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

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00495495
• Collaborator: Tufts University School of Dental Medicine (Other), State University of New York at Buffalo (Other)
• Enrollment: 394
• Locations: 3
• Arms: 2
• Duration (Months): 34
• Patients Per Site: 131.3
• Patients Per Site Per Month: 3.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Dental Caries	Device: Ozone treatment; Device: Placebo treatment	Phase 2/Phase 3

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:

3. Clinical visual examination (utilizing the International Caries Detection and Assessment System [ICDAS] severity scoring)

4. Clinical visual/tactile assessment of caries lesion activity

5. Bitewing x-rays

6. Laser fluorescence measurement (utilizing the DIAGNOdent, KaVo)

7. 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 Design

• Study Type: Interventional
• Actual Enrollment: 394 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Multi-Center Study to Evaluate the Safety and Efficacy of the Use of Ozone for the Management of Fissure Caries
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ozone treatment Ozone treatment of randomly selected study tooth for 60 seconds	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 Names: HealOzone unit
Placebo Comparator: Placebo, no ozone Placebo treatment (no ozone) of randomly selected study tooth for 60 seconds.	Device: Placebo treatment; Placebo treatment applied to randomly selected tooth for a period of 60 seconds at Baseline, Three-, Six- and Nine-Month visits.

Outcome Measures

Primary Outcome Measures

1. ICDAS Severity Value [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. = First visual change in enamel. = Distinct visual change in enamel. = Localized enamel breakdown due to caries with no visible dentin. = Underlying dark shadow from dentin, with or without localized enamel breakdown. = Distinct cavity with visible dentin. = Extensive distinct cavity with visible dentin.

Secondary Outcome Measures

1. Change in Caries Lesion Activity [Baseline and one year]

   Change in caries lesion activity at One Year. All teeth were considered Active at Baseline Caries Lesion Activity score: = 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. = 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.

2. Progression of Radiographic Scores at 12 Months [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

3. Laser Fluorescence Progression-12 Month (Increase From <=20 to >=30) [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.

4. Laser Fluorescence Progression-12 Month (Increase at Least 10) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University School of Dentistry	Indianapolis	Indiana	United States	46202
2	Tufts University School of Dental Medicine	Boston	Massachusetts	United States	02111
3	State University of New York at Buffalo, School of Dental Medicine	Buffalo	New York	United States	14214

Sponsors and Collaborators

• Indiana University
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT00495495
• Other Study ID Numbers: 07-D-187; IDE G50008; Clinical Trials. gov
• First Posted: Jul 3, 2007
• Last Update Posted: Feb 20, 2015
• Last Verified: Feb 1, 2015

• Additional relevant MeSH terms: Dental Caries

Study Results

Participant Flow

Arm/Group Title	Ozone Treatment and Placebo Treatment
Arm/Group Description	60-second Ozone device treatment compared to 60-second Placebo device treatment. Study utilized split-mouth design. The paired treatment assignment for the two teeth within each subject was performed according to a randomization table provided by the Biometrician. Randomization of teeth to Ozone treatment or Placebo treatment was stratifed according to tooth similarity.
Period Title: Overall Study
STARTED	394
COMPLETED	295
NOT COMPLETED	99

Baseline Characteristics

Arm/Group Title	Ozone Treatment/Placebo Treatment
Arm/Group Description	Study utilized split-mouth design. Each participant had two teeth selected at the start of the study. Each participant was then randomized to receive Ozone treatment on a randomly selected study tooth for 60 seconds and Placebo treatment on a randomly selected study tooth for 60 seconds.
Overall Participants	394
Age (Count of Participants)
<=18 years	102 25.9%
Between 18 and 65 years	292 74.1%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.9 (7.2)
Sex: Female, Male (Count of Participants)
Female	202 51.3%
Male	192 48.7%
Region of Enrollment (participants) [Number]
United States	394 100%

Outcome Measures

1. Primary Outcome

Title	ICDAS Severity Value
Description	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. = First visual change in enamel. = Distinct visual change in enamel. = Localized enamel breakdown due to caries with no visible dentin. = Underlying dark shadow from dentin, with or without localized enamel breakdown. = Distinct cavity with visible dentin. = Extensive distinct cavity with visible dentin.
Time Frame	Baseline and One Year

Outcome Measure Data

Analysis Population Description

The study utilized a split-mouth design. The results posted are for the Per Protocol dataset. Subjects who completed all four treatment/examination visits as well as final examination visit without major protocol violations were included in this dataset.

Arm/Group Title	Ozone Treatment	Placebo Treatment
Arm/Group Description	As part of the split-mouth design, subjects were randomized to receive Ozone treatment on a randomly selected study tooth for 60 seconds.	As part of the split-mouth design, subjects were randomized to receive placebo treatment on a randomly selected study tooth for 60 seconds.
Measure Participants	295	295
Measure teeth	295	295
Number of Teeth with Caries Progression	17	22
Number of Teeth with No Caries Progression	278	273

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ozone Treatment
	Comments	Null hypothesis: there is no difference between the HealOzone and Placebo devices in the proportion of teeth with lesion progression after 1 year. Power calculation: the study was sized to have 90% power to detect a 15% difference between treatments in the percentage of teeth with lesion progression at one year (i.e., assuming 45% for the lesions treated with the Placebo device and 30% for the lesions treated with the HealOzone device) with a sample size of 258 subjects completing the study.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1126
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	.02
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Analyses were based on per protocol subjects, defined as all randomized subjects with no major protocol violations. Clinically significant changes for Activity Scores were indicated by a change in caries activity status from active to inactive. It should be noted that all teeth were considered active at baseline.

Arm/Group Title	Ozone Treatment	Placebo Treatment
Arm/Group Description	As part of the split-mouth design, subjects were randomized to receive Ozone treatment on a randomly selected study tooth for 60 seconds.	As part of the split-mouth design, subjects were randomized to receive placebo treatment on a randomly selected study tooth for 60 seconds.
Measure Participants	295	295
Measure teeth	295	295
Number of Active Caries lesions	189	164
Number of Non- Active Caries Lesions	106	131

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ozone Treatment, Placebo Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.9777
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	.08
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Progression of Radiographic Scores at 12 Months
Description	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
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Analyses were based on per protocol subjects, defined as all randomized subjects with no major protocol violations (subjects who completed all four treatment/examination visit at Baseline, 3-, 6-, 9-month as well as Final examination at 12-month.

Arm/Group Title	Ozone Treatment	Placebo Treatment
Arm/Group Description	As part of the split-mouth design, subjects were randomized to receive Ozone treatment on a randomly selected study tooth for 60 seconds.	As part of the split-mouth design, subjects were randomized to receive placebo treatment on a randomly selected study tooth for 60 seconds.
Measure Participants	295	295
Measure teeth	295	295
Number of Teeth with Progression	6	12
Number of Teeth with No Progression	220	214

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ozone Treatment, Placebo Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0416
	Comments
	Method	McNemar
	Comments

4. Secondary Outcome

Title	Laser Fluorescence Progression-12 Month (Increase From <=20 to >=30)
Description	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.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Analyses were based on per protocol subjects, defined as all randomized subjects with no major protocol violations (subjects who completed all four treatment/examination visit at Baseline, 3-, 6-, 9-month as well as Final examination at 12-month.

Arm/Group Title	Ozone Treatment	Placebo Treatment
Arm/Group Description	As part of the split-mouth design, subjects were randomized to receive Ozone treatment on a randomly selected study tooth for 60 seconds.	As part of the split-mouth design, subjects were randomized to receive placebo treatment on a randomly selected study tooth for 60 seconds.
Measure Participants	293	293
Measure teeth	293	293
Number of Teeth with Progression	16	14
Number of Teeth with No Progression	277	279

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ozone Treatment, Placebo Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6585
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	.01
	Confidence Interval	(1-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Laser Fluorescence Progression-12 Month (Increase at Least 10)
Description	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.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Analyses were based on per protocol subjects, defined as all randomized subjects with no major protocol violations.

Arm/Group Title	Ozone Treatment	Placebo Treatment
Arm/Group Description	As part of the split-mouth design, subjects were randomized to receive Ozone treatment on a randomly selected study tooth for 60 seconds.	As part of the split-mouth design, subjects were randomized to receive placebo treatment on a randomly selected study tooth for 60 seconds.
Measure Participants	293	293
Measure teeth	293	293
Number of Teeth with Progression	58	52
Number of Teeth with No Progression	235	241

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ozone Treatment, Placebo Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.7666
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	.02
	Confidence Interval	(1-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The adverse events were collected during the one-year period of the trial.
Arm/Group Title	Ozone Treatment and Placebo Treatment
Arm/Group Description	Study utilized split-mouth design. Each participant had two teeth selected at the start of the study. Each participant was then randominzed to receive Ozone treatment on a randomly selected study tooth for 60 seconds and Placebo treatment on a randomly selected study tooth for 60 seconds.
All Cause Mortality
	Ozone Treatment and Placebo Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ozone Treatment and Placebo Treatment
	Affected / at Risk (%)	# Events
Total	5/394 (1.3%)
General disorders
Appendicitis	1/394 (0.3%)	1
Musculoskeletal and connective tissue disorders
Broken left leg	1/394 (0.3%)	1
Broken left knee	1/394 (0.3%)	1
Reproductive system and breast disorders
Surgery ovarian cyst removal	1/394 (0.3%)	1
surgery breast reduction	1/394 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Ozone Treatment and Placebo Treatment
	Affected / at Risk (%)	# Events
Total	0/394 (0%)

Limitations/Caveats

Study length may have been too brief to permit progression of early stage caries; Low caries increment in study population; Difficult to establish that lesions were truly active at baseline.

More Information

Certain Agreements

Principal Investigators are NOT 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.