Clinical trial NCT01802216
Conditions: Chronic Kidney Disease Periodontal Disease
Keywords: chronic kidney disease progression periodontal disease intensive periodontal disease treatment
Sponsor: University of California, San Francisco
Start date: 2014-02-01; Completion date: 2017-09-01
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is (1) to determine whether a 12-month trial of patients from underserved communities with clinically significant gum disease and kidney disease randomly assigned to intensive gum disease treatment or delayed treatment is feasible and (2) to determine the variability of various tests of kidney function and inflammation in response to intensive gum disease treatment.

Detailed description:
This is a randomized controlled pilot trial to two intention-to-treat treatment arms: intensive periodontal therapy or control-delayed periodontal therapy. The investigators' goals are to test the feasibility of conducting this trial among an underserved (mostly poor and low literacy) population and to determine the variability of renal and inflammatory biomarkers in response to intensive periodontal therapy over a 12 month period among participants with both chronic kidney disease (CKD) and significant periodontal disease.

Randomization will be restricted with respect to diabetes (a strong risk factor for causing/aggravating both CKD and periodontal disease) to prevent an imbalance between the two arms. The investigators will recruit 51 patients from the San Francisco General Hospital (SFGH) Renal Clinic. Participants will be assigned 2:1 to the intervention group for the intensive periodontal treatment protocol (n=34) or to the control/delayed treatment group for rescue periodontal treatment only with intensive treatment at the end of the study (n=17).

Hypothesis:

A large scale randomized controlled trial of intensive periodontal treatment among the underserved will be feasible (with respect to enrollment, randomization, adherence and variability in clinical outcomes).

Specific Aims:

1. To assess the feasibility of recruiting patients to this pilot trial.
2. To determine the variability of kidney biomarkers in response to periodontal disease treatment.

Statistical Analysis:

The investigators will calculate descriptive statistics (mean, standard deviation) of each clinical outcome which will include a traditional marker of kidney function (serum creatinine), markers of kidney structure \[as glomerular injury (albuminuria) and tubular injury (neutrophil gelatinase-associated lipocalin (NGAL))\]; a marker of vascular endothelial injury (asymmetrical dimethylarginine (ADMA)); and markers of systemic inflammation (IL-6 and C-reactive protein) measured at baseline, study month 4, and study month 12. The investigators will use repeated-measures generalized estimating equations (GEE) to compare changes in clinical outcomes over time within each treatment group and to compare differences between treatment groups taking individual change over time into account.

Sample Size Calculation:

This is a pilot study. To the investigators' knowledge, there are no existing data of the anticipated effect size of periodontal treatment to inform sample size calculations. However, because a primary aim is to determine the variability of various renal and inflammatory biomarkers, the investigators seek to enroll at least 30 subjects in the intervention arm of the trial.

Arms: arm 1: Baseline panoramic x-ray (Panorex) and complete oral examinations at every visit. Rescue scaling and root planing only to sites of periodontal disease progression (since prior examination) of greater than 3mm. Subjects will be informed of their assignment to the delayed treatment group and provided referral list of local dentists should patient not feel comfortable waiting until end of study for full intensive periodontal disease treatment. Written and verbal instruction in oral hygiene. Provision of oral hygiene supplies. arm 2: Baseline panoramic x-ray (Panorex) and complete oral examinations at every visit. Intensive periodontal disease treatment to include administration of local anesthetic to up to two quadrants for scaling and root planing with ultrasonic and hand instruments. Minocycline will be applied to any sites with probing depth \>=5mm. Hopeless teeth in scaled quadrants will be extracted. Written and verbal instruction in oral hygiene. Provision of oral hygiene supplies.
Interventions: intervention 1: Scaling and root planing intervention 2: Minocycline
Intervention descriptions: intervention 1: non-surgical periodontal disease treatment intervention 2: antibiotic microspheres

Protocol documents:
Prot_001.pdf: 
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NIH Natl Inst Diabetes & Digest & Kidney 
Clinical Research Protocol 
KIDNEY AND PERIODONTAL DISEASE (KAPD) STUDY 
Protocol Number: 
12-09801 
NCT01802216 
Version Date: 
12/20/2013 
Investigational Product: 
MINOCYCLINE HYDROCHLORIDE, ARESTIN 
Sponsor: 
Dr. Vanessa Grubbs, MD, MPH  
1001 Potrero Ave, SFGH 100 
San Francisco CA 94143 
Funding Organization: 
National Institutes of Health, Robert Wood Johnson 
Foundation 
Principal Investigator: 
Dr. Vanessa Grubbs, MD, MPH 
 
415-206-5649  
 
grubbsv@medsfgh.ucsf.edu 
 
Approval: 
 
 
12/20/13 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing NIH with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential 
and that this confidentiality requirement applies to all study staff at this site. Furthermore, 
on behalf of the study staff and myself, I agree to maintain the procedures required to 
carry out the study in accordance with accepted GCP principles and to abide by the terms 
of this protocol. 
 
