Safety and Tolerability of Antiplaque Chewing Gum in a Gingivitis Population

Study Overview
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Brief Summary
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This study is to assess the safety and tolerability of single doses and multiple doses in reducing plaque and gingivitis when delivered in a chewing gum formulation.

Detailed Description
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This study is a Phase 1/2a placebo-controlled, double-blind, randomized, dose-escalation study to evaluate the safety and proof of concept of Antiplaque Chewing Gum. This is a 2-part trial with 9 dosing cohorts in Phase 1 and 7 dosing cohorts in Phase 2a. For both phases, the oral soft (OST) and oral hard tissues (OHT) will be examined. Changes from baseline, such as soft tissue erythema, ulceration and sloughing, will be noted and assessments will be made by the principal investigator as to whether they might be attributable to the antiplaque chewing gum. In the Phase 2a portion of the study, the efficacy of the antiplaque chewing gum in reducing existing supragingival plaque and gingivitis will also be assessed. Plaque will be assessed using the Turesky Modification of the Quigley-Hein Plaque Index (PI, Turesky et al-1970) and gingivitis will be assessed using both the Modified Gingival Index (MGI, Lobene et al-1986) and the percent of bleeding sites on gentle probing (BOP) using the methods described in Ainamo and Bay-1975.

Official Title
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A Double-Blind, Randomized, Controlled, Dose Escalation Clinical Trial of an Antiplaque Chewing Gum - Phase 1 Safety and Tolerability and Phase 2a Safety, Tolerability, and Proof of Concept in a Gingivitis Population

Conditions
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Plaque, Gingivitis

