RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA HONEY …€¦ · Rosacea is a common chronic...

For peer review only

RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA

HONEY FOR THE TREATMENT OF ROSACEA

Journal: BMJ Open

Manuscript ID: bmjopen-2015-007651

Article Type: Research

Date Submitted by the Author: 12-Jan-2015

Complete List of Authors: Braithwaite, Irene; Medical Research Institute of New Zealand, Hunt, Anna; Medical Research Institute of New Zealand, Riley, Judith; Medical Research Institute of New Zealand, Fingleton, James; Medical Research Institute of New Zealand, Kocks, Janwillem; Medical Research Institute of New Zealand, Corin, Andrew; Clinical Horizons, Helm, Colin; Clinical Horizons, Sheehan, Davitt; Papamoa Pines Medical Centre,

Tofield, Chris; Cameron Medical Clinic, Montgomery, Barney; Optimal Clinical Trials, Holliday, Mark; Medical Research Institute of New Zealand, Weatherall, Mark; University of Otago Wellington, Beasley, Richard; Medical Research Institute of New Zealand,

<b>Primary Subject Heading</b>:

Complementary medicine

Secondary Subject Heading: Complementary medicine, Dermatology, Infectious diseases

Keywords: Rosacea, Kanuka honey, randomised controlled trial

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA HONEY FOR THE

TREATMENT OF ROSACEA

Irene Braithwaite1, Anna Hunt1, Judith Riley1, James Fingleton1, Janwillem Kocks1

Andrew Corin2, Colin Helm2 Davitt Sheahan3, Chris Tofield4, Barney Montgomery5, Mark

Holliday1, Mark Weatherall6, Richard Beasley1

1Medical Research Institute of New Zealand, Wellington, New Zealand, 2 Clinical Horizons,

Tauranga, New Zealand, 3 Papamoa Pines Medical Centre, Tauranga, New Zealand, 4

Cameron Medical Clinic, Tauranga, New Zealand, 5 Optimal Clinical Trials, , Auckland, New

Zealand, 6University of Otago, Wellington

Word count: (Abstract 298), manuscript 2,459

Key words: Rosacea, kanuka honey, randomised controlled trial

Ethics approval: Central Health and Disability Ethics Committee (13/CEN/118) Funding: This study was funded by HoneyLab. HoneyLab provided the medical grade kanuka honey.

Contact: Dr Irene Braithwaite Medical Research Institute of New Zealand Private Bag 7902, Wellington 6242, New Zealand Telephone: +64-4-805 0233 Fax: +64-4-389 5707 Email:[email protected]

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ABSTRACT (298 words including registration statement)

Objective: To investigate the efficacy of topical 90% medical grade kanuka honey and 10%

glycerine (Honevo®) as a treatment for rosacea.

Design: Randomised controlled trial with blinded assessment of primary outcome variable.

Setting: Outpatient primary healthcare population from 5 New Zealand sites.

Participants: 138 adults aged ≥16, with a diagnosis of rosacea, and a baseline blinded

Investigator Global Assessment of Rosacea Severity Score (IGA-RSS) of ≥2. 69 participants

were randomised to each treatment arm. One participant was excluded from the Honevo®

group, and 7 and 15 participants withdrew from the Honevo® and control groups

respectively.

Interventions: Participants were randomly allocated 1:1 to Honevo® or control cream

(cetomacrogol), applied twice daily for 8 weeks.

Main outcome measures: The primary outcome measure was the proportion of subjects

who had a ≥ 2 improvement in the 7-point IGA-RSS at week 8 compared to baseline.

Secondary outcomes included change in IGA-RSS and subject-rated visual analogue score

of change in severity (VAS-CS) on a 100mm scale (0mm ‘much worse’, 100mm ‘much

improved’) at weeks 2 and 8.

Results: 24/68 (34.3%) in the Honevo® group and 12/69 (17.4%) in the control group had a

≥ 2 improvement in IGA-RSS at week 8 compared to baseline (relative risk 2.03; 95% CI

1.11 to 3.72, P=0.020). The change in IGA-RSS for Honevo® compared to control at week 2

minus baseline was -1 (Hodges-Lehman estimate, 95%CI -1 to 0, P=0.03), and at week 8

minus baseline was -1 (Hodges-Lehman estimate, 95%CI -1 to 0, P=0.005). The VAS-CS at

week 2 was 9.1 (95%CI 3.5 to 14.7), P=0.002, and at week 8 was 12.3 (95%CI 5.7 to 18.9)¸

P<0.001 for Honevo® compared to control.

Conclusion: Honevo® is an effective treatment for rosacea.

Trial registration: This trial was registered in the Australian and New Zealand Clinical Trials

Registry ACTRN12614000004662

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WHAT IS KNOWN ABOUT THE TOPIC?

Honey is a potential topical treatment for rosacea as it has antimicrobial and anti-

inflammatory effects. A recent pilot study has demonstrated that medical grade (sterilised

and filtered), kanuka honey is an acceptable and potentially effective treatment for rosacea

WHAT THIS STUDY ADDS

Our study has shown that Honevo® is an effective treatment for rosacea, with clinical

efficacy observed within 2 weeks of treatment.

STRENGTHS AND LIMITATIONS

• This is a randomised placebo-controlled trial of topical 90% medical-grade kanuka

honey and 10% glycerine cream (Honevo®) versus a non-ionic paraffin based cream

(cetomacragol) for the treatment of rosacea

• The primary outcome variable for this study (Investigator Global Assessment of

Rosacea Severity Score) was assessed by investigators who were blinded to

randomisation throughout the trial.

• Due to the nature of the products being assessed, participants were not able to be

blinded to the treatment arms

• Further randomised controlled trials comparing Honevo® with topical metronidazole

and azelaic acid are required to determine its relative efficacy and side effect profile

compared to these agents

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INTRODUCTION

Rosacea is a common chronic inflammatory skin condition which primarily affects the face,

and occurs in up to 10% of the adult population.1-3 There is no cure, and affected individuals

may experience substantial morbidity. There is a range of treatment options, including

several topical and oral antibiotics, however these are only partially effective and side effects

may limit their use3-6 Also there are global concerns about the increasing rates of antibiotic

resistance resulting from the widespread use of antibiotics, particularly with long term use in

chronic conditions.7,8 This has led to the United Kingdom Standing Medical Advisory

Committee recommending that the fewest number of antibiotic courses should be prescribed

for the shortest period possible.9

This has led to the investigation of alternative therapies such as medical grade kanuka

honey, due to its potent antibacterial and anti-inflammatory activities.10-14 The

pathophysiological rationale underlying its use is that rosacea is an inflammatory disorder,

and that antigenic proteins related to the bacterium Bacillus oleronius isolated from the

Demodex folliculorum mite, which infests the skin in rosacea, exacerbates this inflammatory

response.15,16 Furthermore, people with rosacea express abnormally high levels of the

antimicrobial peptide cathelicidin, which promotes the inflammatory response in rosacea.17

A recent pilot study of topical medical-grade kanuka honey as a treatment for rosacea found

it to be an acceptable and potentially effective treatment.18 The addition of 10% glycerine to

the honey has resulted in a product that is easier to apply to the skin. In this randomised

controlled trial we have investigated the efficacy of kanuka honey in the treatment of

rosacea. We designed the trial to overcome the recognised limitations of previous studies, in

particular to ensure that there was blinded investigator assessment of rosacea severity.5

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METHODS

This parallel group randomised controlled trial with assessor blinding was undertaken at a

hospital-based research facility and 4 community-based research and / or primary care sites

in New Zealand. Adults aged 16 or over with a doctor’s diagnosis of rosacea on the face,

and a baseline blinded Investigator Global Assessment of Rosacea Severity Score (IGA-

RSS) of facial rosacea of ≥2 were recruited. The IGA-RSS is a 7-point scale (from 0: ‘clear’,

to 6: ‘severe’) that provides an integrated assessment of rosacea severity based on the

principal facial signs of papules/pustules, inflammatory lesions, erythema and telangiectasia4

(Table S1). Subjects were identified at the time of first presentation or, with their primary

care practitioner’s consent, from pre-existing databases, or by public advertisement.

Exclusion criteria included current requirement for systemic corticosteroids, or systemic

corticosteroid treatment in the 4 weeks prior to Visit 1, current requirement for oral or topical

antibiotic therapy for rosacea, current requirement for topical corticosteroid treatment for

rosacea, known or suspected allergy to honey, or Cetomacrogol control cream, or any other

condition which, at the investigators discretion, it was believed may present a safety risk or

impact the feasibility of the study or the study results.

Participants attended for 3 visits (Table S2). Visit 1 (week 0) consisted of consent, baseline

assessments (the IGA-RSS), a participant-rated rosacea severity visual analogue score

(VAS–S) on a 100mm scale (0mm being ‘mildest possible’ symptoms and 100mm being

‘worst possible’ symptoms), and a participant-rated dermatology quality of life index

(DLQI)19, followed by randomisation to Honevo® or Cetomacrogol cream (control). At Visit 2

(week 2) and Visit 3 (week 8), as well as the IGA-RSS and the DLQI, participants completed

a subjective rosacea ‘change in severity’ visual analogue scale (VAS-CS) on a 100mm scale

(0mm being ‘much worse’ and 100mm being ‘much improved’). Subjects’ diaries were used

throughout the study to capture each participant’s weekly subjective VAS-S, their use of

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randomised treatment throughout the 8 week study period, and any general comments

including adverse events throughout the study.

