ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12607000428460

Ethics application status

Approved

Date submitted

7/06/2007

Date registered

22/08/2007

Date last updated

3/07/2008

Type of registration

Prospectively registered

Titles & IDs

Public title

Randomised, double-blind, placebo controlled study to assess efficacy of topical nicotinamide in the treatment and prevention of actinic keratosis.

Scientific title

Randomised, double-blind, placebo controlled study to assess efficacy of topical nicotinamide in the treatment and prevention of actinic keratosis.

Universal Trial Number (UTN)

Trial acronym

N/A

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Actinic Keratoses

Condition category

Condition code

Skin

Dermatological conditions

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Application of 1% nicotinamide lotion compared with placebo twice daily for six months. Both the active treatment and placebo will be applied topically to symmetrically distributed non-hyperkeratotic actinic keratoses on face / scalp/ upper limbs.

Intervention code [1]

Prevention

Comparator / control treatment

Placebo

Control group

Placebo

Outcomes

Primary outcome [1]

Reduction in total actinic keratosis count at six months compared with baseline count

Timepoint [1]

AK count at baseline and 6 months

Secondary outcome [1]

Reduction in total actinic keratosis count

Timepoint [1]

At three months compared with baseline count

Eligibility

Key inclusion criteria

Symmetrically distributed non-hyperkeratotic AKs on face / scalp/ upper limbs.Minimum of 4 AKs in one or more treatment areas.Patients have received no other treatments for AKs within the last month.

Minimum age

18 Years

Maximum age

N/A

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Pregnant or lactating Taking immunosuppressive or photosensitising medications Taking nicotinamide or other vitamin supplements Patients unable to attend for regular follow up Patients with active dermatitis in the treatment areas.

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Volunteers will be randomized to receive either nicotinamide 1% lotion twice daily (bd) or placebo. Both active treatment and placebo will be contained within identical containers. Allocation will be concealed within sealed opaque envelopes.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

A computer generated random sequence will be used without any restrictions.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

1/09/2007

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Royal prince Alfred ( Provides infrastructural support)

Address [1]

Camperdown, NSW 2006

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal prince Alfred ( Provides infrastructural support)

Address

Camperdown, NSW 2006

Country

Australia

Secondary sponsor category [1]

None

Name [1]

N/A

Address [1]

Country [1]

Secondary sponsor category [2]

None

Name [2]

Address [2]

Country [2]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

SWAHS ethics comittee

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

10/06/2007

Approval date [1]

Ethics approval number [1]

Summary

Brief summary

TITLE 

Randomised, double-blind, placebo controlled study to assess efficacy of topical nicotinamide in the treatment and prevention of actinic keratosis.
 
INTRODUCTION

Background:

  The incidence of skin cancer has reached epidemic proportions. In Australia, despite public health campaigns and widespread sunscreen use, more than 50% of all Caucasian Australians develop non-melanoma skin cancer (NMSC) during their lifetime1, and more than one in 30 will develop melanoma.2 Ultraviolet radiation (UVR) from sunlight is the major cause of NMSC. In humans, both the UVA and UVB wavebands cause immunosuppression and DNA damage and therefore both UVA and UVB are likely to contribute to induction and development of NMSC.3,4 Immunosuppression enhances skin carcinogenesis5, as seen most dramatically in immunosuppressed transplant patients, who have an 82-fold increase in squamous cell carcinoma (SCC) compared with immunologically competent controls.6
   Broad-spectrum sunscreens, which filter both UVB and UVA can reduce UV immunosuppression, but sunscreens are generally much better at preventing sunburn than immunosuppression.7,8 Current cosmetically acceptable sunscreens are poorly effective at filtering wavelengths bordering the visible spectrum. As immunosuppression can occur with less than half the amount of UV needed to cause sunburn9, the immune protection afforded by sunscreens “in the field” is likely to be low.
 Oral nicotinamide (vitamin B3) is available as an over-the-counter vitamin supplement and has been effective for over 50 years in the treatment of autoimmune and inflammatory skin disorders including bullous pemphigoid and rosacea.10 Unlike nicotinic acid, nicotinamide does not cause significant vasodilation or flushing11 and has few or no potential side effects. Although the exact mechanism of action in these settings is unknown, nicotinamide is a known endogenous inhibitor of the nuclear enzyme poly-ADP-ribose polymerase (PARP), which regulates the expression of immunomodulatory proteins such as inducible nitric oxide synthase, ICAM-1, MHC II and NF-kB.12 Nicotinamide is the precursor of NAD and thus a central building block of cellular energy metabolism. 

   In mice, nicotinamide prevents UV-induced carcinogenesis and reduces skin cancer numbers by 60% when applied as a 2.5% lotion.13 Using a delayed type hypersensitivity model our group has demonstrated that nicotinamide lotion completely prevent UV immunosuppression when applied in a double-blinded placebo-controlled manner to the backs of healthy human volunteers. (Submitted for publication). In a subsequent dose-response study, topical nicotinamide was found to be immune protective at concentrations as low as 1%; it could thus be safely and cheaply added to sunscreens or moisturisers to reduce UV immunosuppression and potentially treat or prevent actinic keratosis, premalignant lesions which act as a surrogate marker for squamous cell skin cancers.

Aims:  

This study will compare how effective topical nicotinamide is in the treatment and prevention of actinic keratoses when compared with a placebo lotion over a six month period.

Hypothesis:	

That the twice daily application of topical nicotinamide will reduce the number of new and existing actinic keratoses in a patient population with multiple actinic keratoses when compared with placebo.



RESEARCH PLAN AND METHODS

Participants
Patients to be recruited from general dermatology clinics in RPA.

Inclusion Criteria
Men and women > 18 years old.
Symmetrically distributed non-hyperkeratotic AKs on face / scalp/  upper limbs.
Minimum of 4 AKs in one or more treatment areas.
Patients have received no other treatments for AKs within the last month.

Exclusion criteria

	Under 18 years old		
           Pregnant or lactating
	Taking immunosuppressive or photosensitising medications 
	Taking nicotinamide or other vitamin supplements
           Patients unable to attend for regular follow up
           Patients with active dermatitis

Settings and Location

Department of Dermatology, Royal Prince Alfred Hospital, Sydney, NSW.


Interventions

Volunteers will be randomized to receive either nicotinamide 1% lotion twice daily (bd) or placebo. Blood levels of nicotinamide (NAD) will be measured at baseline and at the completion of the study.
Study drug or placebo will be provided to the patients in identical containers and the formulations will be visually indistinguishable. Each patient will be instructed to apply the lotion to the prescribed treatment area twice daily for six months. 
Containers are returned at each visit and the contents weighed.
All patients will be instructed on proper daily use of sunscreens of SPF 30 or greater during the entire study as well as general protective measures.


Objectives

1.	To compare the efficacy of topical nicotinamide in the prevention of new actinic keratosis with placebo. 

2.	To compare the efficacy of topical nicotinamide in the treatment of actinic keratosis with placebo.


Outcomes

The primary endpoint will be the reduction in total A.K. count at 6 months from baseline. A single observer will count and photograph AKs within the fields of treatment. AKs will be graded as II (visible and palpable) or I (palpable only). Patients with thicker hyperkeratotic AKs (III) will be excluded. There will be a secondary endpoint of total A.K. count at 12 weeks to account for appearance of new / subclinical lesions. All adverse events will be reported. The treatment efficacy compared to placebo will be calculated based on intention to treat.


Sample size

Based on a power of 80% and an average AK count of 10 AKs per patient and a predicted 20% reduction in AK count for nicotinamide treated patients compared to placebo treated patients, a sample size of ~40 patients in each study arm will be required to demonstrate a statistically significant difference using 95% confidence intervals. Should nicotinamide prove more effective at reducing the total AK count at six months, the total sample size required will be reduced.

Randomization

Sequentially numbered identical containers of nicotinamide and placebo will be randomised at source. Patients and investigators will be blinded to group assignment until the study end. Each patient will be individually randomized so that the code can be broken for a given patient should that need arise ( e.g adverse event)
 
 
Statistical methods

Statistical support is available through Patrick Fitzgerald, senior biostatistician in the University of Sydney. Subgroup analyses will include the effect of age, skin type, and treatment site on efficacy. Adjusted analyses will include the intention to treat population excluding those that withdraw prior to any use of the treatment.
 
Significance of the project:
Our preliminary studies have identified an effective topical and oral means of reducing UV immunosuppression in humans, using a compound, which is not limited by toxicity, patent, availability or expense. Changes in numbers of lesions in patients with multiple actinic keratoses can be observed within a period of 6 months.16 We predict that application of topical 1% nicotinamide will result in a 20-40% reduction in actinic keratoses. Confirmatory findings could pave the way for larger scale clinical trials of this agent in high-risk patients to assess subsequent impact on rates of NMSC. In Australia, with more than 374 000 new cases of NMSC each year1, even a modest protective effect of nicotinamide would greatly reduce the morbidity and cost of actinic disease.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Associate Professor Diona Damian

Address

Department of Dermatology
Level 3
Gloucester House
Royal Prince Alfred Hospital
NSW 2006

Country

Australia

Phone

+61 2 95158295

Fax

+61 2 95651048

[email protected]

Contact person for scientific queries

Name

Associate Professor Diona Damian

Address

Department of Dermatology
Level 3
Gloucester House
Royal Prince Alfred Hospital
NSW 2006

Country

Australia

Phone

+61 2 95158295

Fax

+61 2 95651048

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

Documents added manually

Documents added automatically