Omega-3 Fatty Acids Plus Low-dose Aspirin Daily Supplementation in Surgical Therapy to Treat Aggressive Periodontitis

• Sponsor: Universidade Estadual Paulista Júlio de Mesquita Filho (Other)
• Overall Status: Completed
• CT.gov ID: NCT03093207
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 2
• Actual Duration (Months): 37.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The aim of this randomized controlled clinical trial of superiority will be to evaluate the effect of 3 g of omega-3 polyunsaturated fatty acids and 100 mg of aspirin daily supplementation over a period of 180 days as adjunct to surgical therapy of residual pockets from patients with generalized aggressive periodontitis. Probing depth, clinical attachment level, gingival index and concentration of microorganisms and cytokines at baseline, 3, and 6 months after the procedure will be evaluated.

Condition or Disease	Intervention/Treatment	Phase
Residual Disease; Aggressive Periodontitis	Procedure: Open flap debridement; Other: Placebo; Dietary Supplement: Omega-3 polyunsaturated fatty acids; Drug: Aspirin	Phase 2/Phase 3

Detailed Description

The study is designed as a prospective, interventional, parallel, blinded, randomized, controlled clinical trial clinical of superiority, with a 6 month follow-up. The methodology of the present study will follow the standards of CONSORT-STATEMENT 2010 (Moher et al., 2010) and SPIRIT 2013 (Chan et al., 2013) for randomized clinical trials.

Source of data The population will be composed of patients diagnosed with generalized aggressive periodontitis (GAgP) recruited at Institute of Science and Technology - Unesp, in São José dos Campos / SP, who have already undergone non-surgical periodontal treatment and still have pockets with probing depth ≥5 mm and bleeding on probe.

Sample size Sample size calculation was performed using Sealed EnvelopeTM software. For this study, a population of 34 patients will be included. Considering α = 5% and β = 5% (power of 95%) to detect a change of at least 1 mm in clinical attachment level between groups, to a standard deviation of 0.8 mm, 17 patients will be required in each group

Clinical Parameters All clinical parameters will be assessed by a single blinded, trained and calibrated examiner (CFA) before surgical therapy (baseline) and at 3 and 6 months after using a manual probe. Measurements will be done at six sites per tooth (mesiobuccal, buccal, disto-buccal, distolingual, lingual, and mesiolingual) in all teeth, except third molars.

The following clinical parameters will be evaluated: 1) Full-mouth plaque index (PI); 2) Bleeding on probing (BoP); 3) Probing depth (PD): distance from the bottom of sulcus/pocket to gingival margin; 4) Gingival recession (GR): distance from the free gingival margin to cement-enamel junction (CEJ); 5) Clinical attachment level (CAL): distance from bottom of sulcus/pocket to the CEJ. The CEJ will be identified by careful probe on cervical area.

Calibration and Randomization Initially, ten patients with GAgP will be selected. The designated examiner (CFA) will measure CAL and PD in all patients twice within 24 hours, with an interval of ≥ 1 hour between examinations. Then, the measures will be submitted to intraclass correlation test and the examiner will be judged calibrated if reaches 90% agreement.

Patients will be allocated into two groups according to a computer-generated list. The allocation will be implemented by an investigator (NC) who was not directly involved in the examination or treatment procedures.

Selection of sites with residual pockets

After the reevaluation, a residual periodontal pocket with probing depth ≥5 mm and bleeding on probe will be selected from a site not located in furcation region, by chance, to receive one of the following treatments:

• Control group (CG): surgical access for scaling and root planing + placebo pills (n = 17);

• Test group (TG): surgical access for scaling and root planing associated with daily supplementation of 3 g of omega-3 and 100 mg of acetylsalicylic acid for 180 days (n = 17).

