A Companion Treatment Study for Patients With Moderate to Severe Acne Vulgaris

A Prospective, Multicenter, Randomized, Evaluator-Blinded, Study to Evaluate the Safety and Efficacy of AMZEEQ® Companion Treatment With Oral Isotretinoin Therapy in Patients With Moderate to Severe Acne Vulgaris

Acne vulgaris is a common disease of both males and females, usually manifesting initially during adolescence. The use of retinoic acid analogues such as adapalene, tazarotene and isotretinoin are also commonly prescribed to treat inflammation; dysregulated sebum production and comedonal acne. This study seeks to evaluate the efficacy and safety of concomitant use of both AMZEEQ® and oral isotretinoin compared to oral isotretinoin only use and to explore sequence dosing of both products as part of a long-term management protocol for acne vulgaris.

Study Overview

• Status: Completed
• Conditions: Acne Vulgaris
• Intervention / Treatment: Drug: Isotretinoin; Drug: Amzeeq 4% Topical Foam

Detailed Description

Acne vulgaris is a common disease of both males and females, usually manifesting initially during adolescence. The primary pathologic events are initiated in the pilosebaceous units, especially of sebaceous-gland-bearing areas of the face, chest, and back as a result of increased androgen stimulation initiated at adrenarche or puberty. As a result of both abnormal keratinization of the infra-infundibular portion of the pilosebaceous follicle and increased sebum produced in the gland, a blockage of the duct results in the unapparent clinical lesion of the microcomedone. Continued blockage, colonization of the follicle by Cutibacterium acnes (C. acnes), and generation of multiple chemoattractant and proinflammatory moieties may result in non-inflammatory clinical lesions, comedones, and inflammatory lesions: papules, pustules, nodules, and cysts.

Acne treatments vary widely and frequently involve therapy combination approaches to achieve the objectives of initial disease control and long-term maintenance of effect. Antibiotics, especially clindamycin, minocycline, and doxycycline, have been prescribed as acne treatments for many years. These antibiotics effectively control the signs of inflammatory acne while patients continue to use them. Equally, the use of retinoic acid analogues such as adapalene, tazarotene and isotretinoin are also commonly prescribed to treat inflammation; dysregulated sebum production and comedonal acne.

AMZEEQ® is a topical lipophilic foam containing 4% minocycline that was approved in the US for the treatment of acne vulgaris in 2019 although minocycline containing products have been available in the US since the early 1970s. Minocycline is a semi-synthetic, second-generation tetracycline that imparts both a bacteriostatic and anti-inflammatory effect in the treatment of inflammatory acne. In addition, AMZEEQ® has been previously shown in clinical studies to positively impact comedonal acne.

Adverse events relating to oral minocycline use include tissue depigmentation primarily related to the ability of minocycline to complex with metals such as calcium and sequester into a variety of tissues e.g. bone, teeth and skin; CNS effects affecting the vestibular system e.g. dizziness, blurred vision and rare episodes of intracranial hypertension. Oral minocycline has also been implicated in rare but serious reactions such as anaphylaxis, erythema multiforme and DRESS syndrome. Interestingly, these findings do not appear to have much applicability to topically applied minocycline (as AMZEEQ®), likely due to significantly lower systemic exposure to minocycline when dosed by the topical route.

Isotretinoin is a retinoic acid analogue (13-cis-retinoic acid) supplied as oral capsules. and was approved in the US for the treatment of severe acne vulgaris in 1982 under the brand name Accutane®. Isotretinoin is the only therapy that impacts on all of the major aetiological factors implicated in acne. It achieves this by influencing cell-cycle progression, cellular differentiation, cell survival and apoptosis which results in a significant reduction in sebum production, influences comedogenesis, lowers surface and ductal C. acnes and has anti-inflammatory properties.

Although isotretinoin can ameliorate all four of the primary drivers of disease pathology, resulting in impressive clinical outcomes for severe and/or recalcitrant patients, the safety of isotretinoin continues to be a focal point for prescribers. As a teratogen, isotretinoin impacts the function of Hox genes that disrupts genetic control of axial patterning during embryo development. This can lead to developmental defects of the heart, spinal cord, palate, mandible, and other skeletal and neurological disorders such as hydrocephalus, microcephaly, and mental retardation. As such, careful monitoring of patients of both sexes via a risk evaluation and mitigation program (REMS) such as iPledge is a prerequisite for the safe use of the isotretinoin-containing products. Consequently, prescribers seek to discontinue oral isotretinoin use when it is appropriate to do so and to introduce other products with the goal of achieving a sustained long term clinical benefit for the patient.

The combination of these two, well-characterized acne treatments with two separate administration routes presents an intriguing, combined proposition of achieving rapid control of disease coupled with long-term disease management possibilities. As such this study seeks to evaluate the efficacy and safety of concomitant use of both AMZEEQ® and oral isotretinoin compared to oral isotretinoin only use and to explore sequence dosing of both products as part of a long-term management protocol for acne vulgaris.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dripping Springs, Texas, United States, 78620
      • Austin Institute for Clinical Research, Inc.
    • Pflugerville, Texas, United States, 78660
      • Austin Institute for Clinical Research, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Male or female patients will be considered eligible for participation in the study if all of the following inclusion criteria are satisfied prior to randomization:

1. Has completed and signed an appropriately administered Informed Consent Form (ICF) prior to any study-related procedures. Patients less than 18 years of age (or as required by state law) must sign an Assent Form for the study and a parent or legal guardian must sign the ICF.
2. Is 12 years of age or older.
3. Has facial acne vulgaris with an IGA score of moderate (3) or severe (4).
4. Is willing and able (with assistance from a caregiver as necessary) to both apply AMZEEQ® and take oral isotretinoin capsule(s) as directed, comply with study instructions, and commit to all follow-up visits for the duration of the study.
5. If female of child-bearing potential (FOCBP), must have two negative pregnancy tests, one being serologic, within the screening period.
6. Is willing to commit to true abstinence from heterosexual contact (which must be reviewed at each study visit and source documented) or agreed to use, and be able to comply with, effective contraception without interruption, prior to starting treatment as detailed below, during study period. For FOCBP who may participate in the study, the following methods of contraception, if properly used, are generally considered reliable with the following wait periods prior to having relations: oral contraceptives; vaginal contraceptive ring and patch contraceptives (one full cycle; e.g., 4 to 8 weeks); injection contraceptives (more than 7 days); intrauterine device or implantable hormone contraceptives (more than 7 days); surgical sterilization (bilateral tubal ligation) or a vasectomized partner (each, more than 6 months); male condom with intravaginal spermicide or diaphragm/cervical cap with spermicide (effective with proper use without a waiting period).
7. If sexually active male patient, must practice true abstinence (which must be reviewed at each study visit) or agree to use a condom with intravaginal spermicide during sexual contact with a pregnant female or a FOCBP, while participating in the study, during dose interruptions, and for at least 30 days following treatment discontinuation, unless patient has undergone a successful vasectomy. Male patients should refrain from making sperm donations at any time during study participation and for at least 30 days following treatment discontinuation.
8. Is willing to minimize exposure of the treated skin to ultraviolet light (e.g. avoid excessive sunlight, agree to not use tanning beds) and extremes in weather, such as wind or cold, throughout the study.
9. In the investigator's opinion, patient is in good general health and is free of any disease state or physical condition that exposes the patient to an unacceptable risk by study participation or impairs the evaluation of the patient or the treatments by participating in the study.

Exclusion Criteria:

Patients who meet any of the following will be excluded from the study:

1. Female who is pregnant, lactating or breastfeeding, or is planning a pregnancy during the study.
2. Acne conglobata, acne fulminans, secondary acne (chloracne, drug-induced acne), or any dermatological condition of the face (such as seborrhea, atopic dermatitis or basal cell carcinoma) that would require the use of confounding therapies or facial hair (eg, beard, sideburns, mustache) that could either interfere with clinical evaluations.
3. Sunburn on the face.
4. Severe systemic disease that might interfere with the conduct of the study or the interpretation of the results.
5. Abnormal Screening laboratory values that are considered clinically significant.
6. Patient is currently enrolled in another investigational drug or device study or is using or has used an investigational drug or investigational device treatment within 30 days of randomization.
7. Patient, who in the opinion of the investigator, is unable or unlikely to comply with the requirements of the study protocol.

8. Patients who have a history of any of the following will be excluded:

   • Allergy to tetracycline-class antibiotics or to any ingredient in the study drug
   • Pseudomembranous colitis or antibiotic-associated colitis
   • Hepatitis or liver damage or renal impairment
   • Known or suspected premalignant or malignant disease (excluding successfully treated skin cancers)

9. Patients who have used the following medications (topical refers only to the facial area) will not be eligible:

   • Within 1 week prior to randomization:

     • Medicated facial cleansers
     • Topical acne treatments (other than those listed below)

   • Within 4 weeks prior to randomization:

     • Topical retinoids on the face
     • Topical anti-inflammatories eg, PDE-4 inhibitors, calcineurin inhibitors and corticosteroids on the face
     • Topical corticosteroids on body areas other than the face for more than 15 consecutive days and on more than 10% of body surface area. In flexural body areas, such as axillary and inguinal regions, only mild topical corticosteroids and allowed for short term use (≤15 consecutive days).
     • Systemic antibiotics
     • Systemic acne treatments

   • Within 12 weeks prior to randomization:

     • Systemic retinoids
     • Systemic corticosteroids (Note: Intranasal and inhaled corticosteroids may be used throughout the study).
10. The following medications have been used less than the specified length of stable usage and patients must not initiate or change the dosing regimen during the course of the study: 3 months: hormonal contraceptives and therapies which also include testosterone replacement or supplementation.
11. Patient has any acute illness (eg, infection) within 48 hours of randomization, which, in the investigator's opinion, is considered significant.
12. Patient has a history of sensitivity to any of the ingredients in the medications.

13. Documented history of depression or self-harm that is not, in the opinion of the Investigator, currently adequately controlled with medication or in remission. Or, the presence of significant uncontrolled neuropsychiatric disorder, are clinically judged by the investigator to be at risk for suicide, or have a "yes" answer to any of the following at Screening or Baseline:

    1. Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) on the "Suicidal Ideation" portion of the Columbia Suicide Severity Rating Scale (C-SSRS) or
    2. Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the C-SSRS or
    3. Any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "Suicidal Behavior"portion of the C-SSRS.

    Note: A patient does not necessarily have to be excluded if they have self-injurious behavior that would be classified as non-suicidal self-injurious behavior. If this situation arises, the subject should be referred to a psychiatrist or appropriately trained professional as indicated.

14. Drug addiction or alcohol abuse (within the last 2 years).
15. Patient has history of previous use of isotretinoin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Group A; Patients will concomitantly receive once daily treatment of oral isotretinoin and topical AMZEEQ® for 20 weeks, followed by a further 24 weeks of once daily AMZEEQ® only treatment.	Drug: Isotretinoin; Isotretinoin is a retinoic acid analogue (13-cis-retinoic acid) supplied as oral capsules. and was approved in the US for the treatment of severe acne vulgaris in 1982 under the brand name Accutane®.; Other Names: Zenatane™; Drug: Amzeeq 4% Topical Foam; AMZEEQ® is a topical lipophilic foam containing 4% minocycline that was approved in the US for the treatment of acne vulgaris in 2019; Other Names: minocycline
Experimental: Treatment Group B; Patients will receive once daily treatment of oral isotretinoin for 20 weeks, followed by a further 24 weeks of once daily AMZEEQ® only treatment.	Drug: Isotretinoin; Isotretinoin is a retinoic acid analogue (13-cis-retinoic acid) supplied as oral capsules. and was approved in the US for the treatment of severe acne vulgaris in 1982 under the brand name Accutane®.; Other Names: Zenatane™; Drug: Amzeeq 4% Topical Foam; AMZEEQ® is a topical lipophilic foam containing 4% minocycline that was approved in the US for the treatment of acne vulgaris in 2019; Other Names: minocycline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lesion Improvement	Percent change from Baseline in inflammatory and comedonal lesion counts at each visit.	44 weeks
IGA Improvement	IGA Treatment Success (dichotomized as Yes/No) at each visit, where success is defined as an IGA score of 0 or 1, and at least a 2-grade improvement (decrease) from Baseline.	44 weeks

Collaborators and Investigators

• Sponsor: Edward Lain, MD
• Collaborators: Vyne Therapeutics Inc.
• Investigators: Principal Investigator: Edward Lain, MD, MBA, Austin Institute for Clinical Research

Publications and helpful links

General Publications

• Brown SK, Shalita AR. Acne vulgaris. Lancet. 1998 Jun 20;351(9119):1871-6. doi: 10.1016/S0140-6736(98)01046-0. No abstract available.
• AMZEEQ® Prescribing Information - accessed March 10th 2021.
• Raoof TJ, Hooper D, Moore A, Zaiac M, Sullivan T, Kircik L, Lain E, Jankicevic J, Stuart I. Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: A phase 3 study. J Am Acad Dermatol. 2020 Apr;82(4):832-837. doi: 10.1016/j.jaad.2019.05.078. Epub 2019 Jun 1.
• Jones TM, Ellman H, deVries T. Pharmacokinetic Comparison of Once-Daily Topical Minocycline Foam 4% vs Oral Minocycline for Moderate-to-Severe Acne. J Drugs Dermatol. 2017 Oct 1;16(10):1022-1028.
• Accutane® Prescribing Information - access March 10th 2021.
• Fogh K, Voorhees JJ, Astrom A. Expression, purification, and binding properties of human cellular retinoic acid-binding protein type I and type II. Arch Biochem Biophys. 1993 Feb 1;300(2):751-5. doi: 10.1006/abbi.1993.1104.
• Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4. doi: 10.1073/pnas.90.1.30.
• Levin AA, Bosakowski T, Kazmer S, Grippo JF. 13-cis retinoic acid does not bind to retinoic acid receptors alpha, beta and gamma. Toxicologist. 1992; 12: 181.
• Ott F, Bollag W, Geiger JM. Oral 9-cis-retinoic acid versus 13-cis-retinoic acid in acne therapy. Dermatology. 1996;193(2):124-6. doi: 10.1159/000246226.
• Geiger JM, Hommel L, Harms M, Saurat JH. Oral 13-cis retinoic acid is superior to 9-cis retinoic acid in sebosuppression in human beings. J Am Acad Dermatol. 1996 Mar;34(3):513-5. doi: 10.1016/s0190-9622(96)90462-4. No abstract available.
• Tsukada M, Schroder M, Roos TC, Chandraratna RA, Reichert U, Merk HF, Orfanos CE, Zouboulis CC. 13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol. 2000 Aug;115(2):321-7. doi: 10.1046/j.1523-1747.2000.00066.x.
• Nelson AM, Gilliland KL, Cong Z, Thiboutot DM. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes. J Invest Dermatol. 2006 Oct;126(10):2178-89. doi: 10.1038/sj.jid.5700289. Epub 2006 Mar 30.
• Tantibanchachai C, Isotretinoin (Accutane) as a teratogen, Embryo Project Encyclopedia. 2014; ISSN: 1940-5030; http://embryo.asu.edu/handle/10776/8040

Helpful Links

• Tantibanchachai C, Isotretinoin (Accutane) as a teratogen, Embryo Project Encyclopedia.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2021
• Primary Completion (Actual): April 28, 2023
• Study Completion (Actual): April 28, 2023

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: June 23, 2021
• First Posted (Actual): June 28, 2021

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Acneiform Eruptions; Sebaceous Gland Diseases; Acne Vulgaris; Anti-Infective Agents; Dermatologic Agents; Anti-Bacterial Agents; Isotretinoin; Minocycline
• Other Study ID Numbers: V77-123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes