Assessment of the Human Systemic Absorption of Sunscreen Ingredients

• ClinicalTrials.gov Identifier: NCT03582215
• Recruitment Status: Completed
• First Posted: July 10, 2018
• Results First Posted: April 21, 2020
• Last Update Posted: April 21, 2020
• Sponsor: Food and Drug Administration (FDA)
• Collaborator: Spaulding Clinical Research LLC
• Information provided by (Responsible Party): Food and Drug Administration (FDA)

Study Description

Brief Summary:

This study is designed to assess the systemic exposure and pharmacokinetics of sunscreen active ingredients (avobenzone, oxybenzone, ecamsule, octocrylene homosalate, octisalate and octinoxate) when sunscreen product is applied under maximal use conditions.

Part 1 is an open-label, randomized, 4-arm study in 24 healthy adult subjects with the primary objective to explore whether the active components (avobenzone, oxybenzone, ecamsule and octocrylene) of 4 sunscreen products (1 sunscreen product in each arm) are absorbed into the systemic circulation when a sunscreen product is applied under maximal use conditions.

One sunscreen product with the highest avobenzone exposure will be selected for the second part of the study. If there is no quantifiable exposure of avobenzone for any of the sunscreen products, the formulation with the highest oxybenzone exposure will be selected for Part 2. In addition, 3 new sunscreen products are included in Part 2.

Part 2 is an open label, 4-arm study in 48 healthy adult subjects with the primary objective to assess the pharmacokinetics of the active components in the selected product from Part 1 and 3 additional products with a combination of active ingredients (avobenzone, oxybenzone, octocrylene, ecamsule homosalate, octisalate and octinoxate as applicable/contained in the different products).

Condition or disease	Intervention/treatment	Phase
Systemic Exposure to Sunscreen Ingredients	Drug: Part 1: Cream; Drug: Part 1: Lotion; Drug: Part 1: Spray 1; Drug: Part 1: Spray 2; Drug: Part 2: Lotion; Drug: Part 2: Aerosol Spray; Drug: Part 2: Nonaerosol Spray; Drug: Part 2: Pump Spray	Phase 1

Detailed Description:

Part 1

Part 1 is an open label, randomized, 4-arm pilot study to evaluate the effects of multiple applications of 4 different topical sunscreen formulations in healthy adult subjects. Each arm will include 6 subjects (3 male and 3 female) with 1 formulation. A total of 24 subjects (12 male and 12 female) from all 4 arms will be admitted to the clinical research unit (CRU) on Day 0. On the morning of Days 1 through 4, subjects will receive a topical application of the study drug at approximately 0900 hours. The study product will be weighed in advance and applied by a qualified person from the study team. Subjects will then receive 3 more topical applications on the same day at 2, 4, and 6 hours after the first dose.

Part 2

Part 2 is an open label, 4-arm study to evaluate the pharmacokinetics of avobenzone, oxybenzone, octocrylene, ecamsule homosalate, octisalate and octinoxate (as applicable in the different products) after multiple applications of a topical sunscreen formulation in healthy adult subjects. Part 2 will include 48 subjects (24 male and 24 female) and each arm will include 12 subjects (6 male and 6 female). One of the formulations in Part 2 will be selected based on the plasma exposure data from the pilot study (Part 1). A total of 48 subjects (24 male and 24 female) will be admitted to the CRU on Day 0. On the morning of Days 1 through 4, subjects will receive a topical application of the study product at approximately 0900 hours. The study drug will be weighed in advance and applied by a qualified person from the study team. Subjects will only receive one application on Day 1. On Days 2, 3 and 4 subjects will receive an initial dose and 3 more topical applications on the same day at 2, 4, and 6 hours after the first dose.

Parts 1 and 2

In both parts, approximately 2 mg of active sunscreen ingredient per 1 cm2 of body surface (calculation per method of Dubois) will be evenly applied 4 times per study day (except for a one-time application on the first day in part 2) to areas of the body typically exposed to the sun: face, ears, neck, torso, arms, and legs (approximately 75% of the body surface area). The antecubital areas will be avoided when applying the sunscreen due to potential contamination of the sites used for intravenous pharmacokinetic (PK) blood sample collection. The topical applications of study drug will be administered with subjects in swim wear to simulate real world settings as well as for easy application. In addition to swim wear, subjects may wear scrubs in between applications and at other times throughout the day/night. Subjects are required to shower each morning after the first PK blood sample collection (and before the first dose of the day), but not at other times during the day.

Blood samples (approximately 10 mL per sample) will be collected for determination of plasma concentrations for all active ingredients (avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, octisalate and octinoxate, where applicable).

Safety evaluations will include adverse event (AE) monitoring, vital sign measurements, and physical examinations. All AEs reported by the subject or observed by the investigator or clinical research unit (CRU) staff will be recorded. Any AE reported after the informed consent is signed and before study drug application will be recorded as medical history.

Subjects will remain in the CRU after admission on Day 0 until the morning of Day 7 following completion of scheduled end-of-study activities for Part 1. For Part 2, subjects will undergo the same schedule but will return to the clinic for follow-up visits on Days 10, 14 and 21. Subjects will then be discharged following completion of End-of-Study activities.

Subjects are not allowed to use products containing any of these active ingredients from 7 days before check-in until completion of End-of-Study procedures.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Part 1 of the study has 4 parallel arms where 4 different sunscreen products will be studied. Part 2 of the study has 4 parallel arms where 4 sunscreen products (one from Part 1 and 3 new sunscreen products) will be studied.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Assessment of the Human Systemic Absorption of Sunscreen Ingredients
• Actual Study Start Date: July 18, 2018
• Actual Primary Completion Date: February 18, 2019
• Actual Study Completion Date: February 18, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: Cream; Part 1: Cream Ingredients: 2% Avobenzone; 10% Octocrylene; 2% Ecamsule	Drug: Part 1: Cream; Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area; Other Names: Avobenzone; Octocrylene; Ecamsule
Experimental: Part 1: Lotion; Part 1: Lotion Ingredients: 3% Avobenzone; 4% Oxybenzone; 6% Octocrylene	Drug: Part 1: Lotion; Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area; Other Names: Avobenzone; Oxybenzone; Octocrylene
Experimental: Part 1: Spray 1; Part 1: Spray 1 Ingredients: 3% Avobenzone; 6% Oxybenzone; 2.35% Octocrylene; 15% Homosalate; 5% Octisalate	Drug: Part 1: Spray 1; Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area; Other Names: Avobenzone; Homosalate; Octisalate; Octocrylene; Oxybenzone
Experimental: Part 1: Spray 2; Part 1: Spray 2 Ingredients: 3% Avobenzone; 5% Oxybenzone; 10% Octocrylene	Drug: Part 1: Spray 2; Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area; Other Names: Avobenzone; Oxybenzone; Octocrylene
Experimental: Part 2: Lotion; Part 2: Lotion Ingredients: 3% Avobenzone; 4% Oxybenzone; 6% Octocrylene	Drug: Part 2: Lotion; Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area; Other Names: Avobenzone; Oxybenzone; Octocrylene
Experimental: Part 2: Aerosol Spray; Part 2: Aerosol Spray Ingredients: 3% Avobenzone; 6% Oxybenzone; 10% Octocrylene; 15% Homosalate; 5% Octisalate	Drug: Part 2: Aerosol Spray; Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area; Other Names: Avobenzone; Oxybenzone; Octocrylene; Homosalate; Octisalate
Experimental: Part 2: Nonaerosol Spray; Part 2: Nonaerosol Spray Ingredients: 3% Avobenzone; 10% Octocrylene; 10% Homosalate; 5% Octisalate; 7.5% Octinoxate	Drug: Part 2: Nonaerosol Spray; Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area; Other Names: Avobenzone; Octocrylene; Homosalate; Octisalate; Octinoxate
Experimental: Part 2: Pump Spray; Part 2: Pump Spray Ingredients: 3% Avobenzone; 10% Homosalate; 5% Octisalate; 7.5% Octinoxate	Drug: Part 2: Pump Spray; Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area; Other Names: Avobenzone; Homosalate; Octisalate; Octinoxate

Outcome Measures

Primary Outcome Measures :

1. Avobenzone Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, and 144 h for Part 1; same time points and 216, 312, and 480 h for Part 2 ]
   Maximum concentration (observed peak drug concentration) (Cmax)

Secondary Outcome Measures :

1. Oxybenzone Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, and 144 h for Part 1; same time points and 216, 312, and 480 h for Part 2 ]
   Maximum concentration (observed peak drug concentration) (Cmax)
2. Octocrylene Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, and 144 h for Part 1; same time points and 216, 312, and 480 h for Part 2 ]
   Maximum concentration (observed peak drug concentration) (Cmax)
3. Ecamsule Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, and 144 h for Part 1 ]
   Maximum concentration (observed peak drug concentration) (Cmax)
4. Homosalate Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, 144, 216, 312, and 480 h for Part 2 ]
   Maximum concentration (observed peak drug concentration) (Cmax)
5. Octisalate Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, 144, 216, 312, and 480 h for Part 2 ]
   Maximum concentration (observed peak drug concentration) (Cmax)
6. Octinoxate Maximum Concentration [ Time Frame: 0, 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12, 14, 23, 28, 33, 47, 52, 57, 71, 73, 74, 76, 78, 81, 82, 84, 86, 95, 120, 144, 216, 312, and 480 h for Part 2 ]
   Maximum concentration (observed peak drug concentration) (Cmax)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Subjects who meet all of the following inclusion criteria will be eligible to participate in the study:

1. Subject signs an institutional review board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
2. Subject is a healthy man or woman, 18 to 60 years of age, inclusive, who has a body mass index of 18.5 to 29.9 kg/m2, inclusive, at Screening.
3. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead electrocardiogram (ECG) results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
4. Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day 0).
5. Subject has no known or suspected allergies or sensitivities to any components of the sunscreen formulation.
6. Female subjects must be of non-childbearing potential or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before Check in (Day 0) and agree to remain strictly abstinent for the duration of the study and for at least 1 month after the last application of study drug; OR 2) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before Check in (Day 0) until at least 1 month after the last application of study drug.
7. Female subjects must not be pregnant or lactating before enrollment in the study.
8. Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before Check in (Day 0) until at least 1 month after the last application of study drug.
9. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

Note: subjects with any skin type or skin pigment type may be eligible for the study.

