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Efficacy, Safety and Tolerability of AG013 in Oral Mucositis Compared to Placebo When Administered Three Times Per Day

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ClinicalTrials.gov Identifier: NCT03234465
Recruitment Status : Terminated (No efficacy could be demonstrated, sponsor decided to prematurely end the study.)
First Posted : July 31, 2017
Results First Posted : November 23, 2020
Last Update Posted : November 23, 2020
Sponsor:
Information provided by (Responsible Party):
Oragenics, Inc.

Tracking Information
First Submitted Date  ICMJE July 21, 2017
First Posted Date  ICMJE July 31, 2017
Results First Submitted Date  ICMJE October 22, 2020
Results First Posted Date  ICMJE November 23, 2020
Last Update Posted Date November 23, 2020
Actual Study Start Date  ICMJE July 18, 2017
Actual Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2020)
Efficacy of AG013 Compared to Placebo for Reducing OM as Measured by Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4) [ Time Frame: From the start of radiation therapy (RT) until 2 weeks following its completion, 7 to 9 weeks depending on the duration of CRT. ]
Duration (in Days) of Severe Oral Mucositis (WHO Grades 3 or 4)
Original Primary Outcome Measures  ICMJE
 (submitted: July 28, 2017)
  • Efficacy of AG013 compared to placebo for reducing OM as measured by the duration and time to development of OM during the active treatment phase. [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    The WHO grade will be the primary measure for assessing OM. The duration and time to development of OM will be calculated as number of days.
  • Efficacy of AG013 compared to placebo for reducing OM as measured by the overall incidence of OM during the active treatment phase. [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    The WHO grade will be the primary measure for assessing OM. The overall incidence will be calculated as number of subjects in a treatment group.
  • Safety and tolerability [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Safety will be evaluated on the basis of treatment-emergent AEs (TEAEs), vital signs, weight, physical examinations, clinical laboratory assessments and the presence of AG013-sAGX0085 in whole blood. Tolerability (taste, consistency and smell) will be collected from the patient diary.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2017)
  • Patient-reported symptoms [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Pain will be assessed with the Oral Mucositis Daily Questionnaire Question 2.
  • Analgesic use [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Any analgesic use will be recorded.
  • Cumulative radiation dose administered before the onset of OM [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Radiation dose delivery will be documented.
  • Biomarkers [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Primarily pro and anti-inflammatory cytokines
  • PK profile of AG013 in a subset of subjects (AG013-sAGX0085 bacteria) [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Buccal mucosa levels of AG013-sAGX0085 bacteria from buccal smears will be summarized using descriptive statistics.
  • PK profile of AG013 in a subset of subjects (hTFF1) [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Levels of hTFF1 from serum samples and buccal mucosa levels of hTFF1 from buccal smears will be summarized using descriptive statistics.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: July 28, 2017)
  • Exploratory objective:genomic differentiation of AG013 responders/non-responders [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Blood samples to assess differences in genes expression
  • Exploratory objective: efficacy of AG013 in patients with HPV (human papillomavirus) negative tumors/HPV positive tumors [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Recording of HPV status
  • Exploratory objective: effect of AG013 on healthcare resources (US only) - hospitalizations [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of hospitalizations in each treatment group
  • Exploratory objective: effect of AG013 on healthcare resources (US only) - unplanned office visits [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of unplanned office visits in each treatment group
  • Exploratory objective: effect of AG013 on healthcare resources (US only) - gastrostomy tube feedings [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of non-prophylactic gastrostomy tube placements in each treatment group
  • Exploratory objective: effect of AG013 on healthcare resources (US only) - emergency room visits [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of emergency room visits in each treatment group
  • Exploratory objective: frequency of RT interruptions [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of subjects in each treatment group with an unplanned break in radiotherapy
  • Exploratory objective: duration of RT interruptions [ Time Frame: Active treatment phase, beginning from the start of radiation therapy (RT) until 2 weeks following its completion. ]
    Number of days of RT interruptions by treatment group
 
Descriptive Information
Brief Title  ICMJE Efficacy, Safety and Tolerability of AG013 in Oral Mucositis Compared to Placebo When Administered Three Times Per Day
Official Title  ICMJE A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of Topically-applied AG013 for the Attenuation of Oral Mucositis in Subjects With Cancers of the Head and Neck Receiving Concomitant Chemoradiation Therapy
Brief Summary

The purpose of the study is to evaluate the efficacy, safety and tolerability of topically administered AG013 compared to placebo for reducing Oral Mucositis (OM) in patients undergoing chemoradiation for the treatment of head and neck cancer, as measured by the duration, time to development, and overall incidence of OM during the active treatment phase, beginning from the start of chemoradiation therapy (CRT) until 2 weeks following its completion.

The effect of AG013 on patient-reported symptoms and analgesic use during the active treatment phase, and on the cumulative radiation dose administered before the onset of OM will also be evaluated, as will biomarkers and, in a subset of subjects, the PK (pharmacokinetic) profile of AG013.

Detailed Description

This is a Phase 2, double-blind, placebo-controlled, 2-arm, multi-center trial in which subjects will be randomized in a 1:1 ratio to receive either placebo or AG013. AG013 is a mouth rinse formulation of Lactococcus lactis strain sAGX0085, deficient in the gene coding for thymidylate synthase and producing human TFF1 (Trefoil Factor 1).

Approximately 200 subjects will be enrolled in the study. To protect subjects from unanticipated safety risks, enrollment and treatment in the double-blind study will continue until 10 subjects on AG013 have been recruited. The Data Safety Monitoring Board (DSMB) will review safety data after these 10 subjects on AG013 have completed study treatment. If there are no safety signals identified, the study will continue to recruit the planned number of subjects.

There are 4 study periods as described below: screening, active treatment, short term follow-up and long term follow-up. The screening phase will be no longer than 4 weeks. The active treatment phase will be between 7 and 9 weeks depending on the subject's prescribed CRT (chemoradiation therapy) plan. The short term follow-up phase will be 4 weeks in duration. The long term follow-up will continue until 12 months post CRT. Oral mucositis (OM) assessments will begin at the start of CRT and continue until the subject has completed short term follow-up or until the OM resolves (as defined by a WHO (World Health Organization) score of ≤ 1), whichever comes first. Long term follow-up will continue for 12 months to assure that AG013 does not adversely impact the tumor response to anti-neoplastic therapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Oral Mucositis
Intervention  ICMJE
  • Biological: AG013
    AG013 is made up of genetically modified (GM) bacteria called Lactococcus lactis (L. lactis). Wild type L. lactis are commonly used to produce dairy products including cheeses and milk. To make AG013, the DNA of L. lactis has been changed in the laboratory to secrete a protein called human Trefoil Factor 1 (hTFF1). hTFF1 is normally secreted in saliva and intestines. Trefoil factors have been shown to be important in protecting and healing mucosal tissues, such as the tissue in the mouth, when these tissues are damaged by cancer therapies such as chemotherapy and radiation therapy.
  • Other: Placebo
    Subjects assigned to the placebo group will receive appearance- and taste-matched placebo powder.
Study Arms  ICMJE
  • Experimental: AG013: three mouth rinses/day
    Subjects will rinse three times per day with AG013 mouth rinse beginning from the start of radiotherapy until 2 weeks following its completion. The active treatment phase lasts for 7 to 9 weeks, depending on the duration of radiotherapy.
    Intervention: Biological: AG013
  • Placebo Comparator: Placebo: three mouth rinses/day
    Subjects will rinse three times per day with placebo mouth rinse beginning from the start of radiotherapy until 2 weeks following its completion. The active treatment phase lasts for 7 to 9 weeks, depending on the duration of radiotherapy.
    Intervention: Other: Placebo
Publications * Limaye SA, Haddad RI, Cilli F, Sonis ST, Colevas AD, Brennan MT, Hu KS, Murphy BA. Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer. 2013 Dec 15;119(24):4268-76. doi: 10.1002/cncr.28365. Epub 2013 Sep 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 28, 2017)
200
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 13, 2020
Actual Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Willing and able to understand and sign the study specific Informed Consent Form
  2. Pathologically-confirmed squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx or hypopharynx or HPV-positive unknown primaries presumed to be of oropharyngeal, nasopharyngeal or hypopharyngeal origin
  3. Tumor HPV status established
  4. Planned to receive either primary or post-operative CRT
  5. Planned IMRT (Intensity-Modulated Radiotherapy)
  6. Planned administration of cisplatin administered weekly or tri-weekly during RT
  7. Males or females 21 years or older
  8. Karnofsky performance score (KPS) ≥ 70%
  9. Screening laboratory assessments:

    • Hemoglobin ≥ 10g/dl
    • White blood count ≥ 3500 cells/mm3
    • Absolute neutrophil counts ≥ 1500 cells/ mm3
    • Serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x ULN
    • Calculated Creatinine Clearance ≥ 50 ml/min
    • Negative pregnancy test (serum or urine) for females of childbearing potential performed 7 days before IMP (Investigational Medicinal Product) administration.
  10. Subjects of childbearing potential must confirm to use an effective method of birth control during study participation and for 30 days following the last treatment with IMP. Male subjects, when having hetero-sexual intercourse with a female of childbearing potential must use a condom during study participation and 90 days following the last treatment with IMP and their partner should use an effective method of birth control during that period as well.

Exclusion Criteria:

  1. Prior radiation to the head and neck
  2. Increased risk of developing infectious endocarditis
  3. Prior gene therapy
  4. Presence of active infectious oral disease
  5. Presence of any oral lesions that may confound the ability to assess oral mucositis grade
  6. Current use of antibiotic rinses or troches
  7. Herbal, alternative remedies, and alcohol containing over-the-counter mouthwashes are excluded during the course of the study
  8. Current alcohol abuse syndrome
  9. Chronic immunosuppression
  10. Known seropositive for HIV
  11. Use of investigational agent within 30 days of signing informed consent
  12. Tooth extraction prior to radiation in which the extraction site is not epithelialized
  13. Signs and symptoms of active dental disease
  14. Female subjects who are pregnant or nursing
  15. Known allergy to excipients of the IMP
  16. Inability to give informed consent or comply with study requirements
  17. Unwilling or unable to complete subject diary
  18. Any other clinical condition, psychiatric condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable or to comply with follow-up visits
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Germany,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03234465
Other Study ID Numbers  ICMJE AG013-ODOM-201
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  ICMJE
Plan to Share IPD: No
Responsible Party Oragenics, Inc.
Study Sponsor  ICMJE Oragenics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Alan Joslyn, Ph.D. Sponsor GmbH
PRS Account Oragenics, Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP