Clinical trial NCT04838054
Conditions: Peri-implant Mucositis
Sponsor: Rowpar Pharmaceuticals, Inc.
Start date: 2018-03-15; Completion date: 2020-03-04
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A full understanding of etiology and diagnosis of peri-implant diseases is crucial for finding effective treatments for these diseases that are more widely accessible to dentists. Several treatment protocols for peri-implant diseases have been proposed, but no gold standard has been established to date. Thus, the purpose of this study is to analyze efficacy of stabilized chlorine dioxide as a chemical adjuvant for treatment of peri-implant mucositis in a non-surgical treatment protocol with a 3-month follow-up.

Detailed description:
Fifty individuals with peri-implant mucositis will be identified to participate in this study and randomized into two groups to analyze clinical parameters and results of this study: 1) test group (stabilized chlorine dioxide rinse) and 2) control group (placebo). Each group will be associated with periodontal basic therapy.

Treatment Protocol After inclusion of the patients, medical history and initial examination are performed, patients will be randomly divided into the following two groups: 1) test (stabilized chlorine dioxide rinse associated with periodontal basic therapy); and 2) control (placebo associated with periodontal basic therapy).

Periodontal basic therapy will consist of oral hygiene instruction, motivation, retentive factor removal, and an adaptation of the protocol of full-mouth scaling and root planing (stabilized chlorine dioxide mouthwash will be used). Plastic currets are used to instrument the implants and metal currets to instrument teeth. Immediately after instrumentation, chemical solutions of chlorine dioxide or placebo will be dispensed to the subjects.

The subjects will follow their normal oral-hygiene procedures with the addition of using the study rinse toothbrush and toothpaste provided to them.

Arms: arm 1: Subjects will receive CloSYS Ultra Sensitive Rinse arm 2: Subjects will receive oral rinse - no active ingredients
Interventions: intervention 1: Stabilized chlorine dioxide oral rinse intervention 2: Placebo
Intervention descriptions: intervention 1: Patients received stabilized chlorine dioxide rinse associated with periodontal basic therapy. intervention 2: Patients received a rinse containing no active ingredients and periodontal basic therapy.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
The efficacy of stabilized chlorine dioxide 
rinse as a chemical adjuvant for treatment 
of Peri‐Implant Mucositis 
 
 
 
 
NCT04838054 
 
 
 
 
 
March 18, 2021 


  
  
 
 
 
 
 
 
The efficacy of stabilized chlorine dioxide rinse as 
a chemical adjuvant for treatment of  
Peri-Implant Mucositis. 
 
 
Final Report 
 
 
 March 18, 2021


  
  
 
Sponsor: 
Rowpar Pharmaceuticals, Inc. 
15300 N. 90th St. Suite #750 
Scottsdale, Arizona 85260 
 
Principal Investigator: 
Srinivas Rao Myneni Venkatasatya, DDS, PhD 
Assistant Professor  
Department of Periodontology  
108 Rockland Hall 
School of Dental Medicine, Stony Brook University   
Stony Brook, NY 11794-8703  
Phone (631) 632-8739  
Fax (631) 632-3113 
Email: Srinivas.MyneniVenkatasatya@stonybrookmedicine.edu 
 
Co- Investigator: 
Vincent Iacono, DMD 
SUNY Distinguished Service Professor and Chair 
Tarrson Family Professor of Periodontology 
Department of Periodontology 
School of Dental Medicine 
Stony Brook University 
Stony Brook, NY 11794-8703 
Phone (631) 632-8895 
Email: Vincent.Iacono@stonybrookmedicine.edu 
 
Co-Investigator: 
 
 
 
 
 
 
David K. Lam, MD, DDS, PhD, FRCDC, DABOMS  
Professor & Chair, Department of Oral & Maxillofacial 
Surgery,  
School of Dental Medicine, Stony Brook University 
148B Rockland Hall, Stony Brook, NY 11794-8704 
Email: David.Lam@stonybrookmedicine.edu 
 


  
  
Study Site: 
 
School of Dental Medicine,  
Department of Periodontology  
Stony Brook University 
Stony Brook, NY 11794-8703 
 
 
Study Coordinator: 
Jill A. Hughes 
Clinical Research Coordinator 
Department of Periodontology  
105 Rockland Hall 
School of Dental Medicine, Stony Brook University 
Stony Brook, NY 11794-8703  
Phone (631) 632-9703  
Email: Jill.Hughes2@stonybrookmedicine.edu 
Study Statistician: 
J. Michael Menke, DC, PhD 
4444 South Veneto 
Mesa, Arizona 85212 
520 301 0176 cell 
480 354 0141 
michael.menke@gmail.com 
 
 
 
Product: 
Stabilized Chlorine Dioxide Oral Rinse 
ClōSYS® Ultra Sensitive Rinse 
0.1% (w/v) Stabilized Chlorine Dioxide 
 
Sponsor’s Project Manager: 
Jaiprakash G. Shewale 
 
 
 
 
 
Technical Director 
 
 
 
 
 
Phone (480) 948-6997 Ext. 17 


  
  
 
 
 
 
 
Email: jshewale@rowpar.com 
 
 
Sponsor’s Project Monitor:  
Dr. William E. Cooley 
 
 
 
 
 
Consultant 
 
 
 
 
 
Phone: 513-522-3797 
 
 
 
 
 
E mail: billcooley1930@gmail.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
Table of Contents 
[ 1 ] 
INTRODUCTION ......................................................................................................................................... 5 
[ 2 ] 
OBJECTIVE .................................................................................................................................................. 5 
[ 3 ] 
STUDY DESIGN ........................................................................................................................................... 6 
[ 4 ] 
STUDY DESIGN TABLE ............................................................................................................................. 7 
[ 5 ] 
PROTOCOL SYNOPSIS .............................................................................................................................. 8 
[ 6 ] 
STUDY MATERIALS (ORAL HYGIENE KIT) ....................................................................................... 8 
STUDY DRUG ................................................................................................................................................... 8 
ADMINISTRATION ............................................................................................................................................. 9 
[ 7 ] 
SUBJECTS ..................................................................................................................................................... 9 
[ 8 ] 
SUBJECT ELIGIBILITY CRITERIA ........................................................................................................ 9 
INCLUSION CRITERIA ....................................................................................................................................... 9 
EXCLUSION CRITERIA .................................................................................................................................... 10 
ASSIGNMENT .................................................................................................................................................. 10 
WITHDRAWAL ................................................................................................................................................ 10 
[ 9 ] 
STUDY PROCEDURES ............................................................................................................................. 12 
SCREENING .................................................................................................................................................... 12 
VISIT 1 - BASELINE EXAMINATION – DAY 0 ................................................................................................. 12 
VISIT 2 - INTERIM EXAMINATION - DAY 14 .......................................................................................... 13 
VISIT 3 – COMPLIANCE VISIT – DAY 45 .................................................................................................. 14 
VISIT 4 - FINAL EXAMINATION – DAY 90.................................................................................................... 14 
[ 10 ] 
STUDY TIMELINE .................................................................................................................................... 14 
[ 11 ] 
STATISTICAL EVALUATION ................................................................................................................ 15 
 


  
 
5 
 
The efficacy of stabilized chlorine dioxide rinse as a chemical 
adjuvant for treatment of Peri-Implant Mucositis. 
[ 1 ] Introduction 
 
The use of dental implants has revolutionized the treatment of partially and fully edentulous 
patients today. Implants have become a treatment approach for managing a broad range of clinical 
dilemmas due to their high level of predictability and their ability to be used for a wide variety of 
treatment options. While in many cases dental implants have been reported to achieve long-term 
success, they are not immune from complications associated with improper treatment planning, 
surgical and prosthetic execution, material failure, and maintenance. Included in the latter are the 
biologic complications of peri-implant mucositis and peri-implantitis, inflammatory conditions in 
the soft and hard tissues at dental implants. Peri-implant mucositis is characterized by 
inflammation in the mucosa around the implant without signs of bone loss.  If bone loss also 
occurs, the condition is designated as peri-implantitis. Studies reported 43% and 22% prevalence 
of peri-implant mucositis and peri-implantitis, respectively. Peri-implant mucositis is a reversible 
condition, but if left untreated can progress to peri-implantitis. Besides mechanical treatment, other 
therapies have been used for treatment of peri-implant mucositis, namely: 1) triclosan-based 
dentifrice; 2) abrasive air blasting with sodium carbonate and resin curets; 3) mouth rinses with 
0.2% chlorhexidine and 1% gel; 4) 0.5% chlorhexidine gel; and 5) irrigation with 0.12% 
chlorhexidine solution, as well as use of systemic antibiotics.  
Stabilized chlorine dioxide exhibits antimicrobial properties against oral bacteria. Clinical and 
laboratory evidence suggest that stabilized chlorine dioxide oral rinse reduces the number of 
bacteria in the mouth, essentially eliminates oral malodor, reduces the signs of gum disease, and 
has bactericidal properties comparable to other products with additional consumer acceptability 
relating to its non-alcoholic and non-staining features. Thus, the purpose of this study was to 
analyze efficacy of stabilized chlorine dioxide mouth rinse as a chemical adjuvant for treatment of 
peri-implant mucositis in a non-surgical treatment protocol with a 3-month follow-up. 
[ 2 ] Objective 
 
A full understanding of etiology and diagnosis of peri-implant diseases is crucial for finding 
effective treatments for these diseases that are more widely accessible to dentists. Several treatment 
protocols for peri-implant diseases have been proposed, but no gold standard has been established 
to date. Thus, the purpose of this study was to analyze efficacy of stabilized chlorine dioxide as a 
chemical adjuvant for treatment of peri-implant mucositis in a non-surgical treatment protocol with 
a 3-month follow-up. A collection swab was performed for microbiome analysis of the mouth on 
three visits. 
 


  
 
6 
 
[ 3 ] Study Design 
 
Fifty-four individuals with peri-implant mucositis were identified to participate in this study and 
randomized into two groups to analyze clinical parameters and results of this study: 1) test group 
(stabilized chlorine dioxide rinse) and 2) control group (placebo). Each group was associated with 
periodontal basic therapy.  
 
Treatment Protocol 
After inclusion of the patients, medical history and initial examination were performed, patients 
were randomly divided into the following two groups: 1) test (stabilized chlorine dioxide rinse 
associated with periodontal basic therapy); and 2) control (placebo associated with periodontal 
basic therapy). 
 
Periodontal basic therapy consisted of oral hygiene instruction, motivation, retentive factor 
removal, and an adaptation of the protocol of full-mouth scaling and root planing (stabilized 
chlorine dioxide mouthwash will be used). Plastic currets were used to instrument the implants, 
and metal currets to instrument teeth. Immediately after instrumentation, chemical solutions of 
chlorine dioxide or placebo were dispensed to the subjects. 
 
The subjects followed their normal oral-hygiene procedures with the addition of using the study 
rinse toothbrush and toothpaste provided to them. 
 
Overview of the Sample Collection Protocol for Microbiome Analysis 
Samples for microbiome analysis were collected at baseline (Visit 1), Day 14 (Visit 2), and 
Day 90 (Visit 4). Before collecting samples, each patient was asked to rinse with plain 
water prior and rest for 5 minutes. Sample collection was performed by gently wiping the 
buccal and tongue mucosa separately 10 times with three different cotton swabs. Samples 
were allowed to air dry at room temperature and individually placed in labeled containers 
with the patient’s unique sequential subject identification number and day of collection.  
These samples were stored in a secure location at -20°C until utilized for microbiome 
analyses. 
 
 


  
 
7 
 
[ 4 ] Study Design Table 
Protocol Study Design and Schedule of Assessments 
Screening 
Baseline 
(Visit 1) 
Visit 2 
Visit 3 
Visit 4 
Evaluation 
(0-2wks to 
Baseline) 
Day 0 
Day 14 
(± 3 d) 
Day 45 
(± 7 d) 
Day 90 
(± 7 d) 
Informed Consent 
x 
  
  
 
  
Inclusion / Exclusion 
x 
x 
  
 
  
Demographics 
x 
  
  
 
  
Pregnancy Test 
  
x 
  
 
x 
Medical History / Update 
x 
x 
x 
 
x 
Medications / Update 
x 
x 
x 
 
x 
Periodontal History 
x 
  
x 
 
x 
Oral Examination 
x 
x 
x 
 
x 
Collect Specimen w Swab 
 
X 
X 
 
X 
Modified Gingival Index / 
MGI 
  
x 
x 
 
x 
Bleeding On Probing / 
BOP 
x 
  
  
 
x 
Probing depth 
x 
x 
 
 
x 
Turesky modification 
Plaque Index 
  
x 
x 
 
x 
Scaling 
            x 
 
 
 
 
Eligibility  
x 
  
  
 
  
X-rays 
  
x 
  
 
x 
Enrollment / 
Randomization 
  
x 
  
 
  
Dispense oral hygiene kit 
/ Diary 
  
x 
  
 
  
Schedule next appt 
x 
x 
x 
 
  
Collect residual oral 
hygiene kit with Diary 
and distribute oral 
hygiene kit with Diary for 
next phase 
 
 
X 
x 
 
Collect residual oral 
hygiene kit / Diary 
  
  
  
 
x 


  
 
8 
 
 
[ 5 ] Protocol Synopsis 
1. Study Title: The Efficacy and Safety of stabilized chlorine dioxide mouth rinse in Therapy of 
Peri-implant mucositis 
2. Study Design: Single Center, randomized, double blind masking, parallel, two-arm clinical 
study.  
3. Objective: The purpose of this study was to analyze efficacy of stabilized chlorine dioxide as a 
chemical adjuvant for treatment of peri-implant mucositis in a non-surgical treatment protocol with 
a 3-month follow-up. 
 
4. Study Treatments: 1) Stabilized chlorine dioxide (associated with periodontal basic therapy); 
and 2) control (placebo associated with periodontal basic therapy). 
5. Number of Patients: A total of 54 patients in one clinical site at Stony Brook were randomized, 
27 patients received 1) Stabilized chlorine dioxide (associated with periodontal basic therapy); and 
27 patients received 2) control (placebo associated with periodontal basic therapy). 
6. Study Duration and Visits: The study duration was (3 months) and was comprised of a total of 
4 visits: Screening and hygienic phase therapy (weeks -2 to -1), Baseline (Visit 1, Day 0), Visit 2 
(14 days), Visit 3 (45 days), Visit 4 (90 days). 
7. Subjects received an Oral Hygiene Kit at Visit 1. The Modified Gingival Index (MGI), Bleeding 
on Probing (BOP) and Plaque Index (PI), Pocket depth and radiographs were measured, and all 
oral tissues examined (baseline examination). Subjects returned for Visit 2 in 14 days ± 3 days to: 
1) assess and record changes in indices and oral health and any adverse conditions. Visit 3 (45 
days ± 7) was a compliance visit for study drug utilization. Visit 4 (90 days ± 7) was a repeat of 
Visit 1. Samples for microbiome analysis were collected at baseline (Visit 1), Day 14 (Visit 2), 
and Day 90 (Visit 4).   
8. All parameters for clinical exam were calibrated between the examiners involved with the study. 
[ 6 ] Study Materials (Oral Hygiene Kit) 
STUDY DRUG 
Both the active and placebo drugs were provided in liquid form, intended for oral administration. 
Sample products were labeled by the manufacturer and shipped directly to the site. 


  
 
9 
 
ADMINISTRATION 
After tooth brushing in the morning and evening, the study product was administered orally using 
a cup that measures 15 mL of oral rinse, swishing in the oral cavity for 30 seconds and 
expectorating.   
 
[ 7 ] Subjects 
Subject recruitment occurred at the discretion of the Principal Investigator. After being recruited, 
potential subjects were informed of the purpose of the study and guided through HIPAA 
documentation and the informed consent process. Upon their understanding of the study, HIPAA 
regulations, and their agreement with the terms of the informed consent, subjects indicated so by 
signing the forms. The eligibility of potential subjects was determined through a series of screening 
interviews and an oral examination. Following screening, those potential subjects who retained 
eligibility were enrolled in the study at the discretion of the Principal Investigator. Approximately 
75 subjects were screened to provide 54 enrollees. Once these subjects were randomized, study 
enrollment was complete. 
Number of subjects:  
54 subjects 
Age:  
 
 
18 years to 80 years 
Gender: 
 
 
Both male and female subjects entered this study. 
Remaining Natural Teeth:  Minimum of 20   
[ 8 ] Subject Eligibility Criteria 
Each subject was enrolled into the study based upon an initial interview and screening examination 
certifying the following conditions: 
INCLUSION CRITERIA 
Inclusion criteria included systemically healthy, partially edentulous patients rehabilitated with 
functional dental implants and prostheses for at least 1 year, at the Department of Periodontics 
Stony Brook University. All patients were selected from Stony Brook Dental Clinic and were 
detected with different peri-implant diagnoses.  
 
Patients included had: 
1. diagnosis of peri-implant mucositis,  
2. at least at one implant;  
3. minimum of 20 natural teeth   
4. probing depth (PD) ≤5mm;  
5. BOP (bleeding on probing); 
6. No radiographic evidence of bone loss beyond the first two threads of the implant.  


  
 
10 
 
EXCLUSION CRITERIA 
1. Active Periodontitis or Peri-implantitis, which required definitive treatment.  
2. Presence of oral local mechanical factors that could have (in the opinion of the PI) 
influenced the outcome of the study.  
3. Presence of orthodontic appliances, or any removable appliances, that impinged on the 
tissues being assessed. 
4. Presence of soft or hard tissue tumors of the oral cavity.  
5. Patients treated with systemic antibiotic therapy or periodontal/mechanical/local delivery 
therapy within 12 weeks prior to study entry and throughout the study duration.  
6. Patients chronically (i.e. two weeks or more) treated with non-steroidal anti-inflammatory 
drugs (NSAIDs) or any medications known to affect soft tissue condition (excluding 
treatment of Acetylsalicylic acid ≤ 100 mg/day).  
7. Patients with uncontrolled diabetes, of any type, and/or patients with HbA1c test value 
>7.5% dated 3 months prior to the screening visit.  
8. Patients who were receiving radiation therapy to the head and neck area and/or receiving 
immunosuppressive therapy.  
9. The presence of any medical or psychiatric condition or any other condition that, in the 
opinion of the Investigator, could have affected the successful participation of the patient 
in the study.  
10. Drug and alcohol abuse.  
11. Patients who were participants in any other clinical study 30 days prior to the start of the 
study and throughout the study duration.  
12. Subject was pregnant (based on pregnancy result) or lactating. 
13. Subject was a smoker or had been a smoker within the past 6 months. 
14. Any other condition that may have interfered with the study as judged by the PI.  
ASSIGNMENT 
Once a subject had been screened and qualified for study participation, that subject was enrolled 
and assigned the next available randomization number. The study randomization table was 
generated by a third-party statistician. This procedure was used to keep the Study Statistician 
blinded to subject treatments prior to database lock. 
WITHDRAWAL 
Subjects enrolled in the study were able to elect to withdraw at any time for any reason. 
Additionally, subjects were able to have been withdrawn from the study at the request of the 
Principal Investigator for the following reasons: 
1. An adverse event required discontinuation of the study rinse in the judgment of the 
Principal Investigator or designee 
2. Subject refused or failed to comply with the study protocol 


  
 
11 
 
3. There was a protocol violation(s) or deviation(s) that compromised the use of the subject’s 
data 
All patients withdrawn from the study by request or by the Principal Investigator were to be seen, 
if they consented, for a close-out evaluation. The reason for withdrawal would be recorded by the 
Principal Investigator or designee on the End of Study form. Patients who experienced 
complications and discontinued the study on their own were to be scheduled, if they consented, 
for an immediate follow-up/close-out examination to determine whether an adverse event was 
present, and if so, the causation of the adverse event was to be recorded. If treatment was needed 
for any adverse event causing withdrawal, the subject would be monitored until there was a return 
to normal conditions. (Every effort would be made to follow up with subjects who withdrew from 
the study.) 
Test Product: ClōSYS® Ultra Sensitive Rinse 
Placebo: Oral rinse comprising same ingredients as in test product except for stabilized chlorine 
dioxide. 
Materials:  
Sponsor shipped prelabelled ‘Oral Rinse A’ and ‘Oral Rinse X’ products to the Test Site. Both 
products were in 16 oz. size bottle and identical in appearance. 
Each subject received the following supplies at Baseline (Visit 1) i.e. supplies for 0-14 days: 
a. 1 bottle (16oz) of either Oral Rinse Aor Oral Rinse X)) 
b. 35 measuring cups  
c. 1 tube of Crest Cavity Protection Toothpaste, Regular (8.2oz) and  
d. 1 ClōSYS toothbrush 
Each subject received the following supplies at Visit 2 i.e. supplies for 15-45 days: 
a. 2 bottles (16oz) of either Oral Rinse A or Oral Rinse X) 
b. 70 measuring cups  
c. 2 tube of Crest Cavity Protection Toothpaste, Regular (8.2oz) and  
d. 3 ClōSYS toothbrush 
Each subject received the following supplies at i.e. Visit 3 Compliance supplies for 45-90 days: 
a. 3 bottles (16oz) of either Oral Rinse A or Oral Rinse X 
b. 105 measuring cups  
c. 2 tube of Crest Cavity Protection Toothpaste, Regular (8.2oz) and 
d. 3 ClōSYS toothbrush 
Rowpar shipped the following materials to the Study Site (10% extra quantities were included for 
handling unforeseen situations): 
a. 165 bottles of 16-oz Oral Rinse A. 


  
 
12 
 
b. 165 bottles of 16-oz Oral Rinse X. 
c. 116 packs of 100 measuring cups. 
d. 165 tubes of Crest Cavity Protection Toothpaste, Regular (8.2oz) 
e. 220 ClōSYS toothbrushes. 
f. 5 boxes of 28 Ziploc bags-1 Gallon capacity 
 
The study site coordinator arranged to prepare Ziploc bag packets containing required supplies for 
distribution to each Subject. 
[ 9 ] Study Procedures 
SCREENING 
Review of the results of the Informed Consent, Screening Interview and Screening Oral 
Examination, the Principal Investigator or designee determined whether or not a subject was 
enrolled in the study. The following procedures were conducted:  
1. Informed Consent:  
2. Screening Interview: The subject was asked inclusion and exclusion questions, 
demographics, and date of last professional cleaning.  The following was also reviewed as 
reported by the subject: 
a. Medical History and Medications 
b. Periodontal treatment history 
3. Oral Examination:   
a. Extra- and Intra- oral examination 
b. BOP oral examination and probing depth 
4. Eligibility Determination: 
a. If the subject qualified, an appointment date was set for the Baseline Examination 
(Visit 1) to occur within 14 days of the screening examination or could be 
conducted at the same time as the screening visit. 
VISIT 1 - BASELINE EXAMINATION – DAY 0 
This visit took place within two weeks of the initial screening visit or could be conducted at the 
same time as the screening visit.  
The following procedures were conducted:  


