Biomarkers of Periodontal Disease Progression

This multicenter clinical study will investigate biomarkers of periodontal disease
progression. The study will enroll 375 subjects with periodontal disease and 125
periodontally healthy subjects. All subjects will be monitored clinically and have samples
taken every 2 months for 12 months for analysis of inflammatory and immunological biomarkers
and microbial species. Subjects displaying periodontal disease progression greater than an
established threshold will receive periodontal rescue therapy at progressing periodontal
sites and continue with monitoring. Periodontally healthy subjects and non-progressing sites
in subjects with periodontal disease will serve as controls. After 12 months, subjects with
periodontal disease will receive periodontal therapy consisting of 4 quadrants of scaling and
root planing. Periodontally healthy subjects will receive prophylaxis and scaling and exit
the study. Following periodontal therapy, subjects with periodontal disease will be followed
for a maintenance period of 6 months for clinical and biological monitoring. Statistical
analyses will compare biomarkers and microbial species between periodontally healthy subjects
and subjects with periodontal disease, between progressing and non-progressing periodontally
diseased sites, and between periodontally diseased sites before and after periodontal
therapy.

Inclusion Criteria:

General Inclusion Criteria

To be eligible to participate in this study, a subject must meet all of the following
criteria:

1. Ability to understand, and willingness and ability to read and sign, the informed
consent form.

2. Age of at least 25 years.

3. Ability to understand and follow directions for study procedures.

4. Minimum of 20 natural teeth, excluding third molar teeth; at least 12 of these teeth
must be pre-molars, first molars, or second molars.

5. Willingness not to have professional dental prophylaxis or scaling for the duration of
the disease progression and monitoring phase (12 months).

6. Willingness to comply with all study procedures and be available for the duration of
the study.

7. For women with reproductive potential, willingness to use highly effective
contraception (e.g., licensed hormonal contraception, intrauterine device, abstinence,
or vasectomy in partner).

Specific inclusion criteria:

Healthy periodontal subjects must have:

1. Any tooth with 3 mm or less PD, irrespective of the attachment level, will be
acceptable

2. No teeth with PD of 4 mm or more and concomitant attachment loss, with the exception
of the distal of the second molars where a PD of 4 mm and concomitant CAL of up to 2
mm will be acceptable.

3. No radiographic evidence of alveolar bone loss (defined as a distance of greater than
2.0 mm measured radiographically from the CEJ to the crest of the alveolar bone); with
the exception of the mandibular incisors where up to 3.0 mm of alveolar bone loss
measured radiographically from the CEJ to the crest of the alveolar bone will be
accepted.

Mild periodontal disease subject: periodontal loss must meet the following criteria and
must not meet the minimum criteria for severe periodontal loss:

1. At least 4 teeth with at least 1 site of PD of 5 mm or more and concomitant CAL greater
than or equal to 2 mm, and radiographic evidence of mesial or distal alveolar bone loss
around at least 2 of the affected teeth. Alveolar bone loss is defined as a distance of >
2.0 mm measured radiographically from the CEJ to the crest of the alveolar bone.

Subjects with severe periodontal loss must meet all of the following criteria:

1. At least 8 separate teeth with at least 1 site of PD of 5 mm or more and concomitant CAL
greater than or equal to 3 mm, and radiographic evidence of mesial or distal alveolar bone
loss around at least 2 of the affected teeth. Alveolar bone loss is defined as a distance
of > 2.0 mm measured radiographically from the CEJ to the crest of the alveolar bone.

Exclusion Criteria:

1. Presence of orthodontic appliances.

2. The following conditions noted on oral examination:

- Oral lichen planus

- Candidiasis

- Clinical leukoplakia

- Clinical erythroplakia

- Pemphigus

- Pemphigoid

- Other recurrent intraoral or perioral vesiculobullous diseases

- Aphthous ulcerations (major or minor). Subjects presenting with aphthous ulcers
should be rescreened after 2 weeks. They will be eligible if the ulcers have
healed and the subject does not have a history of frequent recurrences.

- Herpetic lesions. Subjects presenting with herpes labialis or intraoral herpes
should be rescreened after 2 weeks. They will be eligible if the lesions have
healed and the subject does not have a history of frequent recurrences.

j. Traumatic ulcers. If a subject presents with a traumatic ulcer, he/she can be
rescreened in 2-3 weeks. The subject will be eligible if the ulcers have healed.

3. Acute necrotizing ulcerative gingivitis or gross tooth decay, as determined by the
investigator.

4. Root fragments, pericoronitis, endo-perio lesions, or other dental abscesses. Subjects
may be rescreened after resolution of these dental conditions.

5. Pregnancy or lactation.

6. Requirement for prophylactic antibiotics for dental procedures (e.g., for certain
heart and orthopaedic conditions*).

7. Periodontal or systemic antibiotic therapy in the previous 6 months. Routine dental
prophylaxis will be allowed.

8. Use of cigarettes or other tobacco products within 1 year before the screening visit.

9. Any medical condition that might influence the course of periodontal disease or
treatment (e.g., diabetes [irrespective of level of control], human immunodeficiency
virus infection or acquired immunodeficiency syndrome, use of medications associated
with gingival hyperplasia).

10. Chronic use of nonsteroidal anti-inflammatory drugs (e.g., for arthritis), defined as
the need, or anticipated need, for over 3 weeks of continuous use at the time of
enrollment or during the course of the study. The use of low-dose aspirin (81 mg/day)
for prophylaxis will be allowed.

11. Current or anticipated use of chronic systemic corticosteroids, cyclosporine, or other
systemic immunosuppressive agent. The use of inhaled corticosteroids will be allowed.

12. Hypersensitivity to tetracyclines (e.g., tetracycline, doxycycline, minocycline).

13. Participation in a clinical study testing a drug, biologic, device, or other
intervention within the last 30 days.

14. Any condition or circumstance that, in the opinion of the investigator, would place
the subject at increased risk or preclude his/her full compliance with or completion
of the study.