Use of Nonmedicated Control Substances in Randomized Clinical Trials of Patients With Chronic Rhinosinusitis: A Systematic Review and Single-Arm Meta-analysis

Lisa Caulley; Joel James; Claire Hopkins

doi:10.1001/jamaoto.2020.3723

. 2020 Nov 12;147(2):123–133. doi: 10.1001/jamaoto.2020.3723

Use of Nonmedicated Control Substances in Randomized Clinical Trials of Patients With Chronic Rhinosinusitis

A Systematic Review and Single-Arm Meta-analysis

Lisa Caulley ^1,^2,³, Joel James ⁴, Claire Hopkins ^5,^✉

PMCID: PMC7662504 PMID: 33180113

Key Points

Question

Can nonmedicated control substances improve patient-reported and observer-reported outcomes in chronic rhinosinusitis?

Findings

This systematic review and meta-analysis of the use of nonmedicated control substances in 38 randomized clinical trials of patients with chronic rhinosinusitis found an improvement in quality-of-life measures (6.21 of 110 points) and in nasal obstruction scores reported using a visual analog scale (0.42 standardized points).

Meaning

This study suggests that nonmedicated control substances are associated with limited improvements in the 22-item Sinonasal Outcome Test and nasal obstruction scores.

Abstract

Importance

The effect of nonmedicated control substances in chronic rhinosinusitis remains unclear.

Objective

To assess the association of nonmedicated control substances in randomized clinical trials with disease outcomes in patients diagnosed with chronic rhinosinusitis.

Data Sources and Study Selection

In this single-arm systematic review and meta-analysis, the Cochrane Library of Systematic Reviews, Ovid MEDLINE, Embase, PubMed, and ClinicalTrials.gov databases were searched for randomized clinical trials with a preintervention and postintervention design for chronic rhinosinusitis that were published between 1946 and January 23, 2019.

Data Extraction and Synthesis

Paired reviewers independently extracted data. The analyses used random-effects models and the Cochrane risk of bias assessment to rate the quality of the evidence.

Main Outcomes and Measures

The primary outcomes were the association of nonmedicated control substances with 22-item Sinonasal Outcome Test (SNOT-22) scores or nasal symptom scores when SNOT-22 was not available.

Results

A total of 2305 abstracts were identified and screened, 725 articles were reviewed in full text, and 38 articles met the study criteria and were included in the meta-analysis. Among the 38 included studies, a total of 2258 adults (mean age range, 27-53 years; 20.0%-72.5% women) were randomized to receive nonmedicated control substances or sham interventions. Topical nonmedicated control substances were associated with significant reduction in SNOT-22 scores (mean difference [MD], −8.81; 95% CI, −12.60 to −5.03). A subgroup analysis of topical therapies, limited to saline irrigation and nasal spray diluents, found that topical diluents were associated with a greater reduction in SNOT-22 scores (MD, −11.45; 95% CI, −13.50 to −9.41) compared with saline irrigation (MD, −13.60; 95% CI, −19.95 to −7.25). Nonmedicated control substances were associated with a significant reduction in nasal obstruction scores (standardized MD [SMD], −0.42; 95% CI, −0.81 to −0.03). No significant change was found in rhinorrhea scores (SMD, −0.34; 95% CI, −1.37 to 0.69), postnasal drip scores (SMD, −0.96; 95% CI, −2.18 to 0.25), facial pain scores (SMD, −0.57; 95% CI, −1.68 to 0.55), or loss of smell scores (SMD, −0.18; 95% CI, −0.68 to 0.32).

Conclusions and Relevance

This systematic review and meta-analysis of the use of nonmedicated control substances in randomized clinical trials of chronic rhinosinusitis outcomes suggests that the use of nonmedicated control substances is associated with limited improvements in SNOT-22 and nasal obstruction scores. These findings highlight potential areas of future research directions and the importance of randomized clinical trials to accurately estimate treatment effect.

This systematic review and meta-analysis assesses the association of nonmedicated control substances in randomized clinical trials with disease outcomes in patients diagnosed with chronic rhinosinusitis.

