LMN-101 in a Campylobacter Human Challenge Model

Overview

Randomized, double-blind, placebo-controlled study of three dose cohorts of LMN-101 followed by campylobacter challenge. Subjects will begin taking their LMN-101 or placebo regimen 3x daily on Day -7. They will document AEs in a diary. After 1 wk of dosing, volunteers will be admitted to an inpatient clinical research facility as they continue the 28-day course of treatment. After 3 doses of LMN-101 or placebo, subjects will receive the C. jejuni challenge on Day 0 following an established campylobacter controlled human infection model (CHIM) protocol (Kirkpatrick et al. 2013; Poly et al. 2008; Rimmer et al. 2018; Tribble et al. 2009). After challenge, safety monitoring will include 24-hour inpatient clinical monitoring, vital signs at least TID (orthostatic blood pressure and heart rate as clinically indicated), daily medical interviews and physical exams, blood culture for fever ≥ 39 °C, and daily stool culture. Specific solicited adverse events include diarrhea, fever, nausea, vomiting, abdominal pain, abdominal cramping, mucoid or bloody stools, headache, fatigue, lack of appetite, muscle pain, chills, and joint pains. Stool output will be measured. Fluid losses will be replaced with oral rehydration or intravenously as clinically indicated.

Subjects will begin taking a 5-day course of azithromycin and ciprofloxacin when they meet early treatment criteria or it has been 144 hours since the campylobacter challenge, whichever is earlier. Subjects will be discharged from the inpatient clinical research facility 48 hours after commencing antibiotics, when all symptoms have resolved or are resolving, and they have had ≥ 2 consecutive stools negative for C. jejuni. Subjects will be provided remaining azithromycin and ciprofloxacin to complete 5-day course at home, along with remaining doses of LMN-101 or placebo to be taken at home to complete the 28-day course. Subjects will be provided a diary card/memory aid and thermometer for outpatient monitoring of solicited adverse events. Subjects will be seen as outpatients on Days 14, 21, 28, 35, 56, and 84 after challenge for protocol-specified evaluations and contacted by telephone 6 months after challenge. For microbial recrudescence, extra visits to the clinic will be necessary and an additional course of azithromycin and ciprofloxacin will be given for 10 days.

Full Title of Study: “A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Dose-De-escalation Study of LMN-101in Healthy Volunteers Challenged With Campylobacter Jejuni”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: January 2021

Detailed Description

Healthy subjects will be randomized within one of the following sequential dose cohorts:

- LMN-101, six 500-mg capsules orally three times daily for 28 days (n=21), or identical-appearing placebo (n=7); or

- LMN-101, two 500-mg capsules and four 500-mg placebo capsules orally three times daily for 28 days (n=21), or identical-appearing placebo (n=7); or

- LMN-101, one 300-mg capsule and five 500-mg placebo capsules orally three times daily for 28 days (n=21), or identical-appearing placebo (n=7).

Campylobacter jejuni CG8421, 1.5 x 10e5 colony-forming units challenge will be administered orally as a single challenge after 7 days of dosing.The C. jejuni CG8421 (capsule type 23, 36) challenge strain lacks all ganglioside mimicry and the genes needed for synthesis of N-acetyl neuraminic acid, necessary for glycolipid mimicry associated with Guillain-Barré (Poly et al. 2008; Tribble et al. 2009).The C. jejuni challenge will be followed 144 hours later by antibiotics for 5 days. Earlier antibiotic treatment will be initiated if subjects meet the criteria to start antibiotics or have any illness that necessitates early treatment in the opinion of the study physician. Additional treatment will be given if microbial recrudescence is observed.

Interventions

  • Biological: LMN-101
    • VHH-derived binding protein designed to bind and inhibit FlaA, flagellin filament protein of Campylobacter jejuni, delivered in whole spray-dried, spirulina biomass

Arms, Groups and Cohorts

  • Active Comparator: 3000-mg cohort
    • LMN-101, six 500-mg capsules orally three times daily for 28 days (n=21), or identical-appearing placebo (n=7)
  • Active Comparator: 1000-mg cohort
    • LMN-101, two 500-mg capsules and four 500-mg placebo capsules orally three times daily for 28 days (n=21), or identical-appearing placebo (n=7)
  • Active Comparator: 300-mg cohort
    • LMN-101, one 300-mg capsule and five 500-mg placebo capsules orally three times daily for 28 days (n=21), or identical-appearing placebo (n=7)

Clinical Trial Outcome Measures

Primary Measures

  • Safety and tolerability of LMN-101
    • Time Frame: First dose to 28 days after last dose
    • Absence of two grade 3 adverse events or a grade 4 adverse event, other than signs and symptoms due to the campylobacter challenge

Secondary Measures

  • Incidence of campylobacteriosis versus placebo
    • Time Frame: 0 to 144 hours after challenge
    • Incidence of campylobacteriosis in high-dose, mid-dose, low-dose and pooled LMN-101 subjects versus placebo subjects. Campylobacteriosis defined as a clinical illness meeting at least one of the following criteria within 144 hours of challenge: Moderate to severe diarrhea (≥ 4 loose stools or ≥ 401 g of loose stools in 24 hours); or Fever (oral temperature ≥ 38.0°C present on at least two occasions, at least 20 minutes apart) with associated symptom (nausea, vomiting, abdominal cramps, tenesmus, or gross blood in ≥ 2 loose stools).
  • Dose-response relationship
    • Time Frame: 0 to 144 hours after challenge
    • Dose-response relationship between LMN-101 and campylobacteriosis incidence
  • Duration of diarrhea
    • Time Frame: 0 to 144 hours after challenge
    • Duration (time to first loose stool, duration of loose stools)
  • Amount of diarrhea, number
    • Time Frame: 0 to 144 hours after challenge
    • Amount (total number of loose stools, maximum number of loose stools in 24 hours) of diarrhea.
  • Amount of diarrhea, weight
    • Time Frame: 0 to 144 hours after challenge
    • Amount (total weight of loose stools, and maximum weight of loose stools in 24 hours) of diarrhea.
  • Illness Severity Index
    • Time Frame: 0 to 144 hours after challenge
    • Illness severity scale grading gastrointestinal symptoms, systemic symptoms, temperature and diarrhea on a scale of 0-16 (Tribble 2010)
  • Campylobacter stool titer
    • Time Frame: 0 to 144 hours after challenge
    • Campylobacter stool titer, median, CFU/g
  • Peak serum drug concentration
    • Time Frame: Day -7 to Day 21
    • Peak serum drug concentration during 28-day course of treatment
  • Area under the curve serum drug concentration
    • Time Frame: Day -7 to Day 21
    • Area under the serum drug concentration versus time curve during 28-day course of treatment and one day following treatment
  • Anti-drug antibodies
    • Time Frame: Day -7 to Day 56
    • Presence of anti-drug immunoglobulin G antibodies in serum

Participating in This Clinical Trial

Inclusion Criteria

1. Male or non-pregnant female between 18 and 50 years of age, inclusive, at time of informed consent

2. Willingness to participate after written informed consent obtained

3. Available for all planned follow-up visits and anticipated to remain available for clinic visits (for examination, blood draws and stool collection) and follow-up monitoring (90 days post-challenge and by phone for 182 days post-challenge)

4. Demonstrated comprehension of the protocol procedures including knowledge of campylobacter illness by passing a written examination (passing grade ≥ 70%)

5. Willingness to ingest LMN-101 or placebo capsules 3 times a day for 28 days

6. General good health, without significant medical illness, abnormal physical examination findings or clinically significant laboratory abnormalities, as determined by the Principal Investigator (PI; may consult with the Medical Monitor on a case-by-case basis)

7. Adequate bone marrow reserve, renal and liver function:

1. Absolute neutrophil count ≥ 1225/µL

2. Lymphocyte count ≥ 750/µL

3. Platelet count ≥ 125,000/µL

4. Hemoglobin ≥ 11 g/dL in males (>10.5 g/dL in females)

5. Serum creatinine ≤1.7x upper limit of normal (ULN)

6. ALT and/or AST ≤ 3x ULN

7. Total bilirubin ≤ 1.5x ULN

8. Females of childbearing potential should be using and committed to continue one of the following acceptable birth control methods consistently for at least 1 month prior to screening through study completion:

1. Sexual abstinence (inactivity); or

2. Condoms with spermicide; or

3. Diaphragm with spermicide,

4. Intrauterine device (IUD); or

5. Stable hormonal contraception; or

6. Surgical sterilization (vasectomy) of male partner at least 6 months prior to study.

9. To be considered of non-childbearing potential, females should be surgically sterilized (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 2 months prior to study) or be post-menopausal and at least 1 year since last menses.

Exclusion Criteria

General health/issues

1. Presence of a significant medical condition (e.g., psychiatric condition; gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis/dyspepsia, inflammatory bowel disease, irritable bowel syndrome (as defined by the Rome III criteria or medical diagnosis); alcohol or illicit drug abuse/dependency) or laboratory abnormalities which in the opinion of the Principal Investigator preclude participation in the study

2. Positive serology results for HIV, HBsAg, or HCV with confirmatory assays

3. Positive urine toxicology screen for opioids, benzodiazepines or amphetamines

4. Significant abnormalities in screening laboratory hematology or serum chemistry, as determined by PI or PI in consultation with the Medical Monitor

5. Use of any medication known to affect the immune function (e.g., corticosteroids and others) within 30 days preceding receipt of the challenge inoculum or planned to be used during the active study period

6. Pregnancy or breastfeeding Study-specific exclusionary conditions based on potential increased risk or complicating outcome ascertainment

7. Personal or documented family history of Guillain-Barré syndrome or neuromuscular disease; or an inflammatory arthritis such as reactive arthritis, Reiter's syndrome, ankylosing spondylitis, or rheumatoid arthritis (not including osteoarthritis or vague history of arthritis relatively late in adulthood)

8. Evidence of neurological abnormalities

9. Evidence of inflammatory arthritis on exam

10. Fever within the 2 weeks prior to time of enrollment

11. Evidence of IgA deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay)

12. HLA-B27 positive (flow cytometry)

13. Allergy or prior intolerance to two or more of the following antibiotics: azithromycin, ciprofloxacin, levofloxacin, erythromycin, doxycycline, ampicillin, or amoxicillin-clavulanate

14. Fewer than 3 stools per week or more than 3 stools per day as the usual frequency

15. History of moderate to serious diarrhea while traveling in a developing country within the last 3 years

16. Regular use of antidiarrheal, antacids, loperamide, bismuth subsalicylate diphenoxylate or similar medication (regular defined as at least weekly)

17. Use of proton pump inhibitors, H2 blockers, or other antacids within 48 hours preceding initiation of LMN-101 or placebo

18. Use of antibiotics during the 7 days preceding initiation of LMN-101 or placebo

19. Use of spirulina other than the study drug in the 30 days preceding initiation of LMN-101 or placebo

20. Use of any investigational product within 30 days preceding initiation of LMN-101 or placebo or planned use during the active study period

21. Use of any medication known to affect the immune system (e.g., systemic corticosteroids) within 30 days preceding initiation of LMN-101 or placebo or planned use during the active study period (excluding inhaled steroids with spacer)

22. History of prior exposure to campylobacter including by vaccination or infection in previous trials, or serum immunoglobulin A (IgA) titer to C. jejuni CG8421 glycine extract >1:4000

23. Other dietary or environmental exposures that may place the subject at high risk for prior campylobacter exposure (to be determined on a case-by-case basis by the PI)

24. Employment as a food handler

25. Any other criteria which, in the Principal Investigator's opinion, would compromise the ability of the subject to participate in the study, the safety of the study or the results of the study

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Lumen Bioscience, Inc.
  • Collaborator
    • Naval Medical Research Center
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Mohamed Al-Ibrahim, MB,ChB, FACP, Principal Investigator, Pharmaron
  • Overall Contact(s)
    • Study Recruiter, (410) 706-8833, baltimore.recruiter@pharmaron-us.com

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