Intervention / Treatment
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* Drug: 2 mg KSL-W
* Drug: 4 mg KSL-W
* Drug: 6 mg KSL-W
* Drug: 10 mg KSL-W
* Drug: 20 mg KSL-W
* Drug: 30 mg KSL-W
* Drug: 50 mg KSL-W
* Drug: 75 mg KSL-W
* Drug: 100 mg KSL-W
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following criteria to be included in the Phase 1 portion of the study: Males and females between 18 and 64 years of age A negative urine pregnancy test and willingness to use a reliable form of contraception for the duration of the study (females of childbearing potential only), with reliable contraception defined as: Abstinence Oral contraceptive, either estrogen progesterone combined, or progesterone alone Injectable progesterone Implants of levonorgestrel Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device or intrauterine system Double barrier method [condom or occlusive cap (diaphragm or cervical vault caps) plus spermicidal agent (foam, gel, film, cream, suppository)] Male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject Good health, as determined by pertinent medical history, physical examination, vital signs, and clinical safety laboratory evaluations A minimum of 16 natural teeth with 2 scorable surfaces (facial and lingual) per tooth Sufficient number of opposing posterior teeth to chew on both sides of the mouth as determined by the examining dentist Teeth that have gross caries, full crowns or extensive restorations on facial and/or lingual surfaces, orthodontic bands, and third molars are not included in the tooth count Ability to comprehend and a willingness to sign an informed consent, which includes the Authorization for the Release of Health Information document Willingness to comply with all study procedures Phase 2a Inclusion Criteria Subjects must meet all the criteria for the phase 1 portion of the study, and in addition must: Have mild to moderate gingivitis and plaque MGI of 1.8 or greater (Ainamo and Bay-1975) PI of 1.95 or greater (Turesky et al-1970) Willing to forgo any optional dental procedures during the study period, such as dental prophylaxis or teeth whitening Exclusion Criteria: Subjects meeting any of the following criteria will be excluded from the study: Acute or chronic medical conditions, organ system disease, or medications that, in the principal investigator's opinion, would impair the subject's ability to participate TMD Self-reported use of tobacco products Use of anticoagulant medications (eg clopidogrel) Gross oral pathology, including widespread caries or chronic neglect, extensive restoration, pre-existing gross plaque or calculus, or soft or hard tissue tumor of the oral cavity Orthodontic appliances or removable partial dentures that will compromise the ability of the potential subject to participate in the study Periodontitis as indicated periodontal pockets greater than 4 millimeters on more than one site Receipt of any investigational drug/test product within 30 days prior to study entry Receipt of antibiotics within 30 days prior to study entry Need for antibiotic prophylaxis prior to invasive dental procedures Receipt of daily anti-inflammatory therapy [eg nonsteroidal anti-inflammatory drugs (NSAID), tumor necrosis factor (TNF) alpha blockers] within 30 days prior to study entry Receipt of prescription antibacterial oral products (eg products containing chlorhexidine) within 30 days prior to study entry Pregnant or breast-feeding female Clinically significant abnormal laboratory tests as determined by the principal investigator An employee of the study site directly involved with the study Inability to comply with assigned treatment regimen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2 mg KSL-W (Phase 1, 1a)<br>one 2 mg KSL-W tablet at day 0 at Phase 1 | Drug: 2 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 4 mg KSL-W (Phase 1, 2a; Phase 2a, 1b)<br>one 4 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. one 4 mg KSL-W tablet on days 1-6; two 4 mg KSL-W tablets on days 7-13 and days 14-20; and three 4 mg tablets at days 21-27 at Phase 2a. | Drug: 4 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 6 mg KSL-W (Phase 1, 3a; Phase 2a, 2b)<br>One 6 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. One 6 mg KSL-W tablet on days 1-6; two 6 mg KSL-W tablets on days 7-13 and days 14-20; and three 6 mg tablets at days 21-27 at Phase 2a. | Drug: 6 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 10 mg KSL-W (Phase 1, 4a; Phase 2a, 3b)<br>One 10 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. One 10 mg KSL-W tablet on days 1-6; two 10 mg KSL-W tablets on days 7-13 and days 14-20; and three 10 mg tablets at days 21-27 at Phase 2a. | Drug: 10 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 20 mg KSL-W (Phase 1, 5a; Phase 2a, 4b)<br>One 20 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. One 20 mg KSL-W tablet on days 1-6; two 20 mg KSL-W tablets on days 7-13 and days 14-20; and three 20 mg tablets at days 21-27 at Phase 2a. | Drug: 20 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 30 mg KSL-W (Phase 1, 6a; Phase 2a, 5b)<br>One 30 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. One 30 mg KSL-W tablet on days 1-6; two 30 mg KSL-W tablets on days 7-13 and days 14-20; and three 30 mg tablets at days 21-27 at Phase 2a. | Drug: 30 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 50 mg KSL-W (Phase 1, 7a; Phase 2a, 6b)<br>One 50 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. One 50 mg KSL-W tablet on days 1-6; two 50 mg KSL-W tablets on days 7-13 and days 14-20; and three 50 mg tablets at days 21-27 at Phase 2a. | Drug: 50 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 75 mg KSL-W (Phase 1, 8a; Phase 2a, 7b)<br>One 75 mg KSL-W tablet on day 0 at both Phase 1 and Phase 2a. One 75 mg KSL-W tablet on days 1-6; two 75 mg KSL-W tablets on days 7-13 and days 14-20; and three 75 mg tablets at days 21-27 at Phase 2a. | Drug: 75 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Experimental: 100 mg KSL-W (Phase 1, 9a)<br>one 100 mg KSL-W tablet at day 0 at Phase 1 | Drug: 100 mg KSL-W<br> <br> * Other names: Antiplaque Chewing Gum;|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Cetylpyridinium chloride (CPC) as an additive, isomalt as a bulk sweetener, peppermint powder for flavoring, sucralose as an intense sweetener, colloidal silicon dioxide is a flow enhancer, magnesium stearate as a process aid, and the proprietary gum base formulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of KSL-W as Measured by Soft Tissue Erythema, Ulceration and Sloughing (AEs and SAEs) | Occurrence of local oral mucosal reactions, systemic reactions such as fever, nausea, headache, and changes in blood pressure, clinical laboratory measures of safety, and serious total body reactions will be assessed (AEs and SAEs) | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proof of Concept of KSL-W in Reducing Plaque in Phase 2a | Data summarizes plaque index scores changes from baseline. Supragingival plaque will be assessed after the MGI and BOP assessments and following use of a disclosing solution on the facial (buccal) and lingual surfaces of a minimum of 16 scorable teeth according to the criteria of the Turesky modification of the Quigley-Hein Plaque Index. Quigley-Hein Plaque Index Scores with Turesky Modifications: 0 No plaque Separate flecks of plaque at the cervical margin of the tooth A thin continuous band of plaque (up to one mm) at the cervical margin of the tooth A band of plaque wider than one mm but covering less than one-third of the crown of the tooth Plaque covering at least one-third but less than two thirds of the crown of the tooth Plaque covering two-thirds or more of the crown of the tooth | days 14, 28, 34 | 
| Proof of Concept of KSL-W in Reducing Gingivitis in Phase 2a | Data summarizes gingival index scores changes from baseline in phase 2a. Gingivitis will be assessed using both the MGI (Modified Gingival Index) and the Gingival Bleeding Index (BOP) The Modified Gingival Index assesses the buccal and lingual gingivae and interdental papillae. Modified Gingival Index Scores: 0 Absence of inflammation Mild inflammation; slight change in color, little change in texture of any portion of but not the entire marginal or papillary gingival unit Mild inflammation; criteria as above but involving the entire marginal or papillary gingival unit Moderate inflammation; glazing, redness, edema and/or hypertrophy of the marginal or papillary gingival unit Severe inflammation; marked redness, edema and/or hypertrophy of the marginal or papillary gingival unit, spontaneous bleeding, congestion, or ulceration. | days 14, 28, 34 | 
| Gingival Bleeding on Probing (BOP) - Percent of Bleeding Sites Upon Probing in Phase 2a | Proof of concept of KSL-W in reducing plaque as measured by percent of bleeding sites upon probing (BOP) in phase 2a. Gingivitis will be assessed using both the MGI (Modified Gingival Index) and the Gingival Bleeding Index (BOP). The Modified Gingival Index assesses the buccal and lingual gingivae and interdental papillae. The Gingival Bleeding Index assesses the percentage of sites that bleed on gentle probing. A periodontal probe (HU-Friedy UNC 15) will be gently inserted into the gingival sulcus until resistance is felt at mid-facial (buccal), mid-lingual, mesial, and distal interproximal sites of all scorable teeth, with the exception of the most posterior distal sites. Presence or absence of bleeding will be recorded for each site and the percentage of bleeding sites per subject will serve as the unit of analysis. | days 0, 14, 28, 34 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reducing plaque, Reducing gingivitis, safety, proof of concept, antiplaque chewing gum