Healozone Study to Evaluate the Safety and Efficacy of the Use of Ozone for Management of Dental Caries

• ClinicalTrials.gov Identifier: NCT00495495
• Recruitment Status: Completed
• First Posted: July 3, 2007
• Results First Posted: December 23, 2010
• Last Update Posted: February 20, 2015
• Sponsor: Indiana University
• Collaborators: Tufts University School of Dental Medicine; State University of New York at Buffalo
• Information provided by (Responsible Party): Indiana University

Tracking Information

• First Submitted Date: July 1, 2007
• First Posted Date: July 3, 2007
• Results First Submitted Date: October 12, 2010
• Results First Posted Date: December 23, 2010
• Last Update Posted Date: February 20, 2015
• Study Start Date: February 2007
• Actual Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 29, 2010)

ICDAS Severity Value [ Time Frame: Baseline and One Year ]

Clinically significant changes indicating caries progression are defined as changes in ICDAS severity values from 1 or 2 to a 3 or higher, or from a 3 or 4 to a 5 or higher. The severity criteria are as follows: 0 = Sound tooth surface.

1. = First visual change in enamel.
2. = Distinct visual change in enamel.
3. = Localized enamel breakdown due to caries with no visible dentin.
4. = Underlying dark shadow from dentin, with or without localized enamel breakdown.
5. = Distinct cavity with visible dentin.
6. = Extensive distinct cavity with visible dentin.

• Original Primary Outcome Measures (submitted: July 1, 2007): Primary efficacy measurement will be the ICDAS severity value [ Time Frame: one year ]

Current Secondary Outcome Measures (submitted: January 5, 2011)

• Change in Caries Lesion Activity [ Time Frame: Baseline and one year ]
  Change in caries lesion activity at One Year. All teeth were considered Active at Baseline Caries Lesion Activity score:

  1. = Inactive - surface of enamel appears whitish, brownish or black. Enamel may be shiny and feels hard and smooth when the tip of the probe is moved gently across the surface.
  2. = Active lesion - surface of enamel appears whitish/yellowish opaque with loss of luster. The surface feels rough when the tip of the probe is moved gently across the surface.
• Progression of Radiographic Scores at 12 Months [ Time Frame: one year ]
  Clinically significant changes for Bitewing x-rays indicating caries progression would be changes in x-ray criterion for lesion presence from "no" to "yes" or for lesion depth to a D1 or higher. The occlusal surface of study teeth will be evaluated using the following scale: Lesion presence: yes /no Lesion depth: E1 = outer half of enamel E2 = inner half of enamel D1 = outer third of dentin D2 = middle third of dentin D3 = inner third of dentin or greater/pulpal exposure
• Laser Fluorescence Progression-12 Month (Increase From <=20 to >=30) [ Time Frame: one year ]
  The change in DIAGNOdent measurements between baseline and twelve-month visits was used as an additional secondary endpoint. Clinically significant changes for DIAGNOdent indicating caries progression would be an increase in DIAGNOdent reading of 10 or more units or an increase in DIAGNOdent reading from below 20 to above 30 units. DIAGNOdent reading using a scale from 00 to 99, with 00 indicating no caries activity and 99 indicating a high level of activity.
• Laser Fluorescence Progression-12 Month (Increase at Least 10) [ Time Frame: one year ]
  The change in DIAGNOdent measurements between baseline and twelve-month visits was used as an additional secondary endpoint. Clinically significant changes for DIAGNOdent indicating caries progression would be an increase in DIAGNOdent reading of 10 or more units. DIAGNOdent reading using a scale from 00 to 99, with 00 indicating no caries activity and 99 indicating a high level of activity.