Protocol Number:  12-09801 
 
Protocol Title:  Kidney and Periodontal Disease Study 
 
Protocol Date:  12/20/2013 
 
 
 
12/20/13 
Investigator Signature  
 
Date 
Vanessa Grubbs, MD, MPH 
Print Name and Title 
Site # 
 
 
Site Name 
San Francisco General Hospital 
Address 
1001 Potrero Ave, SFGH 100  
 
San Francisco, Ca 94143 
 
 
 
 
Phone Number 
415 206-5649 
 


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TABLE OF CONTENTS 
 
1 
BACKGROUND 
 
1.1 
Overview of Clinical Studies ..............................................................................................  
2 
STUDY RATIONALE 
 
2.1 
Risk / Benefit Assessment ..................................................................................................  
3 
STUDY OBJECTIVES 
 
3.1 
Primary Objective ...............................................................................................................  
3.2 
Secondary Objectives .........................................................................................................  
4 
STUDY DESIGN 
 
4.1 
Study Overview ..................................................................................................................  
5 
CRITERIA FOR EVALUATION 
 
5.1 
Primary Efficacy Endpoint .................................................................................................  
5.2 
Secondary Efficacy Endpoints ............................................................................................  
5.3 
Safety Evaluations ..............................................................................................................  
6 
SUBJECT SELECTION 
 
6.1 
Study Population .................................................................................................................  
6.2 
Inclusion Criteria ................................................................................................................  
6.3 
Exclusion Criteria ...............................................................................................................  
7 
CONCURRENT MEDICATIONS 
 
7.1 
Allowed Medications and Treatments ................................................................................  
8 
STUDY TREATMENTS 
 
8.1 
Method of Assigning Subjects to Treatment Groups .........................................................  
8.2 
Supply of Study Drug at the Site ........................................................................................  
8.3 
Supply of Study Drug at the Site ........................................................................................  
8.4 
Study Drug Accountability .................................................................................................  
9 
STUDY PROCEDURES AND GUIDELINES 
 
9.1 
Clinical Assessments ..........................................................................................................  
9.2 
Clinical Laboratory Measurements ....................................................................................  
9.3 
Research Laboratory Measurements (include sections as appropriate) ..............................  
10 EVALUATIONS BY VISIT 
 
10.1 Visit 1 (Screening) .............................................................................................................  
10.2 Visit 2 (Baseline) ................................................................................................................  
10.3 Visit 3 (Month 4) ................................................................................................................  
10.4 Visit 4 (Month 8) ................................................................................................................  
10.5 Visit 5 (Month 12) ..............................................................................................................  
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
 
11.1 Adverse Events ...................................................................................................................  
11.2 Serious Adverse Experiences (SAE) ..................................................................................  
11.3 Medical Monitoring ...........................................................................................................  


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12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
 
12.1 Early Discontinuation of Study and/or Drug .....................................................................  
12.3 Withdrawal of Subjects from the Study .............................................................................  
12.4 Replacement of Subjects ....................................................................................................  
13 PROTOCOL VIOLATIONS 
 
14 DATA SAFETY MONITORING 
 
15 STATISTICAL METHODS AND CONSIDERATIONS 
 
15.1 Data Sets Analyzed ............................................................................................................  
15.2 Demographic and Baseline Characteristics ........................................................................  
15.3 Analysis of Primary Endpoint ............................................................................................  
15.4 Analysis of Secondary Endpoints ......................................................................................  
15.5 Interim Analysis .................................................................................................................  
15.6 Sample Size and Randomization ........................................................................................  
16 DATA COLLECTION, RETENTION AND MONITORING 
 
16.1 Data Collection Instruments ...............................................................................................  
16.2 Data Management Procedures ............................................................................................  
16.3 Data Quality Control and Reporting ..................................................................................  
16.4 Archival of Data .................................................................................................................  
16.5 Availability and Retention of Investigational Records ......................................................  
16.6 Monitoring ..........................................................................................................................  
16.7 Subject Confidentiality .......................................................................................................  
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
 
17.1 Protocol Amendments ........................................................................................................  
17.2 Institutional Review Boards and Independent Ethics Committees ....................................  
17.3 Informed Consent Form .....................................................................................................  
17.4 Publications ........................................................................................................................  
17.5 Investigator Responsibilities ..............................................................................................  
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CRP 
C-reactive protein 
DMC 
Data Monitoring Committee 
DSMB 
eGFR 
Data Safety Monitoring Board 
Epidermal growth factor receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
Serious adverse experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
Kidney and Periodontal Disease (KAPD) Study 
SPONSOR 
Dr. Vanessa Grubbs, MD MPH 
FUNDING 
ORGANIZATION 
 
