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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03400475
Recruitment Status : Completed
First Posted : January 17, 2018
Results First Posted : November 29, 2018
Last Update Posted : December 19, 2018
Sponsor:
Collaborators:
Greater New York Academy of Prosthodontics
American College of Prosthodontists Education Foundation
University of Iowa
Information provided by (Responsible Party):
Ahmed Mohamed Mahrous, University of Iowa

Tracking Information
First Submitted Date  ICMJE January 2, 2018
First Posted Date  ICMJE January 17, 2018
Results First Submitted Date  ICMJE March 8, 2018
Results First Posted Date  ICMJE November 29, 2018
Last Update Posted Date December 19, 2018
Actual Study Start Date  ICMJE April 23, 2015
Actual Primary Completion Date October 24, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2018)
  • Change in Interleukin 1 B at Base to 24 Hours [ Time Frame: 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 1 B at Base to 1 Week [ Time Frame: 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 24 Hours - 1 Week [ Time Frame: 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 at Base to 24 Hours [ Time Frame: 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 6 Baseline to 1 Week [ Time Frame: 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 6 24 Hours - 1 Week [ Time Frame: 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 8 at Base to 24 Hours [ Time Frame: 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 8 at Base to 1 Week [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 at Base to 1 Week [ Time Frame: 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 Tumor Necrosis Factor Alpha 24 Hours to 1 Week [ Time Frame: 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)
Original Primary Outcome Measures  ICMJE
 (submitted: January 8, 2018)
Change in gingival index (derived from an average over the 4 implant sites) [ Time Frame: Baseline, 24 hours, one week, and one month post-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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 28, 2018)
  • Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at Baseline [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Baseline [ Time Frame: 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 [ Time Frame: 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.
  • Probing Depth Level (Averaged Over 6 Sites) at 1 Week [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2018)
  • Change in probing depth (averaged over 6 sites) [ Time Frame: Baseline, 24 hours, one week, and one month post-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.
  • Change in 4 biochemical markers of inflammation, specifically IL-6, IL-8, IL-1-beta and TNF-alpha [ Time Frame: Baseline, 24 hours, and one week post-baseline ]
    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 will be the MILLIPLEX map Human Cytokine/ Chemokine Magnetic Bead Panel- Immunology Multiplex Assay (HCYTOMAG-60K) capable of detecting IL-6, IL-8, IL-1-beta and TNF-alpha.
  • Peri-implant crevicular fluid ( PICF) collection [ Time Frame: Baseline, 24 hours, one week, and one month post-baseline ]
    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 peri-implant crevicular fluid sample. Sampling will be done using paper strips that are inserted with cotton forceps into the gingival crevice until mild resistance is felt. After GCF (gingival crevicular fluid) collection, the volumes will be immediately quantified using the periotron 8000 instrument.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Use of Topical Subgingival Application of Simvastatin Gel in the Treatment of Peri-Implant Mucositis
Official Title  ICMJE The Use of Topical Subgingival Application of Simvastatin Gel in the Treatment of Peri-Implant Mucositis: A Pilot Study
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Only the study coordinator will know whether the intervention is simvastatin or control.
Primary Purpose: Treatment
Condition  ICMJE Peri-implant Mucositis
Intervention  ICMJE
  • Drug: Simvastatin
    One topical application in peri-implant gingival crevice
    Other Name: Simvastatin Powder U.S.P.
  • Other: Placebo
    One topical application in peri-implant gingival crevice
    Other Names:
    • Lecithin/isopropyl palmitate solution, Poloxamer 407 gel
    • Lipoil®, Polox Gel 20%®
Study Arms  ICMJE
  • Experimental: Simvastatin group (Treatment)
    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.
    Intervention: Drug: Simvastatin
  • Placebo Comparator: 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.
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 30, 2018)
46
Original Actual Enrollment  ICMJE
 (submitted: January 8, 2018)
53
Actual Study Completion Date  ICMJE October 24, 2016
Actual Primary Completion Date October 24, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03400475
Other Study ID Numbers  ICMJE 201410714
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ahmed Mohamed Mahrous, University of Iowa
Study Sponsor  ICMJE Ahmed Mohamed Mahrous
Collaborators  ICMJE
  • Greater New York Academy of Prosthodontics
  • American College of Prosthodontists Education Foundation
  • University of Iowa
Investigators  ICMJE
Principal Investigator: Ahmed M Mahrous, B.D.S., M.S. University of Iowa College of Dentistry and Dental Clinics
PRS Account University of Iowa
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP