Peri-implant MucositisPhase 2NCT03400475

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

A Phase 2 study testing Simvastatin in people with Peri-implant Mucositis, run by Ahmed Mohamed Mahrous at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 80 yearsHealthy volunteers can take part
Conditions the study is for: Peri-implant Mucositis
What is being tested?: Simvastatin
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 46 participants
Where: 1 siteUnited States
Study dates: 23 Apr 2015to 24 Oct 2016
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 80 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Show all 11Show fewer

Smokers
Require antibiotic prophylaxis
Take anti-inflammatory medication, immunosuppressive medications or immunosuppressed patients
Have paraben allergies
Have soybean allergies

Trial locations and contacts

1 site in 1 country.

United States1 site

University of Iowa College of Dentistry and Dental Clinics
Iowa City, Iowa, 52242

Other trials in United States

About this study

Official title: The Use of Topical Subgingival Application of Simvastatin Gel in the Treatment of Peri-Implant Mucositis: A Pilot Study

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.

Read the detailed description

Following signing the consent document the following will occur:

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:
Periapical radiographs of the implant to determine bone loss, if bone loss is found the patient will be excluded from the study.
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.
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.
Subject allocation Subjects will be assigned with equal allocation into the following groups:
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.
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.
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:
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.
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
minor inflammation , slight discoloration, minor surface alterations, no bleeding
moderate inflammation, redness, swelling, bleeding upon probing and under pressure
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.
Probing depth: Measured by a calibrated periodontal probe at 6 different locations, mesiobuccal, midbuccal, distobuccal, distolingual, midlingual, and mesiolingual.
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.
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:
PICF collection: procedures identical to those performed on the baseline visit
Gingival index recording: Identical to that performed on the baseline visit
probing depth measurement : procedures identical to that performed at the baseline visit * these measurements will be made by a blinded investigator
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.

Conditions: Peri-implant Mucositis
Being tested: Simvastatin, Placebo
Keywords: topical, subgingival, simvastatin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

SimvastatinDrug
Also called Simvastatin Powder U.S.P.
One topical application in peri-implant gingival crevice
PlaceboOther
Also called Lecithin/isopropyl palmitate solution, Poloxamer 407 gel, Lipoil®, Polox Gel 20%®
One topical application in peri-implant gingival crevice

Study groups in NCT03400475
Study group	Role	What they receive
Simvastatin group (Treatment)	Experimental	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. Receives: Drug: Simvastatin
Control group	Placebo comparator	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. Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in Interleukin 1 B at Base to 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)
Measured: Baseline- 24hrs
Change in Interleukin 1 B at Base to 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)
Measured: Baseline - 1 week
Change in Interleukin 1 B 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)
Measured: 24 hours - 1 week
Change in Interleukin 6 at Base to 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)
Measured: Baseline - 24 hours
Change in Interleukin 6 Baseline to 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)
Measured: Baseline - 1 week
Change in Interleukin 6 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)
Measured: 24 hours - 1 week
Change in Interleukin 8 at Base to 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)
Measured: Baseline - 24 hours
Change in Interleukin 8 at Base to 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)
Measured: Baseline - 1 week
Change in Interleukin 8 24 Hours to 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)
Measured: 24 hours - 1 week
Change in Tumor Necrosis Factor Alpha at Base to 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)
Measured: Baseline- 24hrs
Change in Tumor Necrosis Factor Alpha at Base to 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)
Measured: Baseline - 1 week
Change in Tumor Necrosis Factor Alpha 24 Hours to 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)
Measured: 24hrs - 1 week

Secondary outcomes (6)

Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 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.
Measured: Baseline
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 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.
Measured: 24 hours
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 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.
Measured: 1 week
Probing Depth Level (Averaged Over 6 Sites) at 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.
Measured: Baseline
Probing Depth Level (Averaged Over 6 Sites) at 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.
Measured: 24 hours
Probing Depth Level (Averaged Over 6 Sites) at 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.
Measured: 1 week