• Original Secondary Outcome Measures (submitted: July 1, 2007): Secondary efficacy parameters will be measured by caries lesion activity score, radiographic changes, and Diagnodent measurements. [ Time Frame: one year ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Healozone Study to Evaluate the Safety and Efficacy of the Use of Ozone for Management of Dental Caries
• Official Title: A Multi-Center Study to Evaluate the Safety and Efficacy of the Use of Ozone for the Management of Fissure Caries

Brief Summary

Caries means demineralization with the formation of cavities and pulp symptoms and necrosis as an end result. The acids in the mouth are mainly produced by oral bacteria like Streptococcus mutans from bacterial biofilms adhering to the tooth. Ozone has been shown to have a very strong bactericidal effect on bacteria causing dental caries. Baysan et al reported that there was a statistically significant reduction of streptococci in root caries lesions and saliva samples after ozone application. The positive clinical effect of ozone with respect to arresting caries progression and the remineralization of caries has been shown in vitro and in vivo. In an in vivo study, Baysan and Lynch found that the application of ozone resulted in a significant reduction of bacterial contamination as well as a reduction in size and severity of root caries lesions. In a subsequent study, Baysan and Lynch reported that the severity of root caries lesions was significantly reduced after ozone application as measured by electrical conductance and laser fluorescence. In several studies, the caries reducing effect of ozone was measured with biochemical methods in root surface caries lesions, the biofilm and saliva after ozone application. See Citation section for references.

The objectives of this multi-center clinical study were to determine: (1) the effectiveness of the HealOzone in stopping the progression of fissure caries; and (2) the oral soft tissue safety of the ozone system.

Detailed Description

The proposed study was designed as a twelve-month, multi-center, double-blind, randomized controlled clinical study involving 394 subjects with 788 lesions. There were three sites participating in this trial: Indiana University School of Dentistry (lead site), Tufts University School of Dental Medicine, and SUNY School of Dental Medicine. Each site submitted a version of the protocol to their respective Institutional Review Board ("IRB") that incorporated the specific institutional and state guidelines and regulations applicable to that site.

The two treatment regimens were: (a) placebo treatment and (b) experimental ozone treatment. Selected subjects had to have at least two teeth with similar stages of early active fissure caries. The selection of the study teeth was determined by a review of the visual examination, including the ICDAS severity score and the caries lesion activity score, conducted at the screening visit, in conjunction with the bitewing radiographs. The decision whether a tooth was to be treated with ozone or receive placebo treatment was made randomly.

All clinical personnel involved in the clinical examinations and treatment application were trained at the primary site prior to the initiation of the trial both in the use of the device, and in how to identify the signs and symptoms of ozone toxicity and in how to provide the appropriate medical response should any of these signs or symptoms be observed.

All qualified subjects received the following:

1. Professional dental cleaning and scaling at the Screening Visit (or separate visit prior to baseline visit and after completing the study at 12 months.

2. Diagnostic procedures:

   1. Clinical visual examination (utilizing the International Caries Detection and Assessment System [ICDAS] severity scoring)
   2. Clinical visual/tactile assessment of caries lesion activity
   3. Bitewing x-rays
   4. Laser fluorescence measurement (utilizing the DIAGNOdent, KaVo)
3. Treatment Regimen:

Using a split-mouth design, the assigned investigational treatment regimen was administered on the two selected study teeth at the baseline, and at the three-, six- and nine-month appointments.

After three, six, nine and twelve months, the diagnostic procedures were repeated with the exception of bitewing x-rays, which were only repeated at the twelve-month exam (unless the examining dentist determined that x-rays also were needed at the six- or nine-month visit to confirm whether dentinal caries were present). In addition, optional digital photographs were taken at the Boston site of selected study teeth to document clinical changes over the study period.

If a selected study tooth progressed from an initial caries lesion to a more advanced lesion, which in the judgment of the examining dentist required restorative intervention, the tooth was restored at no cost to the subject and the lesion was recorded as 'progression from baseline' at any remaining examinations. The subject was eligible to remain in the study.

Subjects received a thorough dental cleaning and scaling and topical fluoride treatment at the conclusion of the twelve-month examination.

The primary efficacy parameter will be the ICDAS severity value. The severity criteria used in the ICDAS diagnostic system are as follows:

0 = Sound tooth surface.

1. = First visual change in enamel.
2. = Distinct visual change in enamel.
3. = Localized enamel breakdown due to caries with no visible dentin.
4. = Underlying dark shadow from dentin, with or without localized enamel breakdown.
5. = Distinct cavity with visible dentin.
6. = Extensive distinct cavity with visible dentin.

