Gingivitis, Inflammation, Periodontitis
Conditions
Keywords
Docosahexaenoic acid, DHA, Periodontitis, Gingivitis, Omega-3 fatty acid, Fish oil
Brief summary
The purpose of this study is to determine whether docosahexaenoic acid (DHA) is effective in the treatment of periodontitis in adults.
Detailed description
1. The primary aim of this study is to investigate the effect of docosahexaenoic acid (DHA; 2 gm/day) plus low dose aspirin (ASA 81 mg/day)compared to ASA alone on periodontitis over three months. Our hypothesis is that DHA plus ASA will improve periodontitis as measured by objective periodontal exam, including decreased pocket depth (mm), gingival index (0-3), plaque index (0-3) and bleeding on probing (yes/no) compared to ASA alone. 2. Assess the effect of DHA and ASA exposure on markers of local inflammation, including gingival crevicular fluid (GCF) CRP, IL-1 beta and IL-6 three months after exposure to DHA plus ASA compared to ASA alone. 3. Evaluate potential mechanisms through changes in the periodontal microbial flora which may occur as a result of exposure to DHA and ASA compared to ASA alone. Our hypothesis is that there will be a substantial post therapy change in the microbial flora of dental plaques, favoring bacteria associated with a lower systemic inflammatory state. 4. Assess the effect of DHA and ASA exposure on markers of systemic inflammation, including serum C-Reactive Protein (CRP), interleukin-6 (IL-6) and vascular adhesion molecule (VCAM) compared to ASA. Our hypothesis is that there will be a decrease in serum CRP, IL-6 and VCAM three months after exposure to DHA plus ASA compared to ASA alone. 5. Assess the effect of DHA and ASA exposure on markers of systemic bone turnover, including urine N-terminal telopeptide (NTx) compared to ASA. Our hypothesis is that there will be a decrease in urine NTx three months after exposure to DHA plus ASA compared to ASA alone.
Interventions
DRUGAspirin
DRUGDocosahexaenoic acid
DRUGPlacebo (for Docosahexaenoic acid)
Placebo (corn/soybean oil) capsules manufactured to look identical to DHA capsules
Sponsors
National Center for Research Resources (NCRR)
Harvard Medical School (HMS and HSDM)
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* age \>40 years * \>20 natural teeth (excluding third molars) * no orthodontic appliances * periodontitis defined as \>4 teeth with pocket probing depths \>5 mm
Exclusion criteria
* pregnancy * diabetes * severe chronic diseases * gastrointestinal bleeding * uncontrolled chronic diseases * autoimmune disorders * conditions requiring antibiotic prophylaxis * warfarin * clopidogrel * antimicrobial therapy within 30 days * chronic use of non-steroidal anti-inflammatory drugs (other than aspirin) * omega-3 fatty acid use within 6 months * loose teeth * painful teeth * periodontal abscess * pocket depths \>10 mm in \>1 tooth * periodontal therapy within the past two years * allergy to aspirin * allergy to fish oil * allergy to corn oil * allergy to soybean oil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pocket Depth (mm) | Baseline and 3 months | Pocket probing depth (PD) is the depth a dental probe can be inserted into a gingival pocket at a particular site (6 sites per tooth) measured in millimeters among teeth with PD greater than or equal to 5 mm (N=533 dental sites total). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gingival Crevicular Fluid Interleukin-1 Beta | Baseline and 3 months | Gingival crevicular fluid (GCF) samples were analyzed for Interleukin-1 beta, which is a measure of local gingival inflammation. |
| Serum High-sensitivity C-reactive Protein | Baseline and 3 months | Serum high-sensitivity C-reactive protein is a measure of systemic inflammation. |
| Change in Gingival Index (0-3) | Baseline and 3 months | Gingival Index (GI) is a measure of gingival inflammation, which is assigned a score (0-3). Score Criteria: 0: No inflammation. 1. Mild inflammation, slight change in color, slight edema, no bleeding on probing. 2. Moderate inflammation, moderate glazing, redness, bleeding on probing. 3. Severe inflammation, marked redness and hypertrophy, ulceration, tendency to spontaneous bleeding. |
| Change in Plaque Index (0-3) | Baseline and 3 months | Plaque Index (PI) is a measure of gingival inflammation as induced by bacterial plaque deposition at and under the gum line. Score Criteria: 0: No plaque 1. A film of plaque adhering to the free gingival margin and adjacent area of the tooth, which can not be seen with the naked eye. But only by using disclosing solution or by using probe. 2. Moderate accumulation of deposits within the gingival pocket, on the gingival margin and/ or adjacent tooth surface, which can be seen with the naked eye. 3. Abundance of soft matter within the gingival pocket and/or on the tooth and gingival margin. |
| Sites With Bleeding on Probing (Yes/no) | 3 months | Bleeding On Probing (BOP) is a measure of gingival inflammation and tissue destruction, which describes whether or not bleeding at the dental pocket occurred following probing. |
| Gingival Crevicular Fluid Interleukin-6 | Baseline and 3 months | Gingival crevicular fluid (GCF) samples were analyzed for Interleukin-6, which is a measure of local gingival inflammation. |
| Serum High-sensitivity Interleukin-6 | Baseline and 3 months | Serum high-sensitivity interleukin-6 is a measure of systemic inflammation. |
| Serum Soluble Vascular Cell Adhesion Molecule | Baseline and 3 months | Serum soluble vascular cell adhesion molecule (VCAM) is a measure of systemic inflammation. |
| Urine N-Terminal Telopeptides | Baseline and 3 months | Urine N-Terminal Telopeptides are a measure of systemic bone turnover. |
| Gingival Crevicular Fluid High Sensitivity C-reactive Protein | Baseline and 3 months | Gingival crevicular fluid (GCF) is the fluid bathing the teeth under the gum line. GCF samples were analyzed for high sensitivity C-reactive protein as a measure of local gingival inflammation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Red Blood Cell Membrane Docosahexaenoic Acid | Baseline and 3 months | Red blood cell phospholipid fatty acids were measured at baseline and 3-month follow up as a measure of adherence. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aspirin & Docosahexaenoic Acid Aspirin 81 mg 1 tablet by mouth daily and Docosahexanoic acid (DHA) 500 mg 4 capsules by mouth daily (total daily dose of 2 grams DHA) for 3 months
Aspirin
Docosahexaenoic acid | 24 |
| Aspirin & Placebo Aspirin 81 mg by mouth daily and placebo (50% corn oil/50% soybean oil) 4 capsules by mouth daily for 3 months
Aspirin
Placebo (for Docosahexaenoic acid): Placebo (corn/soybean oil) capsules manufactured to look identical to DHA capsules | 22 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Aspirin & Docosahexaenoic Acid | Total | Aspirin & Placebo |
|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 8 | 55 years STANDARD_DEVIATION 8 | 57 years STANDARD_DEVIATION 8 |
| BMI (kg/m2) Normal (18.5-24.9 kg/m2) | 9 participants | 14 participants | 5 participants |
| BMI (kg/m2) Obese (>30 kg/m2) | 11 participants | 18 participants | 7 participants |
| BMI (kg/m2) Overweight (25-30 kg/m2) | 4 participants | 14 participants | 10 participants |
| Hyperlipidemia Hyperlipidemia | 5 participants | 9 participants | 4 participants |
| Hyperlipidemia No Hyperlipidemia | 19 participants | 37 participants | 18 participants |
| Hypertension Hypertension | 4 participants | 10 participants | 6 participants |
| Hypertension No Hypertension | 20 participants | 36 participants | 16 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Female | 11 Participants | 21 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 25 Participants | 12 Participants |
| Smoking Status Current | 1 participants | 2 participants | 1 participants |
| Smoking Status Former | 7 participants | 13 participants | 6 participants |
| Smoking Status Never | 16 participants | 31 participants | 15 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 27 | 8 / 28 |
| serious Total, serious adverse events | 0 / 27 | 0 / 28 |
Outcome results
Primary
Change in Pocket Depth (mm)
Pocket probing depth (PD) is the depth a dental probe can be inserted into a gingival pocket at a particular site (6 sites per tooth) measured in millimeters among teeth with PD greater than or equal to 5 mm (N=533 dental sites total).
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Change in Pocket Depth (mm) | -0.71 mm | Standard Error 0.07 |
| Aspirin & Placebo | Change in Pocket Depth (mm) | -0.54 mm | Standard Error 0.07 |
Comparison: Intent-to-treat basis with a type I error rate of 0.05. The follow-up pocket depth, was assessed in linear mixed effects models with a compound-symmetry covariance structure and age, sex, BMI, race, baseline pocket depth, baseline red blood cell (RBC) DHA level (dichotomized at median), and intervention group as fixed-effect variables.p-value: <0.05Mixed Models Analysis
Secondary
Change in Gingival Index (0-3)
Gingival Index (GI) is a measure of gingival inflammation, which is assigned a score (0-3). Score Criteria: 0: No inflammation. 1. Mild inflammation, slight change in color, slight edema, no bleeding on probing. 2. Moderate inflammation, moderate glazing, redness, bleeding on probing. 3. Severe inflammation, marked redness and hypertrophy, ulceration, tendency to spontaneous bleeding.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Change in Gingival Index (0-3) | -0.26 GI units | Standard Error 0.04 |
| Aspirin & Placebo | Change in Gingival Index (0-3) | -0.07 GI units | Standard Error 0.04 |
Secondary
Change in Plaque Index (0-3)
Plaque Index (PI) is a measure of gingival inflammation as induced by bacterial plaque deposition at and under the gum line. Score Criteria: 0: No plaque 1. A film of plaque adhering to the free gingival margin and adjacent area of the tooth, which can not be seen with the naked eye. But only by using disclosing solution or by using probe. 2. Moderate accumulation of deposits within the gingival pocket, on the gingival margin and/ or adjacent tooth surface, which can be seen with the naked eye. 3. Abundance of soft matter within the gingival pocket and/or on the tooth and gingival margin.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Change in Plaque Index (0-3) | -0.10 Plaque index units | Standard Error 0.06 |
| Aspirin & Placebo | Change in Plaque Index (0-3) | 0.07 Plaque index units | Standard Error 0.07 |
Secondary
Gingival Crevicular Fluid High Sensitivity C-reactive Protein
Gingival crevicular fluid (GCF) is the fluid bathing the teeth under the gum line. GCF samples were analyzed for high sensitivity C-reactive protein as a measure of local gingival inflammation.
Time frame: Baseline and 3 months
Population: Performed in all participants with baseline and 3 month visits in whom usable GCF samples could be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Gingival Crevicular Fluid High Sensitivity C-reactive Protein | -7.3715 ng/mL | Standard Error 3.9244 |
| Aspirin & Placebo | Gingival Crevicular Fluid High Sensitivity C-reactive Protein | -3.1268 ng/mL | Standard Error 2.0415 |
Secondary
Gingival Crevicular Fluid Interleukin-1 Beta
Gingival crevicular fluid (GCF) samples were analyzed for Interleukin-1 beta, which is a measure of local gingival inflammation.
Time frame: Baseline and 3 months
Population: Performed in all participants with baseline and 3 month visits in whom usable GCF samples could be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Gingival Crevicular Fluid Interleukin-1 Beta | 0.8775 pg/mL | Standard Error 4.7203 |
| Aspirin & Placebo | Gingival Crevicular Fluid Interleukin-1 Beta | 21.5816 pg/mL | Standard Error 8.0491 |
Secondary
Gingival Crevicular Fluid Interleukin-6
Gingival crevicular fluid (GCF) samples were analyzed for Interleukin-6, which is a measure of local gingival inflammation.
Time frame: Baseline and 3 months
Population: Performed in all participants with baseline and 3 month visits in whom usable GCF samples could be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Gingival Crevicular Fluid Interleukin-6 | 0.1422 pg/mL | Standard Error 0.5273 |
| Aspirin & Placebo | Gingival Crevicular Fluid Interleukin-6 | -0.00226 pg/mL | Standard Error 0.3245 |
Secondary
Serum High-sensitivity C-reactive Protein
Serum high-sensitivity C-reactive protein is a measure of systemic inflammation.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Serum High-sensitivity C-reactive Protein | -0.3695 mg/L | Standard Error 0.5558 |
| Aspirin & Placebo | Serum High-sensitivity C-reactive Protein | 0.7114 mg/L | Standard Error 0.7223 |
Secondary
Serum High-sensitivity Interleukin-6
Serum high-sensitivity interleukin-6 is a measure of systemic inflammation.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Serum High-sensitivity Interleukin-6 | 0.3295 pg/mL | Standard Error 0.4149 |
| Aspirin & Placebo | Serum High-sensitivity Interleukin-6 | -0.0690 pg/mL | Standard Error 0.2633 |
Secondary
Serum Soluble Vascular Cell Adhesion Molecule
Serum soluble vascular cell adhesion molecule (VCAM) is a measure of systemic inflammation.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Serum Soluble Vascular Cell Adhesion Molecule | 4.8829 ng/mL | Standard Error 24.3667 |
| Aspirin & Placebo | Serum Soluble Vascular Cell Adhesion Molecule | 27.9409 ng/mL | Standard Error 19.6992 |
Secondary
Sites With Bleeding on Probing (Yes/no)
Bleeding On Probing (BOP) is a measure of gingival inflammation and tissue destruction, which describes whether or not bleeding at the dental pocket occurred following probing.
Time frame: 3 months
Population: Results presented at 3 months; 3-months results also compared to baseline BOP using logistic regression as described in manuscript.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Aspirin & Docosahexaenoic Acid | Sites With Bleeding on Probing (Yes/no) | 202 Sites |
| Aspirin & Placebo | Sites With Bleeding on Probing (Yes/no) | 227 Sites |
Secondary
Urine N-Terminal Telopeptides
Urine N-Terminal Telopeptides are a measure of systemic bone turnover.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Urine N-Terminal Telopeptides | 103.3333 nM BCE | Standard Error 70.5656 |
| Aspirin & Placebo | Urine N-Terminal Telopeptides | 61.8421 nM BCE | Standard Error 90.5793 |
Other Pre-specified
Change in Red Blood Cell Membrane Docosahexaenoic Acid
Red blood cell phospholipid fatty acids were measured at baseline and 3-month follow up as a measure of adherence.
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin & Docosahexaenoic Acid | Change in Red Blood Cell Membrane Docosahexaenoic Acid | 2.723 % of total RBC FA | Standard Error 0.3882 |
| Aspirin & Placebo | Change in Red Blood Cell Membrane Docosahexaenoic Acid | -0.1776 % of total RBC FA | Standard Error 0.1326 |