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

• ClinicalTrials.gov Identifier: NCT03709654
• Recruitment Status: Completed
• First Posted: October 17, 2018
• Results First Posted: August 3, 2020
• Last Update Posted: August 3, 2020
• Sponsor: Naked Biome, Inc.
• Collaborator: Therapeutics, Inc.
• Information provided by (Responsible Party): Naked Biome, Inc.

Tracking Information

• First Submitted Date: October 9, 2018
• First Posted Date: October 17, 2018
• Results First Submitted Date: June 4, 2020
• Results First Posted Date: August 3, 2020
• Last Update Posted Date: August 3, 2020
• Actual Study Start Date: November 1, 2018
• Actual Primary Completion Date: September 30, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 9, 2020)

• Number of Participants With Changes in Local Skin Reactions [ Time Frame: Day 0 through day 80 ]
  Local Skin Reactions (LSRs) including Erythema, edema, erosion/ulceration, scaling/dryness, and scabbing/crusting scored at Baseline (day of first application) and Week 12 (end of treatment) and reported for each visit as: Absent, Mild, Moderate, or Severe. The number of participants (and %) with no change or improvement from Baseline to week 12 visit are reported. The number of participants (and %) whose score worsened from Baseline to week 12 visit are reported.
• Number of Participants With Successful Follicular Engraftment of NB01 [ Time Frame: 12 weeks ]
  Follicular engraftment sampling used Biore® Strips at Screening and day 80 (several days after end of treatment). The number of subjects with "success" at EOT where "success" is defined as a Follicular Biore® sample with "yes" outcome based on recovery of live NB01at day 80.
• Absolute Change in Genotype Markers: Skin Surface Engraftment "Success" [ Time Frame: Day 0 through day 80 ]
  Skin surface engraftment "success" endpoint is defined by a change in genotype (TaqMan) markers compared to Screening; value is percentage of bacterial population containing health-associated genotype. Result is absolute change from screening value.
• Absolute Change From Screening in Acne Lesion Counts [ Time Frame: Day 0 through day 80 ]
  Reporting absolute change in counts.
• Percent Change From Screening in Acne Lesion Counts [ Time Frame: Day 0 through day 80 ]
  Efficacy endpoint: Percent change from Screening lesion counts at Day 80 (end of treatment)
• Number of Participants Achieving "Success" on Investigator Global Assessment (IGA) [ Time Frame: Day 0 through day 80 ]
  The investigator assessed the participant's inflammatory lesions on the face using the Investigator Global Assessment (IGA) 5-point scale. The scale ranges from 0 (best): clear, no evidence of papules or pustules to 4 (worst): severe, inflammatory lesions are more apparent, many papules/pustules. The outcome is the number of subjects in each treatment group achieving "success" at Week 12; "success" defined as an IGA score of "clear (score=0)" or "almost clear (score=1)" and at least a two-point reduction in IGA compared to Baseline.
• Change in Acne QoL Questionnaire Score [ Time Frame: Day 0 through day 80 ]
  At each visit, subjects were asked to complete the Acne Quality of Life [QoL] Questionnaire to assess subjective improvement of acne with 7 response choices ranging from extremely to not at all. The total score ranges from 19 to 114; higher scores reflect improved QoL. Outcome measure is absolute change in Acne QoL (Total Score) from Baseline to Day 80.
• Absolute Change From Screening in Acne Lesion Counts: Outlier Censored [ Time Frame: Day 0 through day 80 ]
  After reviewing the data, one Treatment Arm subject was found to be an extreme outlier and was censored from this ad-hoc analysis. Reporting absolute change in counts.
• Percent Change From Screening in Acne Lesion Counts: Outlier Censored [ Time Frame: Day 0 through day 80 ]
  Efficacy endpoint: Percent change from Screening lesion counts at Day 80 (end of treatment)
• Follicular Engraftment [ Time Frame: 12 weeks ]
  Follicular communities were genotyped for health-associated loci at both Screening and 12-week visits. The percent increase of Cas5 in multiple communities from each subject is reported.

Original Primary Outcome Measures (submitted: October 15, 2018)

• Adverse Events (AEs) [ Time Frame: Day 0 through day 80 ]
  AEs will be assessed by the investigator and the incidence (severity and causality) of any local and systemic AEs will be reported.
• Local Skin Reactions [ Time Frame: Day 0 through day 80 ]
  Local Skin Reactions (LSRs) including Erythema, edema, erosion/ulceration, scaling/dryness, and scabbing/crusting scored by frequency and severity at every visit.
• Follicular Engraftment "Success" [ Time Frame: Day 0 through day 80 ]
  Follicular engraftment sampling will be completed via use of Biore® Strips at baseline and day 80 (end of treatment). Engraftment "Success" Endpoint: The proportion of subjects with "success" at EOT where "success" is defined as a Follicular Biore® sample with "yes" outcome based on recovery of live NB01at day 80
• Skin surface engraftment "Success" [ Time Frame: Day 0 through day 80 ]
  Skin surface engraftment sampling will be completed via cheek swab at each visit. Skin surface engraftment "success" endpoint is defined by a percent change in TaqMan markers compared to Baseline
• Absolute change from baseline in Acne Lesion Counts (total, inflammatory, and non-inflammatory) [ Time Frame: Day 0 through day 80 ]
  Efficacy endpoint: Absolute change from Baseline lesion counts at Day 80 (end of treatment)
• Percent change from baseline in Acne Lesion Counts (total, inflammatory, and non-inflammatory). [ Time Frame: Day 0 through day 80 ]
  Efficacy endpoint: Percent change from Baseline lesion counts at Day 80 (end of treatment)
• Investigator Global Assessment (IGA) [ Time Frame: Day 0 through day 80 ]
  Proportion of subjects in each treatment group achieving "success" at Week 12, with "success" defined as an IGA score of "clear (score=0)" or "almost clear (score=1)" and at least a two-point reduction in IGA compared to Baseline.
• Acne QoL Questionnaire [ Time Frame: Day 0 through day 80 ]
  At each visit, subjects will be asked to complete the Acne QoL Questionnaire to assess subjective improvement of acne with 7 response choices ranging from extremely to not at all. Efficacy Endpoint: Absolute change from Baseline in Acne QoL to Day 80 end of treatment visit.

Current Secondary Outcome Measures (submitted: July 9, 2020)

Absolute Change in Sebum Production. [ Time Frame: Day 0 through day 80 ]

Exploratory Endpoint: Absolute change from Baseline to week 12 in sebum production measured at the mid-glabellar region of the forehead using a Sebumeter.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: October 15, 2018)

Absolute change in sebum production. [ Time Frame: Day 0 through day 80 ]

Exploratory Endpoint: Absolute and percent change from Baseline in sebum production

Descriptive Information

• Brief Title: A Study of the Safety, Engraftment, and Action of Multi-Dosed NB01 in Adults With Moderate Acne
• Official Title: A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Phase 1B Study of the Safety, Short-Term Engraftment and Action of NB01 in Adults With Moderate Acne

Brief Summary

Acne vulgaris is a disease caused my multiple factors including overgrowth of bacteria, clogged pores, excessive sebum production and hormonal changes. Recent literature from the Human Microbiome Project has shown there are bacterial strains specific to healthy and acne disease states (Fitz-Gibbon et al, 2013, Johnson et al, 2016, McDowell et al, 2012, Tomida et al, 2013)

From this data, the investigators hypothesize that by eliminating disease-associated bacterial strains and replacing them with health-associated strains, recurrences or flares 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 multiple application study evaluating the safety, tolerability, and clinical impact that a multiple applications of NB01 have on adult subjects with moderate acne.

Detailed Description

A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Phase 1B Study of the Safety, Short-Term Engraftment and Action of 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 (NB01) to restore the skin to a healthy state via this replacement therapy.

The investigators aim to test this in a Phase 1B multiple application study evaluating the safety, tolerability, and clinical impact that a multiple, daily, applications 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:

1. To determine the safety and tolerability of a multiple application of topical P. acnes microbiome transplant ("NB01").

Exploratory Objectives:

1. To define engraftment duration of NB01.
2. To evaluate preliminary clinical efficacy using Acne Lesion Counts (total, inflammatory, and non-inflammatory), Investigator Global Assessment (IGA), and subjective improvement of acne based on subject reported outcomes (Acne QoL Questionnaire).
3. To evaluate treatment effects, based on sebum production in a subpopulation from sites 02 and 03.

Approximately 36 total male and female adult subjects combined with moderate, non-cyclical acne will be enrolled into the trial. Approximately twenty four (24) subjects will be randomly assigned treatment and twelve (12) subjects will be randomly assigned to vehicle control.

This is a multiple topical application study of live bacteria for the study of acne in adult subjects. Following a 5-7 day pretreatment of gold standard benzoyl peroxide therapy to kill resident facial bacterial, 11 weeks of daily topical application of NB01 will be evaluated.

Subject participation in the trial will approximately 12 weeks.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized Double Blind Vehicle Controlled Trial, dual arm with 2:1 treatment to vehicle assignment

Masking: Double (Participant, Investigator)
Masking Description:

Double blind

Primary Purpose: Treatment

• Condition: Acne Vulgaris

Intervention

• Biological: NB01
  5-7 day pretreatment of gold standard benzoyl peroxide therapy to kill resident facial bacterial followed by 11 weeks of daily topical application of NB01
• Other: Vehicle Control
  5-7 day pretreatment of gold standard benzoyl peroxide therapy to kill resident facial bacterial followed by 11 weeks of daily topical application of vehicle control

Study Arms

• Experimental: Treatment Arm
  Subjects will undergo 1 week lead-in with BPO followed by 11 weeks of NB01 probiotic applied topically.
  Intervention: Biological: NB01
• Placebo Comparator: Vehicle Control
  Subjects will undergo 1 week lead-in with BPO followed by 11 weeks of vehicle applied topically.
  Intervention: Other: Vehicle Control

Publications *

• Fitz-Gibbon S, Tomida S, Chiu BH, Nguyen L, Du C, Liu M, Elashoff D, Erfe MC, Loncaric A, Kim J, Modlin RL, Miller JF, Sodergren E, Craft N, Weinstock GM, Li H. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol. 2013 Sep;133(9):2152-60. doi: 10.1038/jid.2013.21. Epub 2013 Jan 21.
• Johnson T, Kang D, Barnard E, Li H. Strain-Level Differences in Porphyrin Production and Regulation in Propionibacterium acnes Elucidate Disease Associations. mSphere. 2016 Feb 10;1(1):e00023-15. doi: 10.1128/mSphere.00023-15. eCollection 2016 Jan-Feb.
• McDowell A, Barnard E, Nagy I, Gao A, Tomida S, Li H, Eady A, Cove J, Nord CE, Patrick S. An expanded multilocus sequence typing scheme for propionibacterium acnes: investigation of 'pathogenic', 'commensal' and antibiotic resistant strains. PLoS One. 2012;7(7):e41480. doi: 10.1371/journal.pone.0041480. Epub 2012 Jul 30.
• Tomida S, Nguyen L, Chiu BH, Liu J, Sodergren E, Weinstock GM, Li H. Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome. mBio. 2013 Apr 30;4(3):e00003-13. doi: 10.1128/mBio.00003-13.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 10, 2019): 36
• Original Estimated Enrollment (submitted: October 15, 2018): 60
• Actual Study Completion Date: September 30, 2019
• Actual Primary Completion Date: September 30, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject has provided written informed consent.
2. Subject is male or non-pregnant female, 18-40 years of age, inclusive at Screening.
3. Subject has moderate facial acne vulgaris
4. Female subject with non-cyclical acne.
5. Women of childbearing potential (WOCBP) willing to use adequate contraception during study participation
6. Male subjects willing to use an acceptable method of contraception during study participation.
7. Subject has the ability to personally apply benzoyl peroxide (BPO) and study drug, as per protocol.

Exclusion Criteria:

1. Subject has active bacterial, viral, or fungal skin infections.
2. Subject has active nodulocystic acne or acne conglobate, acne fulminans, or other forms of acne (e.g., acne mechanica).
3. Subject is currently participating in an investigational drug, device, or biologic study or has used an investigational drug, biologic or device treatment within 30 days prior to first application of the study drug.
4. Subjects with prosthetic heart valves, pacemakers, intravascular catheters, or other foreign or prosthetic devices/implantable devices/hardware.
5. Subject has a history of chronic human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infections.
6. Subject has a history of malignancy (with the exception of non-melanoma skin cancer).
7. Subject is immunosuppressed (such as resulting from transplantation, immunosuppressive therapy, active HIV infection/acquired immune deficiency syndrome [AIDS], neutropenia).
8. Subject had a 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.
9. Subjects with close contacts (e.g., spouses, children, or members in the same household) that have severe skin barrier defects or are immunocompromised.
10. Female subject is pregnant or lactating or is planning to become pregnant and/or breast feed within the duration of study participation.

Other entry criteria not listed above will be reviewed of each prospective subject by the study staff to confirm eligibility

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 40 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03709654
• Other Study ID Numbers: NB01-P1BMA
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Initially there is no plan to share IPD. This may change later as the clinical plan develops.

• Current Responsible Party: Naked Biome, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Naked Biome, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Therapeutics, Inc.

Investigators

• Study Director: Emma Taylor, MD; Naked Biome

• PRS Account: Naked Biome, Inc.
• Verification Date: July 2020