Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000011684
Ethics application status
Approved
Date submitted
19/12/2022
Date registered
9/01/2023
Date last updated
9/01/2023
Date data sharing statement initially provided
9/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A double-blinded randomised control human clinical trial evaluating the safety and effectiveness of colloidal silver sinonasal rinse versus standard of care on post-operative symptomatic outcomes in the treatment of Chronic Rhinosinusitis in adults.
Scientific title
Randomised Controlled double blinded Human Clinical Trial on the Effectiveness of CS Sinonasal Rinse vs CS Sinonasal Rinse and ABX, vs topical ABX vs oral ABX and saline Sinonasal Rinse (standard of care) in the Management of Patients with CRS
Secondary ID [1] 308607 0
CALHN reference number MYIP 14173
Universal Trial Number (UTN)
U1111-1286-0828
Trial acronym
SFSilver2020
Linked study record
The current study is a follow up to study with AZTCTR registration number ACTRN12616001558415

Health condition
Health condition(s) or problem(s) studied:
chronic rhinosinusitis 328497 0
Condition category
Condition code
Surgery 325525 325525 0 0
Other surgery
Inflammatory and Immune System 325526 325526 0 0
Other inflammatory or immune system disorders
Respiratory 325527 325527 0 0
Other respiratory disorders / diseases
Infection 325528 325528 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with symptomatic chronic rhinosinusitis who have had previous sinus surgery and have evidence of chronic rhinosinusitis on endoscopic examination will be recruited into this trial.

Patients will be blindly, randomly selected into one of three treatment arms (each n=11). Treatments will be dispensed and explained to the participants after informed consent has been gained at the outpatient clinic at The Queen Elizabeth Hospital (TQEH) or the private rooms of the Chief investigator. These tasks will be performed by the laboratory research coordinator.

Arm 2:
One arm (termed Treatment arm 2 in the study protocol) will receive both green synthesised colloidal silver produced at the Basil Hetzel Institute under sterile conditions (10ml stock of 44ppm in 200ml 5% dextrose nasal wash) delivered via sinonasal rinse and culture specific topical antibiotic (mupirocin 10 % nasal irrigation gel is delivered at a final concentration of 0.05% and tobramycin 125 mg/mL nasal irrigation solution at a final concentration of 0.625mg/ml in 200 mL saline nasal wash) for 28 days and placebo oral antibiotics (Microcrystalline cellulose capsules) 1 twice daily for 10 days.

Arm 3:
Another group (Treatment arm 3) will receive culture specific topical antibiotics (mupirocin and tobramycin as above) with placebo colloidal silver (5% dextrose with colouring agents 102, 133 and 124 in 200ml sinonasal wash) via sinonasal rinse for 28 days and placebo oral antibiotics (Microcrystalline cellulose capsules) 1 twice daily for 10 days.

Arm 4:
The final group (Treatment arm 4) will receive colloidal silver (as above) with placebo topical antibiotics (Hypromellose gel) twice daily for 28 days delivered via sinonasal rinse, and placebo oral antibiotics (Microcrystalline cellulose capsules) 1 twice daily for 10 days.
Intervention code [1] 325109 0
Treatment: Drugs
Comparator / control treatment
The control group will receive placebo colloidal silver (5% dextrose with colouring agents 102, 133 and 124 in 200ml sinonasal wash) and placebo topical antibiotics (Hypromellose gel) via sinonasal rinse and culture directed oral antibiotics (either Ciprofloxacin 500mg tablet 1 twice daily for 7 days or amoxicillin 875 mg (as trihydrate) and clavulanic acid 125 mg (as potassium) tablet 1 twice daily for 10 days). This is standard of care for recalcitrant chronic rhinosinusitis (CRS). This is referred to as Treatment arm 1 in the study protocol.
Control group
Active