Treatment

One hour before surgical therapy, patients will receive a single dose of dexamethasone 4 mg. The packaging of the products will be delivered according to the therapy indicated in the randomization. The administration will begin immediately before the surgical treatment, which will be performed by a single operator (CA), following the sequence:

1. 10 mL of 0.1% chlorhexidine digluconate solution (Periogard®, Colgate Palmolive Ltda - Osasco - SP) will be provided to be chewed by the patient for 1 minute for intraoral disinfection;

2. Antisepsis of the perioral region with sterile gauze soaked in chlorhexidine digluconate solution 0.2%;

3. The patient will receive local injectable anesthesia with mepivacaine 2% with epinephrine 1: 100,000 (Mepivacaína®, DFL - Rio de Janeiro / RJ) through an infiltrative technique;

4. Surgical access will be performed by Kirkland modified surgical technique (Kirland, 1931). With a 15c blade, intrasulcular incisions will be made to the bottom of the pocket / sulcus on buccal, lingual and interproximal surfaces. The incisions will extend into the mesial and distal directions of the affected tooth. The gingival tissue will be detached from the bone to allow exposure of the root surface which will be carefully scaled and plained with periodontal curettes after removal of all granulation tissue. After copious irrigation with saline solution, the flap will be repositioned and maintained by interproximal sutures with Ethicon ® 4-0 silk suture (Ethicon Johnsons do Brasil SA, São José dos Campos - SP).

Postoperative Patients will receive the following postoperative recommendations: do not drink alcoholic beverages; do not touch the surgical wound; Do not brush and floss area for 7 days; Ingest only cold liquid (ice cream, yogurt, juices and gelatin) in the first 24 hours; Mouthwash with 0.12% chlorhexidine digluconate (Periogard®) every 12 hours for 14 days. Dipyrone sodium 500 mg every 4 hours will be prescribed in case of pain. The sutures will be removed after 7 days of surgery.

Microbiological evaluation Subgingival microbiological samples will be collected at the baseline, 3 and 6 months after therapy. The site will be isolated with a sterile cotton roller and supragingival biofilm will be carefully removed with periodontal curettes and a sterile paper will be inserted into the periodontal pocket for 30 s (Hartoth et al., 1999). The sample will be stored in sterile microtubes. The samples will then be lyophilized and sent to the Department of Periodontology at the University of Florida, where the samples will be analyzed.

Evaluation of cytokines For the analysis of immunological changes, crevicular gingival fluid (CGF) will be collected at baseline, 3 and 6 months after treatment. Each site will be isolated with a sterile cotton roller and the supragingival biofilm will be removed. After this, the CGF will be collected with Periopaper strips (Periopaper, Oraflow, Plainview, NY, USA), inserted in the pocket for 15 seconds. The volume of collected fluid will be measured (Periotron 8000, Oraflow). The Periopaper strips will be stored in a sterile tube containing 300μl of phosphate saline (PBS) with 5% Tween-20 and stored in a freezer at -20 ° C until the multiplex test. The level of the following cytokines will be measured in the CGF: interferon (IFN) -γ, interleukins (IL) -10, -1β, -4, -6, -8, tumor necrosis factor (TNF) -α, macrophage inflammatory protein 1α (MIP1α), 1α monocyte chemotactic protein (MCP-1α). The 10-plex high sensitivity kit (Millipore Corporation, Billerica, MA, USA) will be used according to the manufacturer's instruction and analyzed using the MAGpixTM platform (MiraiBio, Alameda, CA, USA). Samples will be analyzed individually (each pocket separately) and the concentrations will be calculated using a standard 5-parameter curve in the Xponet program (Millipore Corporation). The concentration of each marker will be given in pg / ml. All analysis of cytokine concentrations will be done in duplicate.

Statistical analysis Two analyzes will be performed: Per Protocol and Intention-to-treat (Moher, 2010; Gupta, 2011; Day, 2008). For each of them, mean and standard deviation will be calculated in each of the parameters. Full-mouth PI, GI, PD, CAL, and GR will be submitted to the Shapiro-Wilk test to evaluate the distribution of these data, and then subjected to the variance test for both intra- and intra-group comparison. In addition, the number of pockets ≥ 5mm, the frequency of closure of these pockets, the mean reduction in PS and the gain in CAL of these pockets will be assessed before and after the therapy by performing intra- and inter-group analyzes.