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

23 Apr 201524 Oct 2016

First posted17 Jan 2018
Study start23 Apr 2015
Primary completion24 Oct 2016
Study completion24 Oct 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (7)Papers the sponsor has linked to this study.
Other trials for Peri-implant MucositisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Investigator, Outcomes assessor
Enrolment: 46 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03400475
Sponsor's protocol ID: 201410714
Status last verified: Nov 2018
First submitted: 2 Jan 2018
Last updated: 19 Dec 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Pradeep AR, Thorat MS. Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: a randomized clinical trial. J Periodontol. 2010 Feb;81(2):214-22. doi: 10.1902/jop.2009.090429.
PubMed 20151799
Liskmann S, Vihalemm T, Salum O, Zilmer K, Fischer K, Zilmer M. Correlations between clinical parameters and interleukin-6 and interleukin-10 levels in saliva from totally edentulous patients with peri-implant disease. Int J Oral Maxillofac Implants. 2006 Jul-Aug;21(4):543-50.
PubMed 16955604
Konttinen YT, Lappalainen R, Laine P, Kitti U, Santavirta S, Teronen O. Immunohistochemical evaluation of inflammatory mediators in failing implants. Int J Periodontics Restorative Dent. 2006 Apr;26(2):135-41.
PubMed 16642902
Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 and IL-8 production in epithelial cells. J Dent Res. 2006 Jun;85(6):520-3. doi: 10.1177/154405910608500608.
PubMed 16723648
Guncu GN, Akman AC, Gunday S, Yamalik N, Berker E. Effect of inflammation on cytokine levels and bone remodelling markers in peri-implant sulcus fluid: a preliminary report. Cytokine. 2012 Aug;59(2):313-6. doi: 10.1016/j.cyto.2012.04.024. Epub 2012 May 14.
PubMed 22592038
Duarte PM, de Mendonca AC, Maximo MB, Santos VR, Bastos MF, Nociti Junior FH. Differential cytokine expressions affect the severity of peri-implant disease. Clin Oral Implants Res. 2009 May;20(5):514-20. doi: 10.1111/j.1600-0501.2008.01680.x. Epub 2009 Mar 11.
PubMed 19302394
Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol. 2000 Aug;36(2):427-31. doi: 10.1016/s0735-1097(00)00771-3.
PubMed 10933353

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Home-Use Dual-Light Antibacterial Photodynamic Therapy for Peri-Implant Mucositis in Full-Arch Implant Prostheses
Peri Implant Mucositis, Dental Implant Rehabilitation
Not yet recruiting
Adjunctive Diode Laser Therapy for Peri-Implant Mucositis
Peri-implant Mucositis
Not yet recruitingObservational study
Short Versus Standard Dental Implants: Clinical and Biomarker Outcomes
Peri-Implant Mucositis
RecruitingObservational study
Impact of Smoking on Immune Responses in Peri-implant Health and Disease
Peri-Implant Health, Peri Implant Mucositis

All Peri-implant Mucositis trials

Study at a glance

From the registry record, last updated by the sponsor on 19 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: The Use of Topical Subgingival Application of Simvastatin Gel in the Treatment of Peri-Implant Mucositis: A Pilot Study
ClinicalTrials.gov ID: NCT03400475
Acronym / sponsor ID: 201410714
Conditions: Peri-implant Mucositis
Keywords: topical, subgingival, simvastatin
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 46 participants (actual)
Lead sponsor: Ahmed Mohamed MahrousUniversity, hospital or other
Collaborators: Greater New York Academy of Prosthodontics, American College of Prosthodontists Education Foundation, University of Iowa
Study start: 23 Apr 2015 (actual)
Primary completion: 24 Oct 2016 (actual)
Study completion: 24 Oct 2016 (actual)
First posted: 17 Jan 2018 (actual)
Results: Posted 29 Nov 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

Following signing the consent document the following will occur:

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:
Periapical radiographs of the implant to determine bone loss, if bone loss is found the patient will be excluded from the study.
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.
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.
Subject allocation Subjects will be assigned with equal allocation into the following groups:
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.
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.
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:
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.
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
minor inflammation , slight discoloration, minor surface alterations, no bleeding
moderate inflammation, redness, swelling, bleeding upon probing and under pressure
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.
Probing depth: Measured by a calibrated periodontal probe at 6 different locations, mesiobuccal, midbuccal, distobuccal, distolingual, midlingual, and mesiolingual.
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.
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:
PICF collection: procedures identical to those performed on the baseline visit
Gingival index recording: Identical to that performed on the baseline visit
probing depth measurement : procedures identical to that performed at the baseline visit * these measurements will be made by a blinded investigator
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 design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Simvastatin group (Treatment)	Experimental	Drug: SimvastatinWill 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 comparator	Other: PlaceboWill 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.

Who may qualify

Ages: 18 to 80 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

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

Key exclusion criteria (11 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
SimvastatinAlso: Simvastatin Powder U.S.P.One topical application in peri-implant gingival crevice	Drug	Simvastatin group (Treatment)
PlaceboAlso: Lecithin/isopropyl palmitate solution, Poloxamer 407 gel, Lipoil®, Polox Gel 20%®One topical application in peri-implant gingival crevice	Other	Control group

Primary outcome

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)

6 secondary outcomes

Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at Baseline
Time frame: Baseline
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 24 Hours
Time frame: 24 hours
Gingival Index Level (Derived From an Average Over the 4 Implant Sites) at 1 Week
Time frame: 1 week
Probing Depth Level (Averaged Over 6 Sites) at Baseline
Time frame: Baseline
Probing Depth Level (Averaged Over 6 Sites) at 24 Hours
Time frame: 24 hours
Probing Depth Level (Averaged Over 6 Sites) at 1 Week
Time frame: 1 week

