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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 4707 0
Condition category
Condition code
Skin 5023 5023 0 0
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] 4471 0
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] 5864 0
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] 5864 0
Actinic Keratosis count at baseline and 4 months
Secondary outcome [1] 241895 0
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] 241895 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
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] 4885 0
Hospital
Name [1] 4885 0
Royal Prince Alfred (provides infrastructural support)
Address [1] 4885 0
Missenden Rd, Camperdown NSW 2050
Country [1] 4885 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred (provide infrastructural support)
Address
Missenden Rd, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 4661 0
None
Name [1] 4661 0
Address [1] 4661 0
Country [1] 4661 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6950 0
Sydney South West Area Health Service ethics comittee
Ethics committee address [1] 6950 0
Ethics committee country [1] 6950 0
Australia
Date submitted for ethics approval [1] 6950 0
Approval date [1] 6950 0
Ethics approval number [1] 6950 0
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 29558 0
Address 29558 0
Country 29558 0
Phone 29558 0
Fax 29558 0
Email 29558 0
Contact person for public queries
Name 12805 0
Associate Professor Diona Damian
Address 12805 0
Department of Dermatology
Level 3
Gloucester House
Royal Prince Alfred Hospital
Missenden Rd, Camperdown, NSW 2050
Country 12805 0
Australia
Phone 12805 0
+61 2 95158295
Fax 12805 0
+61 2 95651048
Email 12805 0
diona.damian@email.cs.nsw.gov.au
Contact person for scientific queries
Name 3733 0
Associate Professor Diona Damian
Address 3733 0
Department of Dermatology
Level 3
Gloucester House
Royal Prince Alfred Hospital
Missenden Rd, Camperdown, NSW 2050
Country 3733 0
Australia
Phone 3733 0
+61 2 95158295
Fax 3733 0
+61 2 95651048
Email 3733 0
diona.damian@email.cs.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
No Results