Methods

2‐arm, non‐blinded, parallel‐group RCT, with a 2‐week duration of treatment and follow‐up

Participants

Location: Spain, 1 site

Setting of recruitment and treatment: rhinology and smell clinic, department of otorhinolaryngology, hospital clinic, Barcelona

Sample size:

Number randomised: 92 (it is unclear if these were all randomised or if the 3 drop‐outs occurred prior to randomisation)

Number completed: 67 in intervention group, 22 in comparison group

Participant (baseline) characteristics:

• Age: 51 ± 12 (22 to 84)

• Gender (%M/%F): 65/35

• Main diagnosis: moderate to severe nasal polyps

• Polyps status: 100% with polyps

• Mean polyps score at baseline: no information

• Previous sinus surgery status: 6 (6.7%)

• Previous courses of steroids: no information

Other important effect modifiers:

• Asthma: oral steroids: 41 (61%); no treatment: 14 (64%)

• Aspirin‐intolerant asthma: Group A: 25 (37%); Group B: 5 (23%)

Inclusion criteria: diagnosis of bilateral nasal polyps was based on the EPOS criteria: "Presence of two or more nasal symptoms, one of which should be either nasal blockage or nasal discharge, and/or the reduction/loss of sense of smell, and/or facial pain for more than 12 weeks, and/or the presence of nasal polyps by nasal endoscopy or mucosal changes within the ostiomeatal complex, and/or paranasal sinuses by computed tomography (CT) scan"

Exclusion criteria: none listed

Interventions

Intervention (n = 67): oral prednisone (30 mg daily for 4 days followed by a 2‐day reduction of 5 mg) and intranasal budesonide 800 μg daily (400 μg twice daily) for 2 weeks

Comparator group (n = 22): no corticosteroid treatment for 2 weeks

Use of additional interventions (common to both treatment arm): both groups had a 4‐week washout period for intranasal and oral steroids. No other adjunct treatment is listed.

Outcomes

Outcomes of interest in the review:

Primary outcomes

1. None presented

Secondary outcomes

1. Polyp grade measured by CT scan of paranasal sinuses, staged using the Lund‐Mackay score (0 ‐ no opacity; 1 – partial opacity; 2 – total opacity for each of the sinuses. The ostiomeatal complex was also bilaterally scored 0 for no obstruction or 2 when obstructed) at 2 weeks.

Other outcomes reported by the study:

• Nasal congestion measured on a 4‐point Likert scale (0 to 3) at 2 weeks

• Loss of sense of smell, measured by Barcelona Smell Test 24 (BAST‐24) at 2 weeks

• Polyp tissue eosinophilia (from biopsies at baseline and after oral steroid treatment)

• Nasal nitric oxide

Funding sources

"This article was partially sponsored by a research project from Fondo de Investigacion Sanitaria (FIS 99–0133), Instituto de Salud Carlos III." There was no information regarding the funding of the original study.

Declarations of interest

No information is provided in the paper

Notes

In the group receiving oral steroids, the treatment period was followed up by a 10‐week course of INCS. The "no steroids treatment" group were not followed up after 2 weeks and so these results have not been presented.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "…randomised…"

Comment: no information about the randomisation procedures for the trial

Allocation concealment (selection bias)

Unclear risk

Comment: there is no information about the allocation concealment. Given the trial was not blinded, there is reason to believe that the study personnel may have been able to influence the groups into which participants were allocated.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: the trial does not appear to be blinded to patients or study personnel. The comparison group had no steroid treatment and did not receive placebo.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: the main outcomes were subjective outcomes rated by patients. There was no mention of blinding of outcome assessors (for endoscopy) included in the paper. Since the control arm received no treatment, the risk of bias is high.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: paper indicates that 92 patients were recruited but only 89 patients are accounted for in the analysis. The 3 drop‐outs are identified but there is no indication if they dropped out prior to randomisation or after randomisation. The impact of the 3 drop‐outs (3%) is likely to be small.

Selective reporting (reporting bias)

Unclear risk

Comment: adverse event data are not presented in the paper. No protocol for the trial could be found.

Other bias

Unclear risk

Comment: only details of the validation of the smell test used in the study (BAST‐24) were provided. No details of validation for other outcomes (e.g. 0‐ to 3‐point Likert scale used to assess nasal congestion).

Methods

2‐arm, non‐blinded, parallel‐group RCT, with 2‐week duration of treatment and follow‐up

Participants

Location: Spain, 1 site

Setting of recruitment and treatment: rhinology unit, ENT department, hospital clinic, Barcelona

Sample size: 84

Number randomised: 63 in intervention group, 21 in comparison group

Number completed: 63 in intervention group, 21 in comparison group

Participant (baseline) characteristics:

• Age: oral steroids: 51 ± 2.8; no treatment: 53 ± 3.8

• Gender: M/F: 55/29

• Main diagnosis: severe nasal polyps

• Polyps status: 100% with polyps

• Previous sinus surgery status: no information

• Previous courses of steroids: information not provided

Other important effect modifiers:

• Aspirin sensitivity: 23 (27.4%) (not given per group)

• Comorbidities of asthma: 40 (47.6%) (not given per group)

Inclusion criteria: diagnosis of severe nasal polyps based on nasal endoscopic examination (mean score of 2.7 over 3 using the Lildholdt score)

Nasal polyps score: 0 – no polyps; 1 – mild polyposis; 2 – moderate polyposis; 3 – severe polyposis

Exclusion criteria: patients with a steroid contraindication

Interventions

Intervention (n = 63): oral prednisone, 30 mg daily for 4 days followed by 2‐day reduction of 5 mg, total duration 14 days

Comparator group (n = 21): no steroid treatment

Use of additional interventions (common to both treatment arms): asthmatic patients did not modify their treatment during the study. No patients were receiving treatment with leukotriene antagonists.

(Note: both groups had a 4‐week washout period for intranasal and oral steroids)

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Disease severity symptom score; measured individual symptoms of nasal obstruction, loss of sense of smell, rhinorrhoea and sneezing, on a 4‐point scale (0 to 3) at baseline and 2 weeks

Secondary outcomes

1. Endoscopy (polyp size); using the Lildholdt scale (see inclusion criteria) at baseline and 2 weeks

Other outcomes reported by the study:·

• Allergy study

• Nasal patency

Funding sources

"Generalitat de Catalunya (2001SGR00384), Red RESPIRA (FIS, V‐2003‐REDC11D‐0) and Fondo de Investigaciones Sanitarias (99‐3121m PI020329)"

Declarations of interest

No information provided

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: study design details that the study was "randomised" but no further details were provided

Allocation concealment (selection bias)

Unclear risk

Comment: no details about allocation concealment were provided in the paper

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: the control group received no steroid treatment or placebo. No mention of blinding of participants or personnel was included in the paper.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: the main outcomes were subjective outcomes rated by patients. There was no mention of blinding of outcome assessors (for endoscopy) included in the paper. Since the control arm received no treatment, the risk of bias is high.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: there was no mention of anyone who dropped out of the trial or had to discontinue for any reason. However, they also did not state how many patients were analysed for each outcome.

Selective reporting (reporting bias)

Unclear risk

Comment: adverse event data are not presented in the paper. No protocol for the trial could be found.

Other bias

Unclear risk

Comment: no information is provided about the validation of the symptom scores used

Methods

2‐arm, double‐blind, parallel‐group RCT, with a 17‐day duration of oral steroid treatment

Participants

Location: Turkey, 1 site

Setting of recruitment and treatment: Department of Otorhinolaryngology ‐ Head and Neck Surgery, Dokuz Eylul University Hospital

Sample size: 23

Number randomised: 11 in intervention group, 12 in comparison group

Number completed: 10 in intervention group, 12 in comparison group

Participant (baseline) characteristics:

• Mean age ± SD: oral steroids: 45.6 ± 11.5; placebo: 26.6 ± 43.3

• Gender (M/F): oral steroids: 9/1; placebo: 8/4

• Main diagnosis: patients with nasal polyps who did not respond to a 6‐week course of fluticasone nasal drops (see notes below)

• Polyps status: 100% with polyps

• Preoperative endoscopic polyp score: score 2/3: oral steroids: 4/6; placebo: 4/8

• Previous sinus surgery status: no information provided

• Previous courses of steroids: no information provided

• Other important effect modifiers: no information provided

Inclusion criteria: nasal polyps, age between 18 and 65 years, endoscopic stage II or III nasal polyposis patients

Nasal polyps score: graded according to the following criteria: 0: no polyp; 1: mild polyposis (small polyps not reaching the upper edge of the inferior turbinate); 2: moderate polyposis (medium polyps between the upper and lower edges of the inferior turbinate); 3: severe polyposis (large polyps reaching the lower edge of the inferior turbinate, polyps from posterior ethmoidal sinuses, or both)

Exclusion criteria: hypertension, type I or II diabetes mellitus, the signs of systemic infection, pregnancy or lactation, any type of M. tuberculosis infection, peptic ulcer, viral infection (measles, chicken pox or ocular herpes), myasthenia gravis, stage I nasal polyposis, aspirin intolerance, previous major head trauma

Interventions

Intervention (n = 11): prednisolone, oral, 60 mg/day (6 tablets per day) for 7 days, then reduced to 10 mg (1 tablet) taken every other day, stopping on day 17

Comparator group (n = 12): placebo, 6 tablets per day for 7 days, then reduced to 1 tablet every other day, stopping on day 17

Use of additional interventions (common to both treatment arms): none listed

Outcomes

Outcomes of interest in the review:

Primary outcomes

1. Disease severity, measured by visual analogue scale of 0 to 10 (0 no complaint to 10 most annoying) for a combination of factors relating to sense of smell, nasal discharge, nasal obstruction and pressure over the sinuses

Other outcomes reported by the study:

• Sense of smell with Connecticut Chemosensory Clinical Research Centre (CCCRC) butanol olfactory threshold test

• Peak nasal inspiratory peak flow (PNIF)

• Video scoring for grading the surgical field based on the Boezaart et al grading system for assessment of bleeding during endoscopic sinus surgery

Funding sources

"The authors have no funding, financial relationships, or conflicts of interest to disclose"

Declarations of interest

"The authors have no funding, financial relationships, or conflicts of interest to disclose"

Notes

The patients who met the inclusion criteria gave informed consent and were prescribed fluticasone nasal drops 1 x/day, 200 mg, for 6 weeks. Patients who did not respond to this medical treatment were evaluated for the study.

All patients in the trial underwent surgery between the 15th and 17th day. Outcomes presented for this review are the pre‐operative results.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Every eight boxes, including four study drug boxes and four placebo drug boxes, respectively, were assembled as a group by the pharmacy department."

Comment: randomisation in blocks of 8 (pg 2042, col 1, para 6)

Allocation concealment (selection bias)

Low risk

Quote: "…The hospital pharmacy department performed the drug/placebo randomization, and the identity of the contents in the boxes was not disclosed to any clinicians interacting with patients throughout the study"

Comment: pg 2042, col 1, para 6

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "…the identity of the contents in the boxes was not disclosed to any clinicians interacting with patients throughout the study"

"The surgeon was blinded to the patient treatment group"

Comment: pg 2042, col 1, para 6/7. It is unclear whether the placebo tablets provide adequate masking in terms of taste, since prednisolone is bitter and may be recognisable to patients.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: from the flowchart on pg 2042 it appears that the codes were broken after all of the data had been collected

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: only 1 patient did not complete the study (4.3%). The drop‐out reason was that the patient was not given the study medication after surgery. No intention‐to‐treat analysis was completed.

Selective reporting (reporting bias)

Low risk

Comment: outcomes appear to be reported well in the paper. No protocol for the trial could be found.

Other bias

Unclear risk

No information about the validation of any outcomes

The mean age of participants in the oral steroid group was 45.6 ± 11.5 and the mean age in the control group was reported as 26.6 ± 43.6. This may be a reporting error since the range in the control group is 26 to 58 years.

Methods

2‐arm, double‐blinded, parallel‐group RCT, with 14 days duration of treatment follow‐up

Participants

Location: Australia, unclear number of sites

Setting of recruitment and treatment: allergy outpatient clinics

Sample size:

Number randomised: 20 in intervention group, 21 in comparison group

Number completed: 20 in intervention group, 20 in comparison group

Participant (baseline) characteristics:

• Age: oral steroids: 49 ± 13; placebo: 48 ± 12

• Gender (M/F): oral steroids: 7/13; placebo: 12/8

• Main diagnosis: symptomatic polyp disease

• Polyps status: 100% with polyps

• Previous sinus surgery status: oral steroids: 17 in 8 participants; placebo: 23 in 13 participants

• Previous courses of steroids: oral steroids: 11; placebo: 12

Other important effect modifiers:

• History of aspirin sensitivity: oral steroids: 2; placebo: 12

• History of atopy: oral steroids: 18; placebo: 20

• Use of intranasal corticosteroids: oral steroids: 11; placebo: 11

• Use of antihistamines: oral steroids: 7; placebo: 6

• Use of nasal decongestants: oral steroids: 5; placebo: 4

Inclusion criteria: aged 18 to 65 years drawn mainly from allergy outpatient clinics who had symptomatic polyp disease diagnosed on nasoendoscopy

Exclusion criteria: previous use of oral steroids, unstable asthma, recent sinus surgery, acute infection within 1 month of recruitment, polyps caused by cystic fibrosis or mucociliary disorders, diabetes mellitus, cataract, glaucoma, fungal sinusitis, contraindications for MRI scanning, or any other significant comorbid condition that contraindicated the use of systemic corticosteroids

Interventions

Intervention (n = 20): prednisolone, 50 mg/day for 14 days

Comparator group (n = 21): placebo, for 14 days

Use of additional interventions (common to both treatment arms): participants were allowed to continue the use of regular antihistamines (13/40), topical corticosteroids (22/40), or both

Outcomes

Outcomes of interest in the review:

Primary outcomes

1. Health‐related quality of life, measured by Rhinosinusitis Outcome Measures‐31 (RSOM‐31) at 2 weeks (Note: the questionnaire was modified to exclude the "importance" parameter)

2. Health‐related quality of life, measured by physician assessment of nasal symptoms (6 scales: congestion, hyposmia, rhinorrhoea, sneezing, postnasal drip and itch) and other related symptoms (4 scales each for eyes and ears and 2 scales for general well‐being) on a visual analogue scale of 1 to 5 (mild to severe) based on the patient history; at 2 weeks

3. Disease severity, measured by physician assessment of nasal symptoms (6 scales: congestion, hyposmia, rhinorrhoea, sneezing, postnasal drip and itch) on a visual analogue scale of 1 to 5 (mild to severe) based on the patient history; at 2 weeks

4. Significant adverse effect: mood or behavioural disturbances

Secondary outcomes:

1. Polyps size measured by endoscopic appearance. Observers selected the group of images showing the more extensive/larger polyps and estimated the percentage reduction in polyp size in the other group. The results from the assessment of 4 clinicians (3 immunologists and 1 ear, nose and throat surgeon) were pooled for analysis.

2. Other adverse effects: gastrointestinal disturbances

3. Other adverse effects: insomnia

Other outcomes reported by the study:

• MRI of the paranasal sinuses before and after treatment

Funding sources

No information provided

Declarations of interest

"P. Wormwald receives royalties from Medtronic Xomed for instruments designed. The rest of the authors have declared that they have no conflict of interest."

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "… randomized by the hospital pharmacy to receive the study medication ..."

Comment: pg 129, col 1, para 2

No information on sequence generation

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "These patients… were blinded to their treatment status"; "study personnel were not informed of the patient’s treatment status until all assessments were completed"

Comment: pg 129, col 1, para 2. It is unclear whether the placebo tablets provide adequate masking in terms of taste, since prednisolone is bitter and may be recognisable to patients.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "study personnel were not informed of the patient's treatment status until all assessments were completed"

Comment: pg 129, col 1, para 2

Blinding of nasoendoscopy scans (pg 129, col 2, para 3) were well documented when describing the outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: 1 patient did not complete the study and their data were not included in the analysis

Selective reporting (reporting bias)

High risk

Comment: nasoendoscopy findings were reported inconsistently within the paper using differing criteria which had not been pre‐specified in the methods section. There was concern that the cut‐off points for reporting could have been chosen after the results were available.

In addition, some of the scales used are unclear. No information is provided for the modified RSOM‐31 instrument or the RSOM‐31 nasal subscale.

No protocol for the trial could be found

Other bias

High risk

The RSOM‐31 was modified, without further evidence of validation, and it is unclear whether the methods for measuring change in polyps size were validated

Methods

4‐arm, unblinded, parallel‐group RCT, with unclear duration of treatment and 7‐day duration of follow‐up

Participants

Location: Turkey, unclear number of sites (probably 1)

Setting of recruitment and treatment: Department of Otorhinolaryngology, GATA medical faculty, Ankara

Sample size:

• Number randomised: 12 in intervention group, 12 in comparison group

• Number completed: 12 in intervention group, 12 in comparison group

Participant (baseline) characteristics: (based on all 4 groups)

• Mean age (range): 32.2 years (20 to 60 years)

• Gender M/F: 40/8

• Main diagnosis: nasal polyposis

• Polyps status: 100% with polyps

• Previous sinus surgery status: 0% had previous polyp surgery

• Previous courses of steroids: information not provided

• Other important effect modifiers: none listed

Inclusion criteria:

Nasal polyps diagnosed by computed tomography

Exclusion criteria: past surgeries for nasal polyps, any glucocorticoid usage for any reason within 1 month, nasal polyp that was not eosinophilic nasal polyp according to the pathology study, fungal chronic sinusitis, age younger than 15 years, Churg‐Strauss syndrome, immunodeficiency, Kartagener's syndrome, Young's syndrome, cystic fibrosis, antrochoanal polyp and unilateral nasal polyp. Additional exclusion criteria were any contraindications for steroid treatment (such as glaucoma, peptic ulcer, acute psychosis, herpetic keratitis, chronic infections, severe osteoporosis, severe hypertension, uncontrolled diabetes mellitus, thromboembolic predisposition, newly formed bowel anastomosis, diverticulitis and Cushing's syndrome)

Interventions

Intervention (n = 12): oral methylprednisolone (Prednol 16 mg tablet, Prednol 4 mg tablet; Mustafa Nevzat Pharmaceutical, Istanbul, Turkey), 1 mg/kg/day. The dose was applied for 3 days and tapered gradually, with a reduction rate of 8 mg/3 days. The duration of drug use varied for each patient changing according to his or her weight.

Comparator group (n = 12): no medication was given

Use of additional interventions (common to both treatment arm): no information

Outcomes

No primary, secondary or adverse events were reported

Other outcomes reported by the study:

• Apoptotic Index. Samples collected on day 7 (Intervention group) and visit 1 (control group)

Funding sources

"None"

Declarations of interest

Competing interests "None"; sponsorships "None"

Notes

2 of the 4 groups within the study were not recorded in this data extraction. The interventions in the 2 additional groups were: intra‐polyp injection and INCS alone (for 30 days).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "…randomly assigned… "

Comment: pg 564, col 1, para 3

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: no medication was given to the comparator group, implying there was no placebo used. It is assumed that the study is not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: no information, but the study only measures objective outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no information. The paper implies that all patients completed treatment and were recorded in the outcomes.

