Clinical Endpoint Study of Ivermectin 1% Cream

• Sponsor: Actavis Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02840461
• Collaborator: (none)
• Enrollment: 630
• Location: 1
• Arms: 3
• Actual Duration (Months): 6
• Patients Per Site Per Month: 104.8

Study Details

Study Description

Brief Summary

A randomized, double-blind, placebo-controlled, parallel-design, multiple-site clinical study to evaluate the therapeutic equivalence and safety of ivermectin cream 1% (Actavis Laboratories UT, Inc.) to SoolantraTM (ivermectin) cream 1% (Galderma) in the treatment of moderate to severe papulopustular rosacea.

Condition or Disease	Intervention/Treatment	Phase
Moderate to Severe Papulopustular Rosacea	Drug: Ivermectin Cream, 1%; Drug: Placebo/Vehicle cream	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 630 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Clinical Study to Evaluate the Therapeutic Equivalence and Safety of Ivermectin Cream 1% (Actavis Laboratories UT, Inc.) to SoolantraTM (Ivermectin) Cream 1% (Galderma) in the Treatment of Moderate to Severe Papulopustular Rosacea
• Actual Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ivermectin Cream, 1% test product, manufactured by Actavis Laboratories UT, Inc.	Drug: Ivermectin Cream, 1%
Active Comparator: SoolantraTM (ivermectin) Cream, 1% reference product, manufactured by Galderma Laboratories, L.P.	Drug: Ivermectin Cream, 1%
Placebo Comparator: Placebo/Vehicle cream Placebo, manufactured by Actavis Laboratories UT, Inc.	Drug: Placebo/Vehicle cream

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline to Week 12 in the Number of Inflamed (Papules/Pustules) Lesions of Rosacea. [Baseline and 12 Weeks]

   Bioequivalence of the test to reference was considered to have been demonstrated if the 90% confidence interval for the test to reference ratio for the percent change from baseline to Week 12 in the number of inflamed lesion counts was within [80%, 125%].

Secondary Outcome Measures

1. The Percentage of Patients With a Clinical Response of "Success". [Baseline to Week 12]

   The secondary endpoint was the percentage of patients with a clinical response of "success" using the IGE at Week 12. At Visit 1, the IGE had to be 3 or 4 for the patient to be eligible for inclusion.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Signed Informed Consent that meets all criteria of current FDA regulations.

2. Healthy male or non-pregnant, non-lactating female greater than or equal to 8 years of age with a clinical diagnosis of moderate to severe papulopustular rosacea, defined as the presence of:

A total of 8 to 50 combined papules/pustules on the face, AND At least moderate erythema, AND Telangiectasia

1. Patient has a baseline Investigator's Global Evaluation (IGE) score of 3 (moderate) or 4 (severe) for rosacea severity (See Appendix A).

2. Females of child bearing potential must not be pregnant or lactating at Screening (as confirmed by a negative urine pregnancy test with a sensitivity of less than 25 mlU/mL or equivalent units of human chorionic gonadotropin). Women of childbearing potential must agree to the use of a reliable method of contraception (e.g., total abstinence, IUD, a double-barrier method [such as condom plus diaphragm with spermicide], oral, transdermal, injected or implanted non- or hormonal contraceptive), throughout the study. If the female is using a hormonal contraceptive, the same product must be taken for 3 months prior to Visit 1 and must agree not to replace with some other hormonal contraceptives during the study. A sterile sexual partner is not considered an adequate form of birth control.

All females will be considered to be of childbearing potential unless they: Are post-menopausal, defined as women who have been amenorrheic for at least 12 consecutive months, without other known or suspected primary cause.

Have been sterilized surgically or who are otherwise proven sterile (i.e., total hysterectomy, or bilateral oophorectomy) with surgery at least 4 weeks before Screening. Tubal ligation will not be considered a surgically sterile method.

Female patients of childbearing potential are defined as Women without prior hysterectomy of at least 4 weeks, or who have had any evidence of menses in the past 12 months.

Females who have been amenorrhea for more than or equal to 12 months, but the amenorrhea is possibly due to other causes, including prior chemotherapy, anti-estrogens, or ovarian suppression.

1. Free from any systemic or dermatologic disorder that, in the opinion of the Investigator, will interfere with the study results or increase the risk of adverse events.

2. Willing to minimize external factors that might trigger rosacea flare-ups (e.g., extreme temperatures, aggressive astringents, known offending foods such as spicy foods and thermally hot foods and drinks, prolonged sun exposure, strong winds, alcoholic beverages, and emotional stress) within 24 hours before the Screening visit.

3. Of any skin type or race, provided the skin pigmentation allows accurate evaluation of papulopustular rosacea.

4. Willingness and capability to cooperate to the extent and degree required by the protocol.

Exclusion Criteria:

1. Females who are pregnant, lactating or planning to become pregnant during the study period.

2. Patient has mild facial rosacea (less than 8 inflammatory lesions on the face) or very severe rosacea (more than 50 inflammatory lesions).

3. Patient has mild erythema.

4. Patient has a baseline IGE score of 0, 1 or 2.

5. Patient has a skin condition on the face that would interfere with the diagnosis or assessment of rosacea (e.g., dermatitis, psoriasis, squamous cell carcinoma, eczema, acneform eruptions caused by medications, steroid acne, steroid folliculitis, bacterial folliculitis).

6. Patients with excessive facial hair, such as beards, sideburns, moustaches, etc., that would interfere with diagnosis or assessment of rosacea.

7. Patients with tattoos or excessive facial scarring that, in the Investigator's opinion, may interfere with the evaluation of the patient's rosacea.

8. Patients with active facial sunburn, peeling from sunburn, or patients that will be exposed to excessive sunlight during the study.

9. Patient has significant history or current evidence of chronic infectious disease, system disorder, organ disorder or other medical condition that in the Investigator's opinion would place the study patient at undue risk by participation.

10. Any patient (male or female) who has started, or changed hormonal therapy within 3 months of the baseline visit (this includes hormonal contraceptives). Patients who have been on stable hormone therapy for at least 3 months and whose therapy is considered unlikely to be changed for the duration of the study will be eligible.

11. History of hypersensitivity or allergy to study drug, or other ingredients of the formulation.

12. Use within 6 months prior to baseline of oral retinoids (e.g., Accutane) or therapeutic vitamin A supplements of greater than 10,000 units/day (multivitamins are allowed).

13. Use for less than 3 months prior to baseline of estrogen- and/or progestin-containing oral, injectable, implant, or transdermal contraceptives; use of such therapy must remain constant throughout the study.

14. Use within 1 month prior to baseline of 1) topical retinoids to the face, 2) systemic (e.g., oral or injectable) antibiotics known to have an impact on the severity of facial rosacea (e.g., containing tetracycline and its derivatives, erythromycin and its derivatives, sulfamethoxazole, or trimethoprim), 3) systemic steroids, 4) photodynamic therapy (including laser and other light therapies), or 6) cosmetic procedures (e.g., superficial chemical peels, exfoliation or microdermabrasion of the face).

15. Use within 2 weeks prior to baseline of 1) topical corticosteroids, 2) topical antibiotics, 3) topical anti-inflammatory agents or 4) topical medications for rosacea (e.g., metronidazole, azelaic acid, sodium sulfacetamide, ivermectin) 5) immunosuppressive drugs, 6) anticoagulant therapy.

16. Use of any other topical products applied to the target site.

17. Use of systemic corticosteroids. The use of inhaled corticosteroids up to less than 1mg per day is acceptable.

18. Use of antipruritics, including antihistamines, within 24 hours of study visits.

19. Patients who use make-up must have used the same brands/types for a minimum period of 14 days before study entry and must agree to not change brand or frequency of use throughout the study.

20. Presence of carcinoid, pheochromocytoma, or other causes of systemic flushing.

21. Presence of acne conglobata, acne fulminans, secondary acne or severe acne requiring systemic treatment.

22. Ocular rosacea (e.g., conjunctivitis, blepharitis, or keratitis) of sufficient severity to require topical or systemic antibiotics.