Introduction

A basic principle of randomized clinical trials (RCTs) is that comparing a drug against a placebo, or nonmedicated control, allows researchers to quantify the effectiveness of the drug. Although control groups in RCTs receive an inert or sham intervention, patients in the control arm of RCTs still derive some benefit when compared with groups that receive the active intervention.^1,2 The effect observed in control arms, or placebo effect, is presumed to be related to (1) observation and assessment (ie, Hawthorne effect); (2) performance of a therapeutic ritual; and (3) patient-practitioner interaction, which has the most robust effect in clinical trials.^1,3,4,5 Increasing evidence suggests that a placebo effect represents a genuine neurobiological phenomenon that is mediated by neurotransmitters and activation of specific, quantifiable, and relevant areas of the brain.^6,7 Furthermore, an estimated 4% to 26% of patients who are randomly assigned to placebos in trials discontinue their use because of perceived adverse or so-called nocebo effects.⁷ Consequently, the question of whether nonmedicated controls or sham interventions have a quantitative effect in the treatment of diseases remains.

Chronic rhinosinusitis (CRS) is a long-term sinus disease that affects 1 in 10 adults in the UK.⁸ Symptoms of CRS include a blocked and runny nose; loss of smell; facial pain; tiredness; and worsening of breathing problems, such as asthma.⁹ A previous study¹⁰ found that sinus disease can have a greater impact on quality of life than heart disease and back pain. Unfortunately, there is a paucity of RCTs, and currently many guidelines base treatment recommendations on outcomes of uncontrolled observational studies. To date, no studies have quantified the effect of nonmedicated control substances on signs and symptoms of CRS. An understanding of the size of the effect of nonmedicated controls on symptom relief will allow observational studies to be better interpreted and will help inform treatment choices.

Methods

The review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews. More detailed information can be found in the eMethods in the Supplement. Because this study was a review of the literature, no ethics approval was required. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.¹¹

Study Selection

Five electronic databases (Cochrane Library of Systematic Reviews, Ovid MEDLINE, Embase, PubMed, and ClinicalTrials.gov) were searched with the assistance of a trained librarian, without language restriction, to identify publications of RCTs of CRS published between 1946 and January 23, 2019. In addition, ClinicalTrials.gov and references of included studies and systematic reviews were searched. Parallel RCTs of adults 18 years or older that specified a placebo group that received a nonmedicated control or a sham procedure were eligible for inclusion in the review. Inclusion criteria required that all patients in each study were diagnosed with CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP) according to the European Position Paper on Rhinosinusitis and Nasal Polyps 2012,⁹ although diagnostic criteria were allowed to vary across individual studies conducted before 2012. Nonmedicated control substances that are known to have a treatment effect in CRS were permitted if the trial was executed as a placebo-controlled trial. Two reviewers (L.C. and J.J.) independently assessed publications for inclusion in the review. A liberal accelerated process was adopted: 1 reviewer was required to include a study but 2 were required to exclude it. The full texts of all records passing level 1 screening were retrieved for level 2 screening to confirm final eligibility. Discrepancies were resolved through discussion by the review team. For more detailed information, see the eMethods in the Supplement.

Data Extraction

Data extraction was performed in Review Manager 5.3 using a standardized data extraction form.¹² Two independent reviewers (L.C. and J.J.) extracted trial details that pertained to the participants, interventions, and results of CRS outcomes. The primary outcome was the association of nonmedicated controls with disease-specific health-related quality of life as measured by the 22-item Sinonasal Outcome Test (SNOT-22) score or disease-severity symptom scores of nasal obstruction, discharge, facial pain, and sense of smell if SNOT-22 was unavailable. SNOT-22 evaluates patient-reported symptom severity and health-related quality of life in sinonasal conditions using a validated instrument on a scale from 0 to 110 (with higher scores indicating poorer outcomes). Other relevant objective outcomes were extracted, such as association with inflammatory markers, Lund-Kennedy endoscopic grading system, Lund-MacKay computed tomography score, generic health-related quality of life as measured by the EuroQol-5D or Medical Outcomes Study 36-Item Short-Form Survey-36 (SF-36), and adverse events. For more detailed information, see the eMethods in the Supplement.

Risk of Bias Assessment

Internal validity of study design and conduct was assessed using the risk of bias tool of the Cochrane Collaboration.¹³ Adequate sequence generation, allocation concealment, patient blinding, addressing incomplete outcome data after randomization, and absence of selective reporting in considering risk of bias were assessed. Two reviewers (L.C. and J.J.) independently judged whether the risk of bias for each criterion was considered low, high, or unclear. Discrepancies were resolved through discussion by the review team.

Data Synthesis

Study results were presented separately for each outcome. Study results extracted from the original publication were transformed into mean differences (MDs) and standardized MDs (SMDs) with the associated 95% CIs or the numbers of participants experiencing an event.^{2,12,14,15,16,17,18} For more detailed information, see the eMethods in the Supplement.

Results

A total of 2305 abstracts were identified and screened, 725 articles were reviewed in full text, and 38 articles that followed a pretreatment and posttreatment design were included in the meta-analysis. A flowchart of study retrieval and selection is provided in Figure 1. The characteristics of the studies are presented in the Table.^{19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56} Among the 38 included studies, a total of 2258 adults (mean age range, 27-53 years; 20.0%-72.5% women) were randomized to receive nonmedicated control substances or sham interventions. Study sizes ranged from 8 to 373 participants, and baseline mean nasal polyp scores in studies that included patients with CRSwNP ranged from 3.1 to 7.2. Among patients who had undergone previous surgery, the proportion of participants who had undergone at least 1 prior surgical procedure ranged from 21.0% to 100.0%. Additional details of the included studies are provided in eTable 1 in the Supplement.

Table. Characteristics of Eligible Randomized Clinical Trials.

Source	No. of patients (No. of patients in control arm of RCT)	Diagnosis	No. (%) of patients with nasal polyps	Bilateral endoscopic nasal polyp score, mean (SD)	No. (%) of patients with ≥1 previous sinus surgery	Type of nonmedicated control substances or sham intervention	Composition of nonmedicated control substance	Follow-up duration
Anzić et al,¹⁹ 2017	60 (27)	CRSsNP	0 (0)	0	0 (0)	Oral	NR	8 wk
Bellussi et al,²⁰ 1990	40 (20)	CRS	NR	NR	NR	Oral	NR	10 d
Ebbens et al,²¹ 2006	116 (57)	Mixed	48 (84)	7.2 (3.7)	57 (100)	Topical irrigation	Cernevit, 3.4 mL/L in sterile water containing 2.5% glucose	13 wk
Esmaeilzadeh et al,²² 2015	34 (16)	CRSwNP	16 (100)	NR	NR	Oral and topical nasal spray	Normal saline and sugar capsules	6 mo
Gevaert et al,²³ 2011	30 (10)	CRSwNP	10 (100)	5.5 (1.65)	8 (80)	Injections	NR	8 wk
Gevaert et al,²⁴ 2013	23 (8)	CRSwNP	8 (100)	6 (6-8)^a	6 (75)	Injections	NR	16 wk
Hamilos et al,²⁵ 1999	21 (11)	CRSwNP	10 (100)	NR	NR	Topical nasal spray	Diluent	4 wk
Hansen et al,²⁶ 2010	20 (10)	CRSsNP	0 (0)	NR	10 (100)	Topical nasal spray	Aqueous medium containing microcrystalline cellulose and carboxymethylcellulose sodium, benzalkonium chloride, EDTA disodium salt dehydrate, dextrose anhydrous, and polysorbate 80	12 wk
Haye et al,²⁷ 1998	45 (22)	CRSwNP	22 (100)	NR	NR	Oral	NR	12 wk
Hissaria et al,²⁸ 2006	41 (20)	CRSwNP	20 (100)	NR	13 (65)	Oral	NR	2 wk
Jiang et al,²⁹ 2015	87 (44)	CRS	16 (41)	4.92 (1.37)	0 (0)	Topical irrigation	Yellowish dye mixed with 60 mL of sterile water	8 wk
Jiang et al,³⁰ 2018	83 (42)	CRS	14 (38.8)	5.31 (1.43)	0 (0)	Topical irrigation	Yellowish dye mixed with 60 mL of sterile water	8 wk
Keith et al,³¹ 2000	104 (52)	CRSwNP	52 (100)	NR	34 (65)	Topical nasal spray	NR	12 wk
Kennedy et al,³² 2005	53 (28)	CRS	NR	NR	NR	Oral	NR	6 wk