Outcomes
Primary outcome [1] 333412 0
Change in burden of CRS bacterial infection in sinonasal tract via microbiology assays (assessment of colony forming units)
Timepoint [1] 333412 0
0 days (baseline), 28 days (primary timepoint) and 6 months after first intervention
Primary outcome [2] 333413 0
Assessment of safety of colloidal silver and topical antibiotic sinonasal rinse via documentation of adverse events. This will be assessed by participant discussion with clinician at time points below and filling in an adverse events diary throughout the study duration.
Timepoint [2] 333413 0
Participant discussion with clinician: 0 days (baseline), 28 days (primary time point) and 6 months after first intervention
Adverse Events diary: Filled out daily by participant from 0 days (baseline) to 6 months after first intervention. Adverse events diary collected by research coordinator at 28 days (primary timepoint) and 6 months after first intervention.
Primary outcome [3] 333414 0
Assessment of CRS symptoms by LKS (Lund Kennedy score) by endoscopic examination of the sinonasal tract by the chief investigator.
Timepoint [3] 333414 0
0 days (baseline), 28 days (primary time point) and 6 months after first intervention
Secondary outcome [1] 416977 0
Makeup of the sinus microbiome as assessed by sequencing of DNA extracted from swabs taken of the microbiome by the chief investigator
Timepoint [1] 416977 0
0 days, 28 days and 6 months after first intervention
Secondary outcome [2] 417204 0
Assessment of CRS symptoms by participant completion of SNOT 22 (Sino-nasal Outcome Test) questionnaire. This is an additional primary outcome.
Timepoint [2] 417204 0
0 days (baseline), 28 days (primary timepoint) and 6 months after initial intervention
Secondary outcome [3] 417205 0
Assessment of CRS symptoms by participant completion of VAS (Visual analogue scale) questionnaire. This is an additional primary outcome.
Timepoint [3] 417205 0
0 days (baseline), 28 days (primary timepoint) and 6 months after initial intervention

Eligibility
Key inclusion criteria
Participants must have had at least two of the following symptoms of chronic rhinosinusitis (nasal discharge, postnasal drip, nasal obstruction, facial pain and pressure or lack of sense of smell) that has been previously persistent for greater than 3 months.
Participants must have had endoscopic sinus surgery (ESS) and be able to start the trial anytime from two weeks post-operative.
Participants must show evidence of chronic sinusitis by direct endoscopic examination. Participants must show evidence of infectious exacerbation by direct endoscopic examination and have a positive culture diagnosis with pathogens that show sensitivity to mupirocin and/or tobramycin and/or oral antibiotic.
Participants must have the ability to administer daily sinus rinses for the duration of the treatment period.
Participants must be aged 18 years or over.
Participants must be able to give written informed consent.
Participants must have the ability and willingness to attend several visits to the outpatients.
Participants must have the willingness and ability to comply with the requirements of the protocol as determined by the Investigator.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants who are unlikely to comply with the study protocol or, in the opinion of the investigator, would not be a suitable candidate for participation in the study. Pregnant and breastfeeding women will also be excluded.
Participants who are actively taking oral steroids or antibiotics will be excluded from the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment by central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation generated by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A total of 44 participants will be enrolled in the study, which will allow for 11 participants in each study arm. This sample size was determined with formal statistical power calculations and accounted for a 10% loss to follow up.
A mean difference in SNOT-22 tests of 9.5 (standard deviation (SD) =15.9) was “a little better” by Hopkins et al. 2009 (Table 3). A mean difference in SNOT-22 tests of 23.3 (standard deviation =18.4) was “much better” by Hopkins et al. 2009 (Table 3).
A two-sample t tests assuming equal variance was performed (Figure 1) assuming “a little better” improvement (mean difference=9.5, SD=15.9), with power of 80%, alpha=0.05 for a 2-sided test. The sample size calculated was 45 per group (so total N=180 for 4 groups).
A two-sample t tests assuming equal variance was performed (Figure 2) assuming “much better” improvement (mean difference=23.3, SD=18.4), with power of 80%, alpha=0.05 for a 2-sided test. The sample size calculated was 11 per group (so total N=44 for 4 groups).

The statistical software used was SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/02/2023
Actual
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
31/03/2024
Actual
Sample size
Target
44
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23740 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 39182 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 312852 0
University
Name [1] 312852 0
The University of Adelaide
Country [1] 312852 0
Australia
Funding source category [2] 312880 0
Hospital
Name [2] 312880 0
The Queen Elizabeth Hospital
Country [2] 312880 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network
Address
CALHN Research Services, Central Adelaide Local Health Network Inc., SA Health.
Level 3, Roma Mitchell Building, 136 North Terrace, Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 314501 0
None
Name [1] 314501 0
Address [1] 314501 0
Country [1] 314501 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312129 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 312129 0
Level 3, Roma Mitchell House
136 North Terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 312129 0
Australia
Date submitted for ethics approval [1] 312129 0
26/08/2021
Approval date [1] 312129 0
30/11/2021
Ethics approval number [1] 312129 0

Summary
Brief summary

Chronic sinusitis is a debilitating and costly disease. Consistent inflammation and infection of the sinuses causes headaches, facial pain, blockage of the nose and discharge from the nose. The cause of this condition is not fully understood, and it is difficult to treat with surgery being the recommended treatment for some patients. But even after surgery, many patient’s symptoms return, and they may need repeat surgeries in the future. We currently recommend sinus rinses after surgery as a way of keeping sinuses clean and clear and to assist with healing and reducing inflammation and infection. We have previously found that proper care post-operatively can reduce the chances of requiring further surgeries and part of our research has been assessing the different rinses. Our laboratory studies have shown that colloidal silver reduces infection load significantly. In the laboratory, we have improved this product’s manufacturing process by using extracts from gum tree fresh leaves which are abundant in Australia. The safety of colloidal silver was tested in the lab and according to the results it is safe to the sinuses. This clinical trial is aimed at assessing 1. The safety of colloidal silver administration by sino-nasal rinse by documenting any adverse effects and 2. The effect of sinonasal rinse of colloidal silver combined with topical antibiotics on infection load in chronic sinusitis, compared to standard-of-care oral antibiotic tablets. This will be assessed by endoscopic assessment of the sino-nasal tract by a doctor, measuring bacterial load in the laboratory and completion of symptom questionnaires by participants.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123582 0
Prof Peter-John Wormald
Address 123582 0
Name: Central Adelaide Local Health Network (CALHN)
Address: The Queen Elizabeth Hospital
Department of Otolaryngology, Head and Neck Surgery
Tower Block 3C
37 Woodville Road
Woodville South SA 5011
Country: Australia
Country 123582 0
Australia
Phone 123582 0
+61882227158
Fax 123582 0
Email 123582 0
pjwormald@gmail.com
Contact person for public queries
Name 123583 0
Prof Peter-John Wormald
Address 123583 0
Name: Central Adelaide Local Health Network (CALHN)
Address: The Queen Elizabeth Hospital
Department of Otolaryngology, Head and Neck Surgery
Tower Block 3C
37 Woodville Road
Woodville South SA 5011
Country: Australia
Country 123583 0
Australia
Phone 123583 0
+61882227158
Fax 123583 0
Email 123583 0
pjwormald@gmail.com
Contact person for scientific queries
Name 123584 0
Prof Peter-John Wormald
Address 123584 0
Name: Central Adelaide Local Health Network (CALHN)
Address: The Queen Elizabeth Hospital
Department of Otolaryngology, Head and Neck Surgery
Tower Block 3C
37 Woodville Road
Woodville South SA 5011
Country: Australia
Country 123584 0
Australia
Phone 123584 0
+61882227158
Fax 123584 0
Email 123584 0
pjwormald@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We will publish the results of the trial in a suitable scientific journal. This will not include individual participant data, summary tables and statistical analysis only


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.