Prevention of Adult Caries Study (PACS)

• Sponsor: Tufts University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00357877
• Collaborator: National Institute of Dental and Craniofacial Research (NIDCR) (NIH)
• Enrollment: 983
• Locations: 4
• Arms: 2
• Duration (Months): 47
• Patients Per Site: 245.8
• Patients Per Site Per Month: 5.2

Study Details

Study Description

Brief Summary

Adult tooth decay is an infectious disease that afflicts the majority of Americans aged 55 and older and is the most common chronic disease at midlife with an ever growing economic toll. Despite the fact that specific bacteria cause tooth decay, no FDA-approved anti-microbial treatment for decay is available to the American dental professional. The Prevention of Adult Caries Study (PACS) is a study designed to evaluate the efficacy of a topical, temporary, 10% w/v chlorhexidine dental coating in reducing new decay in adult dental patients at risk for decay.

Condition or Disease	Intervention/Treatment	Phase
Caries, Dental	Drug: 10% w/v chlorhexidine acetate coating FDA IND #45466; Other: Placebo	Phase 3

Detailed Description

The Prevention of Adult Caries Study (PACS) is a randomized, double-blind, placebo-controlled Phase III clinical trial conducted under F.D.A. Investigational New Drug license #45,466, with a target enrollment of 1000 at four clinical centers with vastly different populations. The centers participating in this proposed research are: Kaiser Permanente's Dental Plan in Portland, Oregon; Tufts University Dental Clinic in central Boston, Massachusetts; Delta Dental Massachusetts' Dental Clinic in Southborough, Massachusetts; and the dental clinic of the Tuba City Regional Health Care Corporation in Tuba City, Arizona. Kaiser Permanente's Center for Health Research in Portland, Oregon will act as the data-coordinating center, and Tufts University will act as the Administrative Center. This study is designed to evaluate the efficacy of a topical, temporary, 10% w/v chlorhexidine dental coating in reducing caries increment in at-risk adult dental patients. This study will treat participants in months 1(4 weekly applications) and 7(1 application) with final outcome measured at 13 months after randomization. Examiners were trained and certified before data collection started and were recalibrated annually. The primary outcome analysis in the intent -to- treat sample compares active to placebo group on the rank-normalized caries increment score, adjusting for examiner, age and age squared. Multiple imputation (data augmentation using MCMC) will be used to replace missing outcome. Planned secondary analysis examine the secondary caries increment outcomes using the same model, as well as parallel analyses in the per-protocol group. Safety of the coating will be evaluated by comparing development of resistant S. mutans or C. albicans as well as incidence of MedDRA-coded adverse events between the two arms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 983 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Prevention of Adult Caries Study
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Dental Coating Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Other: Placebo
Active Comparator: Active Dental Coating 10% w/v chlorhexidine acetate coating FDA IND #45466. Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Drug: 10% w/v chlorhexidine acetate coating FDA IND #45466; Dental coating topically applied by dental professional supragingivally to the full dentition; Other Names: CHX

Outcome Measures

Primary Outcome Measures

1. Total Net D12FS Caries Increment (Total of Non-cavitated Lesions (D1), Cavitated Lesions (D2) and Sound Surfaces (S)) [(V1) to the 13 month follow-up visit]

   Study duration was too short to have progression from D2 (cavitated lesions) to D3 (cavitated lesions that involved dentin). D2 and D3 were treated equivalently for analysis. This measure is computed as the sum of weighted counts of transitions in tooth surface status (root and coronal surfaces combined) from randomization to the 13-month follow-up visit. Disease progression had a positive weight (e.g., S-to-D1 (sound to non-cavitated lesion) or D1-to-D2 (non-cavitated to cavitated lesion) = 1, S-to-D2 (sound to cavitated lesion)= 2). Reversal had a negative weight (e.g., D1-to-S = -1). No change, transitions to or from missing or unscorable, and impossible transitions had 0 weight. Incident fillings and crowns were treated the same as incident D2 lesions for purposes of scoring. More details of the transition weights may be found at Vollmer WM et al. (2010). Design of the Prevention of Adult Caries Study (PACS): a randomized clinical trial assessing the effect of a

Secondary Outcome Measures

1. Cumulative Net D12FS Caries Increment [Visit 1, 7-month follow-up, 13-month follow-up]

   This measure was computed similar to the total net D12FS increment, but separately scored and combined transitions from the baseline to 7-month visits and from the 7- to 13-month visits, rather than simply looking at the baseline to 13-month visits.

