Multicenter, Double-blind, Placebo Controlled Comparing T... | NCT02616601

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Generic Fluorouracil Cream	Experimental	Participants are to apply up to 1 gram of generic fluorouracil 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream is no longer visible. Participants will be instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug should be left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should be continued for the full treatment course even if the actinic keratoses lesions appear to be gone.	Drug: Generic Fluorouracil Cream
Carac® (Fluorouracil) Cream	Active Comparator	Participants are to apply up to 1 gram of Carac (fluorouracil) 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream is no longer visible. Participants will be instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug should be left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should be continued for the full treatment course even if the actinic keratoses lesions appear to be gone.	Drug: Carac® (Fluorouracil) Cream
Vehicle Cream	Placebo Comparator	Participants are to apply up to 1 gram of vehicle topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream is no longer visible. Participants will be instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug should be left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should be continued for the full treatment course even if the actinic keratoses lesions appear to be gone.

Name	Type	Description	Arm Group Labels	Other Names
Generic Fluorouracil Cream	Drug	Topical cream, generic formulation of the brand product.	Generic Fluorouracil Cream

Measure	Description	Time Frame
Percentage of Participants With Treatment Success (Complete Clearance) at Week 6	Percentage of participants with treatment success (complete clearance) at Week 6 (4 weeks after completion of 2 weeks of treatment). Complete clearance was defined as having no (zero) clinically visible actinic keratoses (AK) lesions in the treatment area at the Week 6/End Of Study visit. All AK lesions (baseline and new lesions) independent of size within the treatment area were treated and included in the efficacy lesion count.	Week 6

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Participant is male and/or female, 18 years of age or older.
Participant is willing and able to give written informed consent.
Participant is willing and able to apply the test article(s) as directed, comply with study instructions and commit to all follow-up visits for the duration of the study.
Participant has a clinical diagnosis of actinic keratoses with at least 5 and no more than 10 clinically typical, visible or palpable, discrete, actinic keratoses (AK) lesions, each at least 4 millimeters (mm) in diameter on the face (excluding ears) or balding scalp.
Participant is in good general health and free of any disease state or physical condition that might impair evaluation of AK lesions or which, in the investigator's opinion, exposes the participant to an unacceptable risk by study participation.
Females must be post-menopausal, surgically sterile, or use an effective method of birth control with a negative urine pregnancy test (UPT) at the Baseline Visit.

Exclusion Criteria:

Participant is pregnant, lactating, or is planning to become pregnant during the study.
Participant is currently enrolled in an investigational drug or device study.
Participant has used an investigational drug or investigational device treatment within 30 days prior to the Baseline Visit.
Participant has hyperkeratotic, hypertrophic, or large mat-like AK lesions (for example, an AK lesion >1 cm^2 in size) within the treatment area.
Participant has the need or plans to be exposed to artificial tanning devices or excessive sunlight during the study.
Participant is immunosuppressed (for example, human immunodeficiency virus (HIV), systemic malignancy, graft host disease)
Participant has experienced an unsuccessful outcome from previous topical fluorouracil therapy (an unsuccessful outcome is defined as after a reasonable therapeutic study with no compliance issues and the topical drug did not work).
Participant has a history of sensitivity to any of the ingredients in the test articles.
Participant has known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
Participant used topical creams, lotions, or gels of any kind within the selected treatment area within 1 day prior to entry into the study.
Participant has used topical medications; corticosteroids, alpha hydroxy acids (for example, glycolic acid, lactic acid, etc. >5%), beta hydroxy acid (salicylic acid >2%), urea >5%, 5-fluorouracil, diclofenac, imiquimod, ingenol mebutate; or prescription retinoids (for example, tazarotene, adapalene, tretinoin) within the selected treatment area (face or balding scalp) within 1 month prior to the Baseline Visit.
Participant has had cryodestruction, curettage, photodynamic therapy, surgical excision, or other treatments for AK within the selected treatment area (face or balding scalp) within 1 month prior to the Baseline Visit.
Participant has used oral corticosteroid therapy, interferon, cytotoxic drugs, immunomodulators, immunosuppressive therapies, or retinoids within 1 month prior to the Baseline Visit.
Participant has had dermatologic procedures or surgeries such as: laser resurfacing, Psoralen + ultraviolet A (PUVA) therapy, ultraviolet B therapy, chemical peels, or dermabrasion within the selected treatment area (face or balding scalp) within 6 months prior to the Baseline Visit.
Participant has lesions suspicious for skin cancer (skin cancer not ruled out by biopsy) or untreated skin cancers within the selected treatment area (face or balding scalp).
Participant has any skin pathology or condition on the face or balding scalp that, in the Investigator's opinion, could interfere with the evaluation of the test article or requires the use of interfering topical, systemic, or surgical therapy.
Participant has any condition which, in the Investigator's opinion, would make it unsafe or preclude the participant's ability to fully participate in this research study.
Participant is unable to communicate or cooperate with the Investigator due to language problems, poor mental development, impaired cerebral function, or physical limitations.
Participant is known to be noncompliant or is unlikely to comply with the requirements of the study protocol (for example, due to alcoholism, drug dependency, mental incapacity) in the opinion of the Investigator.
Participant has been previously enrolled in the same study.

Name	Affiliation	Role
Study Director	Actavis Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Investigative Site 2		Fremont	California		United States
Investigative Site 16

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Generic Fluorouracil Cream	Participants applied up to 1 gram of generic fluorouracil 0.5% topical cream once daily for 2 weeks (wks) as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Generic Fluorouracil Cream	Participants applied up to 1 gram of generic fluorouracil 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.
BG001	Carac (Fluorouracil) Cream	Participants applied up to 1 gram of Carac (fluorouracil) 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.
BG002	Vehicle Cream	Participants applied up to 1 gram of vehicle topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG000140 BG001140 BG002142 BG003422

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Participants With Treatment Success (Complete Clearance) at Week 6

Percentage of participants with treatment success (complete clearance) at Week 6 (4 weeks after completion of 2 weeks of treatment). Complete clearance was defined as having no (zero) clinically visible actinic keratoses (AK) lesions in the treatment area at the Week 6/End Of Study visit. All AK lesions (baseline and new lesions) independent of size within the treatment area were treated and included in the efficacy lesion count.

Participants in mlTT population who met inclusion/exclusion criteria, applied 75%-125% applications of study drug, did not miss applications for more than 3 consecutive days, no evidence of dosing noncompliance, and completed evaluation at Week 6 within ±4 days with no protocol violations that would affect treatment evaluation (PP Population).

Posted

Number

percentage of participants

Week 6

ID	Title	Description
OG000	Generic Fluorouracil Cream	Participants applied up to 1 gram of generic fluorouracil 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.
OG001	Carac (Fluorouracil) Cream	Participants applied up to 1 gram of Carac (fluorouracil) 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.
OG002	Vehicle Cream	Participants applied up to 1 gram of vehicle topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.

Units	Counts
Participants	OG000112 OG001121 OG002123

Title

Denominators

Categories

Title	Measurements
	OG00033.9 OG00133.9 OG0023.3

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001						Mean Difference (Net)	0.04			2-Sided	90	-11.03	11.11			90% Wald's confidence interval with a continuity correction for the difference (Generic Fluorouracil Cream - Carac [Fluorouracil] Cream) in complete clearance rates.		Equivalence	If the 90% confidence interval on the percentage difference between generic fluorouracil cream and Carac (fluorouracil) cream lesion clearance were contained within the interval -0.20 to +0.20, and each of these percentages was greater than and statistically different (p<0.05) from the vehicle cream percentage, then generic fluorouracil cream and Carac (fluorouracil) cream were considered to be therapeutically equivalent.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Generic Fluorouracil Cream	Participants applied up to 1 gram of generic fluorouracil 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.	1	140	4	140	21	140
EG001	Carac (Fluorouracil) Cream	Participants applied up to 1 gram of Carac (fluorouracil) 0.5% topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.	0	140	1	140	13	140
EG002	Vehicle Cream	Participants applied up to 1 gram of vehicle topical cream once daily for 2 weeks as a thin film to the skin of the treatment area and rub until the cream was no longer visible. Participants were instructed to apply the study drug 10 minutes after thoroughly washing, rinsing, and drying the entire treatment area and 1 to 2 hours before bedtime. Study drug was to have been left on the skin for approximately 8 hours and then removed by washing the area with mild soap and water. Treatment should have continued for the full treatment course even if the actinic keratoses lesions appeared to be gone.	0	142	2	142	9	142

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0000 events0 affected140 at risk EG0011 events1 affected140 at risk EG0020 events0 affected142 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Eye Irritation	Eye disorders	MedDRA 18.0	Systematic Assessment	EG0004 events2 affected140 at risk EG0010 events0 affected140 at risk EG0020 events0 affected142 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Application site dermatitis	General disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Seasonal Allergy	Immune system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Cytstitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Gout	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Dizziness	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Acute Kidney Injury	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Dermatitis	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Coronary artery disease	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Nausea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Toothache	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Application site erythema	General disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Application site pain	General disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Application site pruritus	General disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Chills	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Influenza like illness	General disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Diverticulitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Herpes zoster	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Nasopharyngitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0013 affected140 at risk EG0021 affected142 at risk
Pneumonia	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Sinusitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Tooth abscess	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Tooth infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Muscle strain	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Headache	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected140 at risk EG0012 affected140 at risk EG0022 affected142 at risk
Haematuria	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Hypertonic bladder	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Urinary retention	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Skin lesion	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk

ID	Term
D011230	Precancerous Conditions
D009369	Neoplasms
D007642	Keratosis
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
D014498	Uracil
D011744	Pyrimidinones
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Urinary tract infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Aortic aneurysm	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Inguinal hernia strangulated	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected140 at risk EG0010 affected140 at risk EG0020 affected142 at risk
Bradycardia	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0011 affected140 at risk EG0020 affected142 at risk
Aortic stenosis	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Asthenia	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected140 at risk EG0010 affected140 at risk EG0021 affected142 at risk