Clinical trial NCT05955924: Nicotinamide Chemoprevention for Keratinocyte Carcinoma in Solid Organ Transplant Recipients - Pivotal Trial
Official title: Nicotinamide Chemoprevention for Keratinocyte Carcinoma in Solid Organ Transplant Recipients: a Multicentre, Pragmatic Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Non-melanoma Skin Cancer
Carcinoma, Squamous Cell
Carcinoma, Basal Cell
Keratinocyte Carcinoma
Lead sponsor: Women's College Hospital
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: University Health Network, Toronto
name: NOW Foods
First posted: 2023-07-21
Enrollment: 396
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, parallel group, placebo-controlled, pragmatic randomized trial with 1:1 allocation and a superiority framework
Primary purpose: PREVENTION

Brief summary: As patients live longer after receiving an organ transplant, there is a need to reduce the long-term side effects of the drugs used to prevent organ rejection. In particular, long-term use of these drugs increases the risk of skin cancer. Skin cancer is now a leading cause of illness and disfigurement after kidney, liver, heart, and lung transplantation. Given the increased risk and burden of skin cancer in transplant recipients, prevention is critical.

Nicotinamide is a form of Vitamin B3 that has been shown to protect against skin cancer in the general population. However, it is unclear whether nicotinamide is effective among immune-suppressed transplant recipients. Investigators will conduct a clinical trial involving multiple transplant centres in Canada to evaluate whether oral nicotinamide (500 mg twice daily) is effective and safe for preventing skin cancer. Investigators will recruit 396 high-risk adult kidney, liver, heart, and lung transplant patients who have previously had at least one skin cancer. Patients will receive nicotinamide or sham tablets for up to 4 years. The results will inform efforts to improve the long-term health of transplant recipients.

Detailed description: Improved survival after solid organ transplantation has created the need to better prevent the long-term adverse effects of immunosuppressant drugs in transplant survivors - particularly cancer development. Keratinocyte carcinoma (non-melanoma skin cancer) is by far the most common form of post-transplant malignancy and has a more aggressive clinical course than in the general population. Preventive measures are thus critical to reduce the burden of skin cancer in the high-risk transplant population.

Nicotinamide is a low-cost, commercially available, over-the-counter Vitamin B3 derivative that has been found to safely reduce the rate of keratinocyte carcinoma in immunocompetent patients with a history of skin cancer. It is unclear whether its efficacy and safety translate to the immunosuppressed transplant population.

Given this uncertainty, Investigators plan to build on our internal pilot study (N=120) to conduct the SPRINTR (Skin cancer PRevention with Nicotinamide in Transplant Recipients) pivotal trial to address these specific aims:

Primary question: Does oral nicotinamide (500 mg twice daily) reduce the rate of further keratinocyte carcinoma compared with placebo when used in addition to standard care for up to 208 weeks in high-risk solid organ transplant recipients?

Secondary questions:

1. What is the safety of nicotinamide when used in addition to standard care for up to 208 weeks in the transplant population?
2. What is the effect of nicotinamide on quality of life related to skin cancer?

Investigators will conduct a multicentre, pragmatic, parallel group, investigator- and patient-blinded, randomized trial with a superiority framework. This pivotal trial will evaluate the efficacy and safety of oral nicotinamide versus placebo to prevent further keratinocyte carcinoma in 396 high-risk solid organ transplant recipients. Data from our previous internal pilot study (N=120 participants) will be combined with data from the current pivotal trial (N=276 additional patients) in the final analysis.

Eligibility criteria: 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

Exclusion Criteria:

* Use of nicotinamide or niacin (≥250 mg daily) within past 12 weeks
* Untreated localized skin cancer at baseline (patient can enrol after skin cancer treatment)
* Biopsy-confirmed acute rejection episode within the past 12 weeks
* Active liver disease (high AST \>3 times or bilirubin \>1.5 times)
* Severe kidney disease (estimated glomerular filtration rate \<20 mL/min/1.73 m2)
* Solid organ or hematologic malignancy, invasive melanoma, Merkel cell carcinoma, or metastatic skin cancer within the past five years
* Pregnancy or lactation
* Need for ongoing carbamazepine or primidone
* Allergy to nicotinamide or any ingredient of the vitamin or placebo capsules

Primary outcomes:
measure: Time to first biopsy-confirmed keratinocyte carcinoma (basal cell carcinoma or invasive cutaneous squamous cell carcinoma)
timeFrame: Up to 208 weeks
Secondary outcomes:
measure: Time to first invasive squamous cell carcinoma during follow-up
timeFrame: Up to 208 weeks
measure: Time to first basal cell carcinoma during follow-up
timeFrame: Up to 208 weeks
measure: Time to multiple keratinocyte carcinomas over follow-up
timeFrame: Up to 208 weeks
measure: Occurrence of adverse events during follow-up
timeFrame: 208 weeks
measure: Acute graft rejection (biopsy-confirmed)
timeFrame: 208 weeks
measure: Graft loss or retransplantation
timeFrame: 208 weeks
measure: High/low cyclosporine or tacrolimus blood concentration requiring dose adjustment
timeFrame: 208 weeks
measure: Change from baseline in annual Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) score
timeFrame: 52 weeks
measure: Change from baseline in annual Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) score
timeFrame: 104 weeks
measure: Change from baseline in annual Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) score
timeFrame: 156 weeks
measure: Change from baseline in annual Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) score
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Montreal Cognitive Assessment (MoCA)
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Montreal Cognitive Assessment (MoCA)
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Montreal Cognitive Assessment (MoCA)
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Montreal Cognitive Assessment (MoCA)
timeFrame: 208 weeks
measure: Neurocognitive substudy - Proportion of participants with cognitive impairment
timeFrame: 52 weeks
measure: Neurocognitive substudy - Proportion of participants with cognitive impairment
timeFrame: 104 weeks
measure: Neurocognitive substudy - Proportion of participants with cognitive impairment
timeFrame: 156 weeks
measure: Neurocognitive substudy - Proportion of participants with cognitive impairment
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Hopkins Verbal Learning Test - Revised
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Hopkins Verbal Learning Test - Revised
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Hopkins Verbal Learning Test - Revised
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Hopkins Verbal Learning Test - Revised
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Trail Making A and B
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Trail Making A and B
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Trail Making A and B
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Trail Making A and B
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Controlled Oral Word Association
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Controlled Oral Word Association
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Controlled Oral Word Association
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Controlled Oral Word Association
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Animal Naming Task
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Animal Naming Task
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Animal Naming Task
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Animal Naming Task
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Wechsler Adult Intelligence Scale-Fourth Edition-Canadian (WAIS-IV-CDN).
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Wechsler Adult Intelligence Scale-Fourth Edition-Canadian (WAIS-IV-CDN).
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Wechsler Adult Intelligence Scale-Fourth Edition-Canadian (WAIS-IV-CDN).
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Wechsler Adult Intelligence Scale-Fourth Edition-Canadian (WAIS-IV-CDN).
timeFrame: 208 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Digit Span subtest
timeFrame: 52 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Digit Span subtest
timeFrame: 104 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Digit Span subtest
timeFrame: 156 weeks
measure: Neurocognitive substudy - Change from baseline in demographically-corrected T score for Digit Span subtest
timeFrame: 208 weeks
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Women's College Hospital
state: Ontario
Study officials:
affiliation: Women's College Hospital
name: An-Wen Chan
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Sang Joseph Kim
role: PRINCIPAL_INVESTIGATOR
References: