RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA HONEY FOR THE TREATMENT OF ACNE · P. Acne...

For peer review only

RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA

HONEY FOR THE TREATMENT OF ACNE

Journal: BMJ Open

Manuscript ID bmjopen-2015-009448

Article Type: Research

Date Submitted by the Author: 20-Jul-2015

Complete List of Authors: Semprini, Alex; Medical Research Institute of New Zealand, Braithwaite, Irene; Medical Research Institute of New Zealand, Corin, Andrew; Clinical Horizons, Sheahan, Davitt; Papamoa Pines Medical Centre, Tofield, Chris; Cameron Medical Clinic, Helm, Colin; Clinical Horizons, Montgomery, Barney; Optimal Clinical Trials, Fingleton, James; Medical Research Institute of New Zealand,

Weatherall, Mark; University of Otago, Beasley, Richard; Medical Research Institute of New Zealand,

<b>Primary Subject Heading</b>:

Complementary medicine

Secondary Subject Heading: Dermatology

Keywords: Acne < DERMATOLOGY, COMPLEMENTARY MEDICINE, Randomised controlled trial, Kanuka honey

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 ACNE

Alex Semprini1, Irene Braithwaite1, Andrew Corin2, Davitt Sheahan3, Christopher

Tofield4,Colin Helm2,Barney Montgomery5, James Fingleton1, 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

Honey Acne Study Team: Judith Riley1, Anna Hunt1, Tony Mallon1, Mark Holliday1

Word Count: Abstract 297. Manuscript 2,625

Key Words: Acne, Kanuka honey, Randomised controlled trial.

Address for correspondence:

Alex Semprini 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

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

glycerine (Honevo™) as a treatment for facial acne.

Design: Randomised controlled trial with single blind assessment of primary outcome

variable.

Setting: Outpatient primary care from three New Zealand localities.

Participants: Of 136 participants aged between 16 and 40 years with a diagnosis of acne

and baseline Investigator Global Assessment for Acne (IGA) score of ≥2 68 participants

were randomised to each treatment arm.

Interventions: All participants applied Protex antibacterial soap twice daily for 12 weeks.

Participants randomised to the Honevo™ treatment arm applied this directly after washing

off the Protex soap, twice daily for 12 weeks.

Outcome measures: The primary outcome was ≥2 point decrease in IGA score from

baseline at 12 weeks. Secondary outcomes included mean lesion counts and changes in

subject-rated acne improvement and severity at weeks four and 12 and withdrawals for

worsening acne. There were 15 and 14 participants who withdrew from the Honevo™/Protex

group and control groups respectively.

Results: 4/53 (7.6%) participants in the Honevo™/Protex group and 1/53 (1.9%) of

participants in the Protex only group had a ≥ 2 improvement in IGA score at week 12,

compared with baseline, odds ratio (95% CI) for improvement 4.2 (0.5 to 39.3), P = 0.17.

There were 15 and 14 participants who withdrew from the Honevo™/Protex group and

control groups respectively.

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Conclusion: This randomised controlled trial did not find evidence that addition of Honevo™

to standard Protex antibacterial soap treatment is more effective than the use of Protex soap

alone in the treatment of acne.

What is know about the topic?

Honey has potent anti-bacterial and anti-inflammatory effects and has been shown to be an

acceptable and effective treatment in wounds and dermatological conditions such as

rosacea.

What this study adds

Whilst this study does not show Honevo™ to be an effective treatment for acne, important

methodological considerations for future studies of topical honey treatments for

dermatological conditions are highlighted.

Strengths and Limitations of this Study

This is 12 week a randomised controlled trial comparing the addition of topical 90% medical

grade kanuka honey and 10% glyercine (Honevo™) to standard antibacterial soap wash

(Protex) with standard antibacterial soap wash alone.

Given the nature of the investigational products participant blinding was not possible.

The primary outcome variable (Investigator Global Assessment of Acne) was assessed by

investigators blinded to randomisation, throughout the study period.

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INTRODUCTION

Acne is a very prevalent inflammatory disorder of the skin. A recent review reports an

85% prevalence in those aged between 12 and 24 years of age in the US1. For many people

acne persists into adulthood. One study reports that in men and women aged between 40

and 49 years about 5% still have acneiform rashes2.

Acne has a range of manifestations including non-inflamed comedones but also inflamed

and painful pustules and nodules. Four underlying pilosebaceous processes are responsible

for the clinical manifestations: ductal obstruction from keratinocyte desquamation and

proliferation, increased sebum production under androgenic influence, Propionibacterium

Acne (P. Acne) colonisation and finally, as a consequence, inflammation. Current

therapeutic interventions address one or more of these processes. The main treatments are

systemic or topical antibiotics, hormones, retinoid therapy, or a combination regimen3.

Retinoids, in particular, have many contraindications and problematic side effects including

skin irritation and systemic retinoid sequale. They are teratogenic which makes use difficult

in women of child-bearing age. P. Acne resistance, in relation to antibiotic use, is an

emerging concern4. Acne control is often not acceptable for many patients and new

treatment options are needed.

Honey is a complementary therapy dating back to Hippocrates 5. The robust evaluation of

medical grade honey is of interest because of its apparent antimicrobial, anti-inflammatory,

and potential immuno-modulatory actions6,7. We recently reported a randomised controlled

trial (RCT) that found a significant improvement in rosacea severity using a topical medical

grade kanuka honey formulation (Honevo™) compared to a standard topical treatment

(Cetomacrogol). The honey treatment had high patient acceptability8. The study reported

here is a RCT investigating the efficacy of the 90% medical grade kanuka honey and 10%

glycerine formulation (Honevo™) in the topical management of acne.

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METHODS

In a single blind RCT, patients with acne were recruited in three ways: by presentation to

their General Practitioner, by a Practice database for records of those with Acne, or directly

through advertisement; in three New Zealand centres, Wellington, Auckland and Tauranga.

Adults aged between 16 and 40 with a baseline facial Investigator Global Assessment (IGA)

score of ≥ 2 (Table 1)9 were recruited.

Exclusion criteria were: current requirement for systemic corticosteroids or antibiotics

treatment or use in the previous four weeks; current requirement for topical corticosteroids or

antibiotics; change in oral contraceptive therapy in the last three months; systemic retinoid in

the past two months; known or suspected allergy to honey or Protex Soap Gentle

Antibacterial; any significant systemic illness or other condition which the investigators felt

presented a safety risk or potentially affected the participant’s ability to complete the study.

Three study visits were: the baseline first visit, designated week zero, where after informed

consent was obtained, baseline measurement occurred and participants were randomised to

a treatment arm. At the second and third visits, after four and 12 weeks, primary and

secondary outcome measures, adverse effects, and general feedback, were obtained.

Table 1: Investigator Global Assessment for Acne

Score Description Details

0 Clear Clear skin with no inflammatory or non-inflammatory lesions

1 Almost clear Rare non-inflammatory lesions with no more than one inflammatory lesion

2 Mild Greater than grade 1; some non-inflammatory lesions with no more than a few

inflammatory lesions. (Papules or pustules only, no nodular lesions)

3 Moderate Greater than grade 2; up to many non-inflammatory lesions and may have

some inflammatory lesions but no more than one small nodular lesion

4 Severe Greater than grade 3; up to many non-inflammatory and inflammatory lesions

but no more than a few nodular lesions

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Treatment applications

All participants were asked to apply Protex soap twice daily to affected areas according to

the manufacturer’s instructions. Participants randomised to the Honveo™ group were asked

to apply Honevo™ to affected areas, following the Protex application, twice daily for between

30 and 60 minutes and then wash it off with warm water. The control group just used the

soap.

Randomisation and blinding

Participants were randomised to the Honevo™/Protex or Protex only trial arms using a

concealed computer generated sequence. After consent was obtained the investigator

opened an opaque envelope revealing the randomised treatment for the participant. A

second investigator performed the IGA at each visit masked as to treatment allocation. The

Honevo™ group were asked not to use the product on the day of assessment to maintain

masking.

Outcome measures

The primary outcome measure was the proportion of subjects who had a greater than two

point decrease in IGA score for acne vulgaris at week 12 relative to baseline.

Secondary outcome measures were as follows:

1. Mean IGA score at weeks four and 12.

2. Mean lesion count at weeks four and 12. Lesion count was subdivided into inflamed

and non-inflamed lesions. Lesions were graded using the Leeds revised acne

grading system10.

3. Change in subject-rated global acne improvement using Visual Analogue Score

(VAS) at weeks four and 12

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4. Subject-rated global acne severity VAS at week four compared to baseline.

5. Dermatology Life Quality Index (DLQI)

6. Daily self-reported use (applications per day)

7. Weekly self-reported global acne severity (VAS scale)

8. Withdrawals due to worsening of acne

Sample size and study power

We anticipated the proportion of participants in the control group that responded would be

between 25 and 50%. A total of 124 participants (62 in each group) had 80% power at 5%

significance to detect an absolute difference of 25% responders. Recruitment of 138 participants

allowed for a 10% drop-out rate.

Statistical methods

Logistic regression was used to estimate the odds ratio (OR) for the proportion of

participants with an IGA score change from baseline of ≥ 2 at 12 weeks and for the

proportion of withdrawals due to worsening acne, comparing Honevo™ to Control. For the

latter this was unable to be estimated due to no withdrawals for worsening acne in the

control group.

The Mann-Whitney test with Hodges-Lehmann estimator and Moses confidence interval was

used for IGA (an ordinal scale variable), and Soap count (where the data was skewed and

an appropriate transformation could not be identified)

Proportional odds logistic regression was also used for IGA. The P value for the unadjusted

analysis is identical to that for the Mann-Whitney test but this method allows for adjusting

variables. This method estimates a common odds ratio for all combinations of summing the

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lower ranked values versus the higher ranked values and in this analysis a higher value for

this odds ratio meant that Honey had a better outcome than Control.

ANOVA and ANCOVA with, as appropriate, the baseline value as a continuous co-variate,

was used for the VAS Improvement, VAS Severity at weeks four and 12, DLQI, and weekly

self-reported VAS. Normality assumptions were reasonably well met for these analyses.

For the lesion count variables the data was skewed and for the ANCOVA normality

assumptions were better met on the logarithm transformed scale. Exponentiation of the

difference in logarithms can be interpreted as the ratio of mean values.

SAS version 9.3 was used.

RESULTS

The flow of participants is shown in Figure 1. There were 68 participants randomised to each

treatment arm. There were similar proportions of males and females the duration of acne

was similar in the two arms. Table 2 describes the participants.

Table 2: Participant ages at enrolment and diagnosis and sex.

Mean (SD) Median (IQR)

Min to Max

Age at enrolment (years)

All N = 135 21.2 (5.8) 18.3 (17.1 to 23.3)

16.0 to 39.7

Honevo™/Protex = 68 21.5 (6.4) 18.5 (17.1 to 23.5)

16.0 to 39.7

Control N = 67 20.9 (5.2) 18.3 (17.2 to 23.3)

16.0 to 38.4

Age at diagnosis (years)

All N = 135 13.9 (2.7) 13 (13 to 14)

10 to 28

Honevo™/Protex = 68 13.7 (2.7) 13 (12.5 to 24)

10 to 28

Control N = 67 14.2 (2.6) 14 (13 to 14)

11 to 26

SD = Standard Deviation IQR = Inter-Quartile Range

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Shortly after randomisation to the Protex soap only arm, one participant was found to exceed

the age criteria and was withdrawn with no data collected. There were 15 (22.1%)

withdrawals in the Honevo™/Protex group (two worsening acne, three use of prohibited

medication, five lost to follow up and five participants who withdrew due to non-adherence

due to reported inconvenience of the treatment). There were 14 (20.6%) withdrawals in the

Protex only group (one adverse event involving a minor skin reaction, one use of a

prohibited medication, 10 were lost to follow up and two participants withdrew due to

inconvenience of the treatment).

136

participants randomised

1 (1.5%) ineligible and

withdrawn

68 (100%) received Honevo™

and Protex soap

68 (100%) received Protex

soap

14 (20.6%) discontinued

treatment

53 (77.9%) completed

treatment

15 (22.1%) discontinued

treatment

53 (77.9%) completed

treatment

• 2 worsening acne • 3 use of prohibited medication

• 5 lost to follow up

• 5 inconvenience/compliance

• 1 adverse event • 1 use of prohibited medication

• 10 lost to follow up

• 2 inconvenience/compliance

Figure 1: Participant flow from randomisation to study completion or withdrawal.

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Primary outcome

4/53 (7.6%) participants in the Honevo™/Protex group and 1/53 (1.9%) of participants in the

Protex only group had a ≥ 2 improvement in IGA assessment at week 12, compared with

baseline; OR (95% CI) 4.2 (0.5 to 39.3), P = 0.17.

Secondary outcomes

The Hodges-Lehmann estimator (95% CI) comparing IGA scores for Honevo™/Protex with

Protex alone at four weeks was 0 (0 to 0), P = 0.54, and at 12 weeks was 0 (0 to 0) P = 0.33.

Proportional odds logistic regression for the IGA score at week four estimated the OR (95%

CI) for improvement of 1.2 (0.6 to 2.4) P = 0.54 without adjustment for baseline IGA score

and 2.1 (1.0 to 4.3) P = 0.055, after adjustment. Proportional odds logistic regression for the

IGA score at week 12 estimated the OR (95% CI) for improvement of 1.4 (0.7 to 2.9), P =

0.33, without adjustment for baseline, and 2.0 (CI 0.9 to 4.2) P = 0.075, after adjustment.

These latter estimates are consistent with weak evidence of improvement in the

Honevo™/Protex group compared to Protex control. Data summaries for IGA are shown in

Table 3.

Table 3: IGA scores at each visit for participants in Honevo™/Protex and Protex only treatment arms with change in IGA score from baseline at visit two and three.

Variable

N (%)

Honevo™/Protex

Control All

IGA - Visit 1 N=68 N=67 N=135 0 0 0 0 1 0 0 0 2 21 (30.9) 23 (34.3) 44 (32.6) 3 37 (54.4) 38 (56.7) 75 (55.6) 4 10 (14.7)

6 (9.0) 16 (11.9)

IGA - Visit 2 N=61 N=56 N=117

0 0 0 0 1 8 (13.1) 3 (5.4) 11 (9.4) 2 24 (39.3) 27 (48.2) 51 (43.6) 3 24 (39.3) 18 (32.1) 42 (35.9) 4 5 (8.2) 8 (14.3) 13 (11.1)

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IGA - Visit 3 N=53 N=53 N=106

0 0 0 0 1 10 (18.9) 7 (13.2) 17 (16.0) 2 25 (47.2) 24 (45.3) 49 (46.2) 3 15 (28.3) 18 (34.0) 33 (31.3) 4 3 (5.7)

4 (7.6) 7 (6.6)

IGA - Visit 2 minus IGA - Visit 1

N=61 N=56 N=117

-2 1 (1.6) 0 (0) 1 (0.9) -1 26 (42.6) 15 (26.8) 41 (35.0) 0 30 (49.2) 35 (62.5) 65 (55.6) 1 4 (6.7)

6 (10.7) 10 (8.6)


N=53 N=53 N=106

-2 4 (7.6) 1 (1.9) 5 (4.7) -1 25 (47.2) 21 (39.6) 46 (43.4) 0 23 (43.4) 26 (49.1) 49 (46.2) 1 1 (1.9) 5 (9.4) 6 (5.7)

The difference (95% CI) in logarithm inflamed lesion count for Honevo™/Protex minus

Protex after adjustment for baseline at week four was -0.28 (-0.61 to 0.06) P = 0.11,

exponent 0.76 (0.54 to 1.06). At week 12 the difference (95% CI) was -0.29 (-0.65 to 0.07),

P = 0.11, exponent 0.75 (0.52 to 1.07). The difference (95% CI) in logarithm non-inflamed

lesion count, Honevo™/Protex minus Protex, at week four count was -0.12 (-0.42 to 0.18), P

= 0.44, exponent 0.89 (0.66 to 1.20), and at week 12 -0.06 (-0.40 to 0.28) P = 0.72,

exponent 0.94 (0.67 to 1.32).

The difference (95% CI) in subject-rated global acne VAS improvement adjusted for

baseline, Honevo™/Protex minus Protex, at week four was 9.6 (3.7 to 15.6), P = 0.002; and

at week 12, 11.0 (4.4 to 17.6) P = 0.001,

The difference (95% CI) in subject-rated global acne severity VAS adjusted for baseline,

Honevo™/Protex minus Protex, at week four was -3.7 (-10.2 to 2.7) P = 0.26; and at week

12 -6.8 (-14.8 to 1.2) P = 0.095.

The difference (95% CI) in DLQI adjusted for baseline, Honevo™/Protex minus Protex, at

week four was 0.12 (-0.73 to 0.97), P = 0.77; and at week 12 0.14 (-0.75 to 1.03) P = 0.76.

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The Hodges-Lehmann estimate (95% CI) of the difference in daily self-reported use of

treatment, between the two study groups was -7 (-13 to -1) P = 0.01, with Honevo™/Protex

users having less applications.

Self-reported global acne severity VAS comparing Honevo™/Protex and Protex alone,

adjusted for week one baseline demonstrated moderate evidence for improved scores using

Honevo™ between weeks 5 and 11.

Withdrawal due to worsening acne occurred in 2/68 (2.9%) of the Honevo™/Protex group

and none of the Protex group.

Adverse events

There were 83 adverse events recorded, of which 55 were deemed by investigators to be

unrelated to the study treatment. There were 28 adverse events, eight in the

Honevo™/Protex group and 20 Protex group which were assessed to be related to the study

treatment. All involved skin related complaints including oily, dry and stinging skin, contact

dermatitis and worsening acne.

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Discussion

This RCT has not found evidence that the addition of 90% medical grade Kanuka honey in

combination with 10% glycerine (Honevo™) to standard Protex antibacterial soap treatment

is more effective than the use of Protex soap alone in the treatment of acne.

Although there was no evidence of improvement in acne severity using the primary outcome

criteria of ≥ 2 point change in IGA a more detailed analysis treating the outcome as an

ordinal variable, with adjustment for baseline severity, suggested that there may be weak

evidence of an improved score in the Honevo™/Protex arm compared to control at 12

weeks, with an OR for an improved category of IGA of 2.0. In this study there were an

unexpectedly high number of withdrawals and a small number of participants who actually

improved by the above criterion. This in turn was likely related to a floor effect for the

measurement instrument because around one third of participants could not have achieved

this ≥ 2 point change in IGA unless their acne entirely resolved, as their baseline IGA score

was two. There were 15 (22.1%) and 14 (20.6%) withdrawals for Protex/Honevo and Protex

respectively.

Secondary outcomes mostly showed no evidence of benefit from the use of Honevo™ for

the treatment of acne. Subject rated improvement according to a VAS at weeks four and 12

was better for the honey treatment. There may have been subjective assessment bias

however because we couldn’t mask participants to honey treatment. In addition this outcome

variable may be subject to Type I error rate inflation as it was a secondary outcome amongst

a number of other secondary outcome variables.

A previous study, which found Honevo™ an effective treatment for rosacea, was of similar

design, size and utilised a primary outcome of a blinded, seven point, Investigator Global

Assessment of Rosacea Severity Score (IGA-RSS) ≥2. 34.3% of participants randomised to

Honevo™ and 17.4% receiving control achieved the primary outcome compared to 7.6%

and 1.9% in the acne study. Given the wider scope for improvement in the Rosacea study

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(seven points as compared to five points in the IGA scale) and the higher proportion of

participants reaching the primary outcome criterion in both arms, further studies of honey in

acne may wish to consider these factors in study design. Furthermore a number of

participant characteristics may be relevant. The mean age of participants with chronic acne,

present on average for 14 years, was 21 years. The total study duration was 12 weeks and

the diary component of the data collection required daily entry of multiple parameters. The

motivation of an individual to adhere to such a treatment and record keeping regimen, and

subsequent quality of data collected, is likely dependent on the perceived acne severity. The

general lifestyle and severity of acne amongst a young cohort of participants, not currently

taking more intensive treatments such as retinoids or antibiotics, may not lead to robust

participation in our study. This was supported by evidence of poor and delayed diary

completion with likely recall bias, as well as the specific reasons given for withdrawal. There

were 22 participants who withdrew for reasons of inconvenience or were lost to follow up. In

contrast to this, the rosacea study reported only one withdrawal for similar reasons, the

average participant age was 58.2 years and the study duration eight weeks.

Whilst an inflammatory process is prominent in the pathogenesis of acne, the relative

contribution of different molecular and immunological pathways are not fully elucidated11,

although it is clear that bacteria such as P. Acnes influence this process. Although the

potential mechanism of action was not the focus of this study, it is possible that the anti-

inflammatory and antibacterial properties of Kanuka honey may not exert an influence

relevant to the specific pathogenic pathways in Acne. This may also explain the negative

findings. In relation to this, effective delivery of honey to the site of inflammation and/or

infection within a lesion must also be considered, and will be influenced by the type of lesion

and whether open or closed. Whilst we recorded lesions as inflammatory or non-

inflammatory, further details were not recorded that may have been relevant to outcomes in

particular sub-groups. The use of Honevo as a targeted topical acne therapy, for example in

open lesions only, is worthy of future study.

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Protex antibacterial soap is a widely available ‘over the counter’ treatment for acne

containing the bacteriostatic agent triclocarban. Incorporating Protex application as both the

control and within the treatment arm has allowed us to examine the effect of Honevo™ when

added to Protex treatment. Direct comparison of protex to Honevo™ in a subsequent non-

inferiority trial would whether Honevo represents a natural treatment option for acne suffers,

with equivalent efficacy as Protex.

In conclusion, this RCT has not shown the addition of Honevo to standard Protex

antibacterial soap wash to be of clinical benefit in the treatment of acne. The study has,

however, highlighted significant methodological and statistical considerations that will be of

value in further studies of natural products such as Honevo™. It is clear that the method of

data collection in studies of this length must be both robust and convenient to patients and to

facilitate this key related outcome measures should be used. Taking this into consideration,

future studies concerning Honevo™ should consider the use of ‘e-Diaries’, simplified data

recording methods and direct comparison of Honevo™ with standard treatment.

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

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

Contributors: IB, JF, RB contributed to study concept and design. CH, DS, AC, CT, CH and

BM contributed to acquisition of the data. AS, IB, RB and MW drafted the manuscript. All the

authors contributed to critical revision of the manuscript for important intellectual content and

also to administrative, technical and material support. MW contributed to statistical analysis.

Funding: This study was entirely funded by HoneyLab®, who provided the Honevo™ (90%

medical grade kanuka honey and 10% glycerine).

Competing interests: None declared

Ethical Approval: Approved by the Central Health and Disabilities Ethics Committee, New

Zealand (13/CEN/119)

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

Trials Registry ACTRN12614000003673

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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References

1. Bhate K, Williams H. Epidemiology of acne vulgaris. Br. J. Dermatol. 2013 168, 474–85

2. Cunliffe W, Gould D. Prevalence of facial acne vulgaris in late adolescence and in adults. Br. Med. J. 1979 1, 1109–10.

3. Sandoval L, Hartel K. & Feldman S. Current and future evidence-based acne treatment: a review. Expert Opin. Pharmacother. 2014 15, 173–92.

4. Leccia, M, Auffret N, Claudel J et al. Topical acne treatments in Europe and the issue of antimicrobial resistance. J. Eur. Acad. Dermatol. Venereol. 2015. doi:10.1111/jdv.12989

5. Hippocrates. On Ulcers. (400BC) Internet Classics Archive. Translated by F Adams at <http://classics.mit.edu/Hippocrates/ulcers.5.5.html>

6. Leong A, Herst P, Harper J. Indigenous New Zealand honeys exhibit multiple anti-inflammatory activities. Innate Immun. 2012 18, 459–66.

7. Lu, J, Carter D, 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.

8. Braithwaite I, Hunt A, Riley J et al. Randomised controlled trial of topical kanuka

honey for the treatment of rosacea, accepted for publication. BMJ Open 2015; 24;5(6):e00765

9. Administration, U. S. D. of H. and H. S. F. and D. & (CDER), C. for D. E. and R. Guidance for Industry Acne Vulgaris: Developing Drugs for Treatment. (2005. at <http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071292.pdf>

10. O’brien S, Lewis J, Cunliffe W. The Leeds revised acne grading system. J. Dermatolog. Treat. 1998 9, 215–220

11. Tanghetti E. The role of inflammation in the pathology of acne. J. Clin. Aesthet. Dermatol. 2013 6, 27–35.

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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 1

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 7

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 8

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

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

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

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

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group 8

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

by original assigned groups

8

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)

8-12

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended n/a

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

pre-specified from exploratory

10

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 12

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 13-15

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 13-15

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 13-15

Other information

Registration 23 Registration number and name of trial registry 16

Protocol 24 Where the full trial protocol can be accessed, if available 16

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 16

*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-2015-009448.R1


Date Submitted by the Author: 08-Dec-2015








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1


TREATMENT OF ACNE

Alex Semprini1, Irene Braithwaite1, Andrew Corin2, Davitt Sheahan3, Christopher

Tofield4,Colin Helm2,Barney Montgomery5, James Fingleton1, Mark Weatherall6, Richard

Beasley1






Word Count: Abstract 279. Manuscript 3, 462



Alex Semprini 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

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

glycerine (Honevo™) as a treatment for facial acne.


variable.





Interventions: All participants applied Protex antibacterial soap twice daily for 12 weeks.

Participants randomised to the Honevo™ treatment arm applied this directly after washing

off the Protex soap, twice daily for 12 weeks.




worsening acne.

Results: 4/53 (7.6%) participants in the Honevo™/Protex group and 1/53 (1.9%) of

participants in the Protex only group had a ≥ 2 improvement in IGA score at week 12,

compared with baseline, odds ratio (95% CI) for improvement 4.2 (0.5 to 39.3), P = 0.17.

There were 15 and 14 participants who withdrew from the Honevo™/Protex group and

control group respectively.

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Conclusion: This randomised controlled trial did not find evidence that addition of Honevo™

to standard Protex antibacterial soap treatment is more effective than the use of Protex soap

alone in the treatment of acne.



What is known about the topic?



rosacea.


Whilst this study does not show Honevo™ to be an effective treatment for acne, important

methodological considerations for future studies of topical honey treatments for

dermatological conditions are highlighted.


This is a 12 week a randomised controlled trial comparing the addition of topical 90%

medical grade kanuka honey and 10% glyercine (Honevo™) to standard antibacterial soap

wash (Protex) with standard antibacterial soap wash alone.




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INTRODUCTION




















trial (RCT) that found a significant improvement in rosacea severity using a topical medical

grade kanuka honey formulation (Honevo™) compared to a standard topical treatment

(Cetomacrogol). The honey treatment had high patient acceptability8. The study reported

here is a RCT investigating the efficacy of the 90% medical grade kanuka honey and 10%

glycerine formulation (Honevo™) in the topical management of acne.

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METHODS










Antibacterial; any significant systemic illness or other condition which the investigators felt

presented a safety risk or potentially affected the participant’s ability to complete the study.















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All participants were asked to apply Protex soap twice daily to affected areas according to

the manufacturer’s instructions. Participants randomised to the Honveo™ group were asked

to apply Honevo™ to affected areas, following the Protex application, twice daily for between

30 and 60 minutes and then wash it off with warm water. The control group just used the

soap. Adherence was assessed by daily recording of applications by participants and a

check for diary completeness at each visit.


Participants were randomised to the Honevo™/Protex or Protex only trial arms using a

concealed computer generated sequence. After consent was obtained the investigator

opened an opaque envelope revealing the randomised treatment for the participant. A

second investigator performed the IGA at each visit masked as to treatment allocation. The

Honevo™ group were asked not to use the product on the day of assessment to maintain

masking.

