Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001331325
Ethics application status
Approved
Date submitted
8/09/2017
Date registered
18/09/2017
Date last updated
23/07/2019
Date data sharing statement initially provided
23/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Nasal High Flow Rhinothermy (rNHF) in Influenza
Scientific title
A randomised, single blind, two arm, parallel group controlled trial of the efficacy of rhinothermy delivered by nasal high flow therapy (rNHF) in the treatment of influenza
Secondary ID [1] 292838 0
MRINZ 17/04
Universal Trial Number (UTN)
U1111-1200-2912
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza 304676 0
Condition category
Condition code
Respiratory 303990 303990 0 0
Other respiratory disorders / diseases
Infection 304013 304013 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are two possible interventions:
1. Standard rNHF: 100% humidified air delivered via the rNHF device at 35L/min and 41°C for 2 hours daily for 5 days. On Day 1 this will be administered under the supervision of investigators at the MRINZ clinic and then participants will go on to self-administer the treatment at home for a further 4 days. The participant will be encouraged to self-administer their rhinothermy in a single 2 hour session on each day of treatment. However, if the participant is unable to do so, then the daily rhinothermy treatment can be split into 2 sessions aiming for the participant to complete a total of 2 hours of rhinothermy each day. Participants may also reduce the flow to a minimum of 30L/min at home according to comfort.
2. ‘Sham’ rhinothermy: 100% humidified air delivered via the myAIRVO 2 device at 10L/min and 31°C for 10 minutes daily for 5 days. On Day 1 this will be administered under the supervision of investigators at the MRINZ clinic and then participants will go on to self-administer the treatment at home for a further 4 days. The participant will be encouraged to self-administer the ‘sham’ rhinothermy in a single 10 minute session on each day of treatment.
Intervention code [1] 299083 0
Treatment: Devices
Comparator / control treatment
‘Sham’ rhinothermy: 100% humidified air delivered via the myAIRVO 2 device at 10L/min and 31°C for 10 minutes daily for 5 days, will be used as the control treatment.
Control group
Active

Outcomes
Primary outcome [1] 303326 0
To compare the area under the curve (AUC) quantitative PCR influenza log10 viral load (Day 1 to Day 5) between the treatment groups using Quantitative PCR influenza log10 viral load Days 1, 3 and 5 per Canterbury District Health Board; Canterbury Health Laboratories (CDHB: CHL) laboratory testing.
The influenza viral load is assessed from the nasopharyngeal swabs taken on Days 1, 3 and 5.
Timepoint [1] 303326 0
Day 1 (primary time point), 3 and 5
Secondary outcome [1] 338631 0
To compare between the treatment groups, the composite Influenza Symptom Score on Day 2 through to Day 14 (as captured in the participant's daily symptom diary) adjusted for baseline (Day 1) score.

The composite Influenza Symptom Score has previously been utliised in trials of antiviral medication (Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rose A, Kinnersley N, Ward P. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000;355:1845-1850 AND Hayden FG, Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA. 1996; 275: 295-299. doi:10.1001/jama.1996.03530280047035), and in a previous trial of the use of paracetamol in the treatment of influenza that the MRINZ undertook in 2013/2014 (Jefferies S, Braithwaite I, Walker S, Weatherall M, Jennings L, Luck M, et al. Randomized controlled trial of the effect of regular paracetamol on influenza infection. Respirology. 2016;21(2):370–7).
Timepoint [1] 338631 0
Daily on day 1 to day 14 inclusive
Secondary outcome [2] 338632 0
To compare between the treatment groups, the number of days until a participant returns to their “normal daily activities” using the day the participant selects that they have returned to [their] normal daily activities in the daily symptom diary..
Timepoint [2] 338632 0
Day 2 to day 14 inclusive
Secondary outcome [3] 338638 0
Time until feeling “a little better” compared to study entry (day 1), as captured in the participant daily symptom diary
Timepoint [3] 338638 0
Day 2 to day 14 inclusive
Secondary outcome [4] 338640 0
To compare between the treatment groups, the daily mean temperature on day 1 to day 5 inclusive. The participant's will measure their own temperature twice daily, using a tympanic thermometer on day 1 to day 5 inclusive. They will record this in their daily symptom diary.
Timepoint [4] 338640 0
Twice daily on day 1 to day 5 inclusive
Secondary outcome [5] 338641 0
To compare between the treatment groups, the time until resolution of symptoms (defined as the start of a 24 hour period in which the composite Influenza Symptom Score was less than or equal to 1 and remained so for 24 hours) as captured in the participant's daily symptom diary.