Randomisation and blinding

Treatment allocation was randomised using a computer generated sequence concealed to

investigators. Subjects were randomised in a 1:1 ratio to the topical application of Honevo®

or control cream. Due to the nature of Honevo® it was not possible to blind the participants

and primary investigators to the treatment allocation. An independent investigator at each

site remained blinded to the treatment allocation throughout the study to perform the blinded

IGA.

Randomised treatments

The Investigational Product was topical medical grade Kanuka honey with 10% glycerine

content (Honevo®). The control cream was Cetomacrogol, a liquid paraffin and white soft

paraffin topical emollient.20,21 The participants were instructed to apply an appropriate

amount of cream to the affected area twice daily for 30-60 minutes per application, for eight

weeks, and to remove the treatment with warm water as desired. Subjects were asked not

to use any additional treatment for their rosacea for the duration of the study, as per the

exclusion criteria.

Outcome measures

The primary outcome measure was the proportion of subjects who had a ≥2 improvement

(reduction) in the IGA-RSS at week 8 (designated ‘responders’). This measure represents a

clinically meaningful improvement in rosacea severity. The secondary outcome measures

included the change from baseline in IGA-RSS at week 2 and week 8; the participant-rated

VAS-CS at weeks 2 and 8; the change from baseline in participant-rated VAS-S at week 2

and week 8; the weekly diary-documented Rosacea severity VAS-S from participant diaries;

the change from baseline in the participant-rated DLQI19 at weeks 2 and 8; withdrawals due

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to worsening of Rosacea; adverse events; and the daily self-reported use of Honevo®

(applications per day).

Sample size and study power

We anticipated the proportion of participants in the control group who respond with a ≥2

reduction in blinded IGA would be between 25 and 50%.5 A total of 124 participants (62 in

each group) has 80% power at 5% significance to detect a 25% response rate in the control

group and a 50% response rate in the Honevo® group. We recruited 138 participants to

allow for a 10% drop-out rate.

Statistical methods

The study was analysed by an intention to treat, with the participants who withdrew

considered to be non-responders. The pre-specified statistical analysis was logistic

regression for the difference in proportions with response.

Relative risks for a ≥2 point change in IGA-RSS at week 8 from baseline and for total study

withdrawal were calculated, with P values using Fishers exact test. Odds ratios were also

calculated from logistic regression

For the Likert scaled variables the Wilcoxon test and Hodges-Lehman estimator of location

shift for the difference between treatments were used. DLQI and VAS variables were

analysed by ANCOVA with the baseline value as a continuous covariate and the

randomization as the main predictor variable. The estimates for these analyses are

interpreted as the difference between randomized groups adjusted for baseline.

Applications per day was analysed by ANOVA with the response variable the mean average

number of applications per day, predictor variable randomization group, and using the

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number of days in the trial as a weight, to account for variations in the number of days of

application.

In a post-hoc analysis, the proportion of participants in whom the IGA-RSS was zero (clear

of rosacea) at week 8 was calculated.

SAS version 9.3 was used.

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RESULTS

The flow of participants in the study is shown in Figure 1. There were 69 subjects

randomised to control and 69 to Honevo®. One Honevo® participant was subsequently

excluded as they were using a prohibited medication on enrolment, and their data was not

used in the consequent analysis. The characteristics of the participants are shown in Table

1. Participants were predominantly aged between 50 and 70, and had had rosacea for a

mean of 15 years. 19% of participants in each group had previously used oral antibiotics for

rosacea, while 44% and 38% had previously used any topical treatments for rosacea in the

Honevo® and control group respectively. There were 7/68 (10.3%) withdrawals in the

Honevo® group (3 worsening rosacea, 2 took prohibited medications, 2 for other reasons

unrelated to the study) and 15/69 (21.7%) withdrawals in the control group (8 worsening

rosacea, 2 took prohibited medications, 1 did not want to take the control medication, 1

found the study inconvenient and 3 for reasons unrelated to the study).

Primary outcome

There were 24/68 (34.3%) in the Honevo® group and 12/69 (17.4%) in the control group

who had a ≥2 improvement in IGA-RSS at week 8 compared to baseline (relative risk 2.03

(95% CI 1.11 to 3.72), P=0.020. The corresponding odds ratio was 2.59 (1.17 to 5.74).

Secondary outcomes

The change from baseline in IGA-RSS for participants who did not withdraw is shown in

Table 2, Table S3 and Figure 2.The change in IGA-RSS for Honevo® compared to control at

week 2 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to 0, P=0.03), and at

week 8 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to 0, P=0.005),(Table

3). The subject-rated VAS-CS at week 2 was 9.1 (CI 3.5 to 14.7), P=0.002, and at week 8

was 12.3 (CI 5.7 to 18.9), P<0.001for Honevo® compared to control, representing greater

improvement with Honevo®. There was no significant difference in diary-captured VAS-S,

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adjusted for baseline, at any of the time points between week 2 and 8 (Table S4).There was

no significant difference in the participant-rated DLQI adjusted for baseline at week 2 (-0.3,

CI-1.1 to 0.6, P=0.51) or week 8 (-0.01, CI -0.7 to 0.7,P=0.97).

The number of applications per day between the randomised treatments was similar (mean

(SD) 1.84(0.23) vs 1.86(0.20) for the Honevo® and control groups respectively, difference: -

0.02 (95% CI -0.10 to 0.05), P=0.55).

In a post hoc analysis, the proportion of participants in whom the IGA-RSS score at week 8

was zero, (i.e. full resolution of rosacea) was 9/68 (13.2%) and 2/69 (2.9%) in the Honevo®

and control groups respectively, relative risk 4.6 (95%CI 1.0 to 20.4, P=0.031).

In the Honevo® group 23 participants reported 31 adverse events; 17 rosacea related, (3 of

which resulted in withdrawal of the participants), and 14 unrelated to rosacea (Table S5). In

the control group, 27 participants reported 36 adverse events; 22 rosacea related, (8 of

which resulted in withdrawal of participants), and 14 unrelated to rosacea.

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DISCUSSION

This randomised controlled trial has demonstrated that topical 90% medical grade kanuka

honey and 10% glycerine (Honevo®) is an effective and well tolerated treatment for rosacea.

About one third of participants had a clinically significant improvement in the IGA-RSS after

8 weeks of Honevo® treatment, two-fold greater than that observed with the control

treatment. We recommend consideration of the use of kanuka honey as a treatment for

rosacea.

There are a number of methodological issues that are important in the consideration of the

study findings. There are no standard validated tools for assessing the severity of rosacea,

which is inherently difficult due to its varied clinical characteristics. The priority with this study

of a honey product was to reduce potential bias by blinding of clinical assessments where

possible, as the participant could not be blinded due to the appearance and smell of

Honevo®. It was for this reason we chose to use the 7 point IGA-RSS representing a global

assessment of rosacea severity that was undertaken by an investigator who was blinded to

treatment. A 2 point reduction in IGA-RSS represents a clinically meaningful improvement,

for example a change from ‘severe’ to ‘moderate’, or from ‘moderate’ to ‘mild’ rosacea

severity. In addition, we assessed patient-reported outcomes, based on participant’s

assessment of current severity of symptoms (VAS-S), participant’s perceived change in

severity (VAS-CS) and the DLQI questionnaire, to provide a comprehensive assessment of

efficacy. The VAS-CS at the 2-week and 8-week clinic visits were significantly better with

Honevo®, but there was no difference with the 2-week and 8-week DLQI assessments or

the weekly diary VAS-S measures. The greater number of withdrawals due to worsening

rosacea in the control group (12% vs 4%), is likely to have led to an under-estimation of the

efficacy of Honevo®, as these participants did not undergo assessment of the secondary

outcome variables following withdrawal.

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Cetomacrogol cream was chosen as a comparator as it is a non-ionic moisturising cream,

often used as a vehicle for delivery of topical medications. The treatment was administered

for 8 weeks to allow both the speed of onset and the duration of effect to be assessed. This

identified that honey had efficacy within 2 weeks of treatment, with further efficacy obtained

during the 8 week treatment period. Adverse event data did not allow us to reliably ascertain

whether the rosacea specific adverse events such as burning, itching, peeling, stinging, dry

skin and pain were associated only with the application of the investigational medicine or

whether they were ongoing rosacea symptoms. However it was reassuring that the number

of participants with rosacea specific adverse events was similar between Honevo® and the

paraffin-based emollient control cream.

It is interesting to compare our findings with those from studies of topical metronidazole or

azelaic acid, two of the more commonly used treatments of rosacea.3-6 While

acknowledging the different primary outcome variables, in placebo controlled studies of

topical metronidazole the relative risk of improvement with the physician’s global evaluation

of improvement was 1.95 (95% CI 1.5 to 2.6), and in the placebo controlled studies of

azelaic cream the relative risk of participant-assessed improvement was 1.52 (95% CI 1.3 to

1.8)5,22. By comparison, the relative risk of IGA-RSS improvement with Honevo® was 2.0

(95%CI 1.1 to 3.7) and in the post hoc analysis the relative risk of resolution was 4.6 (95%CI

1.0 to 20.4). Randomised controlled trials comparing Honevo® with topical metronidazole or

azelaic cream are now indicated.