Results and safety

Results posted to the registry on 29 Nov 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Test Group	24	24
Control Group	22	22

Primary outcome: Change in Interleukin 1 B at Base to 24 Hours

Time frame: Baseline- 24hrs. Mean (Standard Deviation). Unit: Micrograms per deciliter (ug/dl)

Measure	Simvastatin Group ( Treatment ) n = 24	Control Group n = 22
Value	-1.075 (15.587)	1.013 (5.273)

Simvastatin Group ( Treatment ) vs Control Group: Mean Difference (Final Values): -2.088, p = 0.90, Wilcoxon (Mann-Whitney)

Primary outcome: Change in Interleukin 1 B at Base to 1 Week

Time frame: Baseline - 1 week. Mean (Standard Deviation). Unit: Micrograms per deciliter (ug/dl)

Measure	Simvastatin Group ( Treatment ) n = 24	Control Group n = 22
Value	2.5016 (15.4701)	-1.095 (8.6050)

Simvastatin Group ( Treatment ) vs Control Group: Mean Difference (Final Values): 3.59, p = 0.90, Wilcoxon (Mann-Whitney)

Primary outcome: Change in Interleukin 1 B 24 Hours - 1 Week

Time frame: 24 hours - 1 week. Mean (Standard Deviation). Unit: Micrograms per deciliter (ug/dl)

Measure	Simvastatin Group ( Treatment ) n = 24	Control Group n = 22
Value	3.577 (14.137)	-2.108 (10.569)

Simvastatin Group ( Treatment ) vs Control Group: Mean Difference (Final Values): 3.596, p = 0.90, Wilcoxon (Mann-Whitney)

Primary outcome: Change in Interleukin 6 at Base to 24 Hours

Time frame: Baseline - 24 hours. Mean (Standard Deviation). Unit: Micrograms per deciliter (ug/dl)

Measure	Simvastatin Group ( Treatment ) n = 24	Control Group n = 22
Value	0.118 (0.954)	0.201 (0.880)

Simvastatin Group ( Treatment ) vs Control Group: Mean Difference (Final Values): -0.083, p = 0.90, Wilcoxon (Mann-Whitney)

6 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Test Group	0 of 24 (0%)	0 of 24 (0%)	Not reported
Control Group	0 of 22 (0%)	0 of 22 (0%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 20151799Pradeep AR, Thorat MS. Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: a randomized clinical trial. J Periodontol. 2010 Feb;81(2):214-22. doi: 10.1902/jop.2009.090429.
Background: PubMed 16955604Liskmann S, Vihalemm T, Salum O, Zilmer K, Fischer K, Zilmer M. Correlations between clinical parameters and interleukin-6 and interleukin-10 levels in saliva from totally edentulous patients with peri-implant disease. Int J Oral Maxillofac Implants. 2006 Jul-Aug;21(4):543-50.
Background: PubMed 16642902Konttinen YT, Lappalainen R, Laine P, Kitti U, Santavirta S, Teronen O. Immunohistochemical evaluation of inflammatory mediators in failing implants. Int J Periodontics Restorative Dent. 2006 Apr;26(2):135-41.
Background: PubMed 16723648Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 and IL-8 production in epithelial cells. J Dent Res. 2006 Jun;85(6):520-3. doi: 10.1177/154405910608500608.
Background: PubMed 22592038Guncu GN, Akman AC, Gunday S, Yamalik N, Berker E. Effect of inflammation on cytokine levels and bone remodelling markers in peri-implant sulcus fluid: a preliminary report. Cytokine. 2012 Aug;59(2):313-6. doi: 10.1016/j.cyto.2012.04.024. Epub 2012 May 14.
Background: PubMed 19302394Duarte PM, de Mendonca AC, Maximo MB, Santos VR, Bastos MF, Nociti Junior FH. Differential cytokine expressions affect the severity of peri-implant disease. Clin Oral Implants Res. 2009 May;20(5):514-20. doi: 10.1111/j.1600-0501.2008.01680.x. Epub 2009 Mar 11.
Background: PubMed 10933353Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol. 2000 Aug;36(2):427-31. doi: 10.1016/s0735-1097(00)00771-3.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Ahmed M Mahrous, B.D.S., M.S. principal investigator

University of Iowa College of Dentistry and Dental Clinics

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Simvastatin in people with Peri-implant Mucositis, run by Ahmed Mohamed Mahrous at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Interleukin 1 B at Base to 24 Hours (time frame: Baseline- 24hrs). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03400475, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2018.