2. Total Crude D12FS Caries Increment [V1-13-month follow-up]

   Computed analogous to the total net D12FS caries increment, but ignoring reversals (essentially assigned them zero weight). Computed only using baseline to 13-month visit data.

3. Cumulative Crude D12FS Caries Increment [Visit 1, 7-month follow-up, 13-month follow-up]

   This is computed analogous to the cumulative net D12FS increment, but ignoring reversals by assigning them weights of zero.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 18 years of age and older

• at least 20 intact natural teeth, excluding third molars

• 2 or more lesions, of which at least one must be a cavitated D2 or D3

• willing and able to provide informed consent

Exclusion Criteria

• pregnant or planning to become pregnant or planning to become pregnant during the study (breastfeeding is permitted)

• use of fixed orthodontic appliances

• allergic to any of the ingredients of the study medication

• long-term antibiotic therapy

• a history of, or currently active, radiation therapy for cancers of the head or neck

• Sjögren's syndrome

• advanced periodontitis

• consumption of the equivalent of more than five servings of acidic or sugared drinks per day

• having 10 or more lesions requiring restorative care at the time of the screening visit

• remineralization therapy within one month of randomization

• investigator discretion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tuba City Regional Health Care	Tuba City	Arizona	United States	86045-0600
2	Tufts University School of Dental Medicine	Boston	Massachusetts	United States	02111
3	Dental Services of Massachusetts	Boston	Massachusetts	United States	02129
4	Center for Health Research	Portland	Oregon	United States	97227

Sponsors and Collaborators

• Tufts University
• National Institute of Dental and Craniofacial Research (NIDCR)

Investigators

• Principal Investigator: Athena Papas, PhD DMD, Tufts University of Dental Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tufts University
• ClinicalTrials.gov Identifier: NCT00357877
• Other Study ID Numbers: DE017753-01; U01DE017753
• First Posted: Jul 28, 2006
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Dental Caries; Chlorhexidine; Chlorhexidine gluconate

Study Results

Participant Flow

Arm/Group Title	Placebo Dental Coating	Active Dental Coating (CHX)
Arm/Group Description	Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition. 10% w/v chlorhexidine acetate coating FDA IND #45466.
Period Title: Overall Study
STARTED	493	490
COMPLETED	467	460
NOT COMPLETED	26	30

Baseline Characteristics

Arm/Group Title	Placebo Dental Coating	Active Dental Coating	Total
Arm/Group Description	Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Total of all reporting groups
Overall Participants	493	490	983
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	463 93.9%	459 93.7%	922 93.8%
>=65 years	30 6.1%	31 6.3%	61 6.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.8 (14.3)	42.9 (14.3)	42.8 (14.3)
Sex: Female, Male (Count of Participants)
Female	242 49.1%	250 51%	492 50.1%
Male	251 50.9%	240 49%	491 49.9%
Region of Enrollment (participants) [Number]
United States	493 100%	490 100%	983 100%

Outcome Measures

1. Primary Outcome

Title	Total Net D12FS Caries Increment (Total of Non-cavitated Lesions (D1), Cavitated Lesions (D2) and Sound Surfaces (S))
Description	Study duration was too short to have progression from D2 (cavitated lesions) to D3 (cavitated lesions that involved dentin). D2 and D3 were treated equivalently for analysis. This measure is computed as the sum of weighted counts of transitions in tooth surface status (root and coronal surfaces combined) from randomization to the 13-month follow-up visit. Disease progression had a positive weight (e.g., S-to-D1 (sound to non-cavitated lesion) or D1-to-D2 (non-cavitated to cavitated lesion) = 1, S-to-D2 (sound to cavitated lesion)= 2). Reversal had a negative weight (e.g., D1-to-S = -1). No change, transitions to or from missing or unscorable, and impossible transitions had 0 weight. Incident fillings and crowns were treated the same as incident D2 lesions for purposes of scoring. More details of the transition weights may be found at Vollmer WM et al. (2010). Design of the Prevention of Adult Caries Study (PACS): a randomized clinical trial assessing the effect of a
Time Frame	(V1) to the 13 month follow-up visit

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT) sample. Multiple imputation with 8 datasets imputed via Markov Chain Monte Carlo sampling was used to handle missing data.

