Periodontal Diseases, Periodontitis
Conditions
Brief summary
The purpose of this study is to determine in current and non-smokers the clinical and microbiological effects of 3 therapies: scaling and root planing (SRP) alone; SRP in combination with the orally administered antibiotic metronidazole; and SRP with the orally administered antibiotics metronidazole and amoxicillin along with the locally delivered antibiotic doxycycline at periodontal pockets \>= 4 mm.
Detailed description
Cigarette smokers have more severe periodontal disease and more widespread colonization by periodontal pathogens than non smokers. In addition, smokers respond less well to periodontal therapies, particularly mechanical therapies such as scaling and root planing (SRP) and surgery. Recent data from our laboratory have indicated that treatment that included antibiotics produced a better clinical effect in smokers than mechanical therapy alone. Thus, the purpose of the present investigation is to compare the immediate and long-term effects of 3 periodontal therapies on clinical, microbiological and host parameters in current and non smokers. In this double blind, placebo-controlled, randomized study, 108 current smokers and 108 non smokers will be randomly assigned to 1 of 3 treatment groups: SRP alone; SRP + systemically administered metronidazole; SRP + systemically administered amoxicillin and metronidazole and local delivery of doxycycline at pockets \> 4 mm. Plaque Index, Gingival Index, % of sites with bleeding on probing, suppuration, pocket depth and attachment level will be measured at 6 sites per tooth at all teeth excluding 3rd molars at baseline, 3, 6, 12, 18 and 24 months. Subgingival plaque samples taken from the mesial aspect of each tooth at the same time points will be analyzed individually for their content of 40 subgingival species using checkerboard DNA-DNA hybridization. Antibody levels to 20 subgingival species will be measured in serum samples taken at baseline, 6 and 24 months. Levels of IL-1b, IL-10 and IFNg will be measured in GCF samples taken from the 4 deepest pockets at baseline, 3, 6 and 24 months. The major hypothesis to be tested is whether smokers respond better to periodontal therapies that include 1 or more antibiotics. Other hypotheses will test whether host and microbiological parameters differ between smokers and non smokers and if such parameters are comparably altered after therapy in both groups. The results will be of immediate clinical benefit to the large segment of periodontal patients who smoke cigarettes. Smokers make up 26 - 30% of the adult population and form a disproportionately high segment of the population requiring periodontal treatment. They may have special needs in terms of periodontal therapy which should be clarified by the proposed investigation. In addition, the cigarette smoker is an example of a periodontal patient who is compromised in terms of his/her ability to cope with infectious diseases. The proposed investigation should provide a model to examine methods that could be useful in treating compromised patients whether compromised by harmful habits such as smoking, systemic disease or genetic background.
Interventions
PROCEDUREScaling and root planing
Scaling and root planning (SRP) is the mechanical debridement of the tooth and root surfaces and is standard of care in periodontal therapy.
DRUGMetronidazole
Metronidazole (MET) is an antibiotic that is particularly effective against Gram negative bacterial species. The dose for this study is: 250 mg tid x 14d.
DRUGAmoxicillin
Amoxicillin (AMOX) is a broad spectrum antibiotic and was prescribed at 500 mg tid for 14d.
DRUGDoxycycline
The ATRIDOX (doxycycline hyclate) ® product is a subgingival controlled-release product composed of a two syringe mixing system. Syringe A contains 450 mg of the ATRIGEL® Delivery System, which is a bioabsorbable, flowable polymeric formulation composed of 36.7% poly(DLlactide) (PLA) dissolved in 63.3% N-methyl-2-pyrrolidone (NMP). Syringe B contains 50 mg of doxycycline hyclate which is equivalent to 42.5 mg doxycycline. The constituted product is a pale yellow to yellow viscous liquid with a concentration of 10% of doxycycline hyclate. Upon contact with the crevicular fluid, the liquid product solidifies and then allows for controlled release of drug for a period of 7 days. Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline.
Sponsors
National Institute of Dental and Craniofacial Research (NIDCR)
The Forsyth Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* \> 20 teeth * \> 5% sites (approx. 8 sites) with pocket depth \> 4 mm and / or 5% sites with attachment level \> 4 mm and mean AL \< 4.5 mm and mean PD \< 3.9 mm (not including tooth brush abrasions).
Exclusion criteria
* \> 50% of sites with pocket depth or attachment level \> 4 mm * Pregnancy or nursing * Periodontal or antibiotic therapy in the previous 6 months * Any systemic condition which might influence the course of periodontal disease or treatment (e.g. diabetes, AIDS) * Any systemic condition which requires antibiotic coverage for routine periodontal procedures (e.g. heart conditions, joint replacements etc.) * Liver disease * Any known allergy to amoxicillin, metronidazole or doxycycline * Lactose intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Clinical Attachment Level. | Baseline, 3, 6 and 12 months | Periodontal diseases are clinically diagnosed by assessments of gingival inflammation and measurements of tissue destruction. The damage to the apparatus of support of the teeth is quantified using measurements of probing pocket depth (PD) and clinical attachment level (CAL). These measurements are obtained using a periodontal probe which is introduced into the gingival sulcus to determine the distance in millimeters from the gingival margin to the depth of the sulcus or pocket (PD). Since the gingival margin fluctuates in response to inflammation (hyperplasia) or might recede, a more accurate measure of loss of attachment is obtained using the CAL, which measures the distance from a fixed landmark on the tooth such as the cemento-enamel junction to the depth of the pocket. Changes in CAL from baseline were used to assess results obtained with the treatment of periodontal diseases. |
Countries
United States
Participant flow
Recruitment details
Subjects with moderate to advanced chronic periodontitis were recruited to the clinical center at The Forsyth Institute. Subjects were recruited from the Boston area, subjects of any racial / ethnic group were accepted for study.
Pre-assignment details
Only 5 subjects dropped prior to randomization due to conflicts in scheduling or unable to adhere to the monitoring plan.
Participants by arm
| Arm | Count |
|---|---|
| Scaling and Root Planing (SRP) Only Subjects received full mouth scaling and root planing (SRP) under local anesthesia.Maintenance SRP was performed every 3 months for the duration of the study in all subjects. | 49 |
| SRP and Metronidazole (MET) In addition to full mouth scaling and root planing under local anesthesia,subjects received systemically administered metronidazole (250 mg tid x 14 days). Maintenance SRP was performed every 3 months for the duration of the study in all subjects.
Metronidazole is an antibiotic that is particularly effective against Gram negative bacterial species. | 50 |
| SRP and Amoxicillin, MET and Locally Delivered Tetracycline In addition to full mouth scaling and root planing under local anesthesia,subjects received systemically administered metronidazole (250 mg tid x 14 days) together with systemically administered amoxicillin (500 mg tid for 14 days) and local delivery of doxycycline (Atridox) at teeth with pockets \> 4 mm. Maintenance SRP was performed every 3 months for the duration of the study in all subjects.
Tetracycline : Tetracycline is an antibiotic that has proved effective in killing bacteria in the periodontal pocket when applied locally. | 47 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 4 | 7 | 4 | 3 | 5 |
Baseline characteristics
| Characteristic | SRP and Metronidazole (MET) | SRP and Amoxicillin, MET and Locally Delivered Tetracycline | Scaling and Root Planing (SRP) Only | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 3 Participants | 7 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 44 Participants | 42 Participants | 132 Participants |
| Age Continuous | 50.3 years STANDARD_DEVIATION 11.6 | 48.0 years STANDARD_DEVIATION 11.1 | 50.3 years STANDARD_DEVIATION 11.8 | 49.5 years STANDARD_DEVIATION 11.5 |
| Region of Enrollment United States | 50 participants | 47 participants | 49 participants | 146 participants |
| Sex: Female, Male Female | 23 Participants | 20 Participants | 21 Participants | 64 Participants |
| Sex: Female, Male Male | 27 Participants | 27 Participants | 28 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 27 | 4 / 22 | 10 / 30 | 3 / 20 | 6 / 27 | 5 / 20 |
| serious Total, serious adverse events | 1 / 27 | 0 / 22 | 2 / 30 | 2 / 20 | 3 / 27 | 1 / 20 |
Outcome results
Primary
Change in Mean Clinical Attachment Level.
Periodontal diseases are clinically diagnosed by assessments of gingival inflammation and measurements of tissue destruction. The damage to the apparatus of support of the teeth is quantified using measurements of probing pocket depth (PD) and clinical attachment level (CAL). These measurements are obtained using a periodontal probe which is introduced into the gingival sulcus to determine the distance in millimeters from the gingival margin to the depth of the sulcus or pocket (PD). Since the gingival margin fluctuates in response to inflammation (hyperplasia) or might recede, a more accurate measure of loss of attachment is obtained using the CAL, which measures the distance from a fixed landmark on the tooth such as the cemento-enamel junction to the depth of the pocket. Changes in CAL from baseline were used to assess results obtained with the treatment of periodontal diseases.
Time frame: Baseline, 3, 6 and 12 months
Population: Of the 146 subjects, 117 were included in the analysis, who had 2 or fewer missing monitoring visits. 84 subjects had complete data, 23 subjects had one missing visit and 10 subjects had 2 missing visits. For the 33 subjects with missing visits, data were carried forward. 68 subjects were non smokers and 49 subjects were current smokers.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Scaling and Root Planing Only NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 6 months | 0.15 mm | Standard Error 0.06 |
| Scaling and Root Planing Only NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 12 months | 0.11 mm | Standard Error 0.05 |
| Scaling and Root Planing Only NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 3 months | 0.11 mm | Standard Error 0.06 |
| SRP Only Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 12 months | 0.24 mm | Standard Error 0.05 |
| SRP Only Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 6 months | 0.19 mm | Standard Error 0.05 |
| SRP Only Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 3 months | 0.10 mm | Standard Error 0.04 |
| SRP + Metronidazole NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 6 months | 0.19 mm | Standard Error 0.07 |
| SRP + Metronidazole NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 3 months | 0.21 mm | Standard Error 0.05 |
| SRP + Metronidazole NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 12 months | 0.26 mm | Standard Error 0.06 |
| SRP + Metronidazole Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 6 months | 0.13 mm | Standard Error 0.07 |
| SRP + Metronidazole Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 3 months | 0.08 mm | Standard Error 0.06 |
| SRP + Metronidazole Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 12 months | 0.17 mm | Standard Error 0.09 |
| SRP + MET + Amoxicillin + Doxycycline NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 6 months | 0.34 mm | Standard Error 0.07 |
| SRP + MET + Amoxicillin + Doxycycline NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 3 months | 0.29 mm | Standard Error 0.07 |
| SRP + MET + Amoxicillin + Doxycycline NonSmokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 12 months | 0.41 mm | Standard Error 0.07 |
| SRP + MET + Amoxicillin + Doxycycline Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 3 months | 0.28 mm | Standard Error 0.06 |
| SRP + MET + Amoxicillin + Doxycycline Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 12 months | 0.39 mm | Standard Error 0.08 |
| SRP + MET + Amoxicillin + Doxycycline Smokers | Change in Mean Clinical Attachment Level. | Changes in mean CAL from baseline to 6 months | 0.40 mm | Standard Error 0.08 |
Comparison: The null hypothesis of no difference among treatment groups in non-smokers was tested by comparing change in mean CAL in individuals at 3 months post-therapy.p-value: >0.05ANOVA
Comparison: The null hypothesis of no difference among treatment groups in non-smokers was tested by comparing change in mean CAL in individuals at 6 months post-therapy.p-value: >0.05ANOVA
Comparison: The null hypothesis of no difference among treatment groups in non-smokers was tested by comparing change in mean CAL in individuals at 12 months post-therapy.p-value: <0.05ANOVA
Comparison: The null hypothesis of no difference among treatment groups in smokers was tested by comparing change in mean CAL in individuals at 3 months post-therapy.p-value: <0.05ANOVA
Comparison: The null hypothesis of no difference among treatment groups in smokers was tested by comparing change in mean CAL in individuals at 6 months post-therapy.p-value: <0.05ANOVA
Comparison: The null hypothesis of no difference among treatment groups in smokers was tested by comparing change in mean CAL in individuals at 12 months post-therapy.p-value: >0.05ANOVA