Vitamin D Supplementation as a Neoadjuvant for Photodynamic Therapy of Actinic Keratoses

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT04140292
• Collaborator: (none)
• Enrollment: 75
• Location: 1
• Arm: 1
• Actual Duration (Months): 16.4
• Patients Per Site Per Month: 4.6

Study Details

Study Description

Brief Summary

This study is open to individuals with Actinic Keratoses (skin lesions that have the potential to turn into skin cancer), who are receiving photodynamic therapy (PDT) as part of their clinical care. The purpose of this study is to test and demonstrate that vitamin D pre-treatment can enhance PDT efficacy in the treatment of Actinic Keratoses.

Participants will be asked to take vitamin D supplements prior to their standard of care PDT treatment.

Participation in the research will last about 3-4 months.

Condition or Disease	Intervention/Treatment	Phase
Actinic Keratosis	Drug: Photodynamic therapy (PDT); Drug: Vitamin D3	Phase 2

Detailed Description

The primary objective of this study is to determine whether acute supplementation (neoadjuvant Vitamin D3), adjusted according to baseline Vitamin D status, can improve the clinical PDT response relative to participants receiving PDT alone

The secondary objective of this study is to determine whether gene polymorphisms in VDR and CYP27B1 are predictive for the degree of responsiveness to Vitamin D as a neoadjuvant for PDT.

This study is a non-randomized interventional trial, in which the study group will be compared to a baseline cohort of patients from a previous study who received the same regimen of PDT, but without any Vit D. It is anticipated that 30 participants will be involved in this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Study group will be compared to a baseline cohort of patients from a previous study (IRB 16-1615) who received the same regimen of PDT, but without any Vit DStudy group will be compared to a baseline cohort of patients from a previous study (IRB 16-1615) who received the same regimen of PDT, but without any Vit D
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Vitamin D Supplementation as a Neoadjuvant for Photodynamic Therapy of Actinic Keratoses
• Actual Study Start Date: Jan 13, 2020
• Actual Primary Completion Date: Nov 24, 2020
• Actual Study Completion Date: May 27, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Vitamin D3 + Photodynamic therapy (PDT) Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis.

Drug: Photodynamic therapy (PDT); PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered.; Drug: Vitamin D3; D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result

Outcome Measures

Primary Outcome Measures

1. Clinical PDT Response as Measured by Percent Change in AK Lesions From Baseline to 3 Months [3 months after treatment]

   Clinical PDT response as measured by the percent change of AK lesions 3 months after treatment Baseline vitamin D (calcidiol) level will be taken for each patient.

Secondary Outcome Measures

1. Correlation Between Vitamin D Receptor (VDR) Polymorphisms and Percent Reduction in AK [3 months after treatment]

   Whether gene polymorphisms in VDR and CYP27B1 are predictive for the degree of responsiveness (as measured by percent reduction in AK) to Vitamin D as a neoadjuvant for PDT.

2. Number of Participants Reporting 1 or Higher on the Pain Scale [During treatment (at the 5 min mark), and again immediately afterwards.]

   Pain scale recorded on a 0-to-10 visual/analog scale, with higher scores mean more pain; 0 is no pain, 10 is "the worst pain imaginable". Number of participants receiving treatment that reported a pain level greater than 1.

3. Tolerability as Measured by Participants' Symptom Score Sheets [1 week after treatment]

   Participants are asked to recall the symptoms they experienced during the week following PDT. The study physician asks them whether they had experienced each of the following 13 symptoms (YES/NO), and positive (YES) answers were summed to create a Side Effects Score (SES). The maximum and minimum possible values are 13 and 0 respectively, with a higher score correlating to poorer participant outcomes. The 13 possible side effects were: pain, erythema, scabbing, blistering, erosions, edema, warmth, exfoliation, discharge, hemorrhage, tightness, hyperpigmentation, hypopigmentation.

4. Accumulation of Protoporphyrin IX (PpIX) Within AK [3 months after treatment]

   Accumulation of protoporphyrin IX (PpIX) within AK PpIX accumulation in areas of both actinic damage and normal skin will be measured with a fluorescence dosimeter. The level of calcidiol, a clinically accepted marker of vitamin D status, will be measured in each patient to see if supplementation with 10,000 IU of Vitamin D increase the accumulation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Actinic keratoses in sufficient numbers (>10) to warrant PDT therapy in the clinic

• Able to understand and willing to sign a written informed consent document

• Female subjects must not become pregnant during the study:

• The effects of 5-aminolevulinic acid (LevulanTM) on the human fetus are unknown. For this reason, women of child-bearing potential must agree to use contraception (double barrier method of birth control or abstinence) prior to study entry, and throughout study participation. Should a woman become pregnant or suspect that she is pregnant while she is participating in this study, she should inform the treating physician immediately.

Exclusion Criteria:

• Pregnant or nursing.

• At risk for hypercalcemia (renal disease, sarcoidosis, etc.)

• Using topical retinoids, since these can exacerbate the post-PDT erythema reaction.

• Using any topical treatment on their AKs; must stop at least one month prior.

• Currently undergoing treatment for other cancers with medical or radiation therapy.

• Patients with a known hypersensitivity to 5-aminolevulinic acid or any component of the study material.

• Patients with history of a photosensitivity disease, such as porphyria cutanea tarda.

• Currently participating in another clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Case Comprehensive Cancer Center

Investigators

• Principal Investigator: Edward V Maytin, MD, PhD, Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 13, 2022
• Informed Consent Form - Apr 13, 2022

More Information

Publications

None provided.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT04140292
• Other Study ID Numbers: CASE5619; NCT04482322
• First Posted: Oct 25, 2019
• Last Update Posted: Jun 24, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Keratosis, Actinic; Keratosis; Vitamin D; Cholecalciferol

Study Results

Participant Flow

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Participants will be matched to other participants from a prior study (NCT03467789) involving PDT only, based on their baseline vitamin D level. These participants were used as a control group.
Period Title: Overall Study
STARTED	33	42
COMPLETED	29	26
NOT COMPLETED	4	16

Baseline Characteristics

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)	Total
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Data for the participants in this arm are from a previous basic science study that looked at Vit D level that got standard of care PDT. These participants were used as a control group.	Total of all reporting groups
Overall Participants	29	26	55
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 41.4%	13 50%	25 45.5%
>=65 years	17 58.6%	13 50%	30 54.5%
Sex: Female, Male (Count of Participants)
Female	2 6.9%	3 11.5%	5 9.1%
Male	27 93.1%	23 88.5%	50 90.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	29 100%	26 100%	55 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	29 100%	26 100%	55 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Clinical PDT Response as Measured by Percent Change in AK Lesions From Baseline to 3 Months
Description	Clinical PDT response as measured by the percent change of AK lesions 3 months after treatment Baseline vitamin D (calcidiol) level will be taken for each patient.
Time Frame	3 months after treatment

Outcome Measure Data

Analysis Population Description

Participants who received treatment.

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Participants will be matched to other participants from a prior study (NCT03467789) involving PDT only, based on their baseline vitamin D level. These participants were used as a control group.
Measure Participants	29	26
Mean (Standard Deviation) [Percent change of AK lesions]	59.1 (15.9)	72.5 (13.6)

2. Secondary Outcome

Title	Correlation Between Vitamin D Receptor (VDR) Polymorphisms and Percent Reduction in AK
Description	Whether gene polymorphisms in VDR and CYP27B1 are predictive for the degree of responsiveness (as measured by percent reduction in AK) to Vitamin D as a neoadjuvant for PDT.
Time Frame	3 months after treatment

Outcome Measure Data

Analysis Population Description

Unable to obtain any information about the PpIX accumulation levels because fluorescence imaging dosimeter broke down and it was unable to be replaced.