23. Receipt of any drug as part of a research study within 30 days before dosing.

24. Employees of the research center or Investigator.

25. Patients who are illiterate

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigator site 1	Arlington Heights	Illinois	United States	60005

Sponsors and Collaborators

• Actavis Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actavis Inc.
• ClinicalTrials.gov Identifier: NCT02840461
• Other Study ID Numbers: 71591701
• First Posted: Jul 21, 2016
• Last Update Posted: Jun 2, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Rosacea; Ivermectin

Study Results

Participant Flow

Arm/Group Title	Ivermectin Cream, 1%	SoolantraTM (Ivermectin) Cream, 1%	Placebo/Vehicle Cream
Arm/Group Description	Test product, manufactured by Actavis Laboratories UT, Inc. Ivermectin Cream, 1%	Reference product, manufactured by Galderma Laboratories, L.P. Ivermectin Cream, 1%	Placebo, manufactured by Actavis Laboratories UT, Inc. Placebo/Vehicle cream
Period Title: Overall Study
STARTED	259	257	114
COMPLETED	236	235	100
NOT COMPLETED	23	22	14

Baseline Characteristics

Arm/Group Title	Ivermectin Cream, 1%	SoolantraTM (Ivermectin) Cream, 1%	Placebo/Vehicle Cream	Total
Arm/Group Description	Test product, manufactured by Actavis Laboratories UT, Inc. Ivermectin Cream, 1%	Reference product, manufactured by Galderma Laboratories, L.P. Ivermectin Cream, 1%	Placebo, manufactured by Actavis Laboratories UT, Inc. Placebo/Vehicle cream	Total of all reporting groups
Overall Participants	259	257	114	630
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.8 (15.4)	50.3 (15.0)	51.1 (14.1)	51.1 (14.8)
Sex: Female, Male (Count of Participants)
Female	182 70.3%	182 70.8%	85 74.6%	449 71.3%
Male	77 29.7%	75 29.2%	29 25.4%	181 28.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	136 52.5%	133 51.8%	65 57%	334 53%
Not Hispanic or Latino	123 47.5%	124 48.2%	49 43%	296 47%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	0 0%	0 0%	1 0.2%
Asian	0 0%	4 1.6%	0 0%	4 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 0.8%	0 0%	0 0%	2 0.3%
White	253 97.7%	253 98.4%	114 100%	620 98.4%
More than one race	3 1.2%	0 0%	0 0%	3 0.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline to Week 12 in the Number of Inflamed (Papules/Pustules) Lesions of Rosacea.
Description	Bioequivalence of the test to reference was considered to have been demonstrated if the 90% confidence interval for the test to reference ratio for the percent change from baseline to Week 12 in the number of inflamed lesion counts was within [80%, 125%].
Time Frame	Baseline and 12 Weeks

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat Population

Arm/Group Title	Ivermectin Cream, 1%	SoolantraTM (Ivermectin) Cream, 1%	Vehicle Cream
Arm/Group Description	Test product, manufactured by Actavis Laboratories UT, Inc. Ivermectin Cream, 1%	Reference product, manufactured by Galderma Laboratories, L.P. Ivermectin Cream, 1%	Placebo cream (manufactured by Actavis Laboratories UT, Inc.)
Measure Participants	251	248	111
Least Squares Mean (Standard Error) [percentage of change from baseline]	-64.87 (2.03)	-64.87 (2.03)	-55.04 (2.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivermectin Cream, 1%, SoolantraTM (Ivermectin) Cream, 1%
	Comments
	Type of Statistical Test	Equivalence
	Comments	Therapeutic equivalence of the Test product to the Reference product based on the primary endpoint was evaluated in the PP population. If the confidence interval is within 80-125% for the primary endpoint, then the Test and Reference treatments are considered therapeutically equivalent.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	103.51
	Confidence Interval	(2-Sided) 90%; 97.95 to 110.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ivermectin Cream, 1%, Vehicle Cream
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.83
	Confidence Interval	(2-Sided) 95%; -16.24 to -3.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	SoolantraTM (Ivermectin) Cream, 1%, Vehicle Cream
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.83
	Confidence Interval	(2-Sided) 95%; -16.25 to -3.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	The Percentage of Patients With a Clinical Response of "Success".
Description	The secondary endpoint was the percentage of patients with a clinical response of "success" using the IGE at Week 12. At Visit 1, the IGE had to be 3 or 4 for the patient to be eligible for inclusion.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Population

Arm/Group Title	Ivermectin Cream, 1%	SoolantraTM (Ivermectin) Cream, 1%	Vehicle Cream
Arm/Group Description	Test product, manufactured by Actavis Laboratories UT, Inc. Ivermectin Cream, 1%	Reference product, manufactured by Galderma Laboratories, L.P. Ivermectin Cream, 1%	Placebo Cream: manufactured by Actavis Laboratories UT., Inc.
Measure Participants	251	248	111
Count of Participants [Participants]	117 45.2%	108 42%	45 39.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivermectin Cream, 1%, SoolantraTM (Ivermectin) Cream, 1%
	Comments
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval (with Yates correction) for the difference between the proportion of patients in the Test and Reference groups considered to be a clinical success was contained within the pre-defined equivalence limits [-20%, +20%], the therapeutic equivalence of the Test to Reference product was considered supported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 90%; -2.7 to 14.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	6 months
Arm/Group Title	Ivermectin Cream, 1%		SoolantraTM (Ivermectin) Cream, 1%		Placebo/Vehicle Cream
Arm/Group Description	Test product, manufactured by Actavis Laboratories UT, Inc. Ivermectin Cream, 1%		Reference product, manufactured by Galderma Laboratories, L.P. Ivermectin Cream, 1%		Placebo, manufactured by Actavis Laboratories UT, Inc. Placebo/Vehicle cream
All Cause Mortality
	Ivermectin Cream, 1%		SoolantraTM (Ivermectin) Cream, 1%		Placebo/Vehicle Cream
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/259 (0%)		0/257 (0%)		0/114 (0%)
Serious Adverse Events
	Ivermectin Cream, 1%		SoolantraTM (Ivermectin) Cream, 1%		Placebo/Vehicle Cream
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/259 (0%)		0/257 (0%)		0/114 (0%)
Other (Not Including Serious) Adverse Events
	Ivermectin Cream, 1%		SoolantraTM (Ivermectin) Cream, 1%		Placebo/Vehicle Cream
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/259 (6.9%)		24/257 (9.3%)		14/114 (12.3%)
Eye disorders
Dry eye	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Eye irritation	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Vision blurred	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Diarrhoea	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Nausea	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Toothache	1/259 (0.4%)	1	1/257 (0.4%)	1	0/114 (0%)	0
General disorders
Application site eczema	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Application site erythema	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Application site pain	2/259 (0.8%)	3	1/257 (0.4%)	1	0/114 (0%)	0
Pyrexia	1/259 (0.4%)	1	0/257 (0%)	0	0/114 (0%)	0
Infections and infestations
Abscess limb	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Acute sinusitis	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Bronchitis	1/259 (0.4%)	1	0/257 (0%)	0	1/114 (0.9%)	1
Conjunctivitis	1/259 (0.4%)	1	0/257 (0%)	0	0/114 (0%)	0
Hordeolum	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Influenza	1/259 (0.4%)	1	0/257 (0%)	0	0/114 (0%)	0
Nasopharyngitis	3/259 (1.2%)	3	0/257 (0%)	0	0/114 (0%)	0
Oral herpes	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Pharyngitis	1/259 (0.4%)	1	0/257 (0%)	0	0/114 (0%)	0
Pnuemonia	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Sinusitis	1/259 (0.4%)	1	0/257 (0%)	0	1/114 (0.9%)	1
Staphylococcal infection	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Upper respiratory tract infection	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Injury, poisoning and procedural complications
Animal bite	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Laceration	0/259 (0%)	0	1/257 (0.4%)	1	1/114 (0.9%)	1
Muscle strain	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Procedural pain	1/259 (0.4%)	1	1/257 (0.4%)	1	0/114 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Fluid retention	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/259 (0.4%)	1	2/257 (0.8%)	2	0/114 (0%)	0
Myalgia	2/259 (0.8%)	2	1/257 (0.4%)	1	1/114 (0.9%)	1
Pain in extremity	1/259 (0.4%)	1	1/257 (0.4%)	1	0/114 (0%)	0
Sjogren's syndrome	0/259 (0%)	0	0/257 (0%)	0	1/114 (0.9%)	1
Nervous system disorders
Dizziness	0/259 (0%)	0	1/257 (0.4%)	2	0/114 (0%)	0
Headache	2/259 (0.8%)	2	3/257 (1.2%)	6	2/114 (1.8%)	2
Psychiatric disorders
Anxiety	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal congestion	1/259 (0.4%)	1	0/257 (0%)	0	0/114 (0%)	0
Oropharyngeal pain	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Skin and subcutaneous tissue disorders
Acne	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Dermatitis contact	0/259 (0%)	0	2/257 (0.8%)	2	2/114 (1.8%)	2
Hyperhidrosis	0/259 (0%)	0	1/257 (0.4%)	3	0/114 (0%)	0
Rash papular	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Rosacea	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0
Vascular disorders
Hypertension	0/259 (0%)	0	1/257 (0.4%)	1	0/114 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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.