Subjects who meet any of the following exclusion criteria will not be eligible to participate in the study:

1. Subject has broken, irritated, or unhealed skin.
2. Subject has an active sunburn.
3. Subject has used a tanning bed in the previous 4 weeks.
4. Subject has known skin or autoimmune disease(s).
5. Subject is anemic or has any chronic condition(s) that may impact blood sample collection.
6. Subject has any underlying disease or surgical or medical condition (e.g., cancer, human immunodeficiency virus [HIV], severe hepatic or renal impairment) that could put the subject at risk or would normally prevent participation in a clinical study.
7. Subject has known or suspected allergies or sensitivities to any components of the sunscreen formulation.
8. Subject has clinical laboratory test results (hematology and serum chemistry) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator.
9. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
10. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
11. Subject has received or applied the topical sunscreen formulations used in the current study, or any other product containing the active ingredients of the topical sunscreen formulations used in the current study, within 7 days before Check in (Day 0).
12. Subject has used any personal care product(s) containing any active sunscreen ingredient, such sunscreen products, hand or body moisturizing lotion, makeup or foundation, lip balm, or lipstick, within 7 days before Check in (Day 0).
13. Subject is unable or unwilling to tolerate the scent of sunscreen for the duration of the treatment period.

Contacts and Locations

Locations

United States, Wisconsin

Spaulding Clinical Research

West Bend, Wisconsin, United States, 53095

Sponsors and Collaborators

Food and Drug Administration (FDA)

Spaulding Clinical Research LLC

Investigators

• Principal Investigator: Carlos R Sanabria, MD; Spaulding Clinical Research LLC

  Study Documents (Full-Text)

Documents provided by Food and Drug Administration (FDA):

Study Protocol  [PDF] December 13, 2018

Statistical Analysis Plan  [PDF] November 20, 2018

More Information

Study Data/Documents: Individual Participant Data Set 

Deidentified participant data for Part 1 is accessible under Supplement 3

Individual Participant Data Set 

Deidentified participant data for Part 2 is accessible under Supplement 3

Publications of Results:

Matta MK, Zusterzeel R, Pilli NR, Patel V, Volpe DA, Florian J, Oh L, Bashaw E, Zineh I, Sanabria C, Kemp S, Godfrey A, Adah S, Coelho S, Wang J, Furlong LA, Ganley C, Michele T, Strauss DG. Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA. 2019 Jun 4;321(21):2082-2091. doi: 10.1001/jama.2019.5586.

Matta MK, Florian J, Zusterzeel R, Pilli NR, Patel V, Volpe DA, Yang Y, Oh L, Bashaw E, Zineh I, Sanabria C, Kemp S, Godfrey A, Adah S, Coelho S, Wang J, Furlong LA, Ganley C, Michele T, Strauss DG. Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA. 2020 Jan 21;323(3):256-267. doi: 10.1001/jama.2019.20747. Erratum In: JAMA. 2020 Mar 17;323(11):1098.

• Responsible Party: Food and Drug Administration (FDA)
• ClinicalTrials.gov Identifier: NCT03582215
• Other Study ID Numbers: SCR-005
• First Posted: July 10, 2018
• Results First Posted: April 21, 2020
• Last Update Posted: April 21, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified data from the clinical study was included as part of supplementary materials for both publications
• Supporting Materials: Study Protocol; Clinical Study Report (CSR)
• Time Frame: Jan 2020 - supplementary materials included with publications

Access Criteria

Access to JAMA. De-identified data has been included under supplement 3 for Part 1 (Matta et al, 2019 JAMA) and Part 2 (Matta et al, 2020, JAMA) of this clinical study

Part 1 study data:

https://cdn.jamanetwork.com/ama/content_public/journal/jama/938034/jpc190002supp3_prod.xlsx

• 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.: No

Keywords provided by Food and Drug Administration (FDA):

Sunscreen; Pharmacokinetics

Additional relevant MeSH terms:

Salicylates; Avobenzone; Oxybenzone; Homosalate; 2-ethylhexyl salicylate; Octylmethoxycinnamate; Sunscreening Agents; Radiation-Protective Agents; Protective Agents; Physiological Effects of Drugs; Dermatologic Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action