NIH Natl Inst Diabetes & Digest & Kidney 
NUMBER OF SITES 
1 
RATIONALE 
The purpose of this study is (1) to determine whether a 12-month trial 
of patients from underserved communities with clinically significant 
gum disease and kidney disease randomly assigned to intensive gum 
disease treatment or delayed treatment is feasible and (2) to determine 
the variability of various tests of kidney function and inflammation in 
response to intensive gum disease treatment. 
STUDY DESIGN 
This is an unblinded, randomized, controlled pilot trial with 2 intent-
to-treat treatment arms. 
PRIMARY 
OBJECTIVE 
Aim 1:  To assess the feasibility of recruiting patients to this pilot 
trial. 
SECONDARY 
OBJECTIVES 
Aim 2: To determine the variability of kidney biomarkers in response 
to periodontal disease treatment. 
NUMBER OF 
SUBJECTS 
51 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria:  
1. 
Age 20 to 75 years 
2. 
Speaks English or Spanish 
3. 
At least 2 estimated glomerular filtration (eGFR) rate    
measurements of 15-59 mL/min/1.73 m2 within the preceding 12 mo 
4. 
No eGFR increase by ≥ 50% in the preceding 6 months 
5. 
Moderate/severe periodontal disease in accordance with the 
CDC and Prevention/American Academy of Periodontology 
definition AND at least 30% sites with bleeding on probing 
 
Exclusion Criteria: 
1. Under age 20 or over age 75 
2. Unable to understand and provide informed consent 
3. Currently receiving dialysis 
4. Receiving current immunosuppressant therapy 
5. Receiving current anticoagulation therapy resulting in an elevated 
prothrombin time or an International Normalized Ratio (INR) 
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6. Pregnant 
 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Those assigned to the Intensive Intervention Group will undergo 
intensive treatment to include administration of local anesthetic to up 
to 2 oral quadrants for scaling and root planing with ultrasonic and 
hand instruments.  Arestin (minocycline HCl) will be applied to any 
sites with probing depth ≥ 5 mm.   
 
Women with positive urine pregnancy tests (ie, have become pregnant 
while on-study) who are assigned to the Intervention Group will not 
receive Arestin. 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Subjects assigned to the Rescue Treatment Group will undergo 
assessment and documentation of the levels of periodontal disease 
throughout the oral cavity.  They will have extraction of hopeless 
teeth plus scaling and root planing only to sites of disease progression 
(3 mm or more) since screening examination. No administration of the 
product until the end of the study. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 12 months: 
Screening visit 
Baseline visit 
4 month visit 
8 month visit 
12 month (last visit) 
 
The total duration of the study is expected to be 12 months from the 
time of recruitment.   
CONCOMMITANT 
MEDICATIONS 
Allowed: 
 
Prohibited: 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
Repeated scaling and root planing to resolution of periodontal disease 
(no sites with probing depths >3mm and <10% bleeding on probing 
among all sites). 
SECONDARY 
ENDPOINTS 
This is a pilot study intended to determine the variability of various 
renal and inflammatory biomarkers in response to intensive 
periodontal disease treatment as a means of establishing the 
pathophysiologic mechanism(s) of periodontal pathogen injury. 


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OTHER 
EVALUATIONS 
Feasibility and process outcomes: assessment of enrollment, 
randomization, adherence to study protocol, participant and study 
coordinator input. 
SAFETY 
EVALUATIONS 
Adverse events will be ascertained at each study visit. Ascertainment 
will include the event start and stop date, severity, outcome, whether it 
was expected, relationship to study intervention, and any actions taken 
regarding the study intervention.  
PLANNED INTERIM 
ANALYSES  
When approximately 50% of patients have completed the study 
through study month 4, an interim analysis for safety will be 
conducted by an independent data monitoring committee. Serious 
adverse events will be monitored by the committee on an ongoing 
basis throughout the study. 
 
The DSMB will meet twice a year during the intervention phases of 
the randomized controlled trial (approximately an 18-month period).  
This Chairperson will be responsible for overseeing the meetings and 
developing the agenda in consultation with the PI and will also serve 
at the Safety Officer.  The Chair is the contact person for the DSMB 
and for severe adverse event reporting.   
 
STATISTICS 
Primary Analysis Plan 
We will calculate descriptive statistics (mean, standard deviation) of 
each clinical outcome which will include a traditional marker of 
kidney function (serum creatinine), cystatin C, markers of kidney 
structure {as glomerular injury (albuminuria) and tubular injury 
[neutrophil gelatinase-associated lipocalin (NGAL)]};  a marker of 
vascular endothelial injury [asymmetrical dimethylarginine 
(ADMA)];  and markers of systemic inflammation (IL-6 and C-
reactive protein) measured at baseline, study month 4, and study 
month 12.  We will use repeated-measures generalized estimating 
equations (GEE) to compare changes in clinical outcomes over time 
within each treatment group and to compare differences between 
treatment groups taking individual change over time into account. 
Rationale for Number 
of Subjects 
This is a pilot study. To our knowledge, there are no existing data of 
the anticipated effect size of periodontal treatment to inform sample 
size calculations. However, because a primary aim is to determine the 
variability of various renal and inflammatory biomarkers, we seek to 
enroll at least 30 subjects in the intervention arm of the trial. 
  
We assume 25% of patients screened will meet all inclusion/exclusion 
criteria and enroll in the study. 
 


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1 
BACKGROUND 
Chronic kidney disease (CKD) remains a prevalent public health issue despite intense 
efforts targeting traditional risk factors. Periodontal disease, both common and modifiable, 
has been implicated as a promising novel focus for impacting CKD. A few recent studies, 
including our work, have collectively found that subjects with significant periodontal 
disease were 1.5 to 2-fold more likely to have CKD than those without periodontal 
disease. Underserved (poor/uninsured) populations are differentially impacted by both 
CKD and periodontal disease.  
Although periodontal disease is an infection of the oral cavity, periodontal pathogens can 
access systemic circulation through normal oral health procedures like tooth brushing and 
even chewing. As a result, the circulating bacterial coating can bind specific receptors 
found throughout the kidney. Once bound to the bacterial coating, the receptors are 
activated to launch an inflammatory cascade that may lead to deterioration in renal 
function. 
 
1.1 
Overview of Clinical Studies 
This pilot study will be conducted among an underserved patient population. Therefore, 
we expect the prevalence of significant periodontal disease to be due to low rates of dental 
care. In our recently published manuscript21 in which we examined a cohort of 2,235 and 
4,263 adult (≥ 20 years) patients with without CKD, respectively, and at least 1 year of 
follow-up between 2005 and 2010 within the San Francisco Department of Public Health 
Community Health Network, we found that only 245 (11.0%) patients with and 741 
(17.4%) patients without CKD had at least one outpatient dental visit within the Network 
throughout the study period. Those with CKD had a 25% lower likelihood of having a 
dental visit [HR = 0.75, 95% CI (0.64-0.88)] than those without CKD adjustment for age, 
gender, race/ethnicity, language, insurance, and monthly income. 
2 
STUDY RATIONALE 
To our knowledge, there are no existing data of the anticipated effect size of periodontal 
treatment to inform sample size calculations. Further, the pathophysiologic mechanism(s) 
of periodontal pathogen injury has not been established.  Therefore, in addition to 
measuring creatinine as a traditional marker of kidney function, we will measure cystatin 
C; markers of kidney structure {as glomerular injury (albuminuria) and tubular injury 
[neutrophil gelatinase-associated lipocalin (NGAL)]}; vascular endothelial injury 
[asymmetrical dimethylarginine (ADMA)];  and systemic inflammation (IL-6 and C-
reactive protein) to both predict the effect of treatment and determine the specific 
mechanisms through which the periodontal pathogen may exert effects.  Though kidney 
failure (eGFR <15 ml/min/1.73m2 or the initiation of renal replacement therapy) would be 
a definitive clinical end point for a trial evaluating the effect of intensive periodontal 
disease treatment on CKD progression, it is impractical as a primary outcome within the 
time and resource constraints of the career development award funding this project. 


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2.1 
Risk / Benefit Assessment 
This study involves an increase over minimal risk.  The study requires blood draws; data 
collection from medical records;   a periodontal exam;  and periodontal therapy consisting 
of administration of systemic oral antibiotics, scaling and root planing and treatment with 
local delivery minocycline antibiotics (Arestin).  The probability and magnitude of harm 
or discomfort anticipated in this research study presents low risks and improved dental 
care compared to subject baseline that is reasonably commensurate with current medical 
or dental practice.  The likelihood of serious harm to subjects is low. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to test the feasibility of conducting this trial among 
an underserved population (mostly poor and/or low literacy).  
3.2 
Secondary Objectives 
The secondary purpose is to determine the variability of renal and inflammatory 
biomarkers in response to intensive periodontal therapy over a 12-month period among 
participants with both chronic kidney disease (CKD) and significant periodontal disease. 
4 
STUDY DESIGN 
4.1 
Study Overview 
 
This is an unblinded, randomized, controlled pilot trial with 2 intent-to-treat treatment 
arms:  immediate intensive periodontal therapy or delayed intensive periodontal therapy.  
Randomization will be stratified with respect to diabetes (a strong risk factor for 
causing/aggravating both CKD and periodontal disease) to prevent an imbalance between 
the 2 arms.  The accrual target is 51 patients from the San Francisco General Hospital 
(SFGH) Renal Clinic. Participants will be assigned 2:1 to the Intensive Intervention Group 
for the intensive periodontal treatment protocol (n = 34) or to the Rescue Treatment Group 
for rescue periodontal treatment only with intensive treatment at the end of the study  
(n = 17). 
 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  
Subjects who meet oral study criteria and CDC/AAP definition for moderate/severe 
periodontal disease will be randomized 2:1 to either an intensive intervention cohort or a 
rescue treatment cohort 1,2 in blocks of 3, with stratification by presence of diabetes to 
ensure balance between groups.   
 
Total duration of subject participation will be 12 months.  Total duration of the study is 
expected to be 18 months. 


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5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
 Repeated scaling and root planing to resolution of periodontal disease (no sites with 
probing depths >3mm and <10% bleeding on probing among all sites). 
5.2 
Secondary Efficacy Endpoints 
This is a pilot study intended to determine the variability of various renal and 
inflammatory biomarkers in response to intensive periodontal disease treatment as a 
means of establishing the pathophysiologic mechanism(s) of periodontal pathogen injury. 
5.3 
Safety Evaluations 
Adverse events will be ascertained at each study visit. Ascertainment will include the 
event start and stop date, severity, outcome, whether it was expected, relationship to study 
intervention, and any actions taken regarding the study intervention.  
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with at least 2 estimated glomerular filtration (eGFR) rate measurements of 15-
59 mL/min/1.73 m2 within the preceding 12 months and who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
1. Age 20 to 75 years 
2. Speaks English or Spanish 
3. At least 2 estimated glomerular filtration (eGFR) rate measurements of 15-59 
mL/min/1.73 m2 within the preceding 12 months 
4. No eGFR increase by ≥ 50% in the preceding 6 months 
5. Moderate/severe periodontal disease in accordance with the Centers for Disease Control 
and Prevention/American Academy of Periodontology definition AND at least 
30% sites with bleeding on probing 
6.3 
Exclusion Criteria 
1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in 
the study. 
2. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
3. Under age 20 or over age 75 
4. Unable to understand and provide informed consent 
5. Currently receiving dialysis 
6. Receiving current immunosuppressant therapy 


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7. Receiving current anticoagulation therapy resulting in an elevated prothrombin time 
or an International Normalized Ratio (INR) greater than 2.0 
 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy for CKD is allowed except for treatments noted in the exclusion criteria 
described above and as noted in the prohibited medications section below.   
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be 
considered a protocol violation. Subjects who begin taking these medications will be 
withdrawn from the study. 
 
Warfarin (Coumadin) 
Immunosuppressant medications:  
Prednisone 
Cellcept/Mycophenolate/Mofetil/MMF 
Cyclophosphamide/Cytoxan 
Tacrolimus/Prograf 
Siroimus/Rapamune 
Azathioprine/Imuran/Azasan 
Cyclosporine/Gengraf/Neoral/Sandimmune 
Any DMARD: Methotrexate, Etanercept, Adalimumab, Infliximab, 
Leflunomide, Sulfasalazine, Hydroxychloroquine 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Randomization will be stratified with respect to diabetes (a strong risk factor for 
causing/aggravating both CKD and periodontal disease) to prevent an imbalance between 
the 2 arms.  The accrual target is 51 patients from the San Francisco General Hospital 
(SFGH) Renal Clinic. Participants will be assigned 2:1 to the Intensive Intervention Group 
for the intensive periodontal treatment protocol (n = 34) or to the Rescue Treatment Group 
for rescue periodontal treatment only with intensive treatment at the end of the study (n = 
17).  At the end of the study the Rescue Treatment Group will receive the full intensive 
treatment.  


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8.2 
Supply of Study Drug at the Site 
Orapharma, Inc. will ship Arestin to the investigational site.  The Investigator will store 
the drug in a locked office at room temperature. 
8.2.1 
Dispensing 
Investigator and Study Research Coordinator will have access to Arestin and will dispense 
to Study Hygienist as needed for study intervention.  
8.2.2 
Administration Instructions  
The Study Hygienist will apply Arestin to periodontal pockets probing 5mm or more at 
each study visit for subjects in the Intervention Group and at the last study visit for 
subjects in the Rescue Control Group. An exception will be Intervention Group subjects 
who become pregnant during the study. They will not be given Arestin due to risk of 
teratogenicity. 
8.3 
Supply of Study Drug at the Site 
Orapharma will ship Arestin to the investigational site in batches agreed upon with 
Investigator. 
8.3.1 Storage 
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59 
to 86ºF). If the temperature of study drug storage in the clinic/pharmacy exceeds or falls 
below this range, this should be reported to the Sponsor or designee and captured as a 
deviation. Subjects will be instructed to store the medication in original packaging (foil pouch 
and protected from light) at room temperature according to the instructions outlined on the 
Drug Administration Instructions. 
8.4 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject. If appropriate, assent must also be obtained prior to conducting any 
study-related activities. 


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9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and Study Visits 4 months, 8 months, 12 months and at early 
termination when applicable.  Dose, route, unit frequency of administration, and 
indication for administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Baseline. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Baseline. 
9.1.4 Physical Examination 
A complete physical examination will be performed by either the study nurse at Baseline.  
Qualified staff (MD, NP, RN, and PA) may complete the abbreviated physical exam at all 
other visits.  New abnormal physical exam findings must be documented and will be 
followed by a physician or other qualified staff at the next scheduled visit. 
9.1.5 Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes at Baseline, months 4, 8, and 12. 
9.1.6 Oral Examination 
At baseline and every study visit, Mark Ryder/Periodontal Residents will conduct a 
complete oral examination in the SFGH Oral Surgery Clinic including determination of 
PD and CAL at 6 sites per tooth, assessment of BOP, Plaque Index, Gingival Index, and 
determination of hopeless teeth.  Per standard of care, confirmation that teeth are hopeless 
will be on the basis of a Panorex radiograph performed for that purpose. 
9.1.7 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), outcome, treatment and relation to study drug will be 
recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements  
9.2.1 Hematology 
Blood for Hemoglobin A1c (HbA1c, a marker for diabetes) will be sent to the SFGH Lab 
at baseline study visit. 


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9.2.2 
Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study and at each study visit. 
9.2.3 Urinalysis 
Urine will be obtained at study visits baseline, month 4, and month 12 and sent to the 
SFGH clinical laboratory for microalbumin quantification and the UCLA Clinical and 
Research Laboratory for NGAL. Urine for tobacco metabolites (Cotinine 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol [NNAL, a metabolite of the tobacco-
specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 
biomarker for tobacco use) will be sent to the Clinical Pharmacology Laboratory at 
UCSF/SFGH. 
9.3 
Research Laboratory Measurements (include sections as appropriate) 
Blood will be obtained at study visits baseline, month 4, and month 12 for Creatinine, 
Cystatin C, Neutrophil gelatinase-associated lipocalin (NGAL, a marker of renal tubular 
injury), Assymetrical dimethylargine (ADMA, a marker of endothelial injury), 
 Interleukin 6 (IL-6, a biomarker of systemic inflammation), Cotinine (a metabolite of 
nicotine and biomarker for exposure to tobacco smoke), and serum C-reactive protein 
(CRP) and IL-6 determinations for assessment of systemic evidence for infection and/or 
inflammation. Specimens will be collected in appropriate vials, labeled and shipped 
overnight in batches to the UCLA Clinical and Research Laboratory except for ADMA, 
which will be shipped to the Oxonon Laboratory in Oakland, California. Samples will be 
stored at -70°C while waiting to be shipped. 
Dental measurements include collection of saliva, plaque and gingival crevicular fluid at 
each study visit. Samples will be collected in sterile specimen cups, placed in an ice cup 
and kept in an ice cup until delivery to laboratory for processing (within 2 hours) or stored 
a -70°C. 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Screening) 
1. 
Review the study with the subject and obtain written informed consent and HIPAA 
authorization and assent, if appropriate. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record concomitant medications. 
5. 
Administer questionnaires. 
6. 
Oral examination/screening. 
7. 
Schedule subject for Baseline visit and provide payment. 
8. 
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10.2 Visit 2 (Baseline) 
1. 
Concomitant medications review. 
2. 
Perform physical examination. 
3. 
Perform and record vital signs. 
4. 
Collect blood and urine sample. 
5. 
Administer questionnaires. 
6. 
Perform Panorex mouth x-ray. 
7. 
Oral exam and assess disease progression  
8. 
Writes order for extractions, full mouth deep cleaning, & (Arestin if Intensive 
Intervention Group). 
9. 
Provide brushing and flossing education 
10. 
Performs scaling & planing in areas of disease progression. 
11. 
If needed, extract hopeless teeth and provides aftercare instructions. 
12. 
Schedules next appointment and provide visit payment. 
10.3 Visit 3 (Month 4) 
1. 
Record any Adverse Experiences. 
2. 
Record changes to concomitant medications. 
3. 
Perform and record vital signs. 
4. 
Collect blood and urine sample. 
5. 
Administer questionnaires. 
6. 
Oral exam and assess disease progression.  
7. 
If question of hopeless teeth schedule Panorex mouth x-ray. 
8. 
Writes order for extractions (if needed), (full mouth deep cleaning, & Arestin if 
Intensive Intervention Group). 
9. 
Performs scaling & planing in areas of disease progression. 
10. 
If needed, extract hopeless teeth and provides aftercare instructions. 
11. 
Schedule next appointment and provide payment. 
10.4 Visit 4 (Month 8) 
1. 
Record any Adverse Experiences. 
2. 
Record changes to concomitant medications. 
3. 
Perform and record vital signs. 
4. 
Collects blood and urine sample. 
5. 
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6. 
Oral exam and assess disease progression.  
7. 
If question of hopeless teeth schedule Panorex mouth x-ray. 
8. 
Writes order for extractions (if needed), (full mouth deep cleaning, & Arestin if 
Intensive Intervention Group). 
9. 
Performs scaling & planing in areas of disease progression. 
10. 
If needed, extract hopeless teeth and provides aftercare instructions. 
11. 
Schedule next appointment and provide payment. 
10.5 Visit 5 (Month 12) 
1. 
Record any Adverse Experiences. 
2. 
Record changes to concomitant medications. 
3. 
Perform and record vital signs. 
4. 
Collects blood and urine sample. 
5. 
Administer (end of study) questionnaires. 
6. 
Oral exam and assess disease progression.  
7. 
If question of hopeless teeth schedule Panorex mouth x-ray. 
8. 
Writes order for extractions (if needed), (full mouth deep cleaning, & Arestin if 
Intensive Intervention Group). 
9. 
Performs scaling & planing in areas of disease progression. 
10. 
If needed, extract hopeless teeth and provides aftercare instructions. 
11. 
Schedule next appointment and provide payment. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
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The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 


