Oracea Soolantra Association in Participants With Severe Rosacea

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the efficacy of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe Rosacea.

Official Title
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Efficacy Comparison of Ivermectin 1% Topical Cream Associated With Doxycycline 40 mg Modified Release (MR) Capsules Versus Ivermectin 1% Topical Cream Associated With Placebo in the Treatment of Severe Rosacea

Conditions
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Rosacea

Intervention / Treatment
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* Drug: Ivermectin 1% cream
* Drug: Doxycycline 40 mg MR (30 mg Immediate Release & 10 mg Delayed Release beads) capsules
* Other: Oral placebo capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject age ≥ 18 years or older; Subject with a minimum of 20 but not more than 70 inflammatory lesions (papules and pustules) of rosacea on the face at Baseline visit; Subject with severe rosacea with papulopustular lesions (according to the Investigator's Global Assessment (IGA) score rated 4); Female subjects of childbearing potential with a negative urine pregnancy test (UPT); Female subjects of childbearing potential must practice a highly effective method of contraception during the study. Exclusion Criteria: Subjects with particular forms of rosacea or other concomitant facial dermatoses that may be confounded with rosacea; Subjects with more than 2 nodules of rosacea on the face; Subjects with any uncontrolled chronic or serious disease or medical condition that may either interfere with the interpretation of the clinical trial results, or with optimal participation in the study or would present a significant risk to the subject; Subjects with known or suspected allergies or sensitivities to any component of the investigational and non-investigational products, including the active ingredients doxycycline and ivermectin.

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ivermectin 1% cream + Doxycycline 40 mg MR capsules<br> | Drug: Ivermectin 1% cream<br>* Topical to the face, approximately one small pea size amount per facial region (right and left cheeks, forehead, chin, and nose) once a day for 12 weeks<br>Drug: Doxycycline 40 mg MR (30 mg Immediate Release & 10 mg Delayed Release beads) capsules<br>* 1 Capsule once-daily for 12 weeks<br>|
| Placebo Comparator: Ivermectin 1% cream + Oral placebo capsules<br> | Drug: Ivermectin 1% cream<br>* Topical to the face, approximately one small pea size amount per facial region (right and left cheeks, forehead, chin, and nose) once a day for 12 weeks<br>Other: Oral placebo capsules<br>* 1 Capsule once-daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Inflammatory Lesion Count at Week 12 | Percent change from baseline in inflammatory lesion count at week 12 was reported. Inflammatory lesions included facial inflammatory lesions of rosacea (that is [i.e.] papules and pustules) which were defined as follows: Papule - a small, solid elevation less than 1.0 centimeter (cm) in diameter; and Pustule - a small, circumscribed elevation of the skin, which contains yellow white exudates. Papules and pustules were counted separately on each of the 5 facial regions (forehead, chin, nose, right cheek and left cheek). Notably, nodules (i.e. circumscribed, elevated, solid lesions more than 1.0 cm in diameter with palpable depth) were not included in the count of inflammatory lesions. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Inflammatory Lesion Count at Weeks 4 and 8 | Percent change from baseline in inflammatory lesion count at Weeks 4 and 8 was reported. Inflammatory lesions included facial inflammatory lesions of rosacea (i.e. papules and pustules) which were defined as follows: Papule - a small, solid elevation less than 1.0 centimeter in diameter. Pustule - a small, circumscribed elevation of the skin, which contains yellow white exudates. Papules and pustules were counted separately on each of the 5 facial regions (forehead, chin, nose, right cheek and left cheek). Notably, nodules (i.e. circumscribed, elevated, solid lesions more than 1.0 cm in diameter with palpable depth) were not included in the count of inflammatory lesions. | Baseline, Weeks 4 and 8 | 