The composite influenza score has previously been utliised in trials of antiviral medication (Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rose A, Kinnersley N, Ward P. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000;355:1845-1850 AND Hayden FG, Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA. 1996; 275: 295-299. doi:10.1001/jama.1996.03530280047035), and in a previous trial of the use of paracetamol in the treatment of influenza that the MRINZ undertook in 2013/2014 (Jefferies S, Braithwaite I, Walker S, Weatherall M, Jennings L, Luck M, et al. Randomized controlled trial of the effect of regular paracetamol on influenza infection. Respirology. 2016;21(2):370–7).
Timepoint [5] 338641 0
Daily from day 2 to day 14 inclusive.
Secondary outcome [6] 338712 0
Time until feeling “a lot better” compared to study entry (day 1), as captured in the participant daily symptom diary
Timepoint [6] 338712 0
Day 2 to day 14 inclusive
Secondary outcome [7] 342304 0
To compare between the treatment groups, the proportion of participants with undetectable viral load by RT-PCR at Day 3 using the quantitative PCR influenza viral load on Day 3 as per Canterbury District Health Board: Canterbury Health Laboratories (CDHB: CHL) laboratory testing.
Timepoint [7] 342304 0
Day 3
Secondary outcome [8] 342305 0
To compare between the treatment groups, the proportion of participants with >2 log10 decrease in viral load at Day 3 using the quantitative PCR influenza log10 viral load Days 1 and 3 as per Canterbury District Health Board: Canterbury Health Laboratories (CDHB: CHL) laboratory testing.
Timepoint [8] 342305 0
Day 3
Secondary outcome [9] 342306 0
To compare between the treatment groups, the proportion of participants with undetectable viral load by RT-PCR at Day 5 using the quantitative PCR influenza viral load on Day 5 as per Canterbury District Health Board: Canterbury Health Laboratories (CDHB: CHL) laboratory testing.
Timepoint [9] 342306 0
Day 5
Secondary outcome [10] 342307 0
To compare between the treatment groups, the maximum temperature on day 1 to day 5 inclusive. The participant's will measure their own temperature twice daily, using a tympanic thermometer on day 1 to day 5 inclusive. They will record this in their daily symptom diary.
Timepoint [10] 342307 0
Day 1 to day 5 inclusive
Secondary outcome [11] 342308 0
To compare between the treatment groups, the proportion of participants with >2 log10 decrease in viral load at Day 5 using the quantitative PCR influenza log10 viral load on Days 1 and 5 as per Canterbury District Health Board: Canterbury Health Laboratories (CDHB: CHL) laboratory testing.
Timepoint [11] 342308 0
Day 5
Secondary outcome [12] 342309 0
The patterns of use of the rNHF device: mean number of minutes used per day. This will be determined by the device use data downloaded from the device on Day 5.
Timepoint [12] 342309 0
Day 1 to day 5 inclusive
Secondary outcome [13] 342310 0
The patterns of use of the rNHF device: mean number of sessions per day. This will be determined by the device use data downloaded from the device on Day 5.
Timepoint [13] 342310 0
Day 1 to day 5 inclusive
Secondary outcome [14] 342311 0
The patterns of use of the rNHF device: average set flow rate (L/min) This will be determined by the device use data downloaded from the device on Day 5.
Timepoint [14] 342311 0
Day 1 to day 5 inclusive
Secondary outcome [15] 342312 0
The adherence to rNHF therapy (defined as a minimum of 90 minutes use per day, delivered in no more than 2 sessions per day), this will be determined by device use data downloaded from the device on Day 5.
Timepoint [15] 342312 0
Day 1 to day 5 inclusive
Secondary outcome [16] 342313 0
Ease of use of rNHF therapy. This will be determined by the participants on the Tolerability Questionnaire (given to the participants on Day 5) which has been designed specifically for this study.
Timepoint [16] 342313 0
Day 5
Secondary outcome [17] 342314 0
How comfortable the participant found using the rNHF device. This will be determined by the participants on the Tolerability Questionnaire (given to the participants on Day 5) which has been designed specifically for this study.
Timepoint [17] 342314 0
Day 5
Secondary outcome [18] 342315 0
The likelihood of participants using rNHF in the future. This will be determined by the participants on the Tolerability Questionnaire (given to the participants on Day 5) which has been designed specifically for this study.
Timepoint [18] 342315 0
Day 5
Secondary outcome [19] 349222 0
The Modified Jackson Symptom Score on Day 2 to Day 14 inclusive, adjusted for baseline (Day 1) score.

The Modified Jackson Score has previously been validated (Jackson GG, Dowling HF, Spiesman IG, et al. Transmission of the common cold to volunteers under controlled conditions. I. The common cold as a clinical entity. AMA Arch Intern Med 1958;101:267–78.http://www.ncbi.nlm.nih.gov/pubmed/13497324)
Timepoint [19] 349222 0
Daily from day 2 to day 14 inclusive
Secondary outcome [20] 349223 0
The Modified Jackson Symptom Score Area Under The Curve (AUC) between Day 1 and Day 5.
Timepoint [20] 349223 0
Day 1 to Day 5 inclusive

Eligibility
Key inclusion criteria
Aged 18 to 75 years.
• In the Investigator’s opinion, is able and willing to comply with all trial requirements.
• Onset of symptoms within the last 48 hours at time of consent.
• A POSITIVE test for Influenza A or B viruses using the GeneXpert® Xpress Flu/RSV point-of-care test (Cepheid, Ca, USA)
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Immunocompromised condition:
o Conditions causing immunosuppression e.g. HIV/AIDS, active cancer
o Currently prescribed systemic steroids or other immunosuppressant medication
• Nasal conditions such as deviated septum, chronic rhinitis, which the investigator considers could impair nasal breathing.
• Current use of or requirement for oral antibiotics for respiratory tract infection, pneumonia or infective exacerbation of underlying respiratory condition.
• Current use of or requirement for parenteral antibiotics.
• Daily intra-nasal or inhaled steroids will be allowed if part of the participant’s regular therapy. If not taken prior to enrolment, they should be withheld for the duration of this study.
• The investigator believes the participant or their care giver will be unable to safely use rNHF without medical supervision.
• Have any other condition which, at the investigator’s discretion, is believed may present a safety risk or impact the feasibility of the study or the study results.
• Have an implantable medical device.
• Have a notifiable disease
• Have existing travel plans that require them to leave the greater Wellington region during the first 5 days of the study (the period during which the participant will be using the rhinothermy device.
• A NEGATIVE influenza point of care screening test.
• Known pregnancy or a positive pregnancy test during screening.

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)
A computer-generated sequence will be supplied by the study statistician, independent of the investigators. The electronic case report form (eCRF) system will conceal the allocations and will release a participant’s randomisation outcome at the time of randomisation. The randomisation schedule will be accessed only by the study statistician and the eCRF provider; study staff will not have access to the randomisation schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised 1:1 to receive one of two possible treatment arms using a permuted block randomisation method, stratified by duration of illness (less than one day, versus greater than or equal to one day) and temperature (less than 38.5°C versus greater than or equal to 38.5°C)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The standard deviation (SD) for AUC for quantitative PCR influenza viral load for Days 1 & 5 is between 1.4 and 2.2 log10 units (Nicholson et al. Lancet, 2000:355:1845-1850). An RCT of anti-viral therapy in influenza reports a difference from placebo therapy of 2.2 log10 units (Hayden et al. JAMA: 1996; 275: 295-299). If the effect of rhinothermy is half that of the difference found with anti-viral therapy (1.1 units), and using the mean of the SDs above, if there is a 10% drop out rate, a total sample size of 140, with 70 in each of two treatment arms, has 90% power to detect this difference, with a type I error rate of 5%. Although retention was 100% in our previous common cold pilot RCT, the lower confidence limit was 88%, and so a 10% drop out rate is justified.

Statistical analysis will be by intention to treat. The primary outcome variable will be analysed by ANOVA with the log PCR as the response variable and the randomised treatment as an explanatory variable. For the continuous secondary variables ANCOVA will be used with the baseline measurements where appropriate as a continuous covariate.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
4/09/2018
Actual
4/09/2018
Date of last participant enrolment
Anticipated
30/11/2021
Actual
22/05/2019
Date of last data collection
Anticipated
18/12/2021
Actual
22/05/2019
Sample size
Target
140
Accrual to date
Final
6
Recruitment outside Australia
Country [1] 9182 0
New Zealand
State/province [1] 9182 0
Wellington

Funding & Sponsors
Funding source category [1] 297469 0
Commercial sector/Industry
Name [1] 297469 0
Fisher and Paykel Healthcare Limited
Country [1] 297469 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
Fisher and Paykel Healthcare Limited
Address
15 Maurice Paykel Place
East Tamaki
Auckland 2013
New Zealand.
Country
New Zealand
Secondary sponsor category [1] 296467 0
None
Name [1] 296467 0
Address [1] 296467 0
Country [1] 296467 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298574 0
New Zealand Health and Disability Ethics Committee (Southern)
Ethics committee address [1] 298574 0
Ethics committee country [1] 298574 0
New Zealand
Date submitted for ethics approval [1] 298574 0
04/09/2017
Approval date [1] 298574 0
06/12/2017
Ethics approval number [1] 298574 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2030 2030 0 0
/AnzctrAttachments/373616-HDEC_Letter_17-STH-177_expedited_review.pdf (Supplementary information)

Contacts
Principal investigator
Name 77522 0
Dr Irene Braithwaite
Address 77522 0
Medical Research Institute of New Zealand,
Level 7, Clinical Services Building,
Wellington Regional Hospital,
Newtown,
Wellington 6021,
New Zealand
Country 77522 0
New Zealand
Phone 77522 0
+64 4 8050245
Fax 77522 0
+64 4 3895707
Email 77522 0
[email protected]
Contact person for public queries
Name 77523 0
Irene Braithwaite
Address 77523 0
Medical Research Institute of New Zealand,
Level 7, Clinical Services Building,
Wellington Regional Hospital,
Newtown,
Wellington 6021,
New Zealand
Country 77523 0
New Zealand
Phone 77523 0
+64 4 8050245
Fax 77523 0
+64 4 3895707
Email 77523 0
[email protected]
Contact person for scientific queries
Name 77524 0
Irene Braithwaite
Address 77524 0
Medical Research Institute of New Zealand,
Level 7, Clinical Services Building,
Wellington Regional Hospital,
Newtown,
Wellington 6021,
New Zealand
Country 77524 0
New Zealand
Phone 77524 0
+64 4 8050245
Fax 77524 0
+64 4 3895707
Email 77524 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


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.