  
 
13 
 
1. Reviewed any new medication(s) or medical history on respective documents.   
2. Rinsed mouth with water and collected samples for microbiome analysis by use of a cotton 
swab on the inside of the cheek and tongue mucosa. 
3. Performed pregnancy testing on females of childbearing age. 
4. Evaluated oral mucosal irritation or pathology. 
5. Performed a Modified Gingival Index (MGI) grading on all natural teeth and implants in 
the dentition. 
6. Performed a Turesky modification of the Quigley-Hein Plaque Index (PI) grading on all 
natural teeth and implants in the dentition. 
7. Assessed bleeding on probing (BOP) on all natural teeth and implants in the dentition. 
8. Verified data capture.  
9. X-rays 
10. Full mouth Scaling 
11. Randomization and dispensation of the Oral Hygiene Kit and Oral Hygiene Diary.   
12. The subjects then followed their normal oral-hygiene procedures with the addition of using 
the study rinse, toothbrush, and toothpaste provided to them. 
13. Provided diary for recording use of product rinse or placebo. 
14. Provided supplies for 14 days (day 1 to day 14 of the study). Weighed and recorded the 
weight of test rinse or placebo, as applicable, being provided. 
15. Instructed Subject to bring remaining oral rinse or placebo bottle  
16. Scheduled following appointments for Visit 2 (2 weeks after base line) and Visit 3 (3 
months) and noted in their study instructions and diary. Subjects were to be seen within 
plus or minus 7 days.  
VISIT 2 - INTERIM EXAMINATION - DAY 14  
This examination took place within 14 calendar days after Baseline Examination (Visit 1) ± 3 days. 
The following procedures were conducted: 
1. Reviewed any change in medical and dental history  
2. Rinsed mouth with water and collected samples for microbiome analysis by using a cotton 
swab on the inside of the cheek and tongue mucosa. 
3. Evaluated extra- and intra- oral areas for any mucosal irritation or pathology. 
4. Performed a Modified Gingival Index (MGI) grading on all natural teeth and implants in 
the dentition. 
5. Performed a Turesky modification of the Quigley-Hein Plaque Index (PI) grading on all 
natural teeth and implants in the dentition. 
6. Weighed and recorded remaining test rinse or placebo as applicable. 
7. Checked record for use of test rinse or placebo in the diary. 
8. Provided diary for recording use of product rinse or placebo.  
9. Provided supplies for 30 days (day 15 to day 45 of the study). Weighed and recorded the 
weight of test rinse or placebo, as applicable, being provided. 
10. Confirmed appointment date scheduled for the Compliance Visit (Visit 3). The subjects 
were given a reminder call 2 - 3 days prior to their scheduled appointment. 


  
 
14 
 
VISIT 3 – COMPLIANCE VISIT – DAY 45 
This examination took place within 45 calendar days after Baseline Examination (Visit 1) ± 7 days. 
The following procedures were conducted: 
1. Weighed and recorded remaining test rinse or placebo as applicable. 
2. Checked record for use of test rinse or placebo in the diary. 
3. Provided diary for recording use of product rinse or placebo.  
4. Provided supplies for remaining 45 days (day 46 to day 90 of the study). Weighed and 
recorded the weight of test rinse or placebo, as applicable, being provided. 
5. Confirmed appointment date scheduled for the Final Examination Visit (Visit 4). The 
subjects were given a reminder call 2 - 3 days prior to their scheduled appointment. 
VISIT 4 - FINAL EXAMINATION – DAY 90 
This examination took place within 90 days following the Baseline Examination (Visit 1) ± 7 days. 
The following procedures were conducted: 
1. Collected the subject’s diary and unused products at check-in. All partially used products 
were assessed for volume remaining and recorded. Used products were retained until after 
a monitoring visit, and then returned to the Sponsor. 
2. Performed pregnancy testing on females of childbearing age. 
3. Rinsed mouth with water and collected samples for microbiome analysis by use of a cotton 
swab on the inside of the cheek and tongue mucosa. 
4. Asked the subject to report any changes in medical or dental health since the last visit.   
5. Evaluated extra- and intra- oral areas for any mucosal irritation or pathology. 
6. Performed a Modified Gingival Index (MGI) grading on all natural teeth and implants in 
the dentition. 
7. Performed a Turesky modification of the Quigley-Hein Index (PI) grading on all natural 
teeth and implants in the dentition. 
8. Assessed bleeding on probing (BOP) and probing depth on all natural teeth and implants 
in the dentition. 
9. X-rays 
10. Weighed and recorded remaining test rinse or placebo as applicable. 
11. Checked record for use of test rinse or placebo in the diary. 
[ 10 ] Study Timeline 
Using December 2018 as a calendar starting point, the entire month would provide 20 days for 
recruiting.  As the screening, cleaning and baseline visit can be all on the same day we were 
considering that subjects could begin Study Visit 1 between January 2019 and December 2019.  
The final study visits was conducted in March 2020.  A final report concluded by December 2020. 


  
 
15 
 
[ 11 ] Statistical Evaluation 
The primary objective of this study was to analyze efficacy of stabilized chlorine dioxide as a 
chemical adjuvant for treatment of peri-implant mucositis in a non-surgical treatment protocol with 
a 3-month follow-up. 
The primary objective was determined by an examination of the following data: 
a) Gingival inflammation (MGI) 
Secondary analyses were the comparison of data with respect to product effectiveness: 
a) Reduction in bleeding on probing (BOP) and Turesky modification of the Quigley-Hein 
Plaque Index (PI) grading on all natural teeth in the dentition 
 
 
The primary statistical analytic framework was the repeated measures analysis of variance 
on three primary outcomes: probing depth, gingival index, and plaque. The primary hypothesis 
tested was the treatment by time interaction, i.e., did one treatment work better during the 
observations of these three outcomes? In other words, not just the total change, but also the rate of 
that change might differ between treatments. The proposed analysis was based on data that were 
generally normally distributed and similarly. If not, data transformations or link functions were 
used.  
Outcomes 
Raw data were collected from examinations of each tooth with regard to probing depth, 
gingival index, and plaque. Data were collected over three time periods, recorded into patient files, 
and transferred to Excel Workbooks, with one Workbook per patient. Each Workbook contained 
three tabs, one for each visit.  
The raw data were combined as two levels of indexes for the three measures. The first 
outcome was a global score index of probing depth, gingival index, and plaque measurement. The 
global index was derived from individual tooth scores for each measure divided by the number of 
teeth measured. The second index derived from the same raw data described the three measures in 
terms of average scores for implant and non-implant teeth. 
For the second analysis, implanted tooth data were separated from normal teeth data within 
each patient. Implant scores for each patient were averaged for probing depth, gingival index, and 
plaque scores. If a patient had one implant, each score was identical to the single measurement. 
With more than one implant, a single implant score for each patient was derived from averaging 
each of the three measures over the three observation periods. Likewise for each patient, the non-
implanted teeth measures were averaged for each of the three times of assessment.  
Individual patient data of the averages of the implant and non-implant teeth were calculated 
for each time period and transferred to a master data sheet.  
Data Management and Statistical Analysis  


  
 
16 
 
The patients’ data on the three measures were recorded within the Excel Workbooks under 
three tabs representing the first, second, and third clinical observation periods. So each tab 
recorded three measures. The first and last tabs recorded probing depth, gingival index, and plaque. 
The second visit included only gingival index and plaque. Each patient had an individual Excel 
Workbook. Data were sorted into analysis format through two Excel macros that created a single 
master data for global scores and a single one for implant and non-implant scores. Data files were 
saved in comma separated value (csv) format in both wide and long formats for R and SPSS data 
management, inspection, cleaning, and analyses.  
Since many individual variable distributions varied substantially from normal, a gamma 
log-link function was applied to reduce bias in most statistical tests.  
 
Label Key and Lot #s for Peri-Implant Mucositis Study with Stony Brook University 
Rowpar Pharmaceuticals, Inc., released the test material label codes after completion of the clinical 
study and statistical analysis of the data. The products were labelled as follows: 
 
Study Number: SBU-RPR-Peri-Implant Mucositis-2018 
Oral Rinse A: ClōSYS Placebo Oral Rinse, Lot #: 2-80516 
Oral Rinse X: ClōSYS® Ultra Sensitive (Unflavored) Oral Rinse, Lot #: 8122A 14-80430 
 
 


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18 
 
non-
implanted 
teeth 
1.87 (0.039) 
2.32 
(0.101) 
2.72 
(0.099) 
Test Group (Group 
X) 
implants 
26 
39 
2.82 (0.049) 
2.84 
(0.057) 
2.447 
(0.080) 
non-
implanted 
teeth 
2.01 (0.028) 
2.99 
(0.078) 
2.65 
(0.079) 
 
 
Global Score Analyses 
From raw data of individual teeth, each patient received a global index of periodontal 
disease, gingival index, and plaque for each visit. The global index for each of these measurements 
was found by dividing the sums of patient probing depth, gingival index, and plaque findings 
collected for each tooth by the number of teeth assessed. Over the three assessment periods, global 
scores of probing depth, gingival index, and plaque were collected for the first and last visits with 
probing depth scores not collected during on the second visit. These outcomes are measured as 
individual slopes of responses across the three observation visits. The slope represents the rate of 
change. 
The overall view of the response of each measure to the treatment group is summarized in 
the following general linear model Table 2. Table 3 shows the cell statistics for the slopes of each 
condition and outcomes reported in Table 2. 
 
Table 2. Master table of variance components attributable to treatment on individual rates of 
change on the three measures: probing depth, gingival index, and plaque.  
 
 
 
 
 
 
 
Source 
Variable 
Type III SS 
df 
MS 
F 
Sig. 
Group 
Slope of probing 
depth, time 1 to 3 
0.125 
1 
0.125 
1.191 
0.28 
 
Slope of gingivitis 
index, time 1 to 3 
0.485 
1 
0.485 
11.748 
0.001 
 
Slope of plaque 
score, time 1 to 3 
4.019 
1 
4.019 
69.751 
0.000 
Error 
Slope of probing 
depth, time 1 to 3 
5.75 
55 
0.105 
 
 
 
Slope of gingivitis 
index, time 1 to 3 
2.27 
55 
0.041 
 
 
 
Slope of plaque 
score, time 1 to 3 
3.169 
55 
0.058 
 
 
Total 
Slope of probing 
depth, time 1 to 3 
6.519 
57 
 
 
 


  
 
19 
 
 
Slope of gingivitis 
index, time 1 to 3 
6.135 
57 
 
 
 
 
Slope of plaque 
score, time 1 to 3 
18.861 
57 
 
 
 
Corrected 
Total 
Slope of probing 
depth, time 1 to 3 
5.875 
56 
 
 
 
 
Slope of gingivitis 
index, time 1 to 3 
2.755 
56 
 
 
 
 
Slope of plaque 
score, time 1 to 3 
7.187 
56 
 
 
 
R Squared = .021 (Adjusted R Squared = .003) 
 
 
 
R Squared = .176 (Adjusted R Squared = .161) 
 
 
 
R Squared = .559 (Adjusted R Squared = .551) 
 
 
 
 
 
 
Table 3. Details of cell statistics for analysis described in Table 2. 
Descriptive Statistics 
N 
Minimum 
Maximum 
Mean 
Std. Deviation 
Probing depth at time 1 
57 
2.04 
4.63 
2.71614 
0.432843 
Probing depth at time 3 
57 
0 
4.42 
2.50351 
0.804056 
Gingivitis index at time 1 
57 
1.41 
2.23 
1.97158 
0.172065 
Gingivitis index at time 2 
57 
0 
2 
1.71754 
0.364095 
Gingivitis index at time 3 
57 
0 
1.92 
1.48456 
0.451688 
Plaque score at time 1 
57 
1.47 
3.54 
2.67895 
0.555475 
Plaque score at time 2 
57 
0 
3.11 
2.19614 
0.596444 
Plaque score at time 3 
57 
0 
2.92 
1.77386 
0.618124 
Slope of probing depth, time 1 to 3 
57 
-1.47 
0.015 
-0.10632 
0.323886 
Slope of gingivitis index, time 1 to 3 
57 
-0.99 
-0.03 
-0.24351 
0.221807 
Slope of plaque score, time 1 to 3 
57 
-1.53 
-0.045 
-0.45254 
0.358255 
Valid N (listwise) 
57 
 
 
 


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22 
 
 
An analysis of covariance (ANCOVA) with the first visit as covariate was used to 
statistically control for the difference in average plaque scores at intake. ANCOVA results 
confirmed that test group (Group X) produced a significantly lower GPS measures (ANCOVA F 
= 34.82, df = 1, p < 0.0001), even with significant differences in the initial scores.  
To further explore and confirm control rinse (rinse A) and test rinse (rinse X) treatment 
effects on plaque measurement, from Time 1 to Time 3, both a Student’s t-test and a Bayesian 
analysis of group means were employed. The Bayesian analysis supported the ANCOVA results. 
Another t-test showed test group’s (Group X) GPS absolute change and rate of change were 
significantly greater than for control group (Group A): -1.43 versus 0.365, respectively. This 
difference is considered a large effect size, Cohen’s d = 2.21 (t = 8.35, df = 1, p < 0.0001). Thus, 
the changes and rates of change for GPS were greater for the test group (Group X) than the control 
group (Group A). 
 
 
 


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24 
 
Differential Effects of Mouthwashes on Implants in Control Group (Group A) and Test 
Group (Group X) 
Of particular interest was the specific effect that control mouthwash (rinse A) and test 
mouthwash (rinse X) might have on implant and non-implant sites across the three outcomes. 
Table 4 illustrates the overall study results of treatments and implants on the three outcomes. 
Probing depth was not different between treatments for implant and non-implant sites. Plaque and 
gingival indexes were improved significantly under test rinse Treatment (rinse X), with details 
described in Tables 5, 6, and 7 below. In addition, implant sites improved at a faster rate under test 
rinse Treatment (rinse X) conditions for both gingivitis and plaque.  
Table 4. Omnibus test for main effects and interactions of control mouthwash (rinse A) and test 
mouthwash (rinse X) on implant and non-implant sites.  
Sites of Implants responding differently to treatment 
All outcomes: measures in table 
Transformed Variable:  Average outcomes 
Source 
Type III Sum of Squares 
df 
Mean Square 
F 
Sig. 
Intercept 
2790.339 
1 
2790.339 
9371.807 
0.000 
Implant 
2.916 
1 
2.916 
9.793 
0.002 
Measure 
13.625 
1 
13.625 
45.761 
0.000 
Group 
1.954 
1 
1.954 
6.562 
0.011 
Implant * measure 
7.58 
1 
7.58 
25.459 
0.000 
Implant * group 
0.018 
1 
0.018 
0.061 
0.805 
Measure * group 
8.331 
1 
8.331 
27.981 
0.000 
Implant * measure * group 
16.127 
1 
16.127 
54.166 
0.000 
Error 
60.738 
204 
0.298 
 
 
 
 


  
 
25 
 
Implants and Probing depth 
Probing depth scores (PDS) were only collected at initial and last observations visits 1 and 
4. At intake, control group (Group A) patients had significantly higher levels of probing depth 
around implanted teeth (mean = 2.93, SEM = 0.094) than in non-implanted teeth (2.69, 0.063), 
with t = 2.31, df = 53, p = 0.025. In addition, control group (Group A) implant site probing depth 
was greater at intake than for test group (Group X) probing depth at implanted sites, 3.40 (0.109) 
versus 2.45 (0.080) respectively, with t = 7.07, df = 52, p < 0.001.  
Table 5 represents the results in an overall test of significance with PDS as a dependent 
variable. There were two notable interactions. One was a time by group interaction, representing 
that probing depths changed significantly differently over time. Another was a three-way 
interaction time-by-implant-by-group assignment. The time-by-group interaction was seen before 
in the PDS score and while significant, the actual difference was less than 1%. The three-way 
interaction is a false signal in that implant scores probe scores increased slightly in the test group 
(Group X) and decreased slightly in the control group (Group A) – and neither change was 
significant. 
Probing depth scores for implant and non-implant sites did not change significantly in both 
groups did not change significantly in both implant and non-implant sites as observed over time 
for both groups. Figure 8 illustrates the lack of change in implant and non-implant depth scores in 
either group.   
 
Table 5. Summary results of general linear model of probing depth measures for implant sites over 
time. 
Tests of Within-Subjects Contrasts 
Measure:   GGI 
Source 
Type III Sum of Squares 
df 
Mean Square 
F 
Sig. 
Time 
15.113 
1 
15.113 
563.159 
0.000 
Time * implant 
1.507 
1 
1.507 
56.172 
0.000 
Time * group 
0.941 
1 
0.941 
35.047 
0.000 
Time * implant * group 
0.001 
1 
0.001 
0.041 
0.840 
Error(Time) 
2.737 
102 
0.027 


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27 
 
Implants and Gingival Index 
Implant versus normal oral sites also showed a significant main effect (F = 79.0, df = 1, p 
< 0.001) indicating more and faster gingival index improvement in test group (Group X) for both 
implant and non-implant sites. Test group (Group X) implants decreased in gingival index scores 
by 83% while implants in control group (Group A) decreased by 57%. The non-implant sites for 
control group (Group A) decreased by 23% and for test group (Group X) by 50%. The rate of 
change was faster for test group (Group X) implants than for control group (Group A) and faster 
that test group (Group X) non-implant sites. Test Treatment (rinse X) members’ implants decrease 
in gingival index measured 26% versus 19% for those in control group (Group A). 
Table 6 indicates a strong and statistically significant difference between implant and non-
implant sites between and within groups – over time. Figure 9 illustrates the higher gingivitis index 
in test group (Group X) and greater and faster decrease of gingivitis in test group (Group X). 
 
 
Table 6. Summary results of general linear model of gingival index measures. 
Tests of Between-Subjects Effects 
 
Gingivitis  
Source 
Type III Sum of Squares 
df 
Mean Square 
F 
Sig. 
Intercept 
1207.001 
1 
1207.001 
11073.258 
0.000 
implant 
9.949 
1 
9.949 
91.274 
0.000 
group 
9.177 
1 
9.177 
84.187 
0.000 
implant * group 
8.613 
1 
8.613 
79.021 
0.000 
Error 
11.118 
102 
0.109 
 


  
 
28 
 
 
 
Implants and Plaque 
 
Plaque scores (PS) for both implant and non-implant plaque scores were higher in the test 
group (Group X) (2.99 (0.071)) than in the control group (Group A) (2.35 (0.100)) at the first visit, 
t = 5.45, df = 55, p < 0.001. As with gingival index, PS decreased more for test group (Group X) 
patients (-0.799 (0.109)) than for control group (Group A) (-0.156 (0.064)) in both implant and 
non-implant sites, t = 5.75, df = 55, p < 0.001.  
 
Table 7. Summary table of differential effects of control Treatment (rinse A) and test Treatment 
(rinse X) across implant status and group assignment. The group by implant interaction is 
significant, indicating the mouthwashes acted differently on implant versus non-implant sites.  
Tests of Between-Subjects Effects 
Plaque 
Source 
Type III Sum of Squares 
df 
Mean Square 
F 
Sig. 
Intercept 
1596.963 
1 
1596.963 
3282.732 
0.000 
implant 
0.547 
1 
0.547 
1.124 
0.292 
Figure 9. Significant 
differential effects of 
mouthwashes on gingival 
index at implant sites. Both 
groups showed significant 
decreases in plaque, but the 
test group (Group X) reduced 
gingival index scores more 
and at a faster rate. Note the 
difference in gingival index 
scores at the beginning of the 
trial.  


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group 
1.108 
1 
1.108 
2.278 
0.134 
implant * group 
7.532 
1 
7.532 
15.483 
0.000 
Error 
49.62 
102 
0.486 
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30 
 
 
 
Conclusions 
There is a clear advantage to using ClōSYS® Ultra Sensitive oral rinse treatment (test 
rinse X) in terms of plaque and gingival index. In addition, ClōSYS® Ultra Sensitive oral rinse 
(test rinse X) appeared to have a preferential benefit for implant sites, over both control treatment 
(placebo rinse A) and over non-implant sites. The ClōSYS® Ultra Sensitive rinse (test rinse X) 
significantly reduced the plaque index and gingival index as compared to initial measures and 
those in control group (placebo rinse A) (p < 0.001). The observation of higher initial gingivitis 
scores for the ClōSYS® Ultra Sensitive oral rinse (test rinse X) did not affect the superiority of 
this test group treatment. In controlling for the inequality at baseline, and analysis of covariance 
showed the reduction of the plaque score remained significantly better in the ClōSYS® Ultra 
Sensitive oral rinse  group (test rinse X) than for the control group (placebo rinse A) (p < 0.001). 
Also, using pre-post difference scores and slopes of the scores over time showed the treatment 
effect to be robust to the mismatch of initial levels of gingivitis and plaque (P < 0.001 for both).   
Both groups improved from the use of mouthwashes, but the ClōSYS® Ultra Sensitive 
oral rinse (test rinse X) improved more and at a faster rate (p < 0.001) compared to the control 
group (placebo rinse A). There was no apparent effect on periodontitis between the two intervals 
in which it was measured.   
Implant sites were significantly more (p < 0.001) and faster (p < 0.001) improved in the 
ClōSYS® Ultra Sensitive oral rinse  group (test rinse X) than the other non-implanted teeth and 
in the control group (placebo rinse A).   
Both ClōSYS® Ultra Sensitive oral rinse (test rinse X) and placebo rinse (rinse A) tested 
are safe to oral tissues and did not show any adverse effects. 
Both ClōSYS® Ultra Sensitive oral rinse (test rinse X) and placebo rinse (rinse A) tested are safe 
to oral tissues and do not have any adverse effects. 
 
 
 
 
 
 
 
 


  
 
31 
 
Signature Page 
 
Principal Investigator 
Srinivas Rao Myneni Venkatasatya, DDS, PhD 
 
 
 
 
 


  
 
32 
 
REFERENCES 
 
1. 
Ziliak S, McCloskey D. The Cult of Statistical Significance: How the Standard Error 
Costs Us Jobs, Justice, and Lives. Ann Arbor: University of Michigan Press; 2008. 
2. 
Loe H, Silness J. Periodontal disease in pregnancy. Acta Odont Scand. 1963;21:533-551.