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Trial registered on ANZCTR

Registration number

ACTRN12609000490279

Ethics application status

Approved

Date submitted

13/05/2009

Date registered

19/06/2009

Date last updated

19/06/2009

Type of registration

Retrospectively registered

Titles & IDs

Public title

Randomised, double-blind, placebo controlled study to assess efficacy of oral nicotinamide in the treatment and prevention of actinic keratoses

Scientific title

Randomised, double-blind, placebo controlled study to assess efficacy of oral nicotinamide in the treatment and prevention of actinic keratoses

Universal Trial Number (UTN)

Trial acronym

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

Administration of 500 mg nicotinamide tablet compared to placebo twice daily for four months.

Intervention code [1]

Prevention

Comparator / control treatment

Placebo tablet made of lactose. The dose, frequency and duration of treatment are the same as for nicotinamide group (i.e. 500mg twice a day for 4 months).

Control group

Placebo

Outcomes

Primary outcome [1]

Reduction in total actinic keratosis count at 4 months compared with baseline count. This primary outcome will be assesed by blinded clinical examination by a medically qualified observer.

Timepoint [1]

Actinic Keratosis count at baseline and 4 months

Secondary outcome [1]

Reduction in site specific (i.e. face, arms,scalp) actinic keratosis count at 2 and 4 months compared with baseline count. The secondary outcome will be assessed in the same way as the primary outcome (i.e. blinded clinical examination by a medically qualified observer).

Timepoint [1]

Actinic keratosis count at baseline and 2 months

Eligibility

Key inclusion criteria

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

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Pregnant or lactating. Taking immunosuppressive or photosensitizing medications. Taking nicotinamide or other vitamin supplements. Patients unable to attend for regular follow up. Patients with active dermatitis in the treatment areas. Liver disease. Currently taking Carbamazepine.

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 500 mg tablet twice daily 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

Recruiting

Date of first participant enrolment

Anticipated

12/06/2009

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]

Missenden Rd, Camperdown NSW 2050

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal Prince Alfred (provide infrastructural support)

Address

Missenden Rd, Camperdown NSW 2050

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney South West Area Health Service ethics comittee

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

Ethics approval number [1]

X-09 00004
HREC/09/RPAH/2

Summary

Brief summary

TITLE 

Randomised, double-blind, placebo controlled study to assess efficacy of oral nicotinamide in the treatment and prevention of actinic keratoses.
 
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 non-melanoma skin cancer. In humans, both the Ultraviolet A (UVA) and ultraviolet B (UVB) wavebands cause immunosuppression and deoxyribonucleic acid (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 ultraviolet (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. The most commonly used dose in autoimmune blistering disorders is 1500 mg daily10, with these patients often taking nicotinamide for several months. Adverse effects are exceptionally rare at these doses. 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, inter-cellular adhesion molecule 1 (ICAM-1), major histocompatibility II (MHC II) and Nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB).12 Nicotinamide is the precursor of nicotinamide adenine dinucleotide (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 volunteers14. We subsequently found that oral nicotinamide was also immune protective in healthy, Mantoux-positive volunteers15, without adverse effects, at doses of either 500mg daily or 1500mg daily. Recently, we tested topical 1% nicotinamide on numbers of actinic keratoses, and found a significant reduction in numbers of keratoses at 3 months compared to placebo. We now plan to assess the effects of oral nicotinamide at an intermediate dose (500mg twice daily) on actinic keratoses numbers. We hypothesise that nicotinamide will be well-tolerated, and could be used together with sunscreens 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 oral nicotinamide is in the treatment and prevention of actinic keratoses when compared with a placebo tablet over a four month period.

Hypothesis:	

That the twice daily consumption of 500mg 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 Royal Prince Alfred Hospital.

Inclusion Criteria
Men and women > 18 years old.
Symmetrically distributed non-hyperkeratotic actinic keratoses on face / scalp/  upper limbs.
Minimum of 4 actinic keratoses in one or more treatment areas.
Patients have received no other treatments for actinic keratoses 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 on face, scalp or arms
Liver disease (although hepatic effects of nicotinamide are rare, in contrast to nicotinic acid)
Currently taking carbamazepine (case reports of interaction with nicotinamide)

Although nicotinamide is unlikely to have significant drug interactions with oral contraceptives, there is currently no available data to show a definite lack of interaction. Women of childbearing potential who are taking the oral contraceptive pill will thus be advised to use additional, barrier contraception during the study. 

Settings and Location

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

Interventions

Volunteers will be randomized to receive either nicotinamide 500mg (Nature’s Own, Virginia, Queensland; widely available in Australian pharmacies and health food stores) twice daily (bd) or placebo (containing 35mg lactose; Australian Custom Pharmaceutical, Sydney) twice daily. Blood levels of nicotinamide (Nicotinamide adenine dinucleotide) as well as electrolytes, creatinine and liver function and full blood count will be measured at baseline and at 2 months; photographs of the actinic keratoses will also be taken at baseline, 2 and 4 months.
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 take the tablets twice daily for four months and to return the containers on study completion. We do not anticipate any adverse effects of daily consumption of this vitamin.
All patients will be instructed on proper daily use of Sun Protection Factor (SPF) 30+ sunscreens during the entire study as well as general protective measures. Any lesions suspicious for skin cancer will be biopsied and treated as per usual clinical practice. The development of nonmelanoma skin cancer (which is a common event in this population) does not necessitate interruption of or withdrawal from the protocol.

Objective

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

Outcomes

The primary endpoint will be the reduction in total actinic keratoses count at 4 months from baseline. A single observer will count, chart on a diagram and photograph actinic keratoses within the fields of treatment. AKs will be graded as II (visible and palpable) or I (palpable only). Patients with thicker hyperkeratotic actinic keratoses (III) will be excluded. There will be a secondary endpoint of total actinic keratoses count at 2 months 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 actinic keratoses count of 20 per patient and a predicted 20% reduction in actinic keratoses count for nicotinamide treated patients compared to placebo treated patients, a sample size of ~18 patients in each study arm will be required to demonstrate a statistically significant difference using 95% confidence intervals. We thus wish to recruit ~ 50 participants, in anticipation of up to 14 drop-outs during the 4 months of the study.

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

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. We predict that use of 1000mg daily of oral 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.

REFERENCES

1 Staples MP, Elwood M, Burton RC et al. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust 2006; 184: 6-10.
2 Tracey EA, Chen S, Baker D et al. Cancer in New South Wales: Incidence and Mortality 2004. Sydney: Cancer Institute NSW, 2006.
3 Mouret S, Baudouin C, Charveron M et al. Cyclobutane pyrimidine dimers are predominant deoxyribonucleic acid (DNA) lesions in whole human skin exposed to UVA radiation. Proceedings of the National Academy of Sciences of the United States of America 2006; 103: 13765-70.
4 Poon TSC, Barnetson RSC, Halliday GM. Sunlight-induced immunosuppression in humans is initially because of UVB, then UVA, followed by interactive effects. Journal of Investigative Dermatology 2005; 125: 840-6.
5 Ullrich SE. Mechanisms underlying UV-induced immunosuppression. Mutat Res 2005; 571: 185-205.
6 Moloney FJ, Comber H, O'Lorcain P et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006; 154: 498-504.
7 Poon TS, Barnetson RS, Halliday GM. Prevention of immunosuppression by sunscreens in humans is unrelated to protection from erythema and dependent on protection from ultraviolet A in the face of constant ultraviolet B protection. J Invest Dermatol 2003; 121: 184-90.
8 Damian DL, Halliday GM, Barnetson RS. Broad-spectrum sunscreens provide greater protection against ultraviolet-radiation-induced suppression of contact hypersensitivity to a recall antigen in humans. J Invest Dermatol 1997; 109: 146-51.
9 Damian DL, Barnetson RS, Halliday GM. Effects of low-dose ultraviolet radiation on in vivo human cutaneous recall responses. Australas J Dermatol 2001; 42: 161-7.
10 Niren NM. Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review. Cutis 2006; 11: 11-6.
11 Ranchoff RE, Tomecki KJ. Niacin or niacinamide? Nicotinic acid or nicotinamide? What is the difference? J Am Acad Dermatol 1986; 15: 116-7.
12 Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. . Pharmacol Rev 2002; 54: 375-429.
13 Gensler HL. Prevention of photoimmunosuppression and photocarcinogenesis by topical nicotinamide. Nutr. Cancer 1997; 29: 157-62.
14 Damian DL, Patterson CRS, Stapelberg M et al. Ultraviolet radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide. . J Invest Dermatol 2008; 128: 447-54.
15 Yiasemides E, Sivapirabu G, Halliday GM et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis 2008: doi:10.1093/carcin/bgn248 
16 Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993; 329: 1147-51.

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
Missenden Rd, Camperdown, NSW 2050

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
Missenden Rd, Camperdown, NSW 2050

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

Source	Title	Year of Publication	DOI
Dimensions AI	Oral Nicotinamide Reduces Actinic Keratoses in Phase II Double-Blinded Randomized Controlled Trials	2012	https://doi.org/10.1038/jid.2011.459
Embase	An update on clinical trials for chemoprevention of human skin cancer.	2023	https://dx.doi.org/10.20517/2394-4722.2022.99

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically