A Multi-Center Study to Evaluate the Efficacy and Safety of KX2-391 Ointment 1% on Actinic Keratosis on Face or Scalp (AK004)

Study Overview
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Brief Summary
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This Phase III study was designed to evaluate the efficacy and safety of KX2-391 Ointment 1% in adult participants when applied to an area of skin containing 4-8 stable, clinically typical actinic keratosis (AK) lesions on the face or scalp.

Detailed Description
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This study was a double-blinded, multicenter, efficacy, and safety study of KX2-391 ointment administered topically to the face or scalp of participants with AK. The study consisted of Screening, Treatment, Follow-up, and Recurrence Follow-up Periods. Eligible participants received up to 5 consecutive days of topical treatment. Efficacy (lesion counts) and safety evaluations were performed.

Official Title
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A Phase 3, Double-Blind, Vehicle-Controlled, Randomized, Parallel Group, Multicenter, Efficacy and Safety Study of KX2-391 Ointment 1% in Adult Subjects With Actinic Keratosis on the Face or Scalp

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: KX2-391 Ointment 1%
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males and females greater than or equal to (>=) 18 years old. A defined area on the face or scalp contains 4 to 8 clinically typical, visible, and discrete AK lesions. Participants who in the judgment of the Investigator, were in good general health. Females were postmenopausal (greater than [>] 45 years of age with at least 12 months of amenorrhea), surgically sterile (by hysterectomy, bilateral oophorectomy, or tubal ligation); or, if of childbearing potential, were using highly effective contraception for at least 30 days or 1 menstrual cycle, whichever was longer, prior to study treatment and agreed to continue to use highly effective contraception for at least 30 days following their last dose of study treatment. Highly effective contraception includes oral hormonal contraceptives, hormonal contraceptive implant, injection or patch, intrauterine device or complete abstinence from sexual intercourse. Sexually active males who had not had a vasectomy, and whose partner was reproductively capable, must had agreed to use barrier contraception from Screening through 90 days after their last dose of study treatment. All participants must had agreed not to donate sperm or eggs or attempt conception from Screening through 90 days following their last dose of study treatment. Willing to avoid excessive sun or ultraviolet exposure. Able to comprehend and were willing to sign the informed consent form (ICF). Exclusion Criteria Clinically atypical and/or rapidly changing AK lesions on the treatment area. Location of the selected area is: On any location other than the face or scalp. Within 5 centimeters (cm) of an incompletely healed wound. Within 5 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). Been previously treated with KX2-391 Ointment. Anticipated need for in-patient hospitalization or in-patient surgery from Day 1 to Day 57. Treatment with 5-fluorouracil (5-FU), imiquimod, ingenol mebutate, diclofenac, photodynamic therapy, or other treatments for AK within the treatment area or within 2 cm of the treatment area, within 8 weeks prior to the Screening visit. Use of the following therapies and/or medications within 2 weeks prior to the Screening visit: Cosmetic or therapeutic procedures (e.g., use of liquid nitrogen, surgical excision, curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing) within the treatment area or within 2 cm of the selected treatment area. Acid-containing therapeutic products (eg, salicylic acid or fruit acids, such as alpha- and beta-hydroxyl acids and glycolic acids), topical retinoids, or light chemical peels within the treatment area or within 2 cm of the selected treatment area. Topical salves (non-medicated/non-irritant lotion and cream were acceptable) or topical steroids within the treatment area or within 2 cm of the selected treatment area; artificial tanners within the treatment area or within 5 cm of the selected treatment area. Use of the following therapies and/or medications within 4 weeks prior to the Screening visit: Treatment with immunomodulators (eg, azathioprine), cytotoxic drugs (eg, cyclophosphamide, vinblastine, chlorambucil, methotrexate) or interferons/interferon inducers. Treatment with systemic medications that suppress the immune system (eg, cyclosporine, prednisone, methotrexate, alefacept, infliximab). Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene) within 6 months prior to the Screening visit. A history of sensitivity and/or allergy to any of the ingredients in the study medication. A skin disease (e.g., atopic dermatitis, psoriasis, eczema) or condition (e.g., scarring, open wounds) that, in the opinion of the Investigator, might interfere with the study conduct or evaluations, or which exposes the participant to unacceptable risk by study participation. Other significant uncontrolled or unstable medical diseases or conditions that, in the opinion of the Investigator, would expose the participant to unacceptable risk by study participation. Females who were pregnant or nursing. Participated in an investigational drug trial during which an investigational study medication was administered within 30 days or 5 half-lives of the investigational product, whichever was longer, before dosing.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study tested KX2-391 Ointment 1% against a placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KX2-391 Ointment 1%<br>KX2-391 Ointment was applied once daily for 5 consecutive days on the face or scalp. | Drug: KX2-391 Ointment 1%<br>* Dose: 1% (250 mg single-use packets); Dosage form: Ointment; Route of administration: Topical<br>|
| Placebo Comparator: Placebo<br>The Vehicle Ointment was applied once daily for 5 consecutive days on the face or scalp. | Drug: Placebo<br>* Dosage form: Ointment; Route of administration: Topical<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete (100%) Clearance of Actinic Keratosis (AK) Lesions | Complete clearance rate was defined as the percentage of participants at Day 57 with no clinically visible AK lesions in the treatment area. | Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Partial Clearance Rate of Actinic Keratosis Lesions at Day 57 | Partial clearance rate of AK lesions was defined as the percentage of participants with a greater than or equal to (>=) 75% reduction in the number of AK lesions identified at Baseline (Day 1 predose) in the treatment area. | Day 57 | 
| Overall Change From Baseline in Actinic Keratosis Lesion Counts at Days 8, 15, 29 and 57 | Overall the change from baseline in lesion count at each visit were summarized and reported using descriptive statistics by treatment location (face or scalp). | Days 8, 15, 29 and 57 | 
| Percentage of Participants With Recurrence of Actinic Keratosis Lesions Who Achieved Complete Clearance at Day 57 | Recurrence rate was estimated based on Kaplan-Meier method, with recurrence define as appearance of any AK lesions in the treatment area, including those recurred or newly identified. | 3, 6, 9 and 12 months post-Day 57 | 
| Number of Participants With Maximal Post Baseline Local Skin Reaction (LSR) | Maximal post baseline LSR was defined as the highest grade of any LSR reported at any post baseline visits for a participant. The LSR assessment was an Investigator's (or sub-investigator's) assessment of the following signs on the treatment area: erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. The LSRs were graded on a 4-point scale ranging from 0=absent, 1=mild (slightly, barely perceptible), 2=moderate (distinct presence), and 3=severe (marked, intense). | Day 57 | 
| Number of Participants With Pigmentation and Scarring in the Treatment Area | Absence or presence of pigmentation (i.e., hypopigmentation and hyperpigmentation) and scarring in the treatment area were assessed. | Baseline (Day 1 predose), Days 5, 8, 15, 29 and 57 | 
| Number of Participants With Adverse Event (AE), Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Events of Special Interests | An AE was defined as any untoward medical occurrence in participant which does not necessarily have causal relationship with treatment. An AE was any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with use of medicinal product, whether or not considered related to medicinal product. An SAE was any untoward medical occurrence that at any dose resulted in death; was life threatening; required persistent/significant disability/incapacity; resulted in initial or prolonged in patient hospitalization; was congenital anomaly/birth defect or otherwise considered medically important. TEAEs (serious and non-serious) were defined as either those AEs with onset after first dose or those pre-existing AEs that worsen after first dose. Events of special interest included skin cancers (including basal cell carcinoma, squamous cell carcinoma, melanoma and their location and treatment area), ocular exposure, overdose, and pregnancy. | Baseline (Day 1 predose) up to Day 57 | 
| Number of Participants With Adverse Events, Serious Adverse Events, Events of Special Interests Within the Treatment Area After Day 57 and up to 12 Months Post-Day 57 | An AE was defined as any untoward medical occurrence in participant which does not necessarily have causal relationship with treatment. An AE was any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with use of medicinal product, whether or not considered related to medicinal product. An SAE was any untoward medical occurrence that at any dose resulted in death; was life threatening; required persistent/significant disability/incapacity; resulted in initial or prolonged in patient hospitalization; was congenital anomaly/birth defect or otherwise considered medically important. Events of special interest included skin cancers (including basal cell carcinoma, squamous cell carcinoma, melanoma and their location and treatment area), ocular exposure, overdose, and pregnancy. | From Day 57 up to 12-months post-Day 57 | 
| Number of Participants With Clinically Significant Safety Observations- Hematology, Blood Chemistry, Urinalysis | Assessed laboratory parameters included hematology, blood chemistry and urinalysis. Clinical significance and abnormal observations were determined by the investigator. | From Baseline (Day 1 predose) up to Day 57 | 
| Number of Participants With Clinically Significant Safety Observations- Vital Signs | Vital signs included measurement of pulse rate, systolic and diastolic blood pressure, respiratory rate, and body temperature. Clinical significance was determined by the investigator. | From Baseline (Day 1 predose) up to Day 57 | 
| Number of Participants With Clinically Significant Safety Observations- Physical Examination | A physical examination included weight and height measurements was performed. Clinical significance was determined by the investigator. | From Baseline (Day 1 predose) up to Day 57 | 
| Number of Participants With Clinically Significant Safety Observations- Electrocardiograms (ECGs) | ECG parameters included heart rhythm, heart rate, QRS intervals, QT intervals, RR intervals and corrected QT (QTc) intervals. Clinical significance was determined by the investigator. | From Baseline (Day 1 predose) up to Day 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Actinic Keratosis, Keratosis, Keratosis, Actinic, Precancerous Conditions, Neoplasms, Sun Damaged Skin, Actinic Keratoses