The mechanism of action was not assessed in this study, however there a number of

potential mechanisms relevant to the efficacy demonstrated with kanuka honey in this study.

Firstly kanuka honey has a number of different anti-inflammatory effects, including inhibition

of neutrophil superoxide production,12 reduction in inflammatory leucocyte infiltration and

arachidonic- induced oedema,12 and stimulation of macrophage release of tumour necrosis

factor a (TNFa),14 a cytokine with a crucial role in wound healing.23,24 These properties may

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be relevant as rosacea is a chronic inflammatory disorder, characterised by inflammatory cell

infiltration, vascular dilatation and tissue oedema.1,2,5 In addition, kanuka honey has high

antibacterial activities against a wide range of bacteria, including Bacillus subtilis,

Propionibacterium acne and Staph Aureus,10,11,13 properties which may be beneficial in view

of the proposed role of Bacillus oleronius in the inflammatory response in rosacea. The

effect of honey on Bacillus oleronius and the Demodex folliculum mite require further

investigation.

In conclusion, this randomised controlled trial has demonstrated the clinical efficacy and

tolerability of 90% medical grade kanuka honey and 10% glycerine (Honevo®) in the

treatment of rosacea. Honevo® can be recommended for the treatment of rosacea;

however, further randomised controlled trials comparing Honevo® with topical metronidazole

and azelaic acid are now required to determine its relative efficacy and side effect profile

compared to these agents.

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STATEMENTS

Corresponding Author Statement: The Corresponding Author has the right to grant on

behalf of all authors and does grant on behalf of all authors, an exclusive licence on a

worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be

published in BMJ editions and any other BMJPGL products and sublicences such use and

exploit all subsidiary rights, as set out in our licence.

Competing interest statement: All authors have completed the Unified Competing Interest

form atwww.icmje.org/coi_disclosure.pdf (available on request from the corresponding

author) and declare: HoneyLab Ltd provided funding to undertake this study and provided

the product Honevo® for the purpose of the study; Dr Shaun Holt, the Medical Director of

HoneyLab Ltd was previously the Programme Director of Complementary Medicine at the

Medical Research Institute of New Zealand. There are no other competing interests to

declare.

Role of the funding source: HoneyLab was consulted in the design of the study and

preparation of the report, but had no involvement in the collection, analysis and interpretation

of the data, or decision to submit for publication.

Contributorship statement: Study concept and design: JF, JK, MH, MW, RB. Acquisition of

Data: IB, AH, JR, AC, CH, DS, CT, BM. Drafting of the manuscript: RB, IB, MW. Critical

revision of the manuscript for important intellectual content: all authors. Statistical analysis:

MW. Administrative, technical and material support: All authors. Study supervision: MH.

Guarantor: Dr I Braithwaite had access to all the data on the study and takes responsibility

for the integrity of the data and accuracy of the data analysis.

Transparency declaration: The lead author affirms that the manuscript is an honest,

accurate, and transparent account of the study being reported; that no important aspects of

the study have been omitted; and that any discrepancies from the study as planned (and, if

relevant, registered) have been explained

Data sharing statement: Patient level data available from the corresponding author.

Consent was not obtained from participants for data sharing, but the presented data are

anonymised and the risk of identification is low. Data may be obtained by contacting the

corresponding author.

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Table 1: Baseline characteristics of participants

Mean (SD) Median (IQR) Min to Max

Age at enrolment

Honevo® N-68 57.7 (13.7) 58.2 (46.7 to 68.3) 23.4 to 86.5

Control N=69 58.9 (15.9) 60.1 (49.0 to 68.6) 18.2 to 90.1

All N=137 58.3 (14.8) 58.9 (48.1 to 68.6) 18.2 to 90.1

Age at Diagnosis

Honevo® N=64 42.2 (15.4) 40 (30 to 51.5) 19 to 80

Control N=67 43.6 (15.4) 43 (35 to 55) 10 to 79

All N=131 42.9 (15.4) 41 (32 to 54) 10 to 80

Honevo® N (%) N=68

Control N (%) N=69

Female 32 (47.1) 36 (52.2)

History of oral antibiotics 13 (19.1) 13 (18.8)

History of topical therapy 24 (35.3) 20 (29.0)

History of topical steroid 6 (8.8) 6 (8.7)

European 64 (94.1) 68 (98.6)

Maori 4 (5.9) 0 (0)

Asian 0 (0) 1 (1.5)

SD – standard deviation IQR – inter quartile range

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Table 2: Contingency table of blinded Investigator Global Assessment of Rosacea

Severity Score (IGA-RSS) week 8 change from baseline by randomisation in the

subjects who completed the study

Change from baseline Honevo® N/61 (%) Control N/54 (%)

-3 11 (18.0) 1 (1.9)

-2 13 (21.3) 11 (20.4)

-1 20 (32.8) 17 (31.5)

0 14 (23.0) 15 (27.8)

1 3 (4.9) 8 (14.8)

2 0 (0) 2 (3.7)

IGA-RSS: blinded Investigator Global Assessment of Rosacea Severity Score based on a 7 point scale (0 ‘clear’ to 6 ‘severe’

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Table 3: Clinic-based secondary outcome variables (all Honevo® minus control)

Comparison Hodges-Lehman estimate (95% CI)

P

IGA-RSS week 2 0 (-1 to 0) 0.26

IGA-RSS week 8 0 (-1 to 0) 0.06

IGA-RSS week 2 minus baseline -1 (-1 to 0) 0.03

IGA-RSS week 8 minus baseline -1 (-1 to 0) 0.005

Estimate (95% CI) P

IGA-RSS week 8 adjusted for baseline1 -0.6 (-1.1 to -0.2) 0.003

Mean difference (95% CI) P

VAS-CS week 2 9.1 (3.5 to 14.7) 0.002

VAS-CS week 8 12.3 (5.7 to 18.9) <0.001

VAS-S week 2 -3.6 (-9.9 to 2.7) 0.26

VAS-S week 2 minus baseline -2.9 (-9.2 to 3.5) 0.38

VAS-S week 8 -4.5 (-11.6 to 2.6) 0.21

VAS-S week 8 minus baseline -11.0 (-18.0 to -3.9) 0.003

IGA-RSS: blinded Investigator Global Assessment of Rosacea Severity Score, based on a 7 point scale (0 ‘clear’ to 6 ‘severe’) VAS-CS: Participant-rated assessment of Change in Severity of rosacea based on a 100mm VAS scale (0mm ‘much worse’ to 100mm ‘much improved’) VAS-S: Participant-rated assessment of Severity of rosacea based on a 100mm VAS scale (0mm ‘mildest possible’ symptoms and 100mm ‘worst possible’ symptoms) ANOVA with baseline reading as a covariate, normality assumptions not well met

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Supplement Table S1: Blinded Investigator Global Assessment of Rosacea Severity Score (IGA-RSS)

Numerical Score

Definition Description

0 Clear Almost no Rosacea (i.e. no papules and/or pustules); no or residual erythema; mild to moderate degree of telangiectasia may be present

1 Minimal Rare papules and/or pustules; residual to mild erythema; mild to moderate degree of telangiectasia may be present

2 Mild Few papules and/or pustules; mild erythema; mild to moderate degree of telangiectasia may be present

3 Mild to moderate Distinct number of papules and/or pustules; mild to moderate erythema; mild to moderate degree of telangiectasia may be present

4 Moderate Pronounced number of papules and/or pustules; moderate erythema; mild to moderate degree of telangiectasia may be present

5 Moderate to Severe

Many papules and/or pustules, occasionally with large inflamed lesions; moderate erythema; moderate degree of telangiectasia may be present

6 Severe Numerous papules and/or pustules, occasionally with confluent areas of inflamed lesions; moderate to severe erythema; moderate to severe degree of telangiectasia may be present

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Supplement Table S2: Schedule of Assessments

Visit Number Visit 1 Visit 2 Visit 3

Time Point Week 0 Day 1

Week 2 Day 15

Week 8 Day 57

Informed Consent X

Eligibility criteria checked X

Demographics and medical history X

Randomisation X

Administer DLQI X X X

Administer IGA X X X

Participant-rated severity VAS-S completiona X X X

Participant-rated change VAS-CS severity completion

X X

Provision of participant diary X X

Collection of participant diary X X

Safety monitoring X X X

DLQI: Dermatology Life Quality Index

IGA-RSS blinded Investigator Global Assessment of Rosacea Severity Score VAS-S: Participant-rated assessment of severity of rosacea VAS-CS: Participant-rated assessment of change in severity of rosacea a VAS-S to be completed weekly from Visit 1 until Visit 3, within the subject diary

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Supplement Table S3: Clinic-based secondary outcome variables


IGA-RSS week Zero

Control N=69 3 (0.9) 3 (2 to 4) 2 to 5 Honevo® N=68 3 (0.9) 3 (2 to 3.5) 2 to 6

IGA-RSS week 2

Control N=66 2.5 (1.4) 2 (2 to 3) 0 to 6 Honevo® N=66 2.2 (1.2) 2 (1 to 3) 0 to 6

IGA-RSS week 8


Difference IGA-RSS week 2 to week Zero Control N=66 -0.5 (0.9) 0 (-1 to 0) -3 to 1 Honevo® N=66 -0.8 (1.0) -1 (-2 to 0) -3 to 2

Difference IGA-RSS week 8 to week Zero

Control N=54 -0.6 (1.1) 0 (-1 to 0) -3 to 2 Honevo® N=61 -1.2 (1.1) -1 (-2 to 0) -3 to 1

VAS-CS week 2


VAS-CS week 8


VAS-S week Zero

Control N=69 32.0 (19.1) 28 (18 to 44) 1 to 87 Honevo® N=68 36.8 (21.2) 31.5 (21 to 54) 1 to 78

VAS-S week 2

Control N=66 34.9 (19.6) 32.5 (21 to 50) 1 to 84 Honevo® N=66 31.2 (16.9) 29.5 (20 to 42) 1 to 68

VAS-S week 8


Difference VAS-S week 2 to week Zero

Control N=66 3.0 (16.7) 0.5 (-6.0 to 8.0) -30 to 73 Honevo® N=66 -5.2 (16.1) -6 (-16 to 1) -37 to 38


Control N=54 2.1 (14.5) -1 (-9 to 11) -39 to 41 Honevo® N=61 -8.9 (22.4) -10(-24 to 9) -66 to 38

IGA-RSS: blinded Investigator Global Assessment of Rosacea Severity Score, based on a 7 point scale (0 ‘clear’ to 6 ‘severe’) VAS-CS: Participant-rated assessment of Change in Severity of rosacea based on a 100mm VAS scale (0mm ‘much worse’ to 100mm ‘much improved’) VAS-S: Participant-rated assessment of Severity of rosacea based on a 100mm VAS scale (0mm ‘mildest possible’ symptoms and 100mm ‘worst possible’ symptoms)

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Supplement Table S4: Diary-based VAS-S adjusted for baseline

Honevo® minus Control

Estimate (95% CI) P

VAS-S week 2 -4.0 (-8.5 to 0.6) 0.088

VAS-S week 3 -1.3 (-6.8 to 4.2) 0.65

VAS-S week 4 -4.0 (-10.3 to 2.4) 0.21

VAS-S week 5 -2.0 (-7.8 to 3.9) 0.50

VAS-S week 6 -5.3 (-2.5 to 14.2) 0.13

VAS-S week 7 -2.1 (-8.9 to 4.7) 0.54

VAS-S week 8 -5.7 (-6.2 to 13.3) 0.15

VAS-S: Participant-rated assessment of Severity of rosacea based on a 100mm VAS scale (0mm ‘mildest possible’ symptoms and 100mm ‘worst possible’ symptoms)

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Supplement Table S5: Adverse events reported in the Honevo® and Control groups.

Honevo® N

Control N

Rosacea related adverse events resulting in withdrawal

Worsening Rosacea 3 8

Rosacea related adverse events without withdrawal


Itching 5 1

Tingling 3 2

Red spots 2 0

Eczema 1 0

Dry skin 1 0

Peeling 1 0

Pain 1 0

Stinging 0 4

Burning 0 2

Blisters 0 1

Bleeding 0 1

Possible fungal skin infection 0 1

Non-rosacea related adverse events resulting in withdrawal

0 0

Non-rosacea related adverse events without withdrawal

Other skin problem 1 0

Infection 6 7

Trauma 3 1

Indigestion 1 0

Worsening Asthma 1 0

Headache / Migraine 1 2

Elevated PSA 1 0

Cardiovascular 0 2

Allergy / Hayfever 0 2

Note: Participants may report more than one adverse event

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FIGURE LEGENDS

Figure 1: Flow of participants through trial.

Figure 2: The difference from baseline in IGA-RSS at week 8 for control and Honevo®.

Horizontal lines are the 25%, median and 75% quantiles, the symbol is the mean and

the whiskers go from maximum to minimum.

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REFERENCES

1. Buechner SA. Rosacea: an update. Dermatology. 2005;210(2):100-8. 2. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69(5):419-23. 3. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005 Feb 24;352(8):793-803. 4. Elewski BE, Fleischer AB, Jr., Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003 Nov;139(11):1444-50. 5. van Zuuren EJ, Kramer S, Carter B, Graber MA, Fedorowicz Z. Interventions for rosacea. Cochrane Database Syst Rev. (3):CD003262. 6. Elewski BE. Rosacea trial comparing twice-daily azelaic acid gel 15% with once-daily metronidazole gel 1%. Cutis. 2007 Jan;79(1):57-8; author reply 8. 7. World Health O. Antimicrobial resistance: global report on surveillance 2014; 2014. Report No.: ISBN: 978 92 4 156474 8 Contract No.: Document Number|. 8. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ.340:c2096. 9. Department of Health UKSMAC. The path of least resistance. 1998. 10. Wu Q. Antimicrobial effect of Manuka honey and Kanuka honey alone and in combination with the bioactives against the growth of Propionibacterium acnes ATCC 6919: a thesissubmitted in partial fulfilment of the requirements for the degree Master of Food Technology, Massey University, Albany, New Zealand; 2011. 11. Lu J, Carter DA, Turnbull L, Rosendale D, Hedderley D, Stephens J, et al. The effect of New Zealand kanuka, manuka and clover honeys on bacterial growth dynamics and cellular morphology varies according to the species. PLoS One.8(2):e55898. 12. Leong AG, Herst PM, Harper JL. Indigenous New Zealand honeys exhibit multiple anti-inflammatory activities. Innate Immun. Jun;18(3):459-66. 13. Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New Zealand honeys. J Pharm Pharmacol. 1991 Dec;43(12):817-22. 14. Gannabathula S, Skinner MA, Rosendale D, Greenwood JM, Mutukumira AN, Steinhorn G, et al. Arabinogalactan proteins contribute to the immunostimulatory properties of New Zealand honeys. Immunopharmacol Immunotoxicol. Aug;34(4):598-607. 15. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007 Sep;157(3):474-81. 16. Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J Am Acad Dermatol. 1993 Mar;28(3):443-8. 17. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007 Aug;13(8):975-80. 18. Fingleton JS, D. Cave, N. Brinded, A. Weatherall, M. Perrin, K. Beasley,R. Topical kanuka honey for the treatment of rosacea. Focus on Alternative and Complementary Therapies. 2013;18(4):221-2. 19. Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI). J Investig Dermatol Symp Proc. 2004 Mar;9(2):169-80. 20. (Datapharm) ew. Cetomacrogol Cream BP 1988 Formula A. https://wwwmedicinesorguk/emc/medicine/25140. Last accessed Dec 24,2014. 21. Kingdom NNHSU. Cetomacrogol Cream Formula A. http://wwwnhsuk/medicine-guides/pages/MedicineOverviewaspx?medicine=Cetomacrogol%20Cream%20Formula%20A. Last accessed Dec 24, 2014. 22. van Zuuren EJ, Kramer SF, Carter BR, Graber MA, Fedorowicz Z. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. Oct;165(4):760-81. 23. Fu X, Tian H, Hsu S, Wang D, Sheng Z. In vivo effects of tumor necrosis factor-alpha on incised wound and gunshot wound healing. J Trauma. 1996 Mar;40(3 Suppl):S140-3.

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24. Mooney DP, O'Reilly M, Gamelli RL. Tumor necrosis factor and wound healing. Ann Surg. 1990 Feb;211(2):124-9.

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56x67mm (300 x 300 DPI)

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11x9mm (600 x 600 DPI)

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CONSORT 2010 checklist Page 1

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title title

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 4

2b Specific objectives or hypotheses 4

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 5

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons n/a

Participants 4a Eligibility criteria for participants 5

4b Settings and locations where the data were collected 5

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

6

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

6-7

6b Any changes to trial outcomes after the trial commenced, with reasons n/a

Sample size 7a How sample size was determined 8

7b When applicable, explanation of any interim analyses and stopping guidelines n/a

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 6

8b Type of randomisation; details of any restriction (such as blocking and block size) 6

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned

6

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

6

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 6

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assessing outcomes) and how

11b If relevant, description of the similarity of interventions n/a

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 7

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 7

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

9, fig 1

13b For each group, losses and exclusions after randomisation, together with reasons 9, fig 1

Recruitment 14a Dates defining the periods of recruitment and follow-up 5

14b Why the trial ended or was stopped n/a

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group 15

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

9

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

9-10

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended 9-10

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

9-10

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 10

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 11-12

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 11-12

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 12-13

Other information

Registration 23 Registration number and name of trial registry abstract

Protocol 24 Where the full trial protocol can be accessed, if available uploaded

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders title

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

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Journal: BMJ Open

Manuscript ID: bmjopen-2015-007651.R1


Date Submitted by the Author: 17-Apr-2015








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Andrew Corin2, Colin Helm2 Davitt Sheahan3, Chris Tofield4, Barney Montgomery5, Mark

Holliday1, Mark Weatherall6, Richard Beasley1







Funding: This study was funded by HoneyLab. HoneyLab provided the medical grade kanuka honey.


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respectively.


















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• This is a randomised placebo-controlled trial of 8 weeks of treatment for rosacea with

either topical 90% medical-grade kanuka honey and 10% glycerine cream

(Honevo®) or a non-ionic paraffin based cream (cetomacragol).






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INTRODUCTION


and occurs in up to 10% of the adult population.1-4 There is no cure, and affected individuals

may experience substantial morbidity. There is a range of treatment options, including

several topical and oral antibiotics, however these are only partially effective and side effects

may limit their use4-7 Also there are global concerns about the increasing rates of antibiotic

resistance resulting from the widespread use of antibiotics, particularly with long term use in

chronic conditions.8,9 For example, the United Kingdom Standing Medical Advisory

Committee now recommends the fewest number of antibiotic courses should be prescribed

for the shortest period possible.10

Amongst the alternative therapies to antibiotics, medical grade kanuka honey is of interest

due to its potent antibacterial and anti-inflammatory activities.11-15 The pathophysiological

rationale underlying its use is that rosacea is an inflammatory disorder, and that antigenic

proteins related to the bacterium Bacillus oleronius isolated from the Demodex folliculorum

mite, which infests the skin in rosacea, exacerbates this inflammatory response.16,17

Furthermore, people with rosacea express abnormally high levels of the antimicrobial

peptide cathelicidin, which promotes the inflammatory response in rosacea.18


it to be an acceptable and potentially effective treatment.19The addition of 10% glycerine to

the honey has resulted in a product that is easier to apply to the skin. In this randomised



particular to ensure that there was blinded investigator assessment of rosacea severity.6

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METHODS



in New Zealand. Ethics approval was obtained from the Central Health and Disability Ethics

Committee (13/CEN/118). Adults aged 16 or over with a doctor’s diagnosis of rosacea on the

face, and a baseline blinded Investigator Global Assessment of Rosacea Severity Score

(IGA-RSS) of facial rosacea of ≥2 were recruited. The IGA-RSS is a 7-point scale (from 0:

‘clear’, to 6: ‘severe’) that provides an integrated assessment of rosacea severity based on

the principal facial signs of papules/pustules, inflammatory lesions, erythema and

telangiectasia5 (Supplement Table S1). Subjects were identified at the time of first

presentation or, with their primary care practitioner’s consent, from pre-existing databases,

or by public advertisement.







Participants attended for 3 visits (Supplement Table S2). Visit 1 (week 0) consisted of

consent, baseline assessments (the IGA-RSS), a participant-rated rosacea severity visual

analogue score (VAS–S) on a 100mm scale (0mm being ‘mildest possible’ symptoms and

100mm being ‘worst possible’ symptoms), and a participant-rated dermatology quality of life

index (DLQI)20, followed by randomisation to Honevo® or Cetomacrogol cream (control). At

Visit 2 (week 2) and Visit 3 (week 8), as well as the IGA-RSS and the DLQI, participants

completed a subjective rosacea ‘change in severity’ visual analogue scale (VAS-CS) on a

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100mm scale (0mm being ‘much worse’ and 100mm being ‘much improved’). Subjects’

diaries were used throughout the study to capture each participant’s weekly subjective VAS-

S, their use of randomised treatment throughout the 8 week study period, and any general

comments including adverse events throughout the study.



investigators by enclosing the proposed treatment arm in an opaque envelope that was only

opened by primary investigators after informed consent was obtained by each participant.

Subjects were randomised in a 1:1 ratio to the topical application of Honevo® or control

cream. Due to the nature of Honevo® it was not possible to blind the participants and

primary investigators to the treatment allocation. An independent investigator at each site

remained blinded to the treatment allocation throughout the study to perform the blinded

IGA. The blinded investigator undertook only the IGA-RSS assessment for this study, and

was not involved in any other study procedures. Participants were instructed not to

communicate with the blinded investigator during the assessments.




paraffin topical emollient.21,22 The participants were instructed to apply an appropriate




exclusion criteria.

Outcome measures

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the change from baseline in the participant-rated DLQI20 at weeks 2 and 8; withdrawals due

to worsening of Rosacea; adverse events; and the daily self-reported use of Honevo®

(applications per day). Data for all participants was included for analysis up until the time the

participant withdrew from the study or became ineligible due to the use of prohibited

medications.







Statistical methods







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Page 8




randomisation as the main predictor variable. The estimates for these analyses are

interpreted as the difference between randomised groups adjusted for baseline.


number of applications per day, predictor variable randomisation group, and using the


application.




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Page 9

RESULTS



excluded due to the use of a prohibited medication on enrolment, and their data was not










Primary outcome




Secondary outcomes


Table 2, Supplement Table S3 and Figure 2.The change in IGA-RSS for Honevo®

compared to control at week 2 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1

to 0, P=0.03), and at week 8 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to

0, P=0.005),(Table 3). The subject-rated VAS-CS at week 2 was 9.1 (CI 3.5 to 14.7),

P=0.002, and at week 8 was 12.3 (CI 5.7 to 18.9), P<0.001for Honevo® compared to

control, representing greater improvement with Honevo®. There was no significant

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difference in diary-captured VAS-S, adjusted for baseline, at any of the time points between

week 2 and 8 (Supplement Table S4).There was no significant difference in the participant-

rated DLQI adjusted for baseline at week 2 (-0.3, CI-1.1 to 0.6, P=0.51) or week 8 (-0.01, CI

-0.7 to 0.7,P=0.97).



0.02 (95% CI -0.10 to 0.05), P=0.55).





which resulted in withdrawal of the participants), and 14 unrelated to rosacea (Supplement

Table S5). In the control group, 27 participants reported 36 adverse events; 22 rosacea

related, (8 of which resulted in withdrawal of participants), and 14 unrelated to rosacea.

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DISCUSSION






rosacea.








treatment.

The primary outcome variable identified the proportion in each treatment arm who had a 2

point reduction or more in IGA-RSS, representing a clinically meaningful improvement in

rosacea severity, for example a change from ‘severe’ to ‘moderate’, or from ‘moderate’ to

‘mild’. 34% of those who were randomised to Honevo® had an IGA-RSS improvement of 2

or more at 8 weeks compared to 17% of the placebo group, and 13% achieved full resolution

of rosacea compared to 3% in the placebo group. The estimate of the location shift for the

difference between the treatments was -1, (95% CI -1 to 0) at both week 2 and week 8 and

the estimated change in IGA-RSS at week 8 adjusted for baseline was -0.6 (95% CI -1.1 to -

0.2). These findings reflect the variability in response to Honevo®, perhaps dependent on

sub-types of rosacea2 which were not assessed in this study.

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In addition, we assessed patient-reported outcomes, based on participant’s assessment of

current severity of symptoms (VAS-S), participant’s perceived change in severity (VAS-CS)

and the DLQI questionnaire, to provide a comprehensive assessment of efficacy. The VAS-

CS at the 2-week and 8-week clinic visits were significantly better with Honevo®. However,

there was no difference with the 2-week and 8-week DLQI assessments or the weekly diary

VAS-S measures. In the absence of a validated VAS for rosacea severity, it is difficult to

comment on the clinical relevance of a reduction of 11 points from baseline in the VAS-S or

the 12.3 improvement in VAS-CS in the Honevo® group compared to the control group after

8 weeks. As these outcomes were participant assessed and participants could not be

blinded to the interventions, there is a risk of detection bias in this methodology. The DLQI is

a questionnaire non-specific to rosacea and may not have been sensitive enough to capture

changes associated with this condition alone. The greater number of withdrawals due to

worsening rosacea in the control group (12% vs 4%), is likely to have led to an under-

estimation of the efficacy of Honevo®, as these participants did not undergo assessment of

the secondary outcome variables following withdrawal.


often used as a vehicle for delivery of topical medications. The treatment was administered

for 8 weeks to allow both the speed of onset and the duration of effect to be assessed. This

identified that honey had efficacy within 2 weeks of treatment, with further efficacy obtained

during the 8 week treatment period. Adverse event data did not allow us to reliably ascertain

whether the rosacea specific adverse events such as burning, itching, peeling, stinging, dry

skin and pain were associated only with the application of the investigational medicine or

whether they were ongoing rosacea symptoms. However it was reassuring that the number

of participants with rosacea specific adverse events was similar between Honevo® and the

paraffin-based emollient control cream.

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Notwithstanding the limitations of comparing different primary outcome variables utilised in

other studies of rosacea, it is interesting to note the findings from placebo-controlled studies

of topical metronidazole or azelaic acid, two of the more commonly used treatments of

rosacea.4-7 In studies of topical metronidazole the relative risk of improvement with the

physician’s global evaluation of improvement was 1.95 (95% CI 1.5 to 2.6), and in studies of


1.8)6,23. In our study, the relative risk of IGA-RSS improvement with Honevo® was 2.0


1.0 to 20.4). Given the apparent superiority of all three treatments compared to placebo,

randomised controlled trials comparing Honevo® with topical metronidazole or azelaic

cream are now indicated.




of neutrophil superoxide production,13 reduction in inflammatory leucocyte infiltration and

arachidonic- induced oedema,13 and stimulation of macrophage release of tumour necrosis

factor a (TNFa),15 a cytokine with a crucial role in wound healing.24,254 These properties may

be relevant as rosacea is a chronic inflammatory disorder, characterised by inflammatory cell

infiltration, vascular dilatation and tissue oedema.1,3,6 In addition, kanuka honey has high

antibacterial activities against a wide range of bacteria, including Bacillus subtilis,

Propionibacterium acne and Staph Aureus,11,12,14 properties which may be beneficial in view

of the proposed role of Bacillus oleronius in the inflammatory response in rosacea. The

effect of honey on Bacillus oleronius and the Demodex folliculum mite require further

investigation.



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Page 15

STATEMENTS












declare.


















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Age at enrolment

Honevo® N-68 57.7 (13.7) 58.2 (46.7 to 68.3) 23.4 to 86.5

Control N=69 58.9 (15.9) 60.1 (49.0 to 68.6) 18.2 to 90.1

All N=137 58.3 (14.8) 58.9 (48.1 to 68.6) 18.2 to 90.1

Age at Diagnosis

Honevo® N=64 42.2 (15.4) 40 (30 to 51.5) 19 to 80

Control N=67 43.6 (15.4) 43 (35 to 55) 10 to 79

All N=131 42.9 (15.4) 41 (32 to 54) 10 to 80

Honevo® N (%) N=68

Control N (%) N=69

Female 32 (47.1) 36 (52.2)




European 64 (94.1) 68 (98.6)

Maori 4 (5.9) 0 (0)

Asian 0 (0) 1 (1.5)


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-3 11 (18.0) 1 (1.9)

-2 13 (21.3) 11 (20.4)

-1 20 (32.8) 17 (31.5)

0 14 (23.0) 15 (27.8)

1 3 (4.9) 8 (14.8)

2 0 (0) 2 (3.7)


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Comparison N with data Hodges-Lehman

estimate (95% CI) P

Honevo® Control

IGA-RSS week 2 66 66 0 (-1 to 0) 0.26

IGA-RSS week 8 61 54 0 (-1 to 0) 0.06

IGA-RSS week 2 minus baseline 66 66 -1 (-1 to 0) 0.03


Estimate (95% CI) P

IGA-RSS week 8 adjusted for baseline1

61 54 -0.6 (-1.1 to -0.2) 0.003

Mean difference (95% CI)

P

VAS-CS week 2 66 66 9.1 (3.5 to 14.7) 0.002

VAS-CS week 8 61 54 12.3 (5.7 to 18.9) <0.001

VAS-S week 2 66 66 -3.6 (-9.9 to 2.7) 0.26

VAS-S week 2 minus baseline 66 66 -2.9 (-9.2 to 3.5) 0.38

VAS-S week 8 61 54 -4.5 (-11.6 to 2.6) 0.21

VAS-S week 8 minus baseline 61 54 -11.0 (-18.0 to -3.9) 0.003

IGA-RSS: blinded Investigator Global Assessment of Rosacea Severity Score, based on a 7 point scale (0 ‘clear’ to 6 ‘severe’) VAS-CS: Participant-rated assessment of Change in Severity of rosacea based on a 100mm VAS scale (0mm ‘much worse’ to 100mm ‘much improved’) VAS-S: Participant-rated assessment of Severity of rosacea based on a 100mm VAS scale (0mm ‘mildest possible’ symptoms and 100mm ‘worst possible’ symptoms) ANOVA with baseline reading as a covariate, normality assumptions not well met

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FIGURE LEGENDS





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REFERENCES

1. Buechner SA. Rosacea: an update. Dermatology. 2005;210(2):100-8. 2. Wilkin J, Dahl M, Detmar M, Drake L, Liang M, Odom R et al. Standard grading system for rosacea: Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 2004;50:907-12. 3. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69(5):419-23. 4. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005 Feb 24;352(8):793-803. 5. Elewski BE, Fleischer AB, Jr., Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003 Nov;139(11):1444-50. 6. van Zuuren EJ, Kramer S, Carter B, Graber MA, Fedorowicz Z. Interventions for rosacea. Cochrane Database Syst Rev. (3):CD003262. 7. Elewski BE. Rosacea trial comparing twice-daily azelaic acid gel 15% with once-daily metronidazole gel 1%. Cutis. 2007 Jan;79(1):57-8; author reply 8. 8. World Health O. Antimicrobial resistance: global report on surveillance 2014; 2014. Report No.: ISBN: 978 92 4 156474 8 Contract No.: Document Number|. 9. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ.340:c2096. 10. Department of Health UKSMAC. The path of least resistance. 1998. 11. Wu Q. Antimicrobial effect of Manuka honey and Kanuka honey alone and in combination with the bioactives against the growth of Propionibacterium acnes ATCC 6919: a thesissubmitted in partial fulfilment of the requirements for the degree Master of Food Technology, Massey University, Albany, New Zealand; 2011. 12. Lu J, Carter DA, Turnbull L, Rosendale D, Hedderley D, Stephens J, et al. The effect of New Zealand kanuka, manuka and clover honeys on bacterial growth dynamics and cellular morphology varies according to the species. PLoS One.8(2):e55898. 13. Leong AG, Herst PM, Harper JL. Indigenous New Zealand honeys exhibit multiple anti-inflammatory activities. Innate Immun. Jun;18(3):459-66. 14. Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New Zealand honeys. J Pharm Pharmacol. 1991 Dec;43(12):817-22. 15. Gannabathula S, Skinner MA, Rosendale D, Greenwood JM, Mutukumira AN, Steinhorn G, et al. Arabinogalactan proteins contribute to the immunostimulatory properties of New Zealand honeys. Immunopharmacol Immunotoxicol. Aug;34(4):598-607. 16. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007 Sep;157(3):474-81. 17. Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J Am Acad Dermatol. 1993 Mar;28(3):443-8. 18. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007 Aug;13(8):975-80. 19. Fingleton JS, D. Cave, N. Brinded, A. Weatherall, M. Perrin, K. Beasley,R. Topical kanuka honey for the treatment of rosacea. Focus on Alternative and Complementary Therapies. 2013;18(4):221-2. 20. Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI). J Investig Dermatol Symp Proc. 2004 Mar;9(2):169-80. 21. (Datapharm) ew. Cetomacrogol Cream BP 1988 Formula A. https://wwwmedicinesorguk/emc/medicine/25140. Last accessed Dec 24,2014. 22. Kingdom NNHSU. Cetomacrogol Cream Formula A. http://wwwnhsuk/medicine-guides/pages/MedicineOverviewaspx?medicine=Cetomacrogol%20Cream%20Formula%20A. Last accessed Dec 24, 2014.

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23. van Zuuren EJ, Kramer SF, Carter BR, Graber MA, Fedorowicz Z. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. Oct;165(4):760-81. 24. Fu X, Tian H, Hsu S, Wang D, Sheng Z. In vivo effects of tumor necrosis factor-alpha on incised wound and gunshot wound healing. J Trauma. 1996 Mar;40(3 Suppl):S140-3. 25. Mooney DP, O'Reilly M, Gamelli RL. Tumor necrosis factor and wound healing. Ann Surg. 1990 Feb;211(2):124-9.

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56x67mm (300 x 300 DPI)

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11x9mm (600 x 600 DPI)

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Numerical Score










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Week 2 Day 15

Week 8 Day 57

Informed Consent X



Randomisation X





X X






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IGA-RSS week Zero


IGA-RSS week 2


IGA-RSS week 8





VAS-CS week 2


VAS-CS week 8


VAS-S week Zero


VAS-S week 2


VAS-S week 8







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Honevo® minus Control N with data Estimate (95% CI) P

Honevo® Control

VAS-S week 2 52 50 -4.0 (-8.5 to 0.6) 0.088

VAS-S week 3 60 53 -1.3 (-6.8 to 4.2) 0.65

VAS-S week 4 59 54 -4.0 (-10.3 to 2.4) 0.21

VAS-S week 5 55 55 -2.0 (-7.8 to 3.9) 0.50

VAS-S week 6 56 50 -5.3 (-2.5 to 14.2) 0.13

VAS-S week 7 53 50 -2.1 (-8.9 to 4.7) 0.54

VAS-S week 8 48 38 -5.7 (-6.2 to 13.3) 0.15


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Honevo® N

Control N





Itching 5 1

Tingling 3 2

Red spots 2 0

Eczema 1 0

Dry skin 1 0

Peeling 1 0

Pain 1 0

Stinging 0 4

Burning 0 2

Blisters 0 1

Bleeding 0 1



0 0



Infection 6 7

Trauma 3 1

Indigestion 1 0



Elevated PSA 1 0

Cardiovascular 0 2



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Reported on page No

Title and abstract



Introduction

Background and

objectives



Methods







6


were assessed

6-7




Randomisation:

Sequence

generation



Allocation

concealment

mechanism



6


interventions

6


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Results

Participant flow (a

diagram is strongly

recommended)



9, fig 1







9

Outcomes and

estimation



9-10




9-10


Discussion




Other information







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Journal: BMJ Open

Manuscript ID: bmjopen-2015-007651.R2


Date Submitted by the Author: 04-May-2015








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Page 1




Andrew Corin2, Colin Helm2 Davitt Sheahan3, Christopher Tofield4, Barney Montgomery5,

Mark Holliday1, Mark Weatherall6, Richard Beasley1







Funding: This study was funded by HoneyLab. HoneyLab provided the Honevo® (medical grade kanuka honey and 10% glycerine) for the study.


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Page 2










respectively.


















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Page 3









• This is a randomised placebo-controlled trial of 8 weeks of treatment for rosacea with

either topical 90% medical-grade kanuka honey and 10% glycerine cream

(Honevo®) or a non-ionic paraffin based cream (cetomacragol).