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Participants will be matched to other participants from a prior study (NCT03467789) involving PDT only, based on their baseline vitamin D level. These participants were used as a control group.
Measure Participants	0	0

3. Secondary Outcome

Title	Number of Participants Reporting 1 or Higher on the Pain Scale
Description	Pain scale recorded on a 0-to-10 visual/analog scale, with higher scores mean more pain; 0 is no pain, 10 is "the worst pain imaginable". Number of participants receiving treatment that reported a pain level greater than 1.
Time Frame	During treatment (at the 5 min mark), and again immediately afterwards.

Outcome Measure Data

Analysis Population Description

Participants that received treatment.

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)
Arm/Group Description	Participants receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Participants will be matched to other participants from a prior study (NCT03467789) involving PDT only, based on their baseline vitamin D level. These participants were used as a control group.
Measure Participants	29	26
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Tolerability as Measured by Participants' Symptom Score Sheets
Description	Participants are asked to recall the symptoms they experienced during the week following PDT. The study physician asks them whether they had experienced each of the following 13 symptoms (YES/NO), and positive (YES) answers were summed to create a Side Effects Score (SES). The maximum and minimum possible values are 13 and 0 respectively, with a higher score correlating to poorer participant outcomes. The 13 possible side effects were: pain, erythema, scabbing, blistering, erosions, edema, warmth, exfoliation, discharge, hemorrhage, tightness, hyperpigmentation, hypopigmentation.
Time Frame	1 week after treatment

Outcome Measure Data

Analysis Population Description

Participants who received treatment.

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Participants will be matched to other participants from a prior study (NCT03467789) involving PDT only, based on their baseline vitamin D level. These participants were used as a control group.
Measure Participants	29	26
Mean (Standard Deviation) [score on a scale]	3.7 (2.2)	3.7 (1.9)

5. Secondary Outcome

Title	Accumulation of Protoporphyrin IX (PpIX) Within AK
Description	Accumulation of protoporphyrin IX (PpIX) within AK PpIX accumulation in areas of both actinic damage and normal skin will be measured with a fluorescence dosimeter. The level of calcidiol, a clinically accepted marker of vitamin D status, will be measured in each patient to see if supplementation with 10,000 IU of Vitamin D increase the accumulation
Time Frame	3 months after treatment

Outcome Measure Data

Analysis Population Description

Unable to obtain any information about the PpIX accumulation levels because fluorescence imaging dosimeter broke down and it was unable to be replaced.

Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)	Photodynamic Therapy (PDT)
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result	Participants will be matched to other participants from a prior study (NCT03467789) involving PDT only, based on their baseline vitamin D level. These participants were used as a control group.
Measure Participants	0	0

Adverse Events

Time Frame	No AE or SAEs were collected.
Adverse Event Reporting Description	No AE or SAEs were collected.
Arm/Group Title	Vitamin D3 + Photodynamic Therapy (PDT)		Photodynamic Therapy (PDT)
Arm/Group Description	Patients receive Vitamin D3 10,000 IU daily for 5 or 14 days depending on VitD baseline level. They then undergo Photodynamic therapy (PDT) for treatment of actinic keratosis. Photodynamic therapy (PDT): PDT is a technique that combines a photosensitizing drug and an intense light source to kill tumor cells Noninvasive fluorescence dosimetry may be performed on up to 6 lesions. Levulan Kerastick will be applied to each lesion and left to incubate for 30 minutes. Blue light (Blu-U device, 20 J/cm2, 33 minutes) will be administered. Vitamin D3: D3 pills (10,000 IU each) to be taken daily at home, beginning at either day -5 or day -14, as per their assignment Participants will receive a 5-day or 14-day supplementation of Vitamin D10,000 IU depending on their baseline Vitamin D 25 Hydroxy result		Data for the participants in this arm are from a previous basic science study that looked at Vit D level that got standard of care PDT. These participants were used as a control group.
All Cause Mortality
	Vitamin D3 + Photodynamic Therapy (PDT)		Photodynamic Therapy (PDT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Vitamin D3 + Photodynamic Therapy (PDT)		Photodynamic Therapy (PDT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Vitamin D3 + Photodynamic Therapy (PDT)		Photodynamic Therapy (PDT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.