Outcome measures







grading system10.

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There is a lack of prior study utilizing honey as a topical therapy for acne. We therefore

based our power calculations on an anticipated response of 25 to 50% given the 0 to 5 point

score structure and maximum four point improvement available within the ordinal IGA used

to assess the primary outcome variable. A total of 124 participants (62 in each group) had 80%

power at 5% significance to detect an absolute difference of 25% responders. Recruitment of

136 participants allowed for a 10% drop-out rate. Treatment arms were blocked by 136 to ensure

equal participant numbers within each.

Statistical methods

Analysis was per - protocol. Logistic regression was used to estimate the odds ratio (OR) for

the proportion of participants with an IGA score change from baseline of ≥ 2 at 12 weeks and

for the proportion of withdrawals due to worsening acne, comparing Honevo™ to Control.

For the latter this was unable to be estimated due to no withdrawals for worsening acne in

the control group.

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this odds ratio meant that Honey had a better outcome than Control.








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RESULTS

The flow of participants is shown in Figure 1. 68 participants were randomised to each

treatment with similar proportions of males and females and equivalent duration of acne in

each (Table 2).



Min to Max


All N = 135 21.2 (5.8) 18.3 (17.1 to 23.3)

16.0 to 39.7

Honevo™/Protex = 68 21.5 (6.4) 18.5 (17.1 to 23.5)

16.0 to 39.7

Control N = 67 20.9 (5.2) 18.3 (17.2 to 23.3)

16.0 to 38.4


All N = 135 13.9 (2.7) 13 (13 to 14)

10 to 28

Honevo™/Protex = 68 13.7 (2.7) 13 (12.5 to 24)

10 to 28

Control N = 67 14.2 (2.6) 14 (13 to 14)

11 to 26


Shortly after randomisation to the Protex soap only arm, one participant was found to exceed

the age criteria and was withdrawn with no data collected. There were 15 (22.1%)

withdrawals in the Honevo™/Protex group (two worsening acne, three use of prohibited

medication, five lost to follow up and five participants who withdrew because of non-

adherence due to reported inconvenience of the treatment). There were 14 (20.6%)

withdrawals in the Protex only group (one adverse event involving a minor skin reaction, one

use of a prohibited medication, 10 were lost to follow up and two participants withdrew due

to inconvenience of the treatment).

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Primary outcome

4/53 (7.6%) participants in the Honevo™/Protex group and 1/53 (1.9%) of participants in the

Protex only group had a ≥ 2 improvement in IGA assessment at week 12, compared with


Secondary outcomes

The Hodges-Lehmann estimator (95% CI) comparing IGA scores for Honevo™/Protex with

Protex alone at four weeks was 0 (0 to 0), P = 0.54, and at 12 weeks was 0 (0 to 0) P = 0.33.






These latter estimates are consistent with weak evidence of improvement in the

Honevo™/Protex group compared to Protex control. Data summaries for IGA are shown in

Table 3.

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Table 3: IGA scores at each visit for participants in Honevo™/Protex and Protex only treatment

arms with change in IGA score from baseline at visit two and three.

Variable

N (%)

Honevo™/Protex

Control All

IGA - Visit 1 N=68 N=67 N=135 0 0 0 0 1 0 0 0 2 21 (30.9) 23 (34.3) 44 (32.6) 3 37 (54.4) 38 (56.7) 75 (55.6) 4 10 (14.7)

6 (9.0) 16 (11.9)

IGA - Visit 2 N=61 N=56 N=117

0 0 0 0 1 8 (13.1) 3 (5.4) 11 (9.4) 2 24 (39.3) 27 (48.2) 51 (43.6) 3 24 (39.3) 18 (32.1) 42 (35.9) 4 5 (8.2)

8 (14.3) 13 (11.1)

IGA - Visit 3 N=53 N=53 N=106

0 0 0 0 1 10 (18.9) 7 (13.2) 17 (16.0) 2 25 (47.2) 24 (45.3) 49 (46.2) 3 15 (28.3) 18 (34.0) 33 (31.3) 4 3 (5.7)

4 (7.6) 7 (6.6)


N=61 N=56 N=117

-2 1 (1.6) 0 (0) 1 (0.9) -1 26 (42.6) 15 (26.8) 41 (35.0) 0 30 (49.2) 35 (62.5) 65 (55.6) 1 4 (6.7)

6 (10.7) 10 (8.6)


N=53 N=53 N=106

-2 4 (7.6) 1 (1.9) 5 (4.7) -1 25 (47.2) 21 (39.6) 46 (43.4) 0 23 (43.4) 26 (49.1) 49 (46.2) 1 1 (1.9) 5 (9.4) 6 (5.7)

The difference (95% CI) in logarithm inflamed lesion count for Honevo™/Protex minus

Protex after adjustment for baseline at week four was -0.28 (-0.61 to 0.06) P = 0.11, ratio of

mean lesion counts by exponentiation 0.76 (0.54 to 1.06). At week 12 the difference (95%

CI) was -0.29 (-0.65 to 0.07), P = 0.11, ratio of mean lesion counts by exponentiation 0.75

(0.52 to 1.07). The difference (95% CI) in logarithm non-inflamed lesion count,

Honevo™/Protex minus Protex, at week four count was -0.12 (-0.42 to 0.18), P = 0.44, ratio

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of mean lesion counts by exponentiation 0.89 (0.66 to 1.20), and at week 12 -0.06 (-0.40 to

0.28) P = 0.72, ratio of mean lesion counts by exponentiation 0.94 (0.67 to 1.32).


baseline, Honevo™/Protex minus Protex, at week four was 9.6 (3.7 to 15.6), P = 0.002; and

at week 12, 11.0 (4.4 to 17.6) P = 0.001,


Honevo™/Protex minus Protex, at week four was -3.7 (-10.2 to 2.7) P = 0.26; and at week

12 -6.8 (-14.8 to 1.2) P = 0.095.

The difference (95% CI) in DLQI adjusted for baseline, Honevo™/Protex minus Protex, at

week four was 0.12 (-0.73 to 0.97), P = 0.77; and at week 12 0.14 (-0.75 to 1.03) P = 0.76.


treatment, between the two study groups was -7 (-13 to -1) P = 0.01, with Honevo™/Protex


Self-reported global acne severity VAS comparing Honevo™/Protex and Protex alone,

adjusted for week one baseline demonstrated moderate evidence for improved scores using

Honevo™ between weeks 5 and 11.

Withdrawal due to worsening acne occurred in 2/68 (2.9%) of the Honevo™/Protex group

and none of the Protex group.

Adverse events


unrelated to the study treatment. There were 28 adverse events, eight in the

Honevo™/Protex group and 20 Protex group which were assessed to be related to the study

treatment. All involved skin related complaints including oily, dry and stinging skin, contact

dermatitis and worsening acne.

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Discussion

This RCT has not found evidence that the addition of 90% medical grade Kanuka honey in

combination with 10% glycerine (Honevo™) to standard Protex antibacterial soap treatment

is more effective than the use of Protex soap alone in the treatment of acne.


criteria of ≥ 2 point change in IGA, a more detailed analysis treating the outcome as an


evidence of an improved score in the Honevo™/Protex arm compared to control at 12

weeks, with an OR for an improved category of IGA of 2.0 (P=0.075). In this study there

were an unexpectedly high number of withdrawals and a small number of participants who

actually improved by the above criterion. This in turn was likely related to a floor effect for the



was two. There were 15 (22.1%) and 14 (20.6%) withdrawals for Protex/Honevo and Protex

respectively.

Secondary outcomes mostly showed no evidence of benefit from the use of Honevo™ for

the treatment of acne. Subject rated improvement according to a VAS at weeks four and 12

was better for the honey treatment. There may have been subjective assessment bias

however because we could not mask participants to honey treatment. In addition, this

outcome variable may be subject to Type I error rate inflation as it was a secondary outcome

amongst a number of other secondary outcome variables.

Comparision with other studies

We are not aware of an RCT considering a honey-based therapy for acne. A previous study,

which found Honevo™ an effective treatment for rosacea, was of similar design, size and

utilised a primary outcome of a blinded, seven point, Investigator Global Assessment of

Rosacea Severity Score (IGA-RSS) ≥2. 34.3% of participants randomised to Honevo™ and

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17.4% receiving control achieved the primary outcome compared to 7.6% and 1.9% in the

acne study. Given the wider scope for improvement in the Rosacea study (seven points as

compared to five points in the IGA scale) and the higher proportion of participants reaching

the primary outcome criterion in both arms, further studies of honey in acne may wish to

consider these factors in study design. Furthermore a number of participant characteristics

may be relevant. The mean age of participants with chronic acne, present on average for 14

years, was 21 years. The total study duration was 12 weeks and the diary component of the

data collection required daily entry of multiple parameters. We considered that the motivation

of an individual to adhere to such a treatment and record keeping regimen, and subsequent

quality of data collected, is likely dependent on the perceived acne severity however, it is

also possible that adherence in teenagers with acne is poor, even when they are bothered

by their acne. The general lifestyle and severity of acne amongst a young cohort of

participants, not currently taking more intensive treatments such as retinoids or antibiotics,

may not lead to robust participation in our study. There were 22 participants who withdrew

for reasons of inconvenience or were lost to follow up. In contrast to this, the rosacea study

reported only one withdrawal for similar reasons, the average participant age was 58.2 years

and the study duration eight weeks.

Strengths and limitations

Strengths of the study include the co-application of protex soap within the active Honevo

treatment arm, thereby allowing the examination of a true additive effect. Utilising the IGA in

combination with lesion counts as outcome variables allows for the pleomorphic expression

of acne within a group, whilst also providing an absolute quantitative measure of

improvement. The blinding of the assessors generating these outcomes to specific treatment

allocations, also allowed for avoidance of assessment bias.

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The primary, but unavoidable limitation for this study was the lack of blinding for participants

because the Honevo product tasted and smelt of honey (90% Kanuka honey and 10%

glycerine). It is therefore not possible to produce an inert control that matches these

characteristics without containing a high concentration of honey. Further issues were

apparent in terms of data collection, with evidence of poor and delayed diary completion and

likely recall bias, as well as the specific reasons given for withdrawal.

Implications for clinical practice

The results presented do not support a benefit of using honey in addition to a common over

the counter antibacterial soap such as protex. This knowledge may inform both patients and

clinicians when considering alternative therapies for acne, and the study furthers the

knowledge base for commonly used and recommended alternative therapies for

dermatological conditions.

Implications of future research



although it is clear that bacteria such as P. Acnes influence this process. The potential

mechanism of action was not the focus of this study, however it is possible that the anti-

inflammatory and antibacterial properties of Kanuka honey may not exert an influence






particular sub-groups. The use of Honevo as a targeted topical acne therapy, for example in

open lesions only, is worthy of future study.

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containing the bacteriostatic agent triclocarban. Incorporating Protex application as both the

control and within the treatment arm has allowed us to examine the effect of Honevo™ when

added to Protex treatment. Direct comparison of protex to Honevo™ in a subsequent non-

inferiority trial would reveal whether Honevo represents a natural treatment option for acne

suffers, with equivalent efficacy as Protex.

Overall there is a need for robust evidence to support or rebuke claims by alternative

therapies marketed for common medical ailments, some of which have a serious impact on

quality of life. Particular focus on constantly improving the methodology used to answer

these research questions will allow cost effective, well powered and high quality RCTs to

further advance this field.

Conclusion

In conclusion, this RCT has not shown the addition of Honevo to standard Protex

antibacterial soap wash to be of clinical benefit in the treatment of acne. The study has,

however, highlighted significant methodological and statistical considerations that will be of

value in further studies of natural products such as Honevo™. It is clear that the method of

data collection in studies of this length must be both robust and convenient to patients and to

facilitate this key related outcome measures should be used. Taking this into consideration,

future studies concerning Honevo™ should consider the use of ‘e-Diaries’, simplified data

recording methods and direct comparison of Honevo™ with standard treatment.

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Funding: This study was entirely funded by HoneyLab®, who provided the Honevo™ (90%

medical grade kanuka honey and 10% glycerine). The sponsor had no role in the study

design, data collection, management, analysis and interpretation of data, writing of the report

and the decision to submit for publication.










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References









honey for the treatment of rosacea. BMJ Open 2015; 24;5(6):e00765




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Figure 1: Participant flow from randomisation to study completion or withdrawal 181x155mm (300 x 300 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







8

Outcomes and

estimation



8-12




10


Discussion




Other information







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Journal: BMJ Open

Manuscript ID bmjopen-2015-009448.R2


Date Submitted by the Author: 17-Dec-2015








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1


TREATMENT OF ACNE

Alex Semprini1, Irene Braithwaite1, Andrew Corin2, Davitt Sheahan3, Christopher Tofield4,

Colin Helm2, Barney Montgomery5, James Fingleton1, Mark Weatherall6, Richard Beasley1






Word Count: Abstract 278. Manuscript 3,526



Alex Semprini 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] Abstract

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Objective: To investigate the efficacy of Honevo, a topical 90% medical grade kanuka

honey and 10% glycerine (honey product) as a treatment for facial acne.


variable.





Interventions: All participants applied Protex, a triclocarban based antibacterial soap twice

daily for 12 weeks. Participants randomised to the honey product treatment arm applied this

directly after washing off the antibacterial soap, twice daily for 12 weeks.




worsening acne.

Results: 4/53 (7.6%) participants in the honey product group and 1/53 (1.9%) of participants

in the control group had a ≥ 2 improvement in IGA score at week 12, compared with

baseline, odds ratio (95% CI) for improvement 4.2 (0.5 to 39.3), P = 0.17. There were 15 and

14 participants who withdrew from the honey product group and control group respectively.

Conclusion: This randomised controlled trial did not find evidence that addition of medical

grade kanuka honey in combination with 10% glycerine to standard antibacterial soap

treatment is more effective than the use of antibacterial soap alone in the treatment of acne.


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What is known about the topic?



rosacea.


Whilst this study does not show medical grade kanuka honey in combination with 10%

glycerine to be an effective treatment for acne, important methodological considerations for

future studies of topical honey treatments for dermatological conditions are highlighted.


This is a 12 week a randomised controlled trial comparing the addition of topical 90%

medical grade kanuka honey and 10% glycerine to standard antibacterial soap wash with

antibacterial soap wash alone.




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INTRODUCTION




















trial (RCT) that found a significant improvement in rosacea severity using a topical 90%

medical grade kanuka honey/10% glycerine formulation compared to a standard topical

treatment (Cetomacrogol). The honey treatment had high patient acceptability8. The study

reported here is a RCT investigating the efficacy of the medical grade kanuka honey product

in the topical management of acne.

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5

METHODS










Antibacterial/triclocarban; any significant systemic illness or other condition which the

investigators felt presented a safety risk or potentially affected the participant’s ability to

complete the study.















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All participants were asked to apply Protex, an triclocarban based antibacterial soap twice

daily to affected areas according to the manufacturer’s instructions. Participants randomised

to the Honevo, 90% medical grade kanuka honey with 10% glycerine (honey product) group

were asked to apply the honey formulation to affected areas, following the antibacterial soap

application, twice daily for between 30 and 60 minutes and then wash it off with warm water.

The control group just used the soap. Adherence was assessed by daily recording of

applications by participants and a check for diary completeness at each visit.


Participants were randomised to the honey product or control arms using a concealed

computer generated sequence. After consent was obtained the investigator opened an

opaque envelope revealing the randomised treatment for the participant. A second

investigator performed the IGA at each visit masked as to treatment allocation. The honey

product group were asked not to use the treatment on the day of assessment to maintain

masking.

Outcome measures







grading system10.

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There is a lack of prior study utilizing honey as a topical therapy for acne. We therefore

based our power calculations on an anticipated response of 25 to 50% given the 0 to 5 point

score structure and maximum four point improvement available within the ordinal IGA used

to assess the primary outcome variable. A total of 124 participants (62 in each group) had 80%

power at 5% significance to detect an absolute difference of 25% responders. Recruitment of

136 participants allowed for a 10% drop-out rate. Treatment arms were blocked by 136 to ensure

equal participant numbers within each.

Statistical methods

Analysis was per - protocol. Logistic regression was used to estimate the odds ratio (OR) for

the proportion of participants with an IGA score change from baseline of ≥ 2 at 12 weeks and

for the proportion of withdrawals due to worsening acne, comparing honey product to

control. For the latter this was unable to be estimated due to no withdrawals for worsening

acne in the control group.

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this odds ratio meant that honey product had a better outcome than control.








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RESULTS

The flow of participants is shown in Figure 1. 68 participants were randomised to each

treatment with similar proportions of males and females and equivalent duration of acne in

each (Table 2).



Min to Max


All N = 135 21.2 (5.8) 18.3 (17.1 to 23.3)

16.0 to 39.7

Honey product = 68 21.5 (6.4) 18.5 (17.1 to 23.5)

16.0 to 39.7

Control N = 67 20.9 (5.2) 18.3 (17.2 to 23.3)

16.0 to 38.4


All N = 135 13.9 (2.7) 13 (13 to 14)

10 to 28

Honey product = 68 13.7 (2.7) 13 (12.5 to 24)

10 to 28

Control N = 67 14.2 (2.6) 14 (13 to 14)

11 to 26


Shortly after randomisation to the control arm, one participant was found to exceed the age

criteria and was withdrawn with no data collected. There were 15 (22.1%) withdrawals in the

honey product group (two worsening acne, three use of prohibited medication, five lost to

follow up and five participants who withdrew because of non-adherence due to reported

inconvenience of the treatment). There were 14 (20.6%) withdrawals in the control group

(one adverse event involving a minor skin reaction, one use of a prohibited medication, 10

were lost to follow up and two participants withdrew due to inconvenience of the treatment).

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Primary outcome

4/53 (7.6%) participants in the honey product group and 1/53 (1.9%) of participants in the

control only group had a ≥ 2 improvement in IGA assessment at week 12, compared with


Secondary outcomes

The Hodges-Lehmann estimator (95% CI) comparing IGA scores for honey product with

control at four weeks was 0 (0 to 0), P = 0.54, and at 12 weeks was 0 (0 to 0) P = 0.33.






These latter estimates are consistent with weak evidence of improvement in the honey

product group compared to control. Data summaries for IGA are shown in Table 3.

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Table 3: IGA scores at each visit for participants in honey product and control treatment arms

with change in IGA score from baseline at visit two and three.

Variable

N (%)

Honey product

Control All

IGA - Visit 1 N=68 N=67 N=135 0 0 0 0 1 0 0 0 2 21 (30.9) 23 (34.3) 44 (32.6) 3 37 (54.4) 38 (56.7) 75 (55.6) 4 10 (14.7)

6 (9.0) 16 (11.9)

IGA - Visit 2 N=61 N=56 N=117

0 0 0 0 1 8 (13.1) 3 (5.4) 11 (9.4) 2 24 (39.3) 27 (48.2) 51 (43.6) 3 24 (39.3) 18 (32.1) 42 (35.9) 4 5 (8.2)

8 (14.3) 13 (11.1)

IGA - Visit 3 N=53 N=53 N=106

0 0 0 0 1 10 (18.9) 7 (13.2) 17 (16.0) 2 25 (47.2) 24 (45.3) 49 (46.2) 3 15 (28.3) 18 (34.0) 33 (31.3) 4 3 (5.7)

4 (7.6) 7 (6.6)


N=61 N=56 N=117

-2 1 (1.6) 0 (0) 1 (0.9) -1 26 (42.6) 15 (26.8) 41 (35.0) 0 30 (49.2) 35 (62.5) 65 (55.6) 1 4 (6.7)

6 (10.7) 10 (8.6)


N=53 N=53 N=106

-2 4 (7.6) 1 (1.9) 5 (4.7) -1 25 (47.2) 21 (39.6) 46 (43.4) 0 23 (43.4) 26 (49.1) 49 (46.2) 1 1 (1.9) 5 (9.4) 6 (5.7)

The difference (95% CI) in logarithm inflamed lesion count for honey product minus control

after adjustment for baseline at week four was -0.28 (-0.61 to 0.06) P = 0.11, ratio of mean

lesion counts by exponentiation 0.76 (0.54 to 1.06). At week 12 the difference (95% CI) was

-0.29 (-0.65 to 0.07), P = 0.11, ratio of mean lesion counts by exponentiation 0.75 (0.52 to

1.07). The difference (95% CI) in logarithm non-inflamed lesion count, honey product minus

control, at week four count was -0.12 (-0.42 to 0.18), P = 0.44, ratio of mean lesion counts

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by exponentiation 0.89 (0.66 to 1.20), and at week 12 -0.06 (-0.40 to 0.28) P = 0.72, ratio of

mean lesion counts by exponentiation 0.94 (0.67 to 1.32).


baseline, honey product minus control, at week four was 9.6 (3.7 to 15.6), P = 0.002; and at

week 12, 11.0 (4.4 to 17.6) P = 0.001,


honey product minus control, at week four was -3.7 (-10.2 to 2.7) P = 0.26; and at week 12 -

6.8 (-14.8 to 1.2) P = 0.095.

The difference (95% CI) in DLQI adjusted for baseline, honey product minus control, at week

four was 0.12 (-0.73 to 0.97), P = 0.77; and at week 12 0.14 (-0.75 to 1.03) P = 0.76.


treatment, between the two study groups was -7 (-13 to -1) P = 0.01, with honey product


Self-reported global acne severity VAS comparing honey product and control alone, adjusted

for week one baseline demonstrated moderate evidence for improved scores using honey

product between weeks 5 and 11.

Withdrawal due to worsening acne occurred in 2/68 (2.9%) of the honey product group and

none of the control group.

Adverse events


unrelated to the study treatment. There were 47 adverse events, 23 in the honey product

group and 24 control group which were assessed to be related to the study treatment. All

involved skin related complaints including oily, dry and stinging skin, contact dermatitis and

worsening acne.

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Discussion

This RCT has not found evidence that the addition of 90% medical grade kanuka honey in

combination with 10% glycerine to standard antibacterial soap treatment is more effective

than the use of antibacterial soap alone in the treatment of acne.


criteria of ≥ 2 point change in IGA, a more detailed analysis treating the outcome as an


evidence of an improved score in the honey product arm compared to control at 12 weeks,

with an OR for an improved category of IGA of 2.0 (P=0.075). In this study there were an

unexpectedly high number of withdrawals and a small number of participants who actually

improved by the above criterion. This in turn was likely related to a floor effect for the



was two. There were 15 (22.1%) and 14 (20.6%) withdrawals for the honey product and

control groups respectively.

Secondary outcomes mostly showed no evidence of benefit from the use of honey product

for the treatment of acne. Subject rated improvement according to a VAS at weeks four and

12 was better for the honey treatment. There may have been subjective assessment bias

however because we could not mask participants to honey treatment. In addition, this

outcome variable may be subject to Type I error rate inflation as it was a secondary outcome

amongst a number of other secondary outcome variables.

Comparison with other studies

We are not aware of an RCT considering a honey-based therapy for acne. A previous study,

which found the honey product an effective treatment for rosacea, was of similar design, size

and utilised a primary outcome of a blinded, seven point, Investigator Global Assessment of

Rosacea Severity Score (IGA-RSS) ≥2. 34.3% of participants randomised to honey product

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and 17.4% receiving control achieved the primary outcome compared to 7.6% and 1.9% in

the acne study. Given the wider scope for improvement in the Rosacea study (seven points

as compared to five points in the IGA scale) and the higher proportion of participants

reaching the primary outcome criterion in both arms, further studies of honey in acne may

wish to consider these factors in study design. Furthermore a number of participant

characteristics may be relevant. The mean age of participants with chronic acne, present on

average for 14 years, was 21 years. The total study duration was 12 weeks and the diary

component of the data collection required daily entry of multiple parameters. We considered

that the motivation of an individual to adhere to such a treatment and record keeping

regimen, and subsequent quality of data collected, is likely dependent on the perceived acne

severity however, it is also possible that adherence in teenagers with acne is poor, even

when they are bothered by their acne. The general lifestyle and severity of acne amongst a

young cohort of participants, not currently taking more intensive treatments such as retinoids

or antibiotics, may not lead to robust participation in our study. There were 22 participants

who withdrew for reasons of inconvenience or were lost to follow up. In contrast to this, the

rosacea study reported only one withdrawal for similar reasons, the average participant age

was 58.2 years and the study duration eight weeks.

Strengths and limitations

Strengths of the study include the co-application of antibacterial soap within the active honey

product treatment arm, thereby allowing the examination of a true additive effect. Utilising

the IGA in combination with lesion counts as outcome variables allows for the pleomorphic

expression of acne within a group, whilst also providing an absolute quantitative measure of

improvement. The blinding of the assessors generating these outcomes to specific treatment

allocations, also allowed for avoidance of assessment bias.

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The primary, but unavoidable limitation for this study was the lack of blinding for participants

because the honey product tasted and smelt of honey (90% kanuka honey and 10%

glycerine). It is therefore not possible to produce an inert control that matches these

characteristics without containing a high concentration of honey. Further issues were

apparent in terms of data collection, with evidence of poor and delayed diary completion and

likely recall bias, as well as the specific reasons given for withdrawal.

Implications for clinical practice

The results presented do not support a benefit of using honey in addition to a common over

the counter antibacterial soap. This knowledge may inform both patients and clinicians when

considering alternative therapies for acne, and the study furthers the knowledge base for

commonly used and recommended alternative therapies for dermatological conditions.

Implications of future research



although it is clear that bacteria such as P. Acnes influence this process. The potential

mechanism of action was not the focus of this study, however it is possible that the anti-

inflammatory and antibacterial properties of kanuka honey may not exert an influence






particular sub-groups. The use of such a honey product as a targeted topical acne therapy,

for example in open lesions only, is worthy of future study.


containing the bacteriostatic agent triclocarban. Incorporating antibacterial soap application

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as both the control and within the treatment arm has allowed us to examine the effect of the

kanuka honey product when added to antibacterial soap treatment. Direct comparison of an

antibacterial soap to the honey product in a subsequent non-inferiority trial would reveal

whether kanuka honey represents a natural treatment option for acne suffers, with

equivalent efficacy as a widely available, over the counter antibacterial soap.

Overall there is a need for robust evidence to support or rebuke claims by alternative

therapies marketed for common medical ailments, some of which have a serious impact on

quality of life. Particular focus on constantly improving the methodology used to answer

these research questions will allow cost effective, well powered and high quality RCTs to

further advance this field.

Conclusion

In conclusion, this RCT has not shown the addition of medical grade kanuka honey in

combination with 10% glycerine to standard antibacterial soap wash to be of clinical benefit

in the treatment of acne. The study has, however, highlighted significant methodological and

statistical considerations that will be of value in further studies of such natural products. It is

clear that the method of data collection in studies of this length must be both robust and

convenient to patients and to facilitate this key related outcome measures should be used.

Taking this into consideration, future studies concerning topical honey should consider the

use of ‘e-Diaries’, simplified data recording methods and direct comparison of the honey

based product with standard treatment.

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Funding: This study was entirely funded by HoneyLab®, who provided the Honevo (90%

medical grade kanuka honey and 10% glycerine). The sponsor had no role in the study

design, data collection, management, analysis and interpretation of data, writing of the report

and the decision to submit for publication.










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References









honey for the treatment of rosacea, accepted for publication. BMJ Open 2015; 24;5(6):e00765




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Figure 1: Participant flow from randomisation to study completion or withdrawal 181x155mm (300 x 300 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







8

Outcomes and

estimation



8-12




10


Discussion




Other information







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RANDOMISED CONTROLLED TRIAL OF TOPICAL KANUKA HONEY FOR THE TREATMENT OF ACNE · P. Acne...

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