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Page 4

INTRODUCTION


and occurs in up to 10% of the adult population.[1-4] There is no cure, and affected

individuals may experience substantial morbidity. There is a range of treatment options,

including several topical and oral antibiotics, however these are only partially effective and

side effects may limit their use [4-7] Also there are global concerns about the increasing

rates of antibiotic resistance resulting from the widespread use of antibiotics, particularly with

long term use in chronic conditions.[8,9] For example, the United Kingdom Standing Medical

Advisory Committee now recommends the fewest number of antibiotic courses should be

prescribed for the shortest period possible.[10]

Amongst the alternative therapies to antibiotics, medical grade kanuka honey is of interest

due to its potent antibacterial and anti-inflammatory activities.[11-15] The pathophysiological

rationale underlying its use is that rosacea is an inflammatory disorder, and that antigenic

proteins related to the bacterium Bacillus oleronius isolated from the Demodex folliculorum

mite, which infests the skin in rosacea, exacerbates this inflammatory response.[16,17]

Furthermore, people with rosacea express abnormally high levels of the antimicrobial

peptide cathelicidin, which promotes the inflammatory response in rosacea.[18]


it to be an acceptable and potentially effective treatment.[19] The addition of 10% glycerine

to the honey has resulted in a product that is easier to apply to the skin. In this randomised



particular to ensure that there was blinded investigator assessment of rosacea severity.[6]

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Page 5

METHODS



in New Zealand. Ethics approval was obtained from the Central Health and Disability Ethics

Committee (13/CEN/118). Adults aged 16 or over with a doctor’s diagnosis of rosacea on the

face, and a baseline blinded Investigator Global Assessment of Rosacea Severity Score

(IGA-RSS) of facial rosacea of ≥2 were recruited. The IGA-RSS is a 7-point scale (from 0:

‘clear’, to 6: ‘severe’) that provides an integrated assessment of rosacea severity based on

the principal facial signs of papules/pustules, inflammatory lesions, erythema and

telangiectasia [5] (Supplement Table S1). Subjects were identified at the time of first

presentation or, with their primary care practitioner’s consent, from pre-existing databases,

or by public advertisement.







Participants attended for 3 visits (Supplement Table S2). Visit 1 (week 0) consisted of

consent, baseline assessments (the IGA-RSS), a participant-rated rosacea severity visual

analogue score (VAS–S) on a 100mm scale (0mm being ‘mildest possible’ symptoms and

100mm being ‘worst possible’ symptoms), and a participant-rated dermatology quality of life

index (DLQI) [20], followed by randomisation to Honevo® or Cetomacrogol cream (control).

At Visit 2 (week 2) and Visit 3 (week 8), as well as the IGA-RSS and the DLQI, participants

completed a subjective rosacea ‘change in severity’ visual analogue scale (VAS-CS) on a

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Page 6

100mm scale (0mm being ‘much worse’ and 100mm being ‘much improved’). Subjects’

diaries were used throughout the study to capture each participant’s weekly subjective VAS-

S, their use of randomised treatment throughout the 8 week study period, and any general

comments including adverse events throughout the study.



investigators by enclosing the proposed treatment arm in an opaque envelope that was only

opened by primary investigators after informed consent was obtained by each participant.

Subjects were randomised in a 1:1 ratio to the topical application of Honevo® or control

cream. Due to the nature of Honevo® it was not possible to blind the participants and

primary investigators to the treatment allocation. An independent investigator at each site

remained blinded to the treatment allocation throughout the study to perform the blinded

IGA. The blinded investigator undertook only the IGA-RSS assessment for this study, and

was not involved in any other study procedures. Participants were instructed not to

communicate with the blinded investigator during the assessments.




paraffin topical emollient.[21,22] The participants were instructed to apply an appropriate




exclusion criteria.

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Outcome measures







the change from baseline in the participant-rated DLQI [20] at weeks 2 and 8; withdrawals

due to worsening of Rosacea; adverse events; and the daily self-reported use of Honevo®

(applications per day). Data for all participants was included for analysis up until the time the

participant withdrew from the study or became ineligible due to the use of prohibited

medications.







Statistical methods







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Page 8




randomisation as the main predictor variable. The estimates for these analyses are

interpreted as the difference between randomised groups adjusted for baseline.


number of applications per day, predictor variable randomisation group, and using the


application.




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RESULTS



excluded due to the use of a prohibited medication on enrolment, and their data was not










Primary outcome




Secondary outcomes


Table 2, Supplement Table S3 and Figure 2.The change in IGA-RSS for Honevo®

compared to control at week 2 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1

to 0, P=0.03), and at week 8 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to

0, P=0.005),(Table 3). The subject-rated VAS-CS at week 2 was 9.1 (CI 3.5 to 14.7),

P=0.002, and at week 8 was 12.3 (CI 5.7 to 18.9), P<0.001for Honevo® compared to

control, representing greater improvement with Honevo®. There was no significant

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difference in diary-captured VAS-S, adjusted for baseline, at any of the time points between

week 2 and 8 (Supplement Table S4).There was no significant difference in the participant-

rated DLQI adjusted for baseline at week 2 (-0.3, CI-1.1 to 0.6, P=0.51) or week 8 (-0.01, CI

-0.7 to 0.7,P=0.97).



0.02 (95% CI -0.10 to 0.05), P=0.55).





which resulted in withdrawal of the participants), and 14 unrelated to rosacea (Supplement

Table S5). In the control group, 27 participants reported 36 adverse events; 22 rosacea

related, (8 of which resulted in withdrawal of participants), and 14 unrelated to rosacea.

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DISCUSSION






rosacea.








treatment.

The primary outcome variable identified the proportion in each treatment arm who had a 2

point reduction or more in IGA-RSS, representing a clinically meaningful improvement in

rosacea severity, for example a change from ‘severe’ to ‘moderate’, or from ‘moderate’ to

‘mild’. 34% of those who were randomised to Honevo® had an IGA-RSS improvement of 2

or more at 8 weeks compared to 17% of the placebo group, and 13% achieved full resolution

of rosacea compared to 3% in the placebo group. Although these point estimates are

consistent with effectiveness, the confidence intervals are wide which could be consistent

with a small effect or quite large effect. This is especially the case for the post hoc analysis

of IGA-RSS for the proportion of participants with complete resolution, which although it

favours the active treatment, could be consistent with quite a small effect. The estimate of

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the location shift for the difference between the treatments was -1, (95% CI -1 to 0) at both

week 2 and week 8 and the estimated change in IGA-RSS at week 8 adjusted for baseline

was -0.6 (95% CI -1.1 to -0.2). These findings reflect the variability in response to Honevo®,

perhaps dependent on sub-types of rosacea2 which were not assessed in this study.

In addition, we assessed patient-reported outcomes, based on participant’s assessment of

current severity of symptoms (VAS-S), participant’s perceived change in severity (VAS-CS)

and the DLQI questionnaire, to provide a comprehensive assessment of efficacy. The VAS-

CS at the 2-week and 8-week clinic visits were significantly better with Honevo®. However,

there was no difference with the 2-week and 8-week DLQI assessments or the weekly diary

VAS-S measures. Thus the patient assessments were not completely consistent with the

other assessments of efficacy. This could mean that the variability in these lead to

insufficient statistical power to detect a difference, or in the context of rosacea that an ideal

measurement related to efficacy that is sensitive to change needs further development. The

RosaQoL instrument has been recently reviewed in addition to the DLQI and a generic

health-related quality of life instrument, the SF-36, in rosacea, and may be a suitable

instrument for future research.[21] In the absence of a validated VAS for rosacea severity, it

is difficult to comment on the clinical relevance of a reduction of 11 points from baseline in

the VAS-S or the 12.3 improvement in VAS-CS in the Honevo® group compared to the

control group after 8 weeks. As these outcomes were participant assessed and participants

could not be blinded to the interventions, there is a risk of detection bias in this methodology.

The DLQI is a questionnaire non-specific to rosacea and may not have been sensitive

enough to capture changes associated with this condition alone. The drop-out rate for this

study was greater than anticipated, which will need to be factored into future research in

similar clinical studies. The greater number of withdrawals due to worsening rosacea in the

control group (12% vs 4%), and overall withdrawals is likely to have led to an under-

estimation of the efficacy of Honevo®, as these participants did not undergo assessment of

the secondary outcome variables following withdrawal.

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often used as a vehicle for delivery of topical medications.[22,23] The treatment was

administered for 8 weeks to allow both the speed of onset and the duration of effect to be

assessed. This identified that honey had efficacy within 2 weeks of treatment, with further

efficacy obtained during the 8 week treatment period. Adverse event data did not allow us to

reliably ascertain whether the rosacea specific adverse events such as burning, itching,

peeling, stinging, dry skin and pain were associated only with the application of the

investigational medicine or whether they were ongoing rosacea symptoms. However it was

reassuring that the number of participants with rosacea specific adverse events was similar

between Honevo® and the paraffin-based emollient control cream.

Notwithstanding the limitations of comparing different primary outcome variables utilised in

other studies of rosacea, it is interesting to note the findings from placebo-controlled studies

of topical metronidazole or azelaic acid, two of the more commonly used treatments of

rosacea.[4-7] In studies of topical metronidazole the relative risk of improvement with the

physician’s global evaluation of improvement was 1.95 (95% CI 1.5 to 2.6), and in studies of


1.8).[6,24] In our study, the relative risk of IGA-RSS improvement with Honevo® was 2.0


1.0 to 20.4). It is difficult to indirectly compare the results of these studies of two other active

treatments against placebo with the study reported here, as the characteristics of the

research participants may have been quite different and the outcome variable of global

improvement may not correspond to that used in this study. We favour despite this, that we

have found sufficient evidence of efficacy, albeit with wide confidence intervals, that a

reasonable next stage is to conduct randomised controlled trials comparing Honevo® with

topical metronidazole or azelaic cream.

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of neutrophil superoxide production,[13] reduction in inflammatory leucocyte infiltration and

arachidonic- induced oedema,[13] and stimulation of macrophage release of tumour

necrosis factor a (TNFa),[15] a cytokine with a crucial role in wound healing.[25,26] These

properties may be relevant as rosacea is a chronic inflammatory disorder, characterised by

inflammatory cell infiltration, vascular dilatation and tissue oedema.[1,3,6] In addition,

kanuka honey has high antibacterial activities against a wide range of bacteria, including

Bacillus subtilis, Propionibacterium acne and Staph Aureus,[11,12,14] properties which may

be beneficial in view of the proposed role of Bacillus oleronius in the inflammatory response

in rosacea. The effect of honey on Bacillus oleronius and the Demodex folliculum mite

require further investigation.







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STATEMENTS












declare.


















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Age at enrolment

Honevo® N-68 57.7 (13.7) 58.2 (46.7 to 68.3) 23.4 to 86.5

Control N=69 58.9 (15.9) 60.1 (49.0 to 68.6) 18.2 to 90.1

All N=137 58.3 (14.8) 58.9 (48.1 to 68.6) 18.2 to 90.1

Age at Diagnosis

Honevo® N=64 42.2 (15.4) 40 (30 to 51.5) 19 to 80

Control N=67 43.6 (15.4) 43 (35 to 55) 10 to 79

All N=131 42.9 (15.4) 41 (32 to 54) 10 to 80

Honevo® N (%) N=68

Control N (%) N=69

Female 32 (47.1) 36 (52.2)




European 64 (94.1) 68 (98.6)

Maori 4 (5.9) 0 (0)

Asian 0 (0) 1 (1.5)


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-3 11 (18.0) 1 (1.9)

-2 13 (21.3) 11 (20.4)

-1 20 (32.8) 17 (31.5)

0 14 (23.0) 15 (27.8)

1 3 (4.9) 8 (14.8)

2 0 (0) 2 (3.7)


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Page 18


Comparison N with data Hodges-Lehman

estimate (95% CI) P

Honevo® Control

IGA-RSS week 2 66 66 0 (-1 to 0) 0.26

IGA-RSS week 8 61 54 0 (-1 to 0) 0.06



Estimate (95% CI) P

IGA-RSS week 8 adjusted for baseline1

61 54 -0.6 (-1.1 to -0.2) 0.003

Mean difference (95% CI)

P

VAS-CS week 2 66 66 9.1 (3.5 to 14.7) 0.002

VAS-CS week 8 61 54 12.3 (5.7 to 18.9) <0.001

VAS-S week 2 66 66 -3.6 (-9.9 to 2.7) 0.26

VAS-S week 2 minus baseline 66 66 -2.9 (-9.2 to 3.5) 0.38

VAS-S week 8 61 54 -4.5 (-11.6 to 2.6) 0.21

VAS-S week 8 minus baseline 61 54 -11.0 (-18.0 to -3.9) 0.003

IGA-RSS: blinded Investigator Global Assessment of Rosacea Severity Score, based on a 7 point

scale (0 ‘clear’ to 6 ‘severe’)

VAS-CS: Participant-rated assessment of Change in Severity of rosacea based on a 100mm VAS

scale (0mm ‘much worse’ to 100mm ‘much improved’)

VAS-S: Participant-rated assessment of Severity of rosacea based on a 100mm VAS scale (0mm

‘mildest possible’ symptoms and 100mm ‘worst possible’ symptoms)

ANOVA with baseline reading as a covariate, normality assumptions not well met

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FIGURE LEGENDS





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REFERENCES

1. Buechner SA. Rosacea: an update. Dermatology 2005;210:100-8.

2. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: Report of the

National Rosacea Society Expert Committee on the classification and staging of

rosacea. J Am Acad Dermatol 2004;50:907-12.

3. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol.

1989;69:419-23.

4. Powell FC. Clinical practice. Rosacea. N Engl J Med 2005;352:793-803.

5. Elewski BE, Fleischer AB, Jr, Pariser DM. A comparison of 15% azelaic acid gel and

0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of

a randomized trial. Arch Dermatol 2003;139:1444-50.

6. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane

Database Syst Rev 2011;(3):CD003262.

7. Elewski BE. Rosacea trial comparing twice-daily azelaic acid gel 15% with once-daily

metronidazole gel 1%. Cutis 2007;79:57-8; author reply 8.

8. World Health O. Antimicrobial resistance: global report on surveillance 2014. 2014;

Report No. ISBN: 978 92 4 156474 8 Contract No. Document Number|.

9. Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary

care on antimicrobial resistance in individual patients: systematic review and meta-

analysis. BMJ 2010;340:c2096.

10. Department of Health UKSMAC. The path of least resistance. 1998.

11. Wu Q. Antimicrobial effect of Manuka honey and Kanuka honey alone and in

combination with the bioactives against the growth of Propionibacterium acnes ATCC

6919: a thesis submitted in partial fulfilment of the requirements for the degree Master

of Food Technology, Massey University, Albany, New Zealand; 2011.

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12. Lu J, Carter DA, Turnbull L, et al. The effect of New Zealand kanuka, manuka and

clover honeys on bacterial growth dynamics and cellular morphology varies according

to the species. PLoS One 2013;8:e55898.

13. Leong AG, Herst PM, Harper JL. Indigenous New Zealand honeys exhibit multiple anti-

inflammatory activities. Innate Immun 2012;18:459-66.

14. Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New

Zealand honeys. J Pharm Pharmacol 1991;43:817-22.

15. Gannabathula S, Skinner MA, Rosendale D, et al. Arabinogalactan proteins contribute

to the immunostimulatory properties of New Zealand honeys. Immunopharmacol

Immunotoxicol 2012;34:598-607.

16. Lacey N, Delaney S, Kavanagh K, et al. Mite-related bacterial antigens stimulate

inflammatory cells in rosacea. Br J Dermatol 2007;157:474-81.

17. Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J Am

Acad Dermatol 1993;28:443-8.

18. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and

cathelicidin promotes skin inflammation in rosacea. Nat Med 2007;13:975-80.

19. Fingleton JS, D. Cave, N. Brinded, et al. Topical kanuka honey for the treatment of

rosacea. Focus on Alternative and Complementary Therapies 2013;18:221-2.

20. Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI).

J Investig Dermatol Symp Proc. 2004;9:169-80.

21. Van der Linden MM, van Rappard DC, Daams JG, et al. Health-related quality of life in

patients with cutaneous rosacea: a systematic review. Acta Derm Venereol

2015;95:395-400.

22. (Datapharm) ew. Cetomacrogol Cream BP 1988 Formula A.

https://wwwmedicinesorguk/emc/medicine/25140. Last accessed Dec 24,2014.

23. Kingdom NNHSU. Cetomacrogol Cream Formula A. http://wwwnhsuk/medicine-

guides/pages/MedicineOverviewaspx?medicine=Cetomacrogol%20Cream%20Formul

a%20A. Last accessed Dec 24, 2014.

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24. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based

management strategies for rosacea: summary of a Cochrane systematic review. Br J

Dermatol 2011;165:760-81.

25. Fu X, Tian H, Hsu S, et al. In vivo effects of tumor necrosis factor-alpha on incised

wound and gunshot wound healing. J Trauma 1996;40(3 Suppl):S140-3.

26. Mooney DP, O'Reilly M, Gamelli RL. Tumor necrosis factor and wound healing. Ann

Surg 1990;211:124-9.

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56x67mm (300 x 300 DPI)

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Numerical Score










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Week 2 Day 15

Week 8 Day 57

Informed Consent X



Randomisation X





X X






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IGA-RSS week Zero


IGA-RSS week 2


IGA-RSS week 8





VAS-CS week 2


VAS-CS week 8


VAS-S week Zero


VAS-S week 2


VAS-S week 8







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Honevo® minus Control N with data Estimate (95% CI) P

Honevo® Control

VAS-S week 2 52 50 -4.0 (-8.5 to 0.6) 0.088

VAS-S week 3 60 53 -1.3 (-6.8 to 4.2) 0.65

VAS-S week 4 59 54 -4.0 (-10.3 to 2.4) 0.21

VAS-S week 5 55 55 -2.0 (-7.8 to 3.9) 0.50

VAS-S week 6 56 50 -5.3 (-2.5 to 14.2) 0.13

VAS-S week 7 53 50 -2.1 (-8.9 to 4.7) 0.54

VAS-S week 8 48 38 -5.7 (-6.2 to 13.3) 0.15


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Honevo® N

Control N





Itching 5 1

Tingling 3 2

Red spots 2 0

Eczema 1 0

Dry skin 1 0

Peeling 1 0

Pain 1 0

Stinging 0 4

Burning 0 2

Blisters 0 1

Bleeding 0 1



0 0



Infection 6 7

Trauma 3 1

Indigestion 1 0



Elevated PSA 1 0

Cardiovascular 0 2



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11x9mm (600 x 600 DPI)

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Reported on page No

Title and abstract



Introduction

Background and

objectives



Methods







6


were assessed

6-7




Randomisation:

Sequence

generation



Allocation

concealment

mechanism



6


interventions

6


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Results

Participant flow (a

diagram is strongly

recommended)



9, fig 1







9

Outcomes and

estimation



9-10




9-10


Discussion




Other information







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RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA HONEY …€¦ · Rosacea is a common chronic...

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