Kirtsreeakul et al,³³ 2011	112 (47)	CRSwNP	46 (100)	3.09 (1.05)	0 (0)	Oral	NR	14 d
Leopold et al,³⁴ 2019	323 (80)	CRSwNP	80 (100)	3.8 (1.08)	22 (27.5)	Topical nasal drops	Diluent of fluticasone propionate	16 wk^b
Lildholdt et al,³⁵ 1995	126 (40)	CRSwNP	40 (100)	NR	NR	Topical nasal spray	Lactose	4 wk
Lund et al,³⁶ 2004	167 (86)	CRSsNP	0 (0)	0	NR	Topical	NR	20 wk
Mortazavi et al,³⁷ 2017	38 (19)	CRSwNP	19 (100)	NR	NR	Oral	NR	6 mo
Mösges et al,³⁸ 2011	60 (35)	CRSsNP	0 (0)	NR	NR	Topical	NR	16 wk
Palm et al,³⁹ 2017	929 (306)	CRSsNP	0 (0)	NR	NR	Oral	NR	12 wk
Penttilä et al,⁴⁰ 2000	142 (47)	CRSwNP	47 (100)	NR	10 (21)	Topical nasal drops	NR	12 wk
Rössberg et al,⁴¹ 2005	65 (19)	CRSsNP	0 (0)	0	4 (21.1)	Sham acupuncture	NA	12 wk
Sindwani et al,⁴² 2019	323 (82)	CRSwNP	82 (100)	3.8 (0.94)	52 (63.4)	Topical nasal spray	Diluent of fluticasone propionate	16 wk^b
Small et al,⁴³ 2005	354 (117)	CRSwNP	117 (100)	4.25	NR	Topical	Aqueous medium containing glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, sodium citrate, 0.25% wt/wt phenylethyl alcohol, citric acid, benzalkonium chloride, and polysorbate 80	4 mo
Stjärne et al,⁴⁴ 2006a	310 (106)	CRSwNP	106 (100)	4.17	NR	Topical nasal spray	Aqueous medium containing glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, sodium citrate, 0.25% wt/wt phenylethyl alcohol, citric acid, benzalkonium chloride, and polysorbate 80	4 mo
Stjärne et al,⁴⁵ 2006b	298 (145)	CRSwNP	100 (69.0)	NR	38 (26.2)^c	Topical nasal spray	Aqueous medium containing glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, sodium citrate, 0.25% wt/wt phenylethyl alcohol, citric acid, benzalkonium chloride, and polysorbate 80	16 wk
Stjärne et al,⁴⁶ 2009	162 (82)	CRSwNP	44 (64)	NR	NR	Topical nasal spray	NR	168 +/− 7 d
Tait et al,⁴⁷ 2018	74 (34)	Mixed	6 (16)	4.9 (1.9)	12 (32)	Topical irrigation	Normal saline and lactose	4 wk
Vaidyanathan et al,⁴⁸ 2011	60 (30)	CRSwNP	30 (100)	4.8 (0.9)	9 (30)	Oral	NR	2 wk
Vento et al,⁴⁹ 2012	60 (30)	CRSwNP	30 (100)	NR	20 (66.7)	Oral	NR	9 mo
Videler et al,⁵⁰ 2011	60 (31)	CRSwNP	13 (41.9)	NR	NR	Oral	NR	24 wk
Vlckova et al,⁵¹ 2009	109 (55)	CRSwNP	55 (100)	NR	40 (73)	Topical nasal spray	Aqueous medium containing microcrystalline cellulose, carboxymethylcellulose sodium, benzalkonium chloride, EDTA disodium salt dehydrate, dextrose anhydrous, and polysorbate 80	14 wk
Wallwork et al,⁵² 2006	64 (35)	CRSsNP	0 (0)	NR	NR	Oral	NR	24 wk
Wang et al,⁵³ 2015	60 (30)	CRSwNP	30 (100)	4.72 (0.67)	0 (0)	Topical irrigation	Normal saline	14 d
Yousefi et al,⁵⁴ 2017	80 (40)	Mixed	6 (15)	NR	0 (0)	Topical irrigation	Sterile water	12 wk
Yu et al,⁵⁵ 2017	43 (22)	CRS	NR	NR	0 (0)	Topical irrigation	Normal saline	8 wk
Zhou et al,⁵⁶ 2016	748 (373)	CRSwNP	373 (100)	3.7 (1.1)	85 (22.8)	Topical nasal spray	Aqueous medium containing glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, sodium citrate, 0.25% wt/wt phenylethyl alcohol, citric acid, benzalkonium chloride, and polysorbate 80	16 wk

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Abbreviations: CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; mixed, chronic rhinosinusitis with and without nasal polyps; NA, not applicable; NR, not reported; RCT, randomized clinical trial.

^{^a}

Median and interquartile range.

^{^b}

Nasal obstruction scores reported at 4 weeks.

^{^c}

Authors reported values for more than 2 previous operations.

Disease-Specific Health-Related Quality-of-Life Outcomes

Eight studies^{22,29,30,34,37,42,47,50} reported on the effect of nonmedicated control substances on SNOT-22 scores (eTable 2 in the Supplement). The studies were heterogeneous in the formulation of the controls (oral and topical) and duration of treatment (30 days to 6 months). Nonmedicated controls were associated with a significant reduction in SNOT-22 scores (MD, −6.21; 95% CI, −9.91 to −2.50). A subgroup analysis was performed for the formulation of the therapy (Figure 2). Five trials^{29,30,34,42,47} used topical controls, 2 trials^37,50 used oral controls, and 1 trial²² used topical and oral controls. Pooled results from the trials using topical controls showed a significant benefit (MD, −8.81; 95% CI, −12.60 to −5.03), whereas oral controls did not (MD, −1.94; 95% CI, −5.75 to 1.87). Stratification by formulation of topical therapy demonstrated a greater benefit of treatment with topical nasal spray (administered for 4 months) compared with topical irrigation (administered for ≤3 months). A post hoc analysis demonstrated that the 2 studies^34,42 of patients treated with topical nasal spray also had protocols that permitted use of rescue medications in the form of antihistamines after 4 weeks of treatment. Neither study presented details on use of protocol-permitted medications by study participants. There was strong evidence of heterogeneity in the topical irrigation subgroup (I² = 74%). The statistical significance and high level of heterogeneity in this subgroup were accounted for by the trial by Tait et al⁴⁷ of topical irrigation for 30 days. Exclusion of this trial as an outlier decreased the level of heterogeneity to 0%; the measured effect in patients that received topical irrigation decreased to include the possibility of a null effect (MD, −3.09; 95% CI, −7.20 to 1.03). A subgroup analysis of topical therapies, limited to saline irrigation and nasal spray diluents, demonstrated that topical diluents were more effective in reducing SNOT-22 scores (MD, −11.45; 95% CI, −13.50 to −9.41) reported in 2 studies^34,42 compared with saline irrigation (MD, −13.60; 95% CI, −19.95 to −7.25) reported in 1 study.⁴⁷

Figure 2. — The SNOT-22 scores ranged from 0 to 110, with higher scores indicating poorer outcomes, and a minimally clinically important difference of 8.90.⁵⁸

Change in Individual Severity Symptom Scores

The change in patient-reported symptom scores was reported in 7 studies^{21,25,34,42,48,54,56} (eTable 3 in the Supplement). Topical therapy was associated with a significant reduction in nasal obstruction scores (SMD, −0.42; 95% CI, −0.81 to −0.03) (Figure 3). Continued treatment with topical therapy beyond 3 months did not provide any additional benefit (≤3 months: SMD, −0.33; 95% CI, −0.71 to 0.06; 3-6 months: SMD, −0.92; 95% CI, −2.64 to 0.80). A subgroup analysis revealed that the beneficial outcome with topical therapy on nasal obstruction scores was limited to topical nasal spray (nasal irrigation: SMD, −0.16; 95% CI, −0.69 to 0.37; nasal spray: SMD, −0.54; 95% CI, −0.96 to −0.12). Of note, both studies^21,54 in the topical irrigation subgroup used sterile water. A subgroup analysis did not reveal a significant difference in patients by presence of protocol-permitted rescue medications. Two trials^21,56 reported mean change in rhinorrhea scores in patients with CRSwNP following use of nonmedicated control substances with no significant difference observed (SMD, −0.34; 95% CI, −1.37 to 0.69) (eFigure 1A in the Supplement). Similarly, no significant change occurred in postnasal drip scores (SMD, −0.96; 95% CI, −2.18 to 0.25) (eFigure 1B in the Supplement), facial pain scores (SMD, −0.57; 95% CI, −1.68 to 0.55) (eFigure 1C in the Supplement), and loss of smell scores (SMD, −0.18; 95% CI, −0.68 to 0.32) (eFigure 1D in the Supplement).

Generic Health-Related Quality-of-Life Outcomes

Rössberg et al⁴¹ reported outcomes of EuroQoL-5D visual analog scale in patients with CRSsNP and identified no improvement in scores with sham acupuncture (MD, 5.20; 95% CI, −6.93 to 17.33). However, this study was at high risk for bias because of inadequately concealed allocation and blinding of study personnel. In addition, 2 studies^21,41 reported outcomes for SF-36 component scores (Figure 4 and eTable 4 in the Supplement). Nonmedicated control was not associated with physical component scores (MD, 0.62; 95% CI, −1.46 to 2.70) or mental health component scores (MD, 2.06; 95% CI, −0.25 to 4.36). These findings failed to achieve significance with exclusion of the study by Rössberg et al⁴¹ (physical component scores: MD, 1.40; 95% CI, −1.27 to 4.07; mental health component scores: MD, 1.90; 95% CI, −1.06 to 4.86).

Endoscopic and Imaging Outcome Measures

The pooled estimate for the 3 included trials^21,47,55 indicated a reduction in the Lund-Kennedy endoscopic score (MD, −1.75; 95% CI, −2.81 to −0.70) (eTable 5 and eFigure 2 in the Supplement) with topical treatment. A subgroup analysis of 2 trials^47,55 of topical irrigation treatment for 3 months or longer revealed significant improvement in Lund-Kennedy scores (MD, −1.91; 95% CI, −3.41 to −0.41). However, there was substantial heterogeneity in this subgroup (I² = 95%). One study²¹ of topical therapy treatment confirmed a sustained significant improvement in mean Lund-Kennedy scores at 13 weeks (MD, −1.40; 95% CI, −2.36 to −0.44). Placebo treatment was not associated with improved mean Lund-Mackay scores (MD, −0.30; 95% CI, −1.00 to 0.40) (eFigure 3 and eTable 6 in the Supplement).

Inflammatory Markers

Six studies^{19,22,25,48,52,54} reported outcomes from nonmedicated controls on inflammatory markers in plasma serum and nasal secretions (eTable 7 in the Supplement). Wallwork et al⁵² observed an increase in interleukin 8 (MD, 68.00 pg/mL; 95% CI, 53.03-82.97 pg/mL), fucose (MD, 1.20 μmol/L; 95% CI, 0.27-2.13 μmol/L), and α₂-macroglobulin (MD, 0.25 μg/mL; 95% CI, 0.02-0.48 μg/mL) in nasal lavages of patients with CRSsNP after 12 weeks of oral therapy. Yousefi et al⁵⁴ reported a decrease in serum IgE (SMD, −11.49 mg/dL; 95% CI, −22.96 to −0.02 mg/dL) and nasal mucosa eosinophil counts (MD, −1.24/μL; 95% CI, −2.35 to −0.13/μL) after 3 months of topical therapy in 40 patients with CRS. The remaining studies^19,22,25,48 did not identify an effect of nonmedicated control substances on inflammatory markers.

Adverse Events

Eighteen trials^{20,21,23,27,28,30,31,32,33,36,38,39,40,45,48,51,55,56} reported on any adverse events (eFigure 4 in the Supplement). There was a high level of variability among studies in the analysis (I² = 95%). The rate of adverse events was 31% (95% CI, 13.0%-53.0%) in the topical controls and 41.0% (95% CI, 22.0%-62.0%) in the oral controls.

Thirteen trials^{23,26,31,34,35,38,39,40,48,49,51,53,56} reported on serious adverse events (eFigure 5 in the Supplement). Overall, serious adverse events were rarely observed (0%; 95% CI, 0%-0%), irrespective of type of therapy. Thirteen studies^{24,25,26,28,34,38,39,40,43,44,45,46,56} reported on adverse events that led to withdrawal from trials (eFigure 6A in the Supplement). The pooled estimate of adverse events leading to withdrawal from trials was 2.0% (95% CI, 1.0%-4.0%). A subgroup analysis of duration of therapy revealed that the pooled estimate of adverse events leading to withdrawal for topical nasal sprays was 7.0% (95% CI, 1.0%-17.0%) in patients who received treatment for 3 months or less and 2.0% (95% CI, 1.0%-3.0%) in patients who received treatment for 3 to 6 months. A subgroup analysis revealed no significant difference by nasal polyp status (CRSwNP: 3.0%; 95% CI, 1.0%-5.0%; CRSsNP: 3.0%; 95% CI, 0.0%-12.0%) (eFigure 6B in the Supplement).

The presence of rescue medications or continued baseline medications was not associated with overall adverse events, severe adverse events, or withdrawal from studies because of adverse events.

Risk of Bias

The risk of bias assessment is presented in eFigure 7 in the Supplement. Thirty-four trials (89.5%) were at risk for bias for at least 1 of the following domains. However, 32 (84.2%) adequately generated their randomization sequence, 25 (65.8%) adequately concealed allocation, 32 (84.2%) blinded participants and personnel, and 29 (76.3%) blinded outcome assessors. Potential sources of bias resulted from incomplete outcome data (n = 20 [52.6%] trials) and selective reporting (n = 25 [65.8%] trials).

Discussion

Informed consent requires researchers to provide participants with information about research that is accurate, complete, and understandable, including a detailed description of the effect of nonmedicated control substances. To our knowledge, this study is the first systematic review and meta-analysis of the association of nonmedicated control substances and sham interventions with patient-reported and observed outcomes in CRS. The measurable benefits and harms of nonmedicated control substances in this review highlight the importance of RCTs to accurately estimate the effect of interventions and underscores the need to exercise caution in interpreting noncontrolled observational studies.

The pooled estimates of the association with health-related quality of life varied. Although topical nonmedicated control substances in the form of nasal sprays and saline irrigations were significantly associated with improved SNOT-22 outcomes, the reduction met the criteria for only a minimal clinically important difference (a score reduction of 8.90)⁵⁷ in 2 studies^34,42 that used topical nasal sprays in the form of the diluent of fluticasone propionate. Studies of individual symptom severity scores revealed that use of nonmedicated control substances was associated with improvements in nasal obstruction symptoms in topical nonmedicated control substances irrespective of prolonged duration of treatment. Noninert ingredients of the diluent in the topical nasal spray could have an unintended physical effect as another possible explanation for the improvement. The effects of topical diluents may mimic that of xylitol, a 5-carbon sugar alcohol that has gained recent attention as a natural antibacterial agent that can improve symptoms of CRS. Interestingly, the association observed with patient-reported outcomes was limited to local nonmedicated control substances compared with systemic therapy.

Selection of truly inert controls for RCTs of CRS is challenging.⁵⁸ Hypotonic solutions are known to cause mucosal damage that exacerbates CRS.⁵⁹ As such, it is not surprising that in 4 studies,^21,29,30,54 which used sterile water as a nonmedicated control, no improvement in individual symptom scores was observed. By contrast, isotonic irrigations, which assist in dislodging mucus and restoring mucociliary clearance, are well recognized for their ability to improve symptom-based and endoscopic outcome measures.^9,60 In this analysis, topical irrigations were associated with measured improvements in Lund-Kennedy endoscopic scores, in addition to patient-reported outcomes. This observed benefit in topical placebo therapy is expected because several studies^47,53,55 used saline irrigations in the nonmedicated control arm.

Reported adverse events from nonmedicated control substances ranged from 0% to 64% in trials; the rates were comparable in the oral and topical groups. Serious adverse events were rare. The trend in adverse events that led to withdrawal from trials of topical controls suggests that patient dropout was higher in the first 3 months of therapy (range, 13%-15%). With prolonged topical treatment, rates of withdrawal decreased to 2%.

There is a paucity of literature on the natural evolution of untreated CRS, but this study highlights the need for further research in this domain. A small study⁶¹ of untreated patients with CRS without acute exacerbations identified a trend toward subjective improvement in 25% of patients with CRS during a 4-week period. Notably, there were no changes in endoscopic or radiographic outcomes or inflammatory markers during the same period. The additional benefit in subjective and objective parameters observed in the current systematic review could be related to the effect of the use of nonmedicated control substances or the continued observation of patients during a prolonged period. Further research is needed to differentiate these end points and understand the natural history of CRS.