| Percentage of Participants With Clear Inflammatory Lesions at Week 12 | Percentage of participants with clear inflammatory lesions at week 12 was reported. Inflammatory lesions included facial inflammatory lesions of rosacea (i.e. papules and pustules) which were defined as follows: Papule - a small, solid elevation less than 1.0 cm in diameter. Pustule - a small, circumscribed elevation of the skin, which contains yellow white exudates. Papules and pustules were counted separately on each of the 5 facial regions (forehead, chin, nose, right cheek and left cheek). Notably, nodules (i.e. circumscribed, elevated, solid lesions more than 1.0 cm in diameter with palpable depth) were not included in the count of inflammatory lesions. | Week 12 | 
| Percentage of Participants With 100 Percent (%) Reduction in Inflammatory Lesions at Weeks 4, 8 and 12 | Percentage of participants with 100% reduction in inflammatory lesions at Weeks 4, 8 and 12 was reported. Inflammatory lesions included facial inflammatory lesions of rosacea (i.e. papules and pustules) which were defined as follows: Papule - a small, solid elevation less than 1.0 centimeter in diameter. Pustule - a small, circumscribed elevation of the skin, which contains yellow white exudates. Papules and pustules were counted separately on each of the 5 facial regions (forehead, chin, nose, right cheek and left cheek). Notably, nodules (i.e. circumscribed, elevated, solid lesions more than 1.0 cm in diameter with palpable depth) were not included in the count of inflammatory lesions. | Weeks 4, 8 and 12 | 
| Clinician's Erythema Assessment (CEA) Total Score at Weeks 4, 8 and 12 | The evaluator assessed the participant's diffuse persistent facial erythema of rosacea by performing a static (snap shot) evaluation of erythema severity at a social distance of approximately 50 centimeter (cm) using CEA scale, at each visit. CEA is a 5 point scale where 0 = clear (clear skin with no signs of erythema); 1 = almost clear (almost clear; slight redness); 2 = mild (mild erythema; definite redness); 3 = moderate (moderate erythema; marked redness); 4 = severe (severe erythema; fiery redness). A higher score than baseline indicates a worse outcome. | Weeks 4, 8 and 12 | 
| Percentage of Participants in Each Clinician's Erythema Assessment Score Category at Weeks 4, 8 and 12 | The evaluator assessed the participant's diffuse persistent facial erythema of rosacea by performing a static (snap shot) evaluation of erythema severity at a social distance of approximately 50 centimeter (cm) using CEA scale, at each visit. CEA is a 5 point scale where 0 = clear (clear skin with no signs of erythema); 1 = almost clear (almost clear; slight redness); 2 = mild (mild erythema; definite redness); 3 = moderate (moderate erythema; marked redness); 4 = severe (severe erythema; fiery redness). A higher score than baseline indicates a worse outcome. | Weeks 4, 8 and 12 | 
| Investigator's Global Assessment (IGA) Total Score at Weeks 4, 8 and 12 | The evaluator assessed the participant's rosacea by performing a static (snap shot) evaluation, at a social distance of approximately 50 cm, using the IGA score. IGA is a 5 point scale where, 0 = clear (no inflammatory lesions present, no erythema); 1 = almost clear (very small papules/pustules, very mild erythema present); 2 = mild (few small papules/pustules, mild erythema); 3 = moderate (severe small or large papules/pustules, moderate erythema); 4 = severe (numerous small and/or large papules/pustules, severe erythema). | Weeks 4, 8 and 12 | 
| Percentage of Participants in Each Investigator's Global Assessment Score Category at Weeks 4, 8 and 12 | The evaluator assessed the participant's rosacea by performing a static (snap shot) evaluation, at a social distance of approximately 50 cm, using the IGA score. IGA is a 5 point scale where, 0 = clear (no inflammatory lesions present, no erythema); 1 = almost clear (very small papules/pustules, very mild erythema present); 2 = mild (few small papules/pustules, mild erythema); 3 = moderate (severe small or large papules/pustules, moderate erythema); 4 = severe (numerous small and/or large papules/pustules, severe erythema). | Weeks 4, 8 and 12 | 
| Stinging/Burning Severity Score at Weeks 4, 8 and 12 | The evaluator recorded the severity of the participant's facial stinging/burning sensation during the last 24 hours according to the stinging/burning scale. Stinging/burning scale is a 4 point scale where, 0 = none (No stinging/burning ); 1 = mild (slight warm, tingling/stinging sensation, not really bothersome); 2 = moderate (definite warm, tingling/stinging sensation that is somewhat bothersome); 3 = severe (hot, tingling/stinging sensation that has caused definite discomfort). | Weeks 4, 8 and 12 | 
| Percentage of Participants in Each Stinging/Burning Severity Score Category at Weeks 4, 8 and 12 | The evaluator recorded the severity of the participant's facial stinging/burning sensation during the last 24 hours according to the stinging/burning scale. Stinging/burning scale is a 4 point scale where, 0 = none (No stinging/burning ); 1 = mild (slight warm, tingling/stinging sensation, not really bothersome); 2 = moderate (definite warm, tingling/stinging sensation that is somewhat bothersome); 3 = severe (hot, tingling/stinging sensation that has caused definite discomfort). | Weeks 4, 8 and 12 | 
| Global Improvement Total Score at Week 12 (Last Visit/Early Termination) | Participants were evaluated for his/her improvement in rosacea compared to his/her rosacea condition before study, using global Improvement scale. It is a 7 item scale where, 0=complete improvement (all signs and symptoms of disease have resolved [100% improvement]); 1=excellent improvement (nearly all signs and symptoms cleared [90% improvement]. Only minimal residual signs and symptoms remain); 2=very good improvement (majority of the signs and symptoms have resolved [about 75% improvement]); 3=good improvement (significant improvement, but many signs and symptoms remain [about 50% improvement]); 4=minimal improvement (slight overall improvement, but not clinically significant [about 25% improvement]); 5=no change (overall severity similar to baseline); 6=worse (worse than baseline). | Week 12 (last visit/early termination) | 
| Percentage of Participants in Each Global Improvement Score Category at Week 12 (Last Visit/Early Termination) | Participants were to evaluated for his/her improvement in rosacea compared to his/her rosacea condition before study, using global Improvement scale. it is a 7 item scale where, 0=complete improvement (all signs and symptoms of disease have resolved [100% improvement]); 1=excellent improvement (nearly all signs and symptoms cleared [90% improvement]. Only minimal residual signs and symptoms remain); 2=very good improvement (majority of the signs and symptoms have resolved [about 75% improvement]); 3=good improvement (significant improvement, but many signs and symptoms remain [about 50% improvement]); 4=minimal improvement (slight overall improvement, but not clinically significant [about 25% improvement]); 5=no change (overall severity similar to baseline); 6=worse (worse than baseline). . | Week 12 (last visit/early termination) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily had a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE was any untoward medical occurrence that at any dose: results in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect. | From the signing of the informed consent form (ICF) up to Week 12 | 
| Dermatology Life Quality Index (DLQI) Questionnaire Total Score at Week 12 (Last Visit/Early Termination Visit) | DLQI focuses on impact of dermatological diseases on quality of life. It is a 10-item validated quality-of-life questionnaire specific to dermatological conditions. 1) how itchy, sore, painful, stinging?, 2) how embarrassed/self-conscious?, 3) interfere shopping or looking after home or garden?, 4) Influence clothes?, 5) affect social/leisure activity?, 6) difficult to do sport?, 7) prevent from working/studying? or If no, problem at work/studying?, 8) problem with partner or close friend?, 9) cause sexual difficulties?, 10) problem caused by treatment?. Total score ranged from 0-30 (each question had a score range of 0- 3) where, 0-1=no effect at all on life; 2-5=small effect on life; 6-10=moderate effect on life; 11- 20=very large effect on life; 21-30=extremely large effect on life. A higher score indicates a low quality of life due to more severe disease. | Week 12 (last visit/early termination) | 
| Percentage of Participants in Each Dermatology Life Quality Index (DLQI) Questionnaire Score Category | Impact of study treatments on subjects' quality of life was measured by using DLQI questionnaire. DLQI focuses on impact of dermatological diseases on quality of life. It is a 10-item validated quality-of-life questionnaire specific to dermatological conditions. 1) how itchy, sore, painful, stinging?, 2) how embarrassed/self-conscious?, 3) interfere shopping or looking after home or garden?, 4) Influence clothes?, 5) affect social/leisure activity?, 6) difficult to do sport?, 7) prevent from working/studying? or If no, problem at work/studying?, 8) problem with partner or close friend?, 9) cause sexual difficulties?, 10) problem caused by treatment?. Total score ranged from 0-30 (each question had a score range of 0- 3) where, 0-1=no effect at all on life; 2-5=small effect on life; 6-10=moderate effect on life; 11- 20=very large effect on life; 21-30=extremely large effect on life. A higher score indicates a low quality of life due to more severe disease. | Baseline, Week 12 (last visit/early termination) | 
| Percent Change From Baseline in Dermatology Life Quality Index Questionnaire Total Score at Week 12 (Last Visit/Early Termination) | Percent Change from Baseline in Dermatology Life Quality Index questionnaire Total Score at Last Visit. DLQI focuses on impact of dermatological diseases on quality of life. It is a 10-item validated quality-of life questionnaire specific to dermatological conditions. 1) how itchy, sore, painful, stinging?, 2) how embarrassed/self-conscious?, 3) interfere shopping or looking after home or garden?, 4) Influence clothes?, 5) affect social/leisure activity?, 6) difficult to do sport?, 7) prevent from working/studying? or If no, problem at work/studying?, 8) problem with partner or close friend?, 9) cause sexual difficulties?, 10) problem caused by treatment?. Total score ranged from 0-30 (each question had a score range of 0-3) where, 0-1=no effect at all on life; 2-5=small effect on life; 6-10=moderate effect on life; 11- 20=very large effect on life; 21-30=extremely large effect on life. A higher score indicates a low quality of life due to more severe disease. | Baseline, Week 12 (last visit/early termination) | 
| EuroQol-5 Dimension-5 Level (EQ-5D-5L) Questionnaire at Week 12 (Last Visit/Early Termination Visit) | EQ-5D-5L is a 5-level, 5-dimensional format standardized instrument for use as a measure of health outcome used to assess the impact of study treatments on participants quality of life as follows: 1) mobility; 2) self-care; 3) usual activities; 4) pain/discomfort; 5) anxiety/depression. Each dimension comprised of 5 levels with corresponding numeric scores, where 1 indicated no problems, and 5 indicated extreme problems. Participant selected answer for each of 5 dimensions considering response that best matches his/her health today with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). An increase in the EQ-5D-5L total score indicates improvement. | Week 12/Last visit or early termination visit | 
| Percentage of Participants in Each EuroQol-5 Dimension-5 Level Questionnaire Questions Who Reported No Problems at Baseline and Week 12 (Last Visit/Early Termination) | EQ-5D-5L is a 5-level, 5-dimensional format standardized instrument for use as a measure of health outcome used to assess the impact of study treatments on participants quality of life as follows: 1) mobility; 2) self-care; 3) usual activities; 4) pain/discomfort; 5) anxiety/depression. Each dimension comprised of 5 levels with corresponding numeric scores, where 1 indicated no problems, and 5 indicated extreme problems. Participant selected answer for each of 5 dimensions considering response that best matches his/her health today with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). An increase in the EQ-5D-5L total score indicates improvement. | Baseline, Week 12 (last visit/early termination) | 
| Percentage of Participants Reported Work Productivity and Activity Impairment: General Health (WPAI:GH) Questionnaire for Currently Employed Question at Week 12 (Last Visit/Early Termination Visit) | WPAI:GH questionnaire was an instrument to measure impairments in both paid work and unpaid work. It measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problem during the past seven days. Low scores indicate little or no impact of health problems on work and activities, and a negative change in the WPAI score indicates improvement. Currently Employed question was assessed in this outcome measure. | Week 12 (Last visit/early termination visit) | 
