A Study of the Safety, Engraftment, and Action of NB01 in Adults With Moderate Acne

Study Overview
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Brief Summary
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Acne vulgaris is a multifactorial disease caused by overgrowth of Propionibacterium acnes (P. acnes), impaction of hair follicles, excessive sebum production and hormonal dysregulation. Recent literature from the Human Microbiome Project has shown there are unique microbial signatures specific to healthy and acne disease states. From this data, the investigators hypothesize that by eliminating resident disease-associated bacterial strains and replacing them with health-associated strains, recurrences/fares of acne may be improved, mitigated, and prevented. Instead of current approaches which focus on eliminating all bacteria from the skin, the investigators aim to deliver healthy bacteria to restore the skin to a healthy state via this replacement therapy. The investigators aim to test this in a Phase Ib single application study evaluating the safety, tolerability, and clinical impact that a single application of NB01, a live strain of P. acnes, has on adult subjects with moderate acne.

Detailed Description
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A Phase 1B Dose Escalating Study of the Safety, Short-Term Engraftment and Action of a Singly Applied NB01 in Adults with Moderate Acne Acne vulgaris is a multifactorial disease caused by overgrowth of Propionibacterium acnes (P. acnes), impaction of hair follicles, excessive sebum production and hormonal dysregulation. Recent literature from the Human Microbiome Project has shown there are unique microbial signatures specific to healthy and acne disease states. From this data, the investigators hypothesize that by eliminating resident disease-associated bacterial strains and replacing them with health-associated strains, recurrences/fares of acne may be improved, mitigated, and prevented. Instead of current approaches which focus on eliminating all bacteria from the skin, the investigators aim to deliver healthy bacteria to restore the skin to a healthy state via this replacement therapy. The investigators aim to test this in a Phase Ib single application study evaluating the safety, tolerability, and clinical impact that a single application of NB01 has on adult subjects with moderate acne. Investigators will be profiling the change in microbiome over the course of therapy to determine if exogenously delivered bacteria can populate the skin (engraftment) and cause a shift in the microbiome safely and subsequently impact acne biomarkers that may correlate with clinical disease. The investigators intend for this therapy to eventually be used in acne subjects with ages ranging from 13-40, and all disease severities as either monotherapy for mild to mild/moderate acne and as an adjuvant therapy for moderate to severe acne at all body sites, with special attention to facial involvement. This approach is standard to acne therapy whereby mild disease will be treated with a monotherapy (i.e., topical Benzoyl peroxide [BPO]) and moderate/severe disease will be treated with various combinatory regimens (topical antibiotics, BPO, topical retinoids, oral antibiotics). Primary Objectives: To determine the safety profile and tolerability of a singly applied NB01 To define engraftment of a singly applied topical NB01. Dose schedule determination based on engraftment Secondary Objective: To evaluate clinical efficacy using FDA standards of acne clinical assessments, namely the Investigator Global Assessment (IGA) and acne lesion counts of a singly applied NB01. Approximately 10 total male and female adult subjects combined with moderate, non-cyclical acne will be enrolled into the trial. Approximately five (5) subjects will be assigned to each dose schedule This is a single topical application study of live bacteria for the study of acne in adult subjects. Subject participation in the trial will range from 5 weeks to 2 months.

Official Title
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A Phase 1B Dose Escalating Study of the Safety, Short-Term Engraftment and Action of a Singly-Applied NB01 in Adults With Moderate Acne

Conditions
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Acne Vulgaris

Intervention / Treatment
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* Biological: NB01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed e-consent. Males and Females ages 18-40. Acne severity: Moderate (Grade 3 on 5-point IGA scale and Moderate on an acne lesion count scale (Appendix B [Section 12.2], IGA and Lesion Count Acne Grading). Acne treatment-free period (including topical or oral antibiotics, retinoids, laser therapy, topical dapsone, topical azelaic acid, facial peels, dermabrasion, sulfacetamide sulfur, and salicylic acid), of at least 3 weeks prior to e-consent (with the exception of BPO pre-treatment under this protocol). Lesion count: A minimum of at least a total of 15 inflammatory lesions (papules plus pustules), with a minimum of 10 inflammatory lesions within the designated application area (cheek/nose). Females with non-cyclical acne. Females of childbearing potential willing to use adequate contraception (e.g., total abstinence, intrauterine device (IUD), barrier method with spermicide, surgical sterilization or surgically sterilized partner, Depo-Provera®, Norplant®, or NuvaRing® for the duration of the Screening Period and during study participation. All oral contraceptive and hormonal implants will need to have been initiated and on a stable dose for at least 3 months prior to the screening period. Women of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal; postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Male participants willing to use an acceptable method of contraception (e.g., total abstinence, barrier methods with spermicide, surgical sterilization or surgically sterilized partner) during study participation. Exclusion Criteria: Active bacterial, viral, or fungal skin infections. Any noticeable breaks or cracks in the skin on the face, including severely excoriated skin or skin with open or weeping wounds suggestive of an active infection or increased susceptibility to infection. Comorbid skin conditions in the area of application. Active periodontal disease or ongoing procedures (e.g., gum grafting). History/current ocular infections/surgeries within 6 months of enrollment, with the exception of any history of cataracts. History of sarcoidosis. History septic joints/endocarditis. Participants with Netherton's syndrome or other genodermatoses that result in a defective epidermal barrier. Sensitivity to or difficulty tolerating glycerin, polyethylene glycol. History of isotretinoin use, with the exception of sub-therapeutic treatment within 8 weeks of enrollment. Less than 80% compliance with BPO, or less than 5 days' worth of BPO pre-treatment (whichever is greater) during the Screening period. Current major systemic comorbid conditions. Currently participating in (or within 8 weeks of enrollment) another acne trial or other investigational drug. Participants with prosthetic heart valves, pacemakers, intravascular catheters, or other foreign or prosthetic devices/implantable devices/hardware. Participants with close contact (e.g., spouses, children, or members in the same household) with prosthetic heart valves, pacemakers, intravascular catheters, or other foreign or prosthetic devices/implantable devices/hardware. Known chronic human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infections. History of malignancy (with the exception of non-melanoma skin cancer). Immunosuppression (such as resulting from transplantation, immunosuppressive therapy, active HIV infection/acquired immune deficiency syndrome [AIDS], neutropenia). Major surgical procedure, open biopsy, or significant traumatic injury within 14 days of initiating study drug (unless the wound has healed), or anticipation of the need for major surgery during the study. The presence of a medical or psychiatric condition, history of drug or alcohol abuse that, in the opinion of the PI, makes the subject inappropriate for study inclusion. Participants with close contacts (e.g., spouses, children, or members in the same household) that have severe barrier defects or are immunocompromised. Inability or unwillingness of participant to comply with study protocol procedures. Pregnant or lactating females, or females who desire to become pregnant and/or breast feed within the duration of study participation. Imprisonment or under legal guardianship.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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
Intervention Model: Single Group Assignment
Interventional Model Description: Open label.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NB01<br>NB01 is a live probiotic containing a single strain of P. acnes, frozen, on a pad, in a single use pouch, for topical application. Open label and dose escalation of a single application of NB01 to subjects with moderate acne, with approximately 5 subjects assigned to lower bound dose before escalation to upper bound dose. | Biological: NB01<br>* Use an existing therapy designed to kill existing facial bacterial followed by populating facial skin with a single application of NB01<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Successful Engraftment of Probiotic Following a Single Application. | Engraftment is defined as the percentage of bacteria recovered from hair follicles that are health-associated (NB01) as measured with proprietary quantitative polymerase chain assays. Successful follicular engraftment, defined as both deoR/PanBac >40% and Cas5/PanBac >40% in the Day 2 (24H) ) Biore Strip samples. Cas5/PanBac and deoR/PanBac are the percentages of bacteria in a sample containing the CRISPR associated protein Cas5 and a repressor of porphyrin production deoR, respectively. Pan-Bacterial (PanBac) is a loci found in nearly all bacteria found on the face and thus serves as the denominator to calculate the percentage of bacteria with any loci. | 2 Months | 
| Dose Schedule Determination Based on Time to Peak deoR and Cas5 | To determine longevity of the live biotherapeutic after a single application, swab samples were collected at Baseline, 6, 24 and 48 hours after application, and genotyped as above. For each participant the absolute change, from Baseline, in the percentage of the two loci present in the live biotherapeutic (deoR and Cas5) were calculated. A significant positive change is indicative of the continued presence of the live biotherapeutic. | From Baseline to 48 hours after application | 
| Number of Participants With Change in Investigator Global Assessment (IGA) Score | Number of participants with a changed Investigator Global Assessment (IGA) score after single application of NB01; positive number if grade is reduced (e.g. from 3 to 2) or negative number is IGA grade increased. The Investigator Global Assessment 5-Point Score is a standard FDA acne assessment tool with scoring as follows: Grade 0-Clear (Clear skin with no inflammatory or non-inflammatory lesions. The category of clear should represent true absence of disease) Grade1-Almost Clear (A few scattered comedones and no more than one small papule) Grade 2-Mild (Some comedones, some papules and pustules; no nodules) Grade 3-Moderate (Many comedones, papules and pustules; one nodule may be present) Grade 4-Severe (Covered with comedones, numerous papules and pustules and no more than a few nodular lesions) | 28 Days | 
| Safety Profile and Tolerability of a Singly Applied NB01 Using Acne Lesion Counts. | Absolute Lesion Count: All Lesions for the Whole Face; with higher numbers of lesion representing worsening or more severe acne | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Skin Peeling | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Skin Peeling. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Irritant/Allergic Contact Dermatitis | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Irritant/Allergic Contact Dermatitis. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Hyperpigmentation | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Hyperpigmentation. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Ocular Irritation | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Ocular Irritation. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Conjunctival Injection | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Conjunctival Injection. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Mucosal Toxicity | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Mucosal Toxicity. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Skin Erythema. | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Skin Erythema. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months | 
| Number of Participants With Change in Investigator Assessment of Tolerability Score: Skin Dryness. | Safety profile and tolerability of a singly applied NB01 using the Investigator Assessment of Tolerability Scoring (0 = None; 1 = Slight; 2 = Moderate; 3 = Intense) for Skin Dryness. Reference: ClinicalTrials.gov: Investigator Assessment Tolerability Scoring: A Study to Evaluate Tolerability of Two Topical Drug Products in the Treatment of Acne. | From Screening to 28 days after application, typically 2 months |