Nobio Clinical Study - Demineralization Prevention With a New Antibacterial Restorative Composite

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT04059250
• Collaborator: Nobio Ltd. (Industry)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 9.4
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

Nobio has developed dental restorative materials with long term antibacterial properties in order to fight recurrent decay/caries around restorations. These composites with incorporated non-leaching antibacterial agents might overcome the vicious circle of newly developed cavities around freshly placed fillings.

The investigators will ask lower partial denture wearers to allow them to place a "gap model" with the Nobio-composite and enamel slab in one denture flange. In the other denture flange a gap model with a standard composite will be placed as control. In the laboratory the investigators will test with established methods for demineralization/caries prevention in the test and control enamel slabs, respectively.

Condition or Disease	Intervention/Treatment	Phase
Dental Caries; Denture, Partial, Removable	Device: Nobio composite; Device: traditional composite	N/A

Detailed Description

As a major issue in dentistry, it has been stated that two-thirds of all restorative dentistry involves the replacement of failed restorations. Secondary caries indicates a lesion developing at the margins of an existing restoration and is the major reason for replacement of amalgam and composite resin restorations in operative dentistry.

In research the use of experimental intra-oral caries models dealing with caries prevention has increased. The most realistic experimental model is the in vivo model that uses living teeth, followed by the in situ model using specimens with natural surfaces held in the mouth during the experimental period. In situ models have the potential to study both fundamental aspects of the caries process as well as more applied research problems in caries prevention in human subjects without actually causing caries in the natural dentition.

To simulate a failed interface between a tooth and a restoration, a gap can be formed between an enamel slab and the restoration prior to a cariogenic challenge. The "gap-model" will be inserted for instance into the denture flanges, and the cariogenic challenge occurs inside the mouth during the wear period..

Nobio has developed dental restorative materials with long term antibacterial properties in order to fight recurrent decay around restorations. These composites with incorporated non-leaching antibacterial agents might overcome the vicious circle of newly developed cavities around freshly placed fillings. The ongoing caries activity due to bacteria around the filling may be interrupted by quaternary ammonium silica dioxide (QASi) particles incorporated in the test composite at 1.2% (by weight). These particles are members of the Nobio Antimicrobial Particle (NAP) family (Nobio, Israel). QASi are synthesized to form a high concentration of antimicrobial groups that are covalently-bound onto a carrier core, such as silica. The resulting micro or nano-sized QASi particles are mixed with other fillers of the dental composite material, during manufacturing. Following in situ placement and light-initiated polymerization, QASi particles are permanently retained in the final dental restoration. Laboratory studies have shown that the quaternary ammonium silica particles are potent antibacterial agents, do not leach out in contrast to other antimicrobials or caries preventive active substances, inhibit the breakdown of the composite, and maintain antibacterial activity over time.

The study is an in situ study. Subjects, wearing lower partial dentures with acrylic flanges on both sides of the mouth will be recruited. On each side of the denture an enamel slab will be placed next to a composite, separated by a tiny gap. On one side of the denture the composite will be Nobio's antibacterial composite, on the other side a regular composite (a Nobio composite w/o particles or another commercial composite will serve as control material. Enamel slab and composite will be recessed into the flange, allowing microbial plaque to accumulate on top of it and especially in the gap.

After wearing the dentures for four weeks with the slabs, decalcification - ΔZ mineral loss - in the enamel slabs adjacent to the gap will be determined by cross-section microhardness testing in the laboratory. Average ΔZ mineral loss will be calculated for the Nobio group and the control group, and difference will be tested for statistical significance.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: In-situ testing using a gap model inside the two flanges of a removable partial dentureIn-situ testing using a gap model inside the two flanges of a removable partial denture
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: Subjects are not aware, which side of the denture will harbor the gap model with the Nobio composite and which side harbors the traditional composite. Laboratory microhardness measurements will be conducted while keeping the operator blind.
• Primary Purpose: Prevention
• Official Title: Nobio In Situ Clinical Study - Pilot Study
• Actual Study Start Date: May 28, 2019
• Actual Primary Completion Date: Mar 10, 2020
• Actual Study Completion Date: Mar 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nobio flange On the Nobio flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it the Nobio composite.	Device: Nobio composite; Nobio has developed a bactericidal composite, which does not leak out the bactericidal nano fillers
Placebo Comparator: Traditional composite flange On the traditional composite flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it a traditional composite.	Device: traditional composite; traditional composite which has no bactericidal activities

Outcome Measures

Primary Outcome Measures

1. Mineral Loss ΔZ [mineral loss ΔZ is determined after the 4 week wearing period]

   The mineral loss is determined in the laboratory using cross-sectional microhardness testings of the enamel after the 4-weeks wearing period of the gap-model. The overall relative mineral loss, ΔZ, for each sample is calculated by creating a hardness profile curve by plotting normalized volume percent mineral against distance from the outer enamel surface. The area under the curve that represents ΔZ (µm * vol % mineral) is calculated using Simpson's integration rule.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• aged between 18 and 80 years,

• have at least six natural teeth remaining and have a recent history of dental caries

• wearing lower partial denture (with replaced teeth on both sides of the mouth)

• willing to wear their denture during the night

• are in good health, of either gender

• are in good current oral health with no active caries or periodontal disease (but with a history of caries)

• have an understanding of the study

• have saliva flow within the normal range (stimulated saliva flow rate of greater than 0.7 ml/minute)

• no antibiotics for the last three months

• willing to comply with all study procedures and protocols,

• residing in San Francisco or other nearby locales with community water fluoridation (to eliminate water fluoridation as a potential confounding variable)

• able to give written consent themselves

• must be able to read and understand English

• willing to sign the "Authorization for Release of Personal Health Information and Use of Personally Unidentified Study Data for Research" form; data will only be used for research

Exclusion Criteria:

• subjects who have less than 6 natural teeth remaining

• subjects who have used a 5,000 ppm fluoride toothpaste in the last 6 months

• subjects who have used Chlorhexidine or any other antimicrobials (cetylpyridinium etc.) in the last 6 months

• show evidence of extremely poor oral hygiene

• subjects suffering from systemic diseases, significant past or medical history with conditions that may affect oral health or oral flora (i.e. diabetes, HIV, heart conditions that require antibiotic prophylaxis)

• taking medications that may affect the oral flora or salivary flow (e.g. antibiotic use in the past three months, drugs associated with dry mouth / xerostomia)

• other conditions that may decrease the likelihood of adhering to study protocol

• in-office fluoride treatment within the last three months

• subjects who will leave the area and are unable to complete the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF School of Dentistry, Preventive and Restorative Dental Sciences	San Francisco	California	United States	94143

Sponsors and Collaborators

• University of California, San Francisco
• Nobio Ltd.

Investigators

• Principal Investigator: Peter Rechmann, UCSF - School of Dentistry - Preventive and Restorative Dental Sciences

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 10, 2018

More Information

Publications

• Benelli EM, Serra MC, Rodrigues AL Jr, Cury JA. In situ anticariogenic potential of glass ionomer cement. Caries Res. 1993;27(4):280-4.
• Beyth N, Houri-Haddad Y, Baraness-Hadar L, Yudovin-Farber I, Domb AJ, Weiss EI. Surface antimicrobial activity and biocompatibility of incorporated polyethylenimine nanoparticles. Biomaterials. 2008 Nov;29(31):4157-63. doi: 10.1016/j.biomaterials.2008.07.003. Epub 2008 Aug 3.
• Beyth N, Yudovin-Farber I, Bahir R, Domb AJ, Weiss EI. Antibacterial activity of dental composites containing quaternary ammonium polyethylenimine nanoparticles against Streptococcus mutans. Biomaterials. 2006 Jul;27(21):3995-4002. Epub 2006 Mar 27.
• Beyth N, Yudovin-Fearber I, Domb AJ, Weiss EI. Long-term antibacterial surface properties of composite resin incorporating polyethyleneimine nanoparticles. Quintessence Int. 2010 Nov-Dec;41(10):827-35.
• Chatzistavrou X, Velamakanni S, DiRenzo K, Lefkelidou A, Fenno JC, Kasuga T, Boccaccini AR, Papagerakis P. Designing dental composites with bioactive and bactericidal properties. Mater Sci Eng C Mater Biol Appl. 2015;52:267-72. doi: 10.1016/j.msec.2015.03.062. Epub 2015 Mar 28.
• Clasen AB, Ogaard B. Experimental intra-oral caries models in fluoride research. Acta Odontol Scand. 1999 Dec;57(6):334-41. Review.
• Dijkman GE, Arends J. Secondary caries in situ around fluoride-releasing light-curing composites: a quantitative model investigation on four materials with a fluoride content between 0 and 26 vol%. Caries Res. 1992;26(5):351-7.
• Gorton J, Featherstone JD. In vivo inhibition of demineralization around orthodontic brackets. Am J Orthod Dentofacial Orthop. 2003 Jan;123(1):10-4.
• Hals E, Nernaes A. Histopathology of in vitro caries developing around silver amalgam fillings. Caries Res. 1971;5(1):58-77.
• Hollanders ACC, Kuper NK, Maske TT, Huysmans MDNJM. Secondary Caries in situ Models: A Systematic Review. Caries Res. 2018;52(6):454-462. doi: 10.1159/000487200. Epub 2018 Apr 5.
• Kidd EA. Diagnosis of secondary caries. J Dent Educ. 2001 Oct;65(10):997-1000.
• Kuper NK, Montagner AF, van de Sande FH, Bronkhorst EM, Opdam NJ, Huysmans MC. Secondary Caries Development in in situ Gaps next to Composite and Amalgam. Caries Res. 2015;49(5):557-63. doi: 10.1159/000438728. Epub 2015 Sep 26.
• Maupomé G, Sheiham A. Criteria for restoration replacement and restoration life-span estimates in an educational environment. J Oral Rehabil. 1998 Dec;25(12):896-901.
• Zero DT. In situ caries models. Adv Dent Res. 1995 Nov;9(3):214-30; discussion 231-4. Review.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT04059250
• Other Study ID Numbers: P0535966
• First Posted: Aug 16, 2019
• Last Update Posted: Mar 12, 2021
• Last Verified: Mar 1, 2021

• 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: Yes
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of California, San Francisco: composite bactericidal; caries prevention
• Additional relevant MeSH terms: Dental Caries

Study Results

Participant Flow

Recruitment Details	each participant enrolled had TWO flanges (right and left side of the mouth) in her/his removable partial denture; the study design is a split-mouth design - in one side the "Nobio Flange"- the Nobio composite was inserted, one the control side - the "control flange" - the traditional control composite was inserted

Arm/Group Title	Nobio Flange	Traditional Composite Control Flange
Arm/Group Description	On the Nobio flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it the Nobio composite. Nobio composite: Nobio has developed a bactericidal composite, which does not leak out the bactericidal nano fillers	On the traditional control composite flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it a traditional control composite. traditional composite: traditional composite which has no bactericidal activities
Period Title: Overall Study
STARTED	25	25
COMPLETED	25	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All participants received both the Nobio flange and the traditional composite control flange. On the Nobio flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it the Nobio composite. Nobio composite: Nobio has developed a bactericidal composite, which does not leak out the bactericidal nano fillers On the traditional composite control flange side of the lower same partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it a traditional composite. traditional composite: traditional composite which has no bactericidal activities
Overall Participants	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.7 (14.1)
Sex: Female, Male (Count of Participants)
Female	8 32%
Male	17 68%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 12%
Not Hispanic or Latino	22 88%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Mineral Loss ΔZ
Description	The mineral loss is determined in the laboratory using cross-sectional microhardness testings of the enamel after the 4-weeks wearing period of the gap-model. The overall relative mineral loss, ΔZ, for each sample is calculated by creating a hardness profile curve by plotting normalized volume percent mineral against distance from the outer enamel surface. The area under the curve that represents ΔZ (µm * vol % mineral) is calculated using Simpson's integration rule.
Time Frame	mineral loss ΔZ is determined after the 4 week wearing period

Outcome Measure Data

Analysis Population Description

From the original 25 subjects data of the first 5 subjects were used for a sample size calculation. The sample size calculation determined data from 17 subjects would be needed. To account for loss due to follow-up issues, we recruited 20 subjects. 1 subject did not follow the instructions (required wearing time), 2 sample/data sets could not be retrieved due to Covid-19 shelter-in-place restrictions. Results of the first 5 were not included due to statisticians concerns for clean statistics.

Arm/Group Title	Nobio Flange	Traditional Composite Flange
Arm/Group Description	On the Nobio flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it the Nobio composite. Nobio composite: Nobio has developed a bactericidal composite, which does not leak out the bactericidal nano fillers	On the traditional composite flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it a traditional composite. traditional composite: traditional composite which has no bactericidal activities
Measure Participants	17	17
Mean (Standard Deviation) [vol% * μm]]	235 (354)	774 (556)

Adverse Events

Time Frame	Four weeks study period, while wearing the composite inside the denture flanges
Arm/Group Title	Nobio Flange		Traditional Composite Flange
Arm/Group Description	On the Nobio flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it the Nobio composite. Nobio composite: Nobio has developed a bactericidal composite, which does not leak out the bactericidal nano fillers		On the traditional composite flange side of the lower partial denture the gap model will include a double sterilized piece of human enamel, a small gap, and next to it a traditional composite. traditional composite: traditional composite which has no bactericidal activities
All Cause Mortality
	Nobio Flange		Traditional Composite Flange
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Serious Adverse Events
	Nobio Flange		Traditional Composite Flange
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Nobio Flange		Traditional Composite Flange
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.