| Work Productivity and Activity Impairment: General Health (WPAI:GH) Questionnaire - Hours Missed at Work, Impact to Productivity at Work and Daily Activities at Week 12 | WPAI:GH questionnaire is an instrument to measure impairment in both paid and unpaid work during the past week including questions: missed hours from work because of rosacea?, missed hours from work because of other reason?, number of Working hours. It measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problem during the past seven days. Low scores indicate little or no impact of health problems on work and activities, and a negative change in the WPAI score indicates improvement. | Week 12 (Last visit/Early termination visit) | 
| Work Productivity and Activity Impairment: General Health (WPAI:GH) Questionnaire (How Much Rosacea Affect Productivity at Work, How Much Rosacea Affect Daily Activity) at Week 12 (Last Visit/Early Termination Visit) | WPAI:GH questionnaire is an instrument to measure impairment in both paid and unpaid work during the past week, on a scale ranging from 0 (health problems had no effect) to 10 (health problems completely prevented them from working) including questions: 5) how much rosacea affect productivity at work?; 6) how much rosacea affect daily activity?. It measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problem during the past seven days. Low scores indicated little or no impact of health problems on work and activities, and a negative change in the WPAI score indicated improvement. | Week 12 (Last visit/Early termination visit) | 
| Percentage of Participants Who Reported Satisfied for Subject Satisfaction Questionnaire at Week 12 (Last Visit/Early Termination Visit): Part A | Subject's satisfaction questionnaire was used to specifically collect the subjects' feedback on the treatment regimen, the level of satisfaction and future usage. Questionnaire consisted of 4 parts: Part A, B, C and D. where Part A consisted of following 12 questions about study drugs (capsules and cream): 1-Time the study regimen took to work, 2-Improvement of facial lesions, 3-Improvement of facial redness, 4-Improvement of ocular symptoms, 5-Improvement of flushing episodes, 6-How bothered by side effects, 7-Your face looks, 8-You feel, 9-Easy to incorporate in daily routine, 10-Using the study regimen again, 11-Overall satisfaction, 12-Compared to last treatment. Satisfied score of questionnaire meant as participants responded as Very satisfied (Questions-1,2,3,4,5,11), Not bothered at all (Question-6), A lot better (Questions- 7,8,12), yes (Question-10), strongly agree (Question-9). | Week 12 (Last visit/early termination visit) | 
| Percentage of Participants Who Reported Strongly Agree for Subject Satisfaction Questionnaire at Week 12 (Last Visit/Early Termination Visit): Part B | Part B of Questionnaire consisted of following 10 questions about both provided skin care products cleanser and moisturizer: 1-Easy to incorporate into a daily routine, 2-Recommend to my family or friends, 3-Help my skin look healthier, 4-More confident with rosacea, 5-More confident with skin appearance, 6-Positive difference in the appearance, 7-Keep using both skin care products, 8-Make my skin more hydrated, 9-Improve the texture of my skin, 10-Pleasant to use. | Week 12 (Last visit/early termination visit) | 
| Percentage of Participants Who Reported Strongly Agree for Subject Satisfaction Questionnaire at Week 12 (Last Visit/Early Termination Visit): Part C | Part C subject satisfaction questionnaire consisted of following 4 questions about the cosmetic product cleanser: 1-Clean healthy skin feeling, 2-Deep cleansing without stripping moisture, 3-Rinsed off easily, 4-Not make my skin feel tight or dry. | Week 12 (Last visit or early termination visit) | 
| Percentage of Participants Who Reported Strongly Agree for Subject Satisfaction Questionnaire at Week 12 (Last Visit/Early Termination Visit): Part D | Part D of subject satisfaction questionnaire consisted of following 4 questions about the cosmetic product moisturizer: 1-Skin feel soft and smooth, 2-Improve my skin moisture, 3-Leave my skin hydrated and protected, 4-Provide comforting sensation. | Week 12 (Last visit/early termination visit) |