs. 58. randomly.ab. 59. trial.ab. 60. groups.ab. 61. 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 62. exp animals/ not humans.sh. 63. 61 not 62 64. 52 and 63

Appendix 2. Data extraction form

REF ID:	Study title:
Date of extraction:	Extracted by:

General comments/notes (internal for discussion):

Flow chart of trial
	Group A (Intervention)	Group B (Comparison)
No. of people screened
No. of participants randomised ‐ all
No. randomised to each group
No. receiving treatment as allocated
No. not receiving treatment as allocated ‐ Reason 1 ‐ Reason 2
No. dropped out (no follow‐up data for any outcome available)
No. excluded from analysis1 (for all outcomes) ‐ Reason 1 ‐ Reason 2
Number analysed
1This should be the people who received the treatment and were therefore not considered 'drop‐outs' but were excluded from all analyses (e.g. because the data could not be interpreted or the outcome was not recorded for some reason).

Information to go into 'Characteristics of included studies' table
Methods	X arm, double/single/non‐blinded, [multicentre] parallel‐group/cross‐over/cluster‐RCT, with x duration of treatment and x duration of follow‐up
Participants	Location: country, no of sites etc. Setting of recruitment and treatment: Sample size: Number randomised: x in intervention, y in comparison Number completed: x in intervention, y in comparison Participant (baseline) characteristics: Age: Gender: Main diagnosis: [as stated in paper] Polyps status: x % with polyps/no information [add info on mean polyps score if available] Previous sinus surgery status: [x% with previous surgery] Previous courses of steroids: [add info on mean number of courses if available Other important effect modifiers, if applicable (e.g. aspirin sensitivity, comorbidities of asthma): Inclusion criteria:[state diagnostic criteria used for CRS, polyps score if available] Exclusion criteria:
Interventions	Intervention (n = x): drug name, method of administration, dose per day/frequency of administration, duration of treatment Comparator group (n = y): Use of additional interventions (common to both treatment arms):
Outcomes	Outcomes of interest in the review: Primary outcomes: Health‐related quality of life, disease‐specific Disease severity symptom score Significant adverse effects: local reaction at the injection site, including swelling, redness Secondary outcomes: Health‐related quality of life, generic Nasopharyngitis, including sore throat Endoscopy (polyps size or overall score) CT scan
Funding sources	'No information provided'/'None declared'/State source of funding
Declarations of interest	'No information provided'/'None declared'/State conflict
Notes

Bias (ROB 1.0)	Authors' judgement	Support for judgement
Random sequence generation (selection bias)		Quote: "…" Comment:
Allocation concealment (selection bias)		Quote: "…" Comment:
Blinding of participants and personnel (performance bias)		Quote: "…" Comment:
Blinding of outcome assessment (detection bias)		Quote: "…" Comment:
Incomplete outcome data (attrition bias)		Quote: "…" Comment:
Selective reporting (reporting bias)		Quote: "…" Comment:
Other bias (see section 8.15) Insensitive/non‐validated instrument?		Quote: "…" Comment:

Findings of study: continuous outcomes
Results (continuous data table)
Outcome	Group A			Group B			Other summary stats/Notes
	Mean	SD	N	Mean	SD	N	Mean difference (95% CI), P values etc.
Disease‐specific HRQL (instrument name/range) Time point:
Generic HRQL (instrument name/range) Time point:
Symptom score (overall) (instrument name/range) Time point:
Added total ‐ if scores reported separately for each symptom (range) Time point:
Nasal blockage/obstruction/congestion (instrument name/range)
Nasal discharge (instrument name/range)
Facial pain/pressure (instrument name/range)
Smell (reduction) (instrument name/range)
Headache (instrument name/range)
Cough (in children) (instrument name/range)
Endoscopy score (nasal polyp size score or Lund‐Kennedy) (instrument name/range)
CT score (instrument name/range)
Comments:

Results (dichotomous data table)
Outcome	Group A		Group B		Other summary stats/notes
	No. of people with events	No. of people analysed	No. of people with events	No. of people analysed	P values, RR (95% CI), OR (95% CI)
Local reaction at the injection site, including swelling, redness
Nasopharyngitis, including sore throat
Comments:

Contributions of authors

Lee‐Yee Chong: scoped, designed and drafted the protocol with the help of the other authors.

Patorn Piromchai: commented on the draft protocol and agreed the final version.

Steve Sharp: advised on the search strategy, commented on the draft protocol and agreed the final version.

Kornkiat Snidvongs: commented on the draft protocol and agreed the final version.

Carl Philpott: clinical guidance at all stages of project scoping and protocol development; commented on the draft protocol and agreed the final version.

Claire Hopkins: clinical guidance at all stages of project scoping and protocol development; commented on the draft protocol and agreed the final version.

Martin J Burton: clinical guidance at all stages of project scoping and protocol development; edited the draft protocol and agreed the final version.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research, UK.

  Infrastructure funding for Cochrane ENT

• National Institute for Health Research, UK.

  Cochrane‐NIHR Incentive Award 2019

Declarations of interest

Lee‐Yee Chong: none known.

Patorn Piromchai: none known.

Steve Sharp: Steve Sharp's employer, the National Institute for Health and Care Excellence (NICE), has produced guidance on related topics such as sinusitis, which he has not contributed to.

Kornkiat Snidvongs: none known.

Carl Philpott: Carl Philpott has previously received consultancy fees for Acclarent, Navigant, Aerin Medical and Entellus, and is a trustee of the patient charity Fifth Sense. He is an investigator on a clinical trial that may be included in this review, but will have no role in the data extraction, risk of bias assessment or data analysis for this study.

Claire Hopkins: Claire Hopkins has participated in advisory boards for Olympus, Chordate, Smith & Nephew and Sanofi to provide expertise with regards to study design and outcome assessment, and interpretation of trial data. She is an investigator on a clinical trial that may be included in this review, but will have no role in the data extraction, risk of bias assessment or data analysis for this study.

Martin J Burton: Professor Martin Burton is joint Co‐ordinating Editor of Cochrane ENT, but had no role in the editorial process for this protocol and will have no role in the editorial process for the review.

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