The concentration of each cytokine will be analyzed by test of variance for intra and intergroup comparison.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Evaluation of Omega-3 Polyunsaturated Fatty Acids Plus Low-dose Aspirin Daily Supplementation in Surgical Therapy to Treat Generalized Aggressive Periodontitis: Randomized Controlled Clinical Trial
• Actual Study Start Date: May 15, 2017
• Actual Primary Completion Date: Oct 1, 2018
• Actual Study Completion Date: Jun 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Control group In this group (n = 17), patients will take placebo pills and open flap debridement will be performed to treat residual pockets.	Procedure: Open flap debridement; Open flap debridement will be performed to decontaminate root surface; Other Names: Surgical therapy ; Other: Placebo; Placebo pills over a period of 180 days
Experimental: Test Group In this group (n = 17), patients will take 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement will be performed to treat residual pockets.	Procedure: Open flap debridement; Open flap debridement will be performed to decontaminate root surface; Other Names: Surgical therapy ; Dietary Supplement: Omega-3 polyunsaturated fatty acids; 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days; Other Names: Fish oil ; Drug: Aspirin; 100 mg of aspirin daily supplementation over a period of 180 days; Other Names: acetylsalicylic acid

Outcome Measures

Primary Outcome Measures

1. Clinical Attachment Level at Baseline, 3 Months and 6 Months [Baseline, 3 and 6 months]

   Evaluate the difference between baseline and 6 months CAL measures. CAL: distance from bottom of sulcus/pocket to the cement-enamel junction (CEJ). The CEJ will be identified by careful probe on cervical area.

Secondary Outcome Measures

1. Probing Depth at Baseline, 3 Months and 6 Months [Baseline, 3 and 6 months]

   Evaluate the difference between baseline and 6 months PB measures. PB: distance from the bottom of sulcus/pocket to gingival margin.

2. Percentage of Sites With Bleeding on Probe at Baseline, 3 Months and 6 Months [Baseline, 3 and 6 months]

   Evaluate the difference between baseline and 6 months BoP measures. BoP: bleeding that is induced by gentle probing of the sulcus/pocket.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria

• Diagnosis of generalized aggressive periodontitis (Armitage, 1999; American Academy of Periodontology, 2015);

• Have undergone a first approach for periodontal treatment (full-mouth ultrasonic debridement);

• Present at least one residual pocket of probing depth ≥ 5 mm and bleeding on probe not located in furcation region;

• Good general health;

• Agree to participate in the study and sign the informed consent form (TCLE) after explaining the risks and benefits;

Exclusion Criteria

• Systemic problems (cardiovascular alterations, blood dyscrasias, immunodeficiency - ASA III / IV / V) that contraindicate the periodontal procedure;

• Have used antibiotics and anti-inflammatories in the last six months;

• Smoke ≥ 10 cigarettes/day;

• Pregnant or nursing;

• Chronic use of medications that may alter the response of periodontal tissues;

• Indication of antibiotic prophylaxis for dental procedures;

• History of allergic reaction to acetylsalicylic acid, fish or seafood.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	College of Dentistry - São José dos Campos, Sao Paulo State University	Sao Jose dos Campos	SP	Brazil	12245-310

Sponsors and Collaborators

• Universidade Estadual Paulista Júlio de Mesquita Filho

Investigators

• Principal Investigator: Mauro Santamaria, Professor, Universidade Estadual Paulista "Julio de Mesquita Filho", ICT/UNESP

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 15, 2017

More Information

Publications

• El-Sharkawy H, Aboelsaad N, Eliwa M, Darweesh M, Alshahat M, Kantarci A, Hasturk H, Van Dyke TE. Adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 Fatty acids and low-dose aspirin. J Periodontol. 2010 Nov;81(11):1635-43. doi: 10.1902/jop.2010.090628. Epub 2010 Jun 23.

• Responsible Party: Mauro Pedrine Santamaria, PhD Adjunt professor, Universidade Estadual Paulista Júlio de Mesquita Filho
• ClinicalTrials.gov Identifier: NCT03093207
• Other Study ID Numbers: HMT+OFD CFA
• First Posted: Mar 28, 2017
• Last Update Posted: Nov 17, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Mauro Pedrine Santamaria, PhD Adjunt professor, Universidade Estadual Paulista Júlio de Mesquita Filho: Aggressive periodontitis; Aspirin; Omega-3 polyunsaturated fatty acids; Surgical therapy
• Additional relevant MeSH terms: Periodontitis; Aggressive Periodontitis; Aggression; Aspirin

Study Results

Participant Flow

Arm/Group Title	Control Group	Test Group
Arm/Group Description	In this group (n = 17), patients received placebo pills and open flap debridement to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Placebo: Placebo pills over a period of 180 days	In this group (n = 17), patients received 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Omega-3 polyunsaturated fatty acids: 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days Aspirin: 100 mg of aspirin daily supplementation over a period of 180 days
Period Title: Overall Study
STARTED	17	17
COMPLETED	17	17
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Control Group	Test Group	Total
Arm/Group Description	In this group (n = 17), patients will take placebo pills and open flap debridement will be performed to treat residual pockets. Open flap debridement: Open flap debridement will be performed to decontaminate root surface Placebo: Placebo pills over a period of 180 days	In this group (n = 17), patients will take 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement will be performed to treat residual pockets. Open flap debridement: Open flap debridement will be performed to decontaminate root surface Omega-3 polyunsaturated fatty acids: 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days Aspirin: 100 mg of aspirin daily supplementation over a period of 180 days	Total of all reporting groups
Overall Participants	17	17	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 100%	17 100%	34 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.06 (5.13)	34.17 (4.9)	33.61 (5.01)
Sex: Female, Male (Count of Participants)
Female	13 76.5%	13 76.5%	26 76.5%
Male	4 23.5%	4 23.5%	8 23.5%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Brazil	17 100%	17 100%	34 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Attachment Level at Baseline, 3 Months and 6 Months
Description	Evaluate the difference between baseline and 6 months CAL measures. CAL: distance from bottom of sulcus/pocket to the cement-enamel junction (CEJ). The CEJ will be identified by careful probe on cervical area.
Time Frame	Baseline, 3 and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Test Group	Control Group
Arm/Group Description	In this group (n = 17), patients received 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Omega-3 polyunsaturated fatty acids: 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days Aspirin: 100 mg of aspirin daily supplementation over a period of 180 days	In this group (n = 17), patients received placebo pills over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface
Measure Participants	17	17
Measure Pockets treated with surgery	17	17
Baseline	5.5 (0.25)	5.29 (0.16)
3 months	4.64 (0.29)	4.73 (0.28)
6 months	4.64 (0.22)	4.97 (0.25)

2. Secondary Outcome

Title	Probing Depth at Baseline, 3 Months and 6 Months
Description	Evaluate the difference between baseline and 6 months PB measures. PB: distance from the bottom of sulcus/pocket to gingival margin.
Time Frame	Baseline, 3 and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Test Group	Control Group
Arm/Group Description	In this group (n = 17), patients received 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Omega-3 polyunsaturated fatty acids: 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days Aspirin: 100 mg of aspirin daily supplementation over a period of 180 days	In this group (n = 17), patients received placebo pills over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface
Measure Participants	17	17
Measure Pockets treated with surgery	17	17
Baseline	5.17 (0.2)	5.14 (0.14)
3 months	4.08 (0.21)	3.76 (0.2)
6 months	4 (0.15)	3.94 (0.2)

3. Secondary Outcome

Title	Percentage of Sites With Bleeding on Probe at Baseline, 3 Months and 6 Months
Description	Evaluate the difference between baseline and 6 months BoP measures. BoP: bleeding that is induced by gentle probing of the sulcus/pocket.
Time Frame	Baseline, 3 and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Test Group	Control Group
Arm/Group Description	In this group (n = 17), patients received 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Omega-3 polyunsaturated fatty acids: 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days Aspirin: 100 mg of aspirin daily supplementation over a period of 180 days	In this group (n = 17), patients received placebo pills over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface
Measure Participants	17	17
Measure Pockets treated with surgery	17	17
Baseline	100	100
3 months	76.47	100
6 months	64.7	64.7

Adverse Events

Time Frame	During the 6 months post-treatment
Arm/Group Title	Control Group		Test Group
Arm/Group Description	In this group (n = 17), patients received placebo pills and open flap debridement to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Placebo: Placebo pills over a period of 180 days		In this group (n = 17), patients received 3 g of omega-3 polyunsaturated fatty acids plus 100 mg of aspirin daily supplementation over a period of 180 days and open flap debridement was performed to treat residual pockets. Open flap debridement: Open flap debridement was performed to decontaminate root surface Omega-3 polyunsaturated fatty acids: 3 g of omega-3 polyunsaturated fatty acids daily supplementation over a period of 180 days Aspirin: 100 mg of aspirin daily supplementation over a period of 180 days
All Cause Mortality
	Control Group		Test Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)
Serious Adverse Events
	Control Group		Test Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)
Gastrointestinal disorders
Stomachache	0/17 (0%)	0	0/17 (0%)	0
Internal bleeding	0/17 (0%)	0	0/17 (0%)	0
Other (Not Including Serious) Adverse Events
	Control Group		Test Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.