Use of Topical Subgingival Application of Simvastatin Gel in the Treatment of Peri-Implant Mucositis

Phase 2

Completed

Conditions: Peri-implant Mucositis

Interventions: Drug: Simvastatin
Other: Placebo

Registration Number: NCT03400475

Lead Sponsor: Ahmed Mohamed Mahrous

Brief Summary: This study seeks to test the recently discovered anti-inflammatory action of statins on inflamed mucosa surrounding dental implants.

Hypothesis: The application of 1.2% simvastatin gel will decrease peri-implant inflammation.

The pilot study will involve 44 subjects divided into a test and control group. The test group shall receive topical simvastatin gel administered around the implant with a blunt tipped needle. The control group will receive a placebo.

Inflammatory state shall be determined at baseline as well as follow up visits at 24 hours, 1 week, and 1 month by clinical indices of inflammation as well as biochemical markers of inflammation gathered from around the implants.

Detailed Description: Following signing the consent document the following will occur:

1. Screening Patients will complete standard medical and dental health history forms, followed by a study specific screening questionnaire. if the patient is deemed eligible, the patient will be examined clinically. The clinical examination will include diagnostic procedures typical of an implant recall visit. Initially, the sulcus will be probed with a periodontal probe; if bleeding on probing is elicited, then a radiograph will be made.

The following shall be done to screen the patients:

1. Periapical radiographs of the implant to determine bone loss, if bone loss is found the patient will be excluded from the study.

2. Bleeding on probing will be assessed by using a periodontal probe passed along the gingival crevice, and bleeding scores will be assessed passing the probe with a force of 0.25 N.

3. If a woman is of childbearing age and suspected of being pregnant, a urine pregnancy test shall be made at this time.

If the patient exhibits no bleeding on probing, or signs of mesial/distal bone loss greater than 1mm from the accepted reference point on the implant system the patient will be excluded from the study.

2. Subject allocation

Subjects will be assigned with equal allocation into the following groups:

1. Test group: will receive 0.1 ml prepared Simvastatin in 1.2% (W/V) Lecithin/isopropyl palmitate solution (Lipoil®), Poloxamer 407 gel (Polox Gel 20%®) applied topically into the peri-implant gingival sulcus using a plastic syringe with a blunt cannula.

2. Control group: will receive a placebo of 0.1 ml 40% (W/V) Lecithin/isopropyl palmitate solution (Lipoil®), Poloxamer 407 gel (Polox Gel 20%®) applied topically into the peri implant gingival sulcus using a plastic syringe with a blunt cannula.

3. Baseline measurements Baseline measurements will be made at least 48 hours after screening (allowing time for complete hemostasis of peri-implant crevicular mucosa after bleeding induced by probing in the screening visit).

Following baseline measurements, Test and Control interventions will be administered.

The baseline measurements include the following:

1. Peri-implant crevicular fluid (PICF) collection: Each implant site will be isolated with cotton rolls and light air will be applied over the side to eliminate ambient salivary contamination of the PICF sample. Sampling will be done using paper strips that are inserted with cotton forceps into the gingival crevice until mild resistance is felt. After gingival crevicular fluid (GCF) collection, the volumes are immediately quantified using the Periotron 8000 instrument.

2. Gingival Index: Using the Gingival index by Loe and Sillness 1963, the inflammatory state of the buccal, lingual, mesial and distal surfaces of the gingiva will be scored using the following score system:

0= normal gingival without signs of inflammation, no inflammation, no bleeding

1. minor inflammation , slight discoloration, minor surface alterations, no bleeding

2. moderate inflammation, redness, swelling, bleeding upon probing and under pressure

3. strong inflammation, strong redness and swelling, tendency toward spontaneous bleeding, ulcerations After a score is given to each site, the scores will be summed together and divided by 4 to reach an overall score.

3. Probing depth: Measured by a calibrated periodontal probe at 6 different locations, mesiobuccal, midbuccal, distobuccal, distolingual, midlingual, and mesiolingual.

4. Administration of test and control intervention will be delivered into the peri- implant gingival sulcus using a plastic syringe with a blunt cannula following baseline measurements. 0.1ml of gel will be administered with a blunt cannula evenly distributed in the peri-implant sulcus. The investigator will not know whether the subject is receiving the active or control intervention.

5. Recall appointments and measurements Both Test and Control subjects will be scheduled recall visits. Recalls will be done at 24 hours (+ or - 3 hours), 1 week (+ or - 12 hours), and 1 month (+ or - 11 days).

On each recall visit, the following procedures will take place:

1. PICF collection: procedures identical to those performed on the baseline visit

2. Gingival index recording: Identical to that performed on the baseline visit

3. probing depth measurement : procedures identical to that performed at the baseline visit \* these measurements will be made by a blinded investigator

6. Cytokine analysis Due to study constraints, not all PICF samples collected from subjects will be analyzed in the pilot study. The samples that will be analyzed will be selected randomly from the study population. Cytokine samples from only 13 randomly selected subjects from the test group, as well as 13 randomly selected subjects from the control group will be analyzed. Of these randomly selected samples, only those collected at baseline, 24 hours, and at 1 week will be analyzed. The remaining cytokine samples will be evaluated as part of a later study. Cytokine quantities will be determined using; a commercial 22 multipixed fluorescent bead based immunoassay and luminex 100 IS instrument. The kit used is the MILLIPLEX map Human Cytokine/ Chemokine Magnetic Bead Panel- Immunology Multiplex Assay (HCYTOMAG-60K) capable of detecting IL-1Beta;, TNF-Alpha;, IL-6, IL-8.

The study in total will take 1 month and 2 days. All visits will generally take 0.5-1.5 hours. No long term follow up will be required.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 46

Inclusion Criteria

Read, understand, and sign the informed consent forms
Have at least 1 dental implant
Have no evidence of peri-implantitis as evidenced by mesial and distal bone loss more than 1 mm from the accepted reference point round the implants on the periapical radiograph
Demonstrate peri-implant mucositis as evidenced by bleeding on probing with 0.25 N/cm

Exclusion Criteria

Have allergic reactions to simvastatin
Have peri-implantitis as evidenced by more than 1 mm of mesial and distal bone loss from an accepted reference point on the implants on the periapical radiograph
Demonstrate no bleeding on probing with 0.25 N/ cm
Have uncontrolled systemic disease
Pregnancy or females who suspect/may be pregnant, as well as nursing and breast feeding mothers
Take statin / HMG-CoA reductase inhibitor medications
Smokers
Require antibiotic prophylaxis
Take anti-inflammatory medication, immunosuppressive medications or immunosuppressed patients
Have paraben allergies
Have soybean allergies

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Simvastatin group (Treatment)	Simvastatin	Will receive 0.1 ml prepared Simvastatin in 1.2% (W/V) Lecithin/isopropyl palmitate solution (Lipoil®), Poloxamer 407 gel (Polox Gel 20%®) applied topically into the peri-implant gingival sulcus using a plastic syringe with a blunt cannula.
Control group	Placebo	Will receive a placebo of 0.1 ml 40% (W/V) Lecithin/isopropyl palmitate solution (Lipoil®), Poloxamer 407 gel (Polox Gel 20%®) applied topically into the peri-implant gingival sulcus using a plastic syringe with a blunt cannula.

Primary Outcome Measures

Name	Time	Method
Change in Interleukin 6 24 Hours - 1 Week	24 hours - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 1 B 24 Hours - 1 Week	24 hours - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 6 Baseline to 1 Week	Baseline - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 8 at Base to 24 Hours	Baseline - 24 hours	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Tumor Necrosis Factor Alpha at Base to 1 Week	Baseline - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 1 B at Base to 24 Hours	Baseline- 24hrs	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 6 at Base to 24 Hours	Baseline - 24 hours	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 1 B at Base to 1 Week	Baseline - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 8 24 Hours to 1 Week	24 hours - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Tumor Necrosis Factor Alpha at Base to 24 Hours	Baseline- 24hrs	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Tumor Necrosis Factor Alpha 24 Hours to 1 Week	24hrs - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)
Change in Interleukin 8 at Base to 1 Week	Baseline - 1 week	Measuring the change in Cytokine levels in the peri implant crevicular fluid ( Fluid around the implant) by extracting the fluid and measuring the levels of the interlukins in the fluids in Micrograms per dicileter ( ug/dl)

Secondary Outcome Measures

Name	Time	Method
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at Baseline	Baseline	Using the Gingival index by Loe and Sillness 1963, the inflammatory state of the Buccal, Lingual, Mesial and Distal Surfaces of the gingiva will be scored using the following score system: 0= normal gingival without signs of inflammation, no inflammation, no bleeding 1. minor inflammation , slight discoloration, minor surface alterations, no bleeding 2. moderate inflammation, redness, swelling, bleeding upon probing and under pressure 3. strong inflammation, strong redness and swelling, tendency toward spontaneous bleeding, ulcerations After a score is given to each site the scores are summed together and divided by 4 to reach an overall score.
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 24 Hours	24 hours	Using the Gingival index by Loe and Sillness 1963, the inflammatory state of the Buccal, Lingual, Mesial and Distal Surfaces of the gingiva will be scored using the following score system: 0= normal gingival without signs of inflammation, no inflammation, no bleeding 1. minor inflammation , slight discoloration, minor surface alterations, no bleeding 2. moderate inflammation, redness, swelling, bleeding upon probing and under pressure 3. strong inflammation, strong redness and swelling, tendency toward spontaneous bleeding, ulcerations After a score is given to each site the scores are summed together and divided by 4 to reach an overall score.
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 1 Week	1 week	Using the Gingival index by Loe and Sillness 1963, the inflammatory state of the Buccal, Lingual, Mesial and Distal Surfaces of the gingiva will be scored using the following score system: 0= normal gingival without signs of inflammation, no inflammation, no bleeding 1. minor inflammation , slight discoloration, minor surface alterations, no bleeding 2. moderate inflammation, redness, swelling, bleeding upon probing and under pressure 3. strong inflammation, strong redness and swelling, tendency toward spontaneous bleeding, ulcerations After a score is given to each site the scores are summed together and divided by 4 to reach an overall score.
Probing Depth Level (Averaged Over 6 Sites) at 1 Week	1 week	Depth will be measured by a calibrated periodontal probe at 6 different locations, Mesiobuccal, Mid Buccal, Distobuccal, Disto Lingual, Mid Lingual and Mesio Lingual. The longitudinal course will be characterized with respect to the categorical outcome, presence of any bleeding on probing, with initial emphasis being placed upon transition approaches, with specific attention given to shifts from clinically unacceptable to clinically acceptable designations. probing depth is considered variable from one person to the other however a decrease or a shallower probing depth overtime is gererally seen as an improvement , thus any decrease in probing depth would be seen as signs of healing.
Probing Depth Level (Averaged Over 6 Sites) at Baseline	Baseline	Depth will be measured by a calibrated periodontal probe at 6 different locations, Mesiobuccal, Mid Buccal, Distobuccal, Disto Lingual, Mid Lingual and Mesio Lingual. The longitudinal course will be characterized with respect to the categorical outcome, presence of any bleeding on probing, with initial emphasis being placed upon transition approaches, with specific attention given to shifts from clinically unacceptable to clinically acceptable designations. probing depth is considered variable from one person to the other however a decrease or a shallower probing depth overtime is gererally seen as an improvement , thus any decrease in probing depth would be seen as signs of healing.
Probing Depth Level (Averaged Over 6 Sites) at 24 Hours	24 hours	Depth will be measured by a calibrated periodontal probe at 6 different locations, Mesiobuccal, Mid Buccal, Distobuccal, Disto Lingual, Mid Lingual and Mesio Lingual. The longitudinal course will be characterized with respect to the categorical outcome, presence of any bleeding on probing, with initial emphasis being placed upon transition approaches, with specific attention given to shifts from clinically unacceptable to clinically acceptable designations. probing depth is considered variable from one person to the other however a decrease or a shallower probing depth overtime is gererally seen as an improvement , thus any decrease in probing depth would be seen as signs of healing.