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11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• death 
• a life-threatening adverse experience 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
11.3 Medical Monitoring 
Vanessa Grubbs should be contacted directly at these numbers to report medical concerns 
or questions regarding safety. 
Phone: (415) 206-5649 
Pager: (415) 443-4406 
   
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study and/or Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:   
• Subject withdrawal of consent (or assent) 
• Subject is not compliant with study procedures 
• Adverse event that in the opinion of the investigator would be in the best interest of 
the subject to discontinue study treatment 
• Protocol violation requiring discontinuation of study treatment 
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If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures. 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Visit 5 (Month 12)) should have an early 
discontinuation visit. Refer to Section 10 for early termination procedures.  Subjects who 
withdraw after Visit 1 (screening) but prior to Visit 5 (Month 12) should be encouraged to 
come in for a final visit (and the procedures to be followed would include those for their 
next scheduled visit).   
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
Subjects who withdraw from the study will not be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or staff fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
• Failure to meet inclusion/exclusion criteria 
• Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
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When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
14 DATA SAFETY MONITORING  
The UCSF Data Safety Monitoring Board (DSMB) will establish a Data Monitoring 
Committee (DMC) to review data relating to safety and efficacy, to conduct and review 
interim analyses, and to ensure the continued scientific validity and merit of the study, 
according to the UCSF Data Safety Monitoring Board Operations Manual and a DMC 
Charter to be established for this protocol. There will be (number of reviews, if any) 
interim review(s) conducted by the DMC for the purpose of monitoring study conduct and 
assessing patient safety.  Further details regarding the timing and content of the interim 
reviews is included in the statistical section below. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
Randomization will be stratified with respect to diabetes (a strong risk factor for 
causing/aggravating both CKD and periodontal disease) to prevent an imbalance between 
the 2 arms.  Participants will be assigned 2:1 to the Intensive Intervention Group for the 
intensive periodontal treatment protocol (n = 34) or to the Rescue Treatment Group for 
rescue periodontal treatment only with intensive treatment at the end of the study (n = 17).  
All eligible patients who are randomized into the study and receive at least one dose of the 
study drug (the Safety Population) will be included in the safety analysis. 
15.2 Demographic and Baseline Characteristics 
The expected study population age 20 to 75 years consists primarily of impoverished 
individuals who may have low health literacy and/or may speak primarily Spanish with 
low English literacy.  Usual dental care in this population is essentially very limited or 
none until teeth have to be extracted, and perhaps not then. 
15.3 Analysis of Primary Endpoint 
Clinical assessment for resolution of periodontal disease (no sites with probing depths 
>3mm and <10% bleeding on probing among all sites) at each follow-up study visit. 
15.4 Analysis of Secondary Endpoints 
We will calculate descriptive statistics (mean, standard deviation) of each clinical 
outcome which will include a traditional marker of kidney function (serum creatinine), 
cystatin C, markers of kidney structure {as glomerular injury (albuminuria) and tubular 
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endothelial injury [asymmetrical dimethylarginine (ADMA)];  and markers of systemic 
inflammation (IL-6 and C-reactive protein) measured at baseline, study month 4, and 
study month 12.  We will use repeated-measures generalized estimating equations (GEE) 
to compare changes in clinical outcomes over time within each treatment group and to 
compare differences between treatment groups taking individual change over time into 
account. 
Safety and tolerability data will be summarized by treatment group.   
Adverse event rates will be coded by body system and MedDra classification 
term.  Adverse events will be tabulated by treatment group and will include the number of 
patients for whom the event occurred, the rate of occurrence, and the severity and 
relationship to study drug.   
15.5 Interim Analysis 
When approximately 50% of patients have completed the study through study month 4, an 
interim analysis for safety will be conducted by an independent data monitoring 
committee. 
15.6 Sample Size and Randomization 
This is a pilot study. To our knowledge, there are no existing data of the anticipated effect 
size of periodontal treatment to inform sample size calculations. However, because a 
primary aim is to determine the variability of various renal and inflammatory biomarkers, 
we seek to enroll at least 30 subjects in the intervention arm of the trial. Subjects who 
meet oral study criteria and CDC/AAP definition for moderate/severe periodontal disease 
will be randomized 2:1 to either an intensive intervention cohort or a rescue treatment 
cohort in blocks of 3, with stratification by presence of diabetes to ensure balance between 
groups.  
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.   
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) when the 
information corresponding to that visit is available.  Subjects will not be identified by 
name in the study database or on any study documents to be collected by the Sponsor (or 
designee), but will be identified by a subject number. 
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the 
person entering or updating eCRF data and creates an electronic audit trail.   
The Investigator is responsible for all information collected on subjects enrolled in this 
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completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. The 
study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented. 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason. 
16.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing 
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appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number will identify all study 
subjects on CRFs and other documentation submitted to the Sponsor.  Additional subject 
confidentiality issues (if applicable) are covered in the Clinical Study Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor or designee prior to the shipment of study 
supplies to the site.  This approval must refer to the study by exact protocol title and 
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Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects must be given ample opportunity to inquire about details of the study.  
If appropriate and required by the local IRB/IEC, assent from the subject will also be 
obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed 
consent form (and assent) will be given to the subject and the original will be maintained 
with the subject’s records. 
17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
17.5 Investigator Responsibilities 
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1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 


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APPENDIX 1.  EXAMPLE OF SCHEDULE OF STUDY VISITS 
 
VISIT 1 
(Screening)a 
VISIT 2 
(Baseline)a 
VISIT 3 
(Month 4)a 
VISIT 4 
(Month 8)a 
VISIT 5 
(Month 12) 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Complete Physical Exam 
 
 
 
 
 
Height  
 
X 
X 
X 
X 
Weight  
 
X 
X 
X 
X 
Vital Signs  
 
X 
X 
X 
X 
Pregnancy Test (Urine or Serum)  
 
X 
X 
X 
X 
Hematology 
 
X 
X 
X 
X 
C-Reactive Protein 
 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
Dispensing or Administration of 
Study Drug 
 
X 
X 
X 
X 
Perform Panorex mouth x-ray 
X 
 
 
 
 
Oral exam and assess disease 
progression 
X 
X 
X 
X 
X 
Writes order for extractions, full 
mouth deep cleaning, & (Arestin 
if Intensive Intervention Group). 
X 
X 
X 
X 
X 
Performs scaling & planing in 
areas of disease progression 
X 
X 
X 
X 
X 
Provide brushing and flossing 
education 
X 
 
 
 
 
Tooth Extraction 
X 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Adverse Experiences 
X 
X 
X 
X 
X 
a  
±2 week


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KIDNEY AND PERIODONTAL DISEASE (KAPD) STUDY 
NCT01802216 
11/21/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Data analysis and sample size 
We will calculate descriptive statistics as appropriate for each feasibility, process, and 
clinical outcomes at each visit. Generalized linear mixed models (GLMMs) for repeated 
continuous, binary, and count outcomes will be used to assess treatment effects on study 
outcomes at 4, 8, and 12 months; the baseline outcome will be included in the analysis to 
control for any between-group differences at baseline, with treatment effects captured 
using time-by-treatment interactions. Outcomes will be transformed as needed to meet 
model assumptions, and random effects will be used to account for within-participant 
correlation of the outcomes. GLMMs for tooth-specific periodontal outcomes including 
pocket depth (PD), clinical attachment loss (CAL), and bleeding on probing (BOP), will 
include tooth and site as fixed effects, and account for the nested correlation of teeth 
within participant within occasion. In addition, we will assess summary periodontal 
measures including the gingival and plaque indices. If treatment effects on the 
periodontal measures are detected, we will conduct exploratory analyses of mediation of 
treatment effects on kidney function outcomes by improvements in the periodontal 
measures. Specifically, we will assess the independent effects of the periodontal 
measures on each outcome, controlling for treatment, and also assess the attenuation of 
the treatment effect after adjustment for the periodontal measures. Results will be 
considered statistically significant at p < 0.05. 
 
The accrual target of 51 participants assigned 2:1 to intensive (n=34) or rescue treatment 
(n=17) is typical for a pilot study and feasible given available resources. In the overall 
sample, we will be able to estimate the means of feasibility and process outcomes within 
margins of sampling error (MSEs) of ±14 percentage points (ppts) for binary measures 
and 0.28 standard deviations (SDs) for continuous ones; within the treated group, 
corresponding MSEs will be 18 ppts and 0.35 SDs. In providing preliminary estimates to 
inform sample size calculations for a definitive trial, we will be able to estimate the net 
effect of intensive vs delayed intensive periodontal treatment on CKD biomarkers at 12 
months within MSEs of 0.35-0.51 SDs, depending on the degree of within subject 
correlation, after accounting for loss to follow-up of 20% of participants by 12 months.