The secondary efficacy parameters will be measured by:

Caries Lesion Activity score:

1. = Inactive - surface of enamel appears whitish, brownish or black. Enamel may be shiny and feels hard and smooth when the tip of the probe is moved gently across the surface.
2. = Active lesion - surface of enamel appears whitish/yellowish opaque with loss of luster. The surface feels rough when the tip of the probe is moved gently across the surface.

Radiographic Changes:

The occlusal surface of study teeth will be evaluated using the following scale:

Lesion presence: yes /no

Lesion depth:

E1 = outer half of enamel E2 = inner half of enamel D1 = outer third of dentin D2 = middle third of dentin D3 = inner third of dentin or greater/pulpal exposure

Laser fluorescence measurement:

DIAGNOdent reading using a scale from 00 to 99, with 00 indicating no caries activity and 99 indicating a high level of activity.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Dental Caries

Intervention

• Device: Ozone treatment
  Ozone treatment applied to randomly selected tooth for a period of 60 seconds at Baseline, Three, Six and Nine-Month visits.
  Other Name: HealOzone unit
• Device: Placebo treatment
  Placebo treatment applied to randomly selected tooth for a period of 60 seconds at Baseline, Three-, Six- and Nine-Month visits.

Study Arms

• Experimental: Ozone treatment
  Ozone treatment of randomly selected study tooth for 60 seconds
  Intervention: Device: Ozone treatment
• Placebo Comparator: Placebo, no ozone
  Placebo treatment (no ozone) of randomly selected study tooth for 60 seconds.
  Intervention: Device: Placebo treatment

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 16, 2009): 394
• Original Estimated Enrollment (submitted: July 1, 2007): 402
• Actual Study Completion Date: December 2009
• Actual Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

To be eligible for study participation, subjects had to:

1. provide written informed consent, HIPAA authorization and medical history information prior to their participation; 2. be between the ages of 10 and 40 years of age; 3. if female and of childbearing potential, agree to:

• a urine pregnancy test, which must be negative;
• use one form of medically accepted contraceptive measures which include oral contraceptives, condom, or diaphragm with spermicide, Intra Uterine Device (IUD), Depo-Provera, Norplant during the study and for at least 30 days after the last treatment. (Females who are post menopausal, i.e. amenorrhea for the previous 12 months, or surgically sterile may be included.) 4. be in good general health as evidenced by a review of the medical history; 5. have good oral health; 6. agree to comply with all subjects' responsibilities as stated in the protocol (e.g. attendance at appointments, turning off of cell phone during appointment, etc.); and 7. have two posterior (molar or premolar) teeth with active fissure caries as defined by ICDAS severity score between 1 and 4, a caries lesion activity score of 2, and with radiographic evidence indicating that there is no extension past the dentinal enamel junction. Lesions within the same subject ideally should have the same ICDAS criterion; however, the following deviations will be acceptable - teeth with ICDAS criterion 1 paired with a 2, and a 3 paired with a 4.

Exclusion Criteria:

Any of the following excluded subjects from participating:

1. a medical condition that requires antibiotic therapy prior to dental work;
2. any medical condition that could be expected to interfere with the subject's safety, such as a pacemaker or similar powered implant;
3. selected study teeth with occlusal restorations, sealants, carious lesions extending into dentin, hypomineralization or fluorosis;
4. generalized severe gingivitis or gross unrestored caries;
5. orthodontic appliances that interfere with access to selected study teeth;
6. pregnant or nursing.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 10 Years to 40 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00495495
• Other Study ID Numbers: 07-D-187; IDE G50008; Clinical Trials. gov ( Registry Identifier: ClinicalTrials.gov protocol registration system )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Indiana University
• Study Sponsor: Indiana University

Collaborators

• Tufts University School of Dental Medicine
• State University of New York at Buffalo

Investigators

• Principal Investigator: Domenick T Zero, DDS MS; Indiana University
• Principal Investigator: Athena Papas, DMD, PhD; Tufts University School of Dental Medicine
• Principal Investigator: Sebastian Ciancio, DDS, PhD; SUNY School of Dental Medicine

• PRS Account: Indiana University
• Verification Date: February 2015