Skin Cancer Prevention With Nicotinamide in Transplant Recipients - Pilot Trial

Study Overview
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Brief Summary
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A common long-term side effect of anti-rejection (immunosuppressant) medications is skin cancer. This pilot clinical trial evaluates the feasibility of conducting a larger pivotal trial to examine the efficacy and safety of nicotinamide for prevention of keratinocyte carcinoma in solid organ transplant recipients. This pilot trial will transition into the pivotal trial if all feasibility targets are met.

Official Title
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Nicotinamide Chemoprevention for Keratinocyte Carcinoma in Solid Organ Transplant Recipients: A Pilot, Placebo-controlled, Randomized Trial

Conditions
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Non-melanoma Skin Cancer, Carcinoma, Squamous Cell, Carcinoma, Basal Cell

Intervention / Treatment
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* Drug: Nicotinamide
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old Kidney, liver, heart, or lung transplant at least two years ago History of at least one prior histologically-confirmed keratinocyte carcinoma or squamous cell carcinoma in situ Currently immunosuppressed with a calcineurin inhibitor-based regimen (cyclosporine or tacrolimus) Able to attend follow-up visits Able to speak and understand English (only for cognitive substudy) Exclusion Criteria: Use of mTOR inhibitor (sirolimus, everolimus) within the past 12 weeks Biopsy-confirmed acute rejection episode within the past 12 weeks Active liver disease (elevated AST or ALT >3 times normal) Severe renal failure (estimated glomerular filtration rate <20 mL/min/1.73 m2) Current carbamazepine or primidone use Pregnancy and lactation Gorlin syndrome or other genetic skin cancer syndrome Solid organ or hematologic malignancy, invasive Stage II melanoma, Merkel cell carcinoma, or metastatic skin cancer within the past five years, or invasive Stage I melanoma within the past two years Untreated localized skin cancer (invasive squamous cell carcinoma, basal cell carcinoma, or keratoacanthoma) at baseline (the patient can enrol after skin cancer treatment) Use of nicotinamide or niacin (250 mg or more daily) within the past 12 weeks Use of field therapy for actinic keratoses within the past 12 weeks Initiation of systemic chemoprevention within the past 12 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide<br> | Drug: Nicotinamide<br>* Oral nicotinamide (500 mg) twice daily for at least 52 weeks<br>* Other names: niacinamide;|
| Placebo Comparator: Placebo<br> | Drug: Placebo oral capsule<br>* Matching placebo taken twice daily for at least 52 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility (pertaining to patient recruitment) | Proportion of patients who consent to data linkage to provincial administrative databases | 1 year | 
| Feasibility (pertaining to appropriateness of eligibility criteria) | Reasons for exclusion of screened patients | 1 year | 
| Feasibility (pertaining to adherence to intervention) | Proportion of capsules returned, reasons for non-adherence | 1 year | 
| Feasibility (pertaining to adherence to follow-up assessments) | Proportion of missed assessments and incomplete questionnaire data variables, proportion of patients who withdraw from the trial, patient perception of trial participation | 1 year | 
| Feasibility (pertaining to data linkage) | Proportion of patients who consent to data linkage to provincial administrative databases | 1 year | 
| Preliminary pooled keratinocyte carcinoma event rate | Pooled keratinocyte carcinoma event rate to be used for sample size re-estimation in the pivotal trial. | 1 year | 
| Drug interactions | Proportion of patients with a clinically relevant increase in cyclosporine or tacrolimus blood concentration at 1 week. An increased level will be classified as clinically relevant if the transplant physician reduces the immunosuppressant dose in response to the increased drug level. | 1 week | 
| Drug interactions | Proportion of patients with a clinically relevant increase in cyclosporine or tacrolimus blood concentration at 2 weeks. This measurement will be dropped if all cases of clinically relevant drug interactions manifest at 1 week in the first 20 enrolled participants. | 2 weeks | 
| Serious adverse events | Descriptive tabulation (preliminary safety) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of recruiting for neurocognitive substudy | Proportion of enrolled participants who consent to participate in the neurocognitive substudy | 1 year | 
| Baseline prevalence of cognitive impairment (substudy) | Montreal Cognitive Assessment (MoCA) score <26, scored out of 30. | 1 year | 
| Pooled standard deviation of MoCA test scores (substudy) | Montreal Cognitive Assessment (MoCA), raw scores are scored out of 30, with a higher score representing better cognitive function | 1 year | 
| Pooled standard deviation of Hopkins Verbal Learning Test - Revised scores (substudy) | Hopkins Verbal Learning Test - Revised, a memory test scored out of 60, with a higher score representing better memory | 1 year | 
| Pooled standard deviation of Trail Making A and B test scores (substudy) | Trail Making A and B, a visual attention test. This records the time (in seconds) to completion, with a faster time representing better cognitive function | 1 year | 
| Pooled standard deviation of Controlled Oral Word Association test scores (substudy) | Controlled Oral Word Association, a verbal fluency test, measures the production of words belonging to the same letter. This records total number of words produced, with a higher number representing better verbal fluency. | 1 year | 
| Pooled standard deviation of Animal Naming Task scores (substudy) | Animal Naming Task, a verbal fluency task, measures the total number of animals named in one minute, with a higher number representing better verbal fluency | 1 year | 
| Pooled standard deviation of cognitive test scores (substudy) | Wechsler Adult Intelligence Scale - Revised, Digit Span subtest, a number sequencing memory test, measures the number of correctly repeated sequences with maximum score of 48. The higher score represents better cognitive function | 1 year | 
| Pooled standard deviation of serum phosphate levels (substudy) |  | 1 year |