Selective reporting (reporting bias)

Unclear risk

Comment: no outcomes directly relevant to patients were reported. No protocol for the trial could be found.

Other bias

Unclear risk

Comment: no information about the validation of outcomes

Methods

2‐arm, double‐blind, parallel‐group RCT, with 14 days oral steroid treatment duration and 12‐week follow‐up period

Participants

Location: 1 site, Thailand

Setting of recruitment and treatment: Allergy and Rhinology Clinic, Prince of Songkla University

Sample size: 117

Number randomised: 69 in intervention group, 48 in comparison group

Number completed: 67 in intervention group, 47 in comparison group

Participant (baseline) characteristics:

• Age: oral steroids: 45.3; placebo: 46.4

• Gender (M/F): oral steroids: 43/24; placebo: 29/18

• Main diagnosis: bilateral nasal polyps

• Polyps status: 100% with polyps

• Previous sinus surgery status: no information provided

• Previous courses of steroids: no information provided

• Concurrent disease:

  • Aspirin sensitivity: oral steroids: 4; placebo: 4

  • Asthma: oral steroids: 17; placebo: 14

  • Positive allergy skin test: oral steroids: 37; placebo: 25

  • Positive meatal discharge: oral steroids: 29; placebo: 18

  • Positive sinus radiography: oral steroids: 52; placebo: 40

  • Baseline total nasal polyps score: oral steroids: 3.37 +/‐ 1.37; placebo: 3.13 +/‐ 1.09

Inclusion criteria: patients with benign bilateral nasal polyps diagnosed clinically and confirmed by nasal endoscopy

Nasal polyps score: graded on a 4‐point scale (0 to 3): 0 ‐ no polyps, 1 – mild polyposis (small polyps, extending downward from the upper nasal cavity but not below the upper edge of the inferior turbinate, causing only slight obstruction), 2 – moderate polyposis (medium‐sized polyps, extending downward from the upper nasal cavity and reaching between the upper and lower edges of the inferior turbinate, causing troublesome obstruction), 3 – severe polyposis (large‐sized polyps, extending downward from the upper nasal cavity and reaching below the lower edge of the inferior turbinate, causing total or almost total obstruction). The total nasal polyps score was calculated as the sum of the polyps scores for each nostril.

Exclusion criteria: patients with symptoms or physical signs suggestive of renal disease, hepatic disease, diabetes mellitus, cataract, glaucoma, cardiovascular disease, unstable asthma, cystic fibrosis, mucociliary disorders, immunocompromise, severe septal deviation or acute infection within the previous 2 months. Patients who had used nasal, inhaled or systemic steroids within 2 months; an antihistamine within 2 to 7 days; and/or a decongestant within 2 days or had had previous sinonasal surgery were also excluded.

Interventions

Intervention (n = 67): oral prednisolone 50 mg daily for 14 days

Comparator group (n = 47): placebo tablet daily for 14 days

Use of additional interventions (common to both treatment arms): at the end of the "test treatment" stage all patients were then treated with administration of mometasone furoate nasal spray (MFNS) at 200 µg twice daily for 10 weeks

Medications for rhinitis or allergy or nasal saline irrigation were not allowed during their participation in the study

Outcomes

Primary outcomes

1. Disease severity at 2, 7 and 12 weeks, measured the following symptoms; blocked nose, runny nose, sneezing, nasal itching, hyposmia, postnasal drip, cough and sinonasal pain. Each symptom was measured on a 7‐point Likert scale.

Secondary outcomes

1. Nasal polyp size measured by endoscopic appearance. Scored on a scale of 0 to 3 (see inclusion criteria for details) for each nostril and then combined for a total nasal polyp score.

2. Other adverse effects: gastrointestinal disturbances

3. Other adverse effects: insomnia

Other outcomes reported by the study:

• Nasal patency (tested with nasal and oral peak expiratory flow index)

Funding sources

"Funded by the Faculty of Medicine, Prince of Songkla University"

Declarations of interest

"The authors have no conflicts of interest to declare pertaining to this article"

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomly assigned at a 3:2 ratio"

Comment: pg 456, col 1, last para. There is no information regarding the method of sequence generation.

Allocation concealment (selection bias)

Unclear risk

Quote: "The study personnel were not informed of the treatment modality of the patients until all assessments were completed"

Comment: no details on how the patients were allocated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "... prednisolone or placebo", "… were blinded to their treatment regimen." (pg 455, col 2, last para)

"The study personnel were not informed of the treatment modality of the patients until all assessments were completed" (pg 456, col 2, para 1)

Comment: it is unclear whether the placebo tablets provide adequate masking in terms of taste, since prednisolone is bitter and may be recognisable to patients

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The study personnel were not informed of the treatment modality of the patients until all assessments were completed"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: low numbers of patients dropped out – unlikely to affect the overall result

Selective reporting (reporting bias)

Low risk

Comment: appears that all of the outcomes listed were adequately reported in the paper. No protocol for the trial could be found.

Other bias

Unclear risk

Comment: no information about the validation of the "total nasal symptom score"

Methods

2‐arm, double‐blind, parallel‐group RCT, with 2‐week duration of oral steroid treatment, followed by a 6‐month duration of intranasal steroid treatment and duration of follow‐up

Participants

Location: Scotland, 1 site

Setting of recruitment and treatment: speciality referral clinic

Sample size:

Number randomised: 30 in intervention group, 30 in comparison group

Number completed: 27 in intervention group, 24 in comparison group

Participant (baseline) characteristics:

• Mean age (range): oral steroids: 49 (24 to 70); placebo: 52 (17 to 78)

• Gender male/female: oral steroids: 14/16; placebo: 20/10

• Main diagnosis: non‐smoking adults who had CRS with nasal polyposis, with or without asthma

• Polyps status: 100% with polyps

• Mean baseline polyps grade (scale of 0 to 6): oral steroids: 4.7; placebo: 4.8

• Previous sinus surgery status: oral steroids: 7 (23%); placebo: 9 (30%)

• Previous courses of steroids: oral steroids: 3 (10%); placebo: 4 (13%)

Other important effect modifiers

• History of aspirin intolerance: oral steroids: 7 (23%); placebo: 9 (30%)

• Atopy: oral steroids: 13 (43%); placebo: 16 (53%)

• Asthma: oral steroids: 11 (37%); placebo: 16 (53%)

Inclusion criteria: diagnosis of CRS with nasal polyposis made on the basis of the EPOS 2007 criteria

Inclusion criteria were the presence on nasoendoscopy of bilateral moderate‐sized to large nasal polyps (grade > 1) according to the Lildholdt scale and at least 2 of anterior or posterior nasal discharge, nasal obstruction or decreased sense of smell for more than 12 weeks

Lildholdt nasal polyps scale: 0, no nasal polyps; 1, small polyps confined to the middle meatus; 2, moderate sized polyps not crossing the lower edge of the inferior turbinate; 3, large polyps crossing the lower edge of the inferior turbinate

Exclusion criteria: exclusion criteria included treatment with an oral corticosteroid in the past 3 months, sinus surgery in the past year, recent upper respiratory tract infection, mechanical nasal airway obstruction of more than 50% due to septal deviation, or pregnancy or lactation

Interventions

Intervention (n = 30): prednisolone tablets, 25 mg/day, 2 weeks

Comparator group (n = 30): placebo tablets, daily, 2 weeks

Use of additional interventions (common to both treatment arm):

All patients underwent a 2‐week 'run‐in' period prior to the trial during which therapy for CRS with nasal polyps was stopped.

After the 2‐week oral steroid treatment period both study arms received fluticasone propionate nasal drops, 400 µg twice daily, for 8 weeks then fluticasone propionate nasal spray, 200 µg twice daily for a further 18 weeks

No other rhinitis medications were permitted, including antihistamines, leukotriene receptor antagonists, intranasal corticosteroids or nasal decongestants. No antibiotics were permitted during the study.

Outcomes

Primary outcomes

1. Health‐related quality of life, measured by Juniper mini Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at time point 2 weeks and 6 months

2. Disease severity, measured by total nasal symptoms score (no further details) at 2 weeks and 6 months. (In addition, sense of smell was assessed at 2 weeks and 6 months in 2 ways: 10 cm visual analogue scale and Pocket Smell Test).

Secondary outcomes

1. Endoscopic score (nasal polyp score) measured at 2 weeks and 6 months

Other outcomes reported by the study:

• Peak nasal inspiratory flow rate

• Serum eosinophil‐derived neurotoxin

• High‐sensitivity C‐reactive protein levels

• Overnight urinary free cortisol

• Overnight urinary cortisol corrected for creatinine

• 08:00 am serum cortisol

• Low‐dose 1 µg adrenocorticotropic hormone‐simulation test

• Markers of bone turnover

Funding sources

"Chief Scientist Office, Scotland; National Health Service Tayside Small Grants Scheme; and an Anonymous Trust grant from University of Dundee."

Declarations of interest

The link from the paper to the website does not appear to list any declarations of interests

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "An independent, off‐site clinical trials pharmacist (Pharmacy Production Unit, Western Infirmary, Glasgow, United Kingdom) used a computer‐generated random allocation sequence to randomize the trial, using block randomization with a block size of 4."

Comment: pg 294, col 2, para 5

Allocation concealment (selection bias)

Low risk

Quote: "Tablets were distributed in sealed opaque envelopes at the research unit, in sequential order, by a laboratory technician who was not directly involved with the study."

Comment: pg 294, col 2, para 5

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "The same pharmacist masked and blinded the 25‐mg prednisolone tablet and an identical placebo tablet to double‐blind the study from the investigator and participants." (pg 294, col 2, para 5)

"Three patients in the prednisolone group and 4 in the placebo group had previously received oral steroids" (pg 297, col 2)

Comment: it is unclear whether the placebo tablets provide adequate masking in terms of taste, since prednisolone is bitter and may be recognisable to patients

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Standard video sequences were stored on a computer and viewed by 2 independent observers, who were blinded to patient, treatment, and sequence. Disagreements were resolved by discussion."

Comment: pg 295, col 2, para 1

Patients and the main outcome assessors should remain adequately blinded throughout. The other outcomes were assessed by 2 blinded outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "… We included all patients who received the allocated intervention in the analysis"

Comment: pg 295, col 2, para 3

5 patients discontinued after the 2‐week treatment with oral corticosteroids; 4 of these were in the oral steroids group. Another 2 dropped out from each group by the 3‐month follow‐up (total 9/60, 15% overall; 10% in treatment group, 20% in control group)

The results table gives different numbers of participants included in each analysis, which are closer to the number of patients available, rather than patients randomised. It is unclear why there is a discrepancy.

Selective reporting (reporting bias)

Unclear risk

Comment: all outcomes were reported in the results as described in the methods section. The methods for collecting data for adverse events (other than biological assays) were not reported. The paper reports that no oral steroid‐specific adverse events were reported, but it is unclear whether the patients were specifically asked.

The protocol document was available (NCT00788749) and the outcomes appear to be consistent between the protocol and the paper.

Other bias

Unclear risk

Comment: there is no information about the total symptom score (e.g. validation)

Study used the RQLQ (Rhinoconjunctivitis Quality of Life Questionnaire), which is validated for patients with allergy. Many of the items are not relevant for CRS patients, while items related to smell and sinonasal pain were not included.

Methods

3‐arm, double‐blind, multicentre, parallel‐group RCT, with 20 days duration of treatment and 12 weeks duration of follow‐up

Participants

Location: 5 sites in Belgium, Germany, Holland and Australia

Setting of recruitment and treatment: not given

Sample size: 47

Number randomised: 14 in oral steroids, 19 in placebo

Number completed: 14 in oral steroids, 12 in placebo

Participant (baseline) characteristics:

• Mean age (SEM): oral steroids: 48.89 (3.23); placebo: 54.67 (3.07)

• Gender (M/F): oral steroids: 12/2; placebo: 15/4

• Main diagnosis: recurrent bilateral nasal polyps after surgery or massive bilateral nasal polyps (grade 3 or 4)

• Polyps status: 100% with polyps

• Mean total polyp score (SEM): oral steroids: 5.86 (0.27); placebo: 6.16 (0.29)

• Previous sinus surgery status: 100% with previous surgery

• Previous courses of steroids: no information

Other important effect modifiers:

• Allergy (%): oral steroids: 5 (35.7); placebo: 11 (57.9)

• Asthma (%): oral steroids: 6 (42.9); placebo: 5 (26.3)

• Aspirin intolerance (%): oral steroids: 2 (14.3); placebo: 5 (26.3)

Inclusion criteria:

Participants had to be at least 18 years with a diagnosis of bilateral nasal polyps at screening and baseline that have recurred after surgical resection or nasal polyps that are grades 3 or 4 in both nares using the polyp scoring system.

Women of childbearing potential had to use a medically acceptable form of birth control as defined by the study. Male participants had to agree to use an adequate form of birth control for the duration of the study as defined by the study.

Participants with concurrent asthma had to be maintained on no more than 1000 µg/day beclomethasone dipropionate or the equivalent.

Nasal polyp score: 0 ‐ no polyp; 1 ‐ small polyps in the middle meatus not reaching below the inferior border of the middle concha; 2 ‐ polyps reaching below the lower border of the middle turbinate; 3 ‐ large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha, 4 ‐ large polyps causing almost complete congestion/obstruction of the inferior meatus

Exclusion criteria: the following are exclusion criteria for the study: pregnancy, breast‐feeding or premenarcheal;

oral corticosteroids within the 3 months before screening; systemic fungoid infections; known allergic reaction on methylprednisolone or tetracyclines; hypertension; diabetes (type 1 and 2); glaucoma; tuberculosis; herpes infection; zona ophthalmica; antineutrophil cytoplasmic antibodies such as Wegener granulomatosis, Churg‐Strauss syndrome and microscopic polyangiitis

Participants with acute sinusitis or concurrent nasal infection or participants who have had a nasal or upper respiratory tract infection within 2 weeks of the screening visit; cystic fibrosis, primary ciliary dysfunction or Kartagener syndrome by history; those diagnosed with a parasitic infection; HIV‐positive or positive to hepatitis B surface antigen or C antibodies.