The results of this study add to the limited evidence that suggests an effect of nonmedicated control substances on chronic diseases. Studies^62,63 have found that people are willing to try open-label placebo treatments if given enough information from their health care practitioners. There is a possibility of reporting bias in these trials because patients are aware of their allocation, so the true effect may be difficult to estimate. Multiple randomized trials of open-label placebo treatments in various conditions have demonstrated that open-label treatments can improve symptoms when compared with treatment as usual or no treatment arms in cancer-related fatigue, back pain, allergy symptoms, and irritable bowel disease symptom severity.^{64,65,66,67,68,69,70,71,72,73} The studies of placebo effect on rhinology are limited. One trial in patients with allergic rhinitis found active treatment of oral phenylephrine hydrochloride noninferior to open-label placebo treatments in relieving nasal congestion in adults.⁷⁴ Open-label placebo treatments are not effective in wound healing, suggesting that the effect of open-label placebos is limited to pain and symptom relief.⁷⁵

Limitations

This study has limitations. Heterogeneity associated with pooled estimates for patient-reported quality of life, endoscopic outcomes, and adverse events among trials may have reduced evidence quality. Subgroup analyses were performed when possible to try to understand the source of heterogeneity in these studies. Too few studies reported details on the use of protocol-permitted medications in their results to allow for subgroup analyses. Studies are needed to determine whether additional treatment is an effect modifier for the placebo. The pooled estimate of the pre-effect and posteffect sizes cannot differentiate between the effects of treatment and natural processes. Research is needed to understand whether there is a role for the use of nonmedicated control substances that complements the natural history of untreated CRS. Studies of the compositions of nonmedicated control substances may also lend insight into the potential effect of active ingredients in controls in CRS.

Repeated measurements introduce the risk of regression to the mean. Therefore, pre-effect and posteffect sizes are at risk for bias because the pretest and posttest outcome measures are not independent of each other.⁷⁶ To account for this, our analysis imputed the SD within groups and corrected for the correlation between the paired observations. Most trials did not report both measurement variances and change variances, so the assumed correlation was 0.5, which is a reasonable assumption given that the mean correlation for 2 trials that reported both measurement variances and change variances for SNOT-22 was 0.54.^17,47,50

Conclusions

This study provides an estimate of the effect of nonmedicated control substances in CRS to fill a knowledge gap and guide future research directions. The pooled effect estimate identified settings in which nonmedicated control substances can influence patient-reported quality-of-life assessments as well as endoscopic outcome measures. The significant effect of nonmedicated control substances is further evidence to support cautious interpretation of results from noncontrolled observational studies.

Supplement.

eMethods. Supplementary Methods

eTable 1. Additional Details of Included Studies

eTable 2. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on the 22-Item Sinonasal Outcome Test (SNOT-22; Range of 0 to 110 [Higher Scores Indicate Poorer Outcomes] and a Minimally Clinically Important Difference of 8.90)

eTable 3. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Symptom Severity Scores Based on Visual Analogue Scale for (A) Nasal Obstruction or Congestion (B) Rhinorrhea (C) Post-Nasal Drip (D) Facial Pain (E) Loss of Smell

eTable 4. Randomized Clinical Trials of the Effect of Non-Medicated Controls on SF-36 Scores. (A) Physical Component Score; (B) Mental Health Component Score. SF-36: Short-Form Survey-36

eTable 5. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Lund Kennedy Endoscopic Score

eTable 6. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Lund Mackay CT Score

eTable 7. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Inflammatory Markers

eFigure 1. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Symptom Severity Scores Based on Visual Analogue Scale (A) Rhinorrhea; (B) Post-Nasal Drip; (C) Facial Pain; (D) Loss of Smell

eFigure 2. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Lund Kennedy Endoscopic Score

eFigure 3. Randomized Clinical Trials of the Effect of Non-Medicated Control Substances on Lund Mackay CT Score

eFigure 4. Adverse Events Reported in Randomized Clinical Trials of the Effect of Non-Medicated Control Substances

eFigure 5. Serious Adverse Events Reported in Randomized Clinical Trials of the Effect of Non-Medicated Control Substances

eFigure 6. Adverse Events Leading to Study Withdrawal Reported in Randomized Clinical Trials of the Effect of Non-Medicated Control Substances (A) All Studies; (B) Subgroup Analysis by Nasal Polyp Status

eFigure 7. Risk of Bias Summary: Review Authors' Judgements About Each Risk of Bias Item for Each Included Study

Click here for additional data file.^{(1.4MB, pdf)}

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