Arm/Group Title	Placebo	Active
Arm/Group Description	Participants received a placebo dental coating containing no chlorhexidine diacetate (CHX).	Participants received a dental coating containing chlorhexidine diacetate (CHX) 10% weight per volume.
Measure Participants	493	490
Mean (Standard Error) [weighted increment units/13 months]	2.43 (0.32)	2.68 (0.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active
	Comments	We hypothesized a lower increment score for the active treatment group but carried out two-tailed hypothesis testing. Sample size was estimated with simulated data with rank normalized scores. We calculated that 832 participants would yield a power of 90% to detect a 20% reduction in caries incidence (from a hypothesized mean increment of 1.5), and adopted a target of 1000 randomized participants to allow for attrition.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.56
	Comments	No interim analyses were done and no adjustment made for multiple comparisons. Identical analyses were run on each imputed dataset, with results combined with SAS® PROC MIANALZE to obtain final p-values.
	Method	Regression, Linear
	Comments	The primary outcome analysis included treatment and site as class variables and age and age-squared as continuous covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -0.60 to 1.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.44
	Estimation Comments

2. Secondary Outcome

Title	Cumulative Net D12FS Caries Increment
Description	This measure was computed similar to the total net D12FS increment, but separately scored and combined transitions from the baseline to 7-month visits and from the 7- to 13-month visits, rather than simply looking at the baseline to 13-month visits.
Time Frame	Visit 1, 7-month follow-up, 13-month follow-up

Outcome Measure Data

Analysis Population Description

Intention-to-Treat sample

Arm/Group Title	Placebo Dental Coating	Active Dental Coating (CHX)
Arm/Group Description	Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition. 10% w/v chlorhexidine acetate coating FDA IND #45466.
Measure Participants	493	490
Mean (Standard Error) [caries increment units/13 months]	5.53 (0.42)	5.88 (0.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active
	Comments	hypothesized a reduced caries increment in active arm, though conducted two-tailed hypothesis test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments	No adjustment for multiple comparisons. Identical analyses were run on each imputed dataset, with results combined with SAS® PROC MIANALYZE to obtain final p-values.
	Method	Regression, Linear
	Comments	Model included treatment and site as class variables and age and age-squared as continuous covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; -0.77 to 1.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.57
	Estimation Comments

3. Secondary Outcome

Title	Total Crude D12FS Caries Increment
Description	Computed analogous to the total net D12FS caries increment, but ignoring reversals (essentially assigned them zero weight). Computed only using baseline to 13-month visit data.
Time Frame	V1-13-month follow-up

Outcome Measure Data

Analysis Population Description

Intention-to-Treat sample

Arm/Group Title	Placebo Dental Coating	Active Dental Coating (CHX)
Arm/Group Description	Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition. 10% w/v chlorhexidine acetate coating FDA IND #45466.
Measure Participants	493	490
Mean (Standard Error) [caries increment units/13 months]	6.47 (0.27)	5.96 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active
	Comments	Hypothesized lower increment in active arm, though hypothesis testing was two-sided.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments	No adjustment for multiple comparisons. Identical analyses were run on each imputed dataset, with results combined with SAS® PROC MIANALYZE to obtain final p-values.
	Method	Regression, Linear
	Comments	treatment and site included as class variables and age and age-squared as continuous covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -1.25 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.38
	Estimation Comments

4. Secondary Outcome

Title	Cumulative Crude D12FS Caries Increment
Description	This is computed analogous to the cumulative net D12FS increment, but ignoring reversals by assigning them weights of zero.
Time Frame	Visit 1, 7-month follow-up, 13-month follow-up

Outcome Measure Data

Analysis Population Description

Intention-to-Treat sample

Arm/Group Title	Placebo Dental Coating	Active Dental Coating (CHX)
Arm/Group Description	Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition	Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition. 10% w/v chlorhexidine acetate coating FDA IND #45466.
Measure Participants	493	490
Mean (Standard Error) [caries increment units/13 months]	11.39 (0.42)	10.72 (0.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active
	Comments	Hypothesized a lower increment for active treatment arm, although hypothesis testing was two-sided.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments	No adjustment for multiple comparisons. Identical analyses were run on each imputed dataset, with results combined with SAS® PROC MIANALYZE to obtain final p-values.
	Method	Regression, Linear
	Comments	Model included treatment and site as class variables, and age and age-squared as continuous covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -1.80 to 0.45
	Parameter Dispersion	Type: Standard Deviation; Value: 0.57
	Estimation Comments

Adverse Events

Time Frame	Adverse events were reported at any time throughout the study and were systematically screened for at the 6-month and 1-year visit.
Adverse Event Reporting Description	Systematic assessment of adverse events evaluated during routine completion of standard questionnaire.
Arm/Group Title	Placebo		Active
Arm/Group Description	Participants received a placebo dental coating containing no chlorhexidine diacetate (CHX).		Participants received a dental coating containing chlorhexidine diacetate (CHX) 10% weight per volume.
All Cause Mortality
	Placebo		Active
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Active
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/493 (6.3%)		28/490 (5.7%)
Blood and lymphatic system disorders
Anaemia	1/493 (0.2%)	1	0/490 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/493 (0%)	0	1/490 (0.2%)	1
Angina pectoris	0/493 (0%)	0	2/490 (0.4%)	2
Cardiovascular disorder	1/493 (0.2%)	1	0/490 (0%)	0
Coronary artery disease	0/493 (0%)	0	1/490 (0.2%)	1
Endocrine disorders
Goitre	1/493 (0.2%)	1	0/490 (0%)	0
Gastrointestinal disorders
Diverticulum	1/493 (0.2%)	1	0/490 (0%)	0
Haematochezia	1/493 (0.2%)	1	0/490 (0%)	0
Hiatus hernia	0/493 (0%)	0	1/490 (0.2%)	1
Large intestine perforation	0/493 (0%)	0	1/490 (0.2%)	1
Pancreatitis	0/493 (0%)	0	1/490 (0.2%)	1
General disorders
Non-cardiac chest pain	0/493 (0%)	0	1/490 (0.2%)	1
Hepatobiliary disorders
Cholecystitis	1/493 (0.2%)	1	0/490 (0%)	0
Infections and infestations
Cellulitis	1/493 (0.2%)	1	0/490 (0%)	0
Cellulitis of male external genital organ	1/493 (0.2%)	1	0/490 (0%)	0
Cystitis	0/493 (0%)	0	1/490 (0.2%)	1
Diverticulitis	1/493 (0.2%)	1	0/490 (0%)	0
Gastroenteritis viral	1/493 (0.2%)	1	0/490 (0%)	0
Kidney infection	2/493 (0.4%)	2	1/490 (0.2%)	1
Osteomyelitis	0/493 (0%)	0	1/490 (0.2%)	1
Pneumonia	1/493 (0.2%)	1	2/490 (0.4%)	2
Postoperative wound infection	0/493 (0%)	0	1/490 (0.2%)	1
Pyelonephritis	1/493 (0.2%)	1	0/490 (0%)	0
Sepsis	1/493 (0.2%)	1	0/490 (0%)	0
Upper respiratory tract infection	0/493 (0%)	0	1/490 (0.2%)	1
Urinary tract infection	1/493 (0.2%)	1	0/490 (0%)	0
Abdominal wall abscess	0/493 (0%)	0	1/490 (0.2%)	1
Injury, poisoning and procedural complications
Cervical vertebral fracture	0/493 (0%)	0	1/490 (0.2%)	1
Clavicle fracture	1/493 (0.2%)	1	0/490 (0%)	0
Concussion	0/493 (0%)	0	1/490 (0.2%)	1
Facial bones fracture	1/493 (0.2%)	1	0/490 (0%)	0
Incisional hernia	0/493 (0%)	0	1/490 (0.2%)	1
Ligament rupture	0/493 (0%)	0	1/490 (0.2%)	1
Lung injury	1/493 (0.2%)	1	0/490 (0%)	0
Pelvic fracture	1/493 (0.2%)	1	0/490 (0%)	0
Rib fracture	1/493 (0.2%)	1	1/490 (0.2%)	1
Scapula fracture	1/493 (0.2%)	1	0/490 (0%)	0
Tibia fracture	1/493 (0.2%)	1	0/490 (0%)	0
Traumatic liver injury	1/493 (0.2%)	1	0/490 (0%)	0
Musculoskeletal and connective tissue disorders
Arthritis	1/493 (0.2%)	1	0/490 (0%)	0
Cervical spine stenosis	1/493 (0.2%)	1	0/490 (0%)	0
Osteoarthritis	1/493 (0.2%)	1	1/490 (0.2%)	1
Trismus	1/493 (0.2%)	1	0/490 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/493 (0%)	0	1/490 (0.2%)	1
Benign pancreatic neoplasm	0/493 (0%)	0	1/490 (0.2%)	1
Gastric cancer	1/493 (0.2%)	1	0/490 (0%)	0
Head and neck cancer	1/493 (0.2%)	1	1/490 (0.2%)	1
Malignant melanoma	0/493 (0%)	0	1/490 (0.2%)	1
Multiple myeloma	1/493 (0.2%)	1	0/490 (0%)	0
Prostate cancer	0/493 (0%)	0	1/490 (0.2%)	1
Thyroid cancer	1/493 (0.2%)	1	0/490 (0%)	0
Uterine leiomyoma	1/493 (0.2%)	1	2/490 (0.4%)	2
Nervous system disorders
Cerebral ventricle dilation	1/493 (0.2%)	1	0/490 (0%)	0
Convulsion	1/493 (0.2%)	1	0/490 (0%)	0
Transient ischaemic attack	1/493 (0.2%)	1	0/490 (0%)	0
Psychiatric disorders
Completed suicide	1/493 (0.2%)	1	0/490 (0%)	0
Mental disorder	0/493 (0%)	0	1/490 (0.2%)	1
Suicidal ideation	0/493 (0%)	0	1/490 (0.2%)	1
Renal and urinary disorders
Nephrolithiasis	0/493 (0%)	0	1/490 (0.2%)	1
Ureteric stenosis	1/493 (0.2%)	1	0/490 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/493 (0%)	0	1/490 (0.2%)	1
Dyspnoea	0/493 (0%)	0	1/490 (0.2%)	1
Pleurisy	1/493 (0.2%)	1	0/490 (0%)	0
Social circumstances
Exposure to communicable disease	1/493 (0.2%)	1	0/490 (0%)	0
Surgical and medical procedures
Gastric bypass	0/493 (0%)	0	1/490 (0.2%)	1
Hernia repair	0/493 (0%)	0	1/490 (0.2%)	1
Hip arthroplasty	1/493 (0.2%)	1	1/490 (0.2%)	1
Hysterectomy	0/493 (0%)	0	1/490 (0.2%)	1
Knee arthroplasty	1/493 (0.2%)	1	0/490 (0%)	0
Rectal fistula repair	1/493 (0.2%)	1	0/490 (0%)	0
Urinary bladder excision	0/493 (0%)	0	1/490 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Active
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	87/493 (17.6%)		84/490 (17.1%)
Gastrointestinal disorders
Sensitivity of teeth	32/493 (6.5%)	36	26/490 (5.3%)	29
Infections and infestations
Nasopharyngitis	43/493 (8.7%)	44	30/490 (6.1%)	31
Social circumstances
Pharmaceutical product complaint	12/493 (2.4%)	12	28/490 (5.7%)	28

Limitations/Caveats

[Not Specified]

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.