Participants must not have had an acute asthmatic attack requiring admission to a hospital (excluding emergency department visits that resulted in direct discharge without hospitalisation) within the 4 weeks before screening

Participants must not have received immunotherapy within the previous 3 months

Interventions

Intervention (n = 14): oral methylprednisolone (32 mg/day on days 1 to 5; 16 mg/day on days 6 to 10; 8 mg/day on days 11 to 20)

Control (n = 19): placebo, unlabelled lactose capsules, 20 days

Use of additional interventions (common to all treatment arm):

Systemic or local corticosteroids or antibiotics were not allowed; if necessary nasal corticosteroids were permitted as rescue medication 2 months after dosing with the study medication

Outcomes

Primary outcomes:

1. Disease severity, measured by patient‐assessed symptoms (anterior rhinorrhoea, nasal obstruction, post‐nasal drip and loss of sense of smell) at 20 days and 12 weeks. Details on the scales used to record symptoms are not provided within the paper.

2. Significant adverse effect: mood or behavioural disturbances

Secondary outcomes:

1. Polyps size measured by endoscopic appearance using scale as presented in the inclusion criteria

2. Other adverse effects: gastrointestinal disturbances

3. Other adverse effects: insomnia

Other outcomes reported by the study:

• Nasal peak inspiratory flow

• Blood analysis for eosinophils, eosinophilic cationic protein and soluble IL‐5 receptor α

• Nasal secretion analysis for eosinophilic cationic protein, IL‐5, IgE, matrix metalloprotease‐9, myeloperoxidase

• Need for rescue surgery and need for rescue nasal steroids

Funding sources

"Supported by a grant from the Flemish Scientific Research Board, FWO Nr. A12/5‐HBKH 3 (holder of a Fundamenteel Klinisch Mandaat), by a postdoctoral grant from the Research Foundation Flanders (FWO), and by postdoctoral mandate from the Research Foundation Flanders (FWO)."

Declarations of interest

"Disclosure of potential conflict of interest: P. J. Wormald has received royalties from Medtronic ENT, is a consultant for NeilMed, and has received research support from the Garnett Passe and Rodney Williams Foundation. W. Fokkens has received research support from GlaxoSmithKline and Stallergenes. A. Beule has received research support from the European Union. The rest of the authors have declared that they have no conflict of interest."

Notes

3rd arm of the study was antibiotics (doxycycline). Results for this arm of the study are included in Head 2016b.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Eligible patients were randomly assigned to 3 groups by individuals not involved in the study."

Comment: pg 1070, col 1, para 3. No information was provided about how the sequence was generated. The number randomised was small and there is a risk that it was not balanced (14 versus 19)

Allocation concealment (selection bias)

Unclear risk

Quote: "… patients were randomly assigned to 3 groups by individuals not involved in the study"

Comment: pg 1070, col 1, para 3
There is no information about allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "… double‐blind… " "... Placebo (lactose) in unlabelled capsules"

Comment: pg 1069, abstract: methods, pg 1070 methods

Details of blinding not clear within the paper and it does not detail whether the placebo (and antibiotic) medications were given on the same dosing schedule with medication in an identical form

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "Study participants and personnel were blind during the duration of the study. Randomisation codes were revealed to researchers after recruitment,data collection, and data entry"

Comment: details of blinding not clear within the paper and it is not clear whether the oral steroids and antibiotic medications were given on the same dosing schedule and were an identical form, which could compromise blinding

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: only 7/47 patients dropped out of the study (14.9%) but all were from the placebo group 7/19 (36.8%). This is an imbalance in drop‐out rate and the reasons for drop‐out include "unsatisfactory therapeutic effects", "withdrawal of consent" and "serious adverse events (asthma attack)". Patients who dropped out were still included in the analysis using the last observed carried forward. This may have had an effect on the overall results and no sensitivity analysis appears to have been completed to identify the impact.

Selective reporting (reporting bias)

Unclear risk

Comment: all outcomes in the methods section were reported in the full paper, although many of them were presented graphically, without providing values at key time periods. The data were not reported in a way that is sufficient to be included in the meta‐analysis of the review.

The protocol document was available (NCT00480298) and the outcomes appear to be consistent between the protocol and the paper

Other bias

Unclear risk

Comment: details of the scales used to measure symptoms were not provided in the paper and there is no information on validation of the outcomes

There was an imbalance in the number of participants with "allergy" (oral steroids: 35.7; placebo: 57.9%; antibiotics: 14.3%) and "aspirin intolerant" in the baseline characteristics (oral steroids: 14.3%; placebo: 26.3%; antibiotics: 7.1%). This was not a statistical difference between the groups due to the study size being small. A sensitivity analysis was completed by the study authors to determine if this affected the results.