Pilot and Feasibility Clinical Research Grants in Kidney or Urologic Diseases (R21)
Phase: NA
Conditions: Chronic Periodontitis, End Stage Renal Disease
Sponsor: UConn Health

i – information sheet
Title:
Novel PAradigm to improve Inflammatory burden in ESRD (rePAIR): A pilot and feasibility 
Randomized Controlled Trial
May 7, 2018
Sponsor:
Effie Ioannidou 
UConn Health
263 Farmington Avenue
Farmington, CT 06030
Principal Investigator:
Effie Ioannidou
Director, Dental Clinical Research Center 
UConn Health
263 Farmington Avenue
Farmington, CT 06030
Phone:
(860) 679-2367
Fax:
(860) 679-1027
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TABLE OF CONTENTS
TITLE PAGE
1
1.
BACKGROUND…………………………………………………………………………
2.
HYPOTHESES, AIMS AND OBJECTIVES ………………………………………… 
3.
STUDY DESIGN & PROCEDURES……...…………………………………………. 
4.
INCLUSION CRITERIA……………………………………………………………… 
5.
EXCLUSION CRITERIA……………………………………………………………… 
6.
TIMETABLE…………………………………………………………………………… 
7.
BUDGET / RESOURCES………………………………………………………..…….
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1. Title: Novel PAradigm to improve Inflammatory burden in ESRD (rePAIR): A pilot and feasibility Randomized 
Controlled Trial
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2. Background
Why is the project being proposed?: Given the importance of inflammation as a predictor of 
cardiovascular mortality in ESRD21, 24, reductions in biochemical inflammatory markers have been 
proposed as critical target outcomes in this population25. Several anti-inflammatory strategies have been 
utilized in this direction assessing nutritional26 as well as pharmacological interventions23, 27, 28. Although 
the results of these trials hold promise, many investigators recognized different sources of inflammation 
in these patients, which need to be resolved in order to achieve the most optimal responses21, 29. As 
expected, the inflammatory modulation requires concurrent therapy of the multiple comorbidities, 
which characterize this population30, 31 32. The present multidisciplinary proposal is significant because 
it promises to:
1.
Reduce inflammatory burden in ESRD through systematic and ongoing oral health and 
behavioral interventions treating oral infections within dialysis units.
2.
Improve access to care and quality of life in ESRD as measured by validated surveys and 
biomarkers.
3.
Facilitate care quality improvement and management  of ESRD patients as well as expand 
performance of dialysis units.
This proposal focuses on targeting chronic periodontitis, a chronic inflammatory disease of biofilm 
etiology, which causes connective tissue and bone destruction and, consequently, leads to tooth loss1 33. 
Chronic periodontitis is associated with increased risk for atherosclerosis, adverse pregnancy outcomes, 
rheumatoid arthritis, chronic obstructive pulmonary disease and aspiration pneumonia34, 35 36-38. 
Although recent epidemiological evidence showed a severe periodontitis prevalence of ~8.5% in the 
general US population2, this prevalence increased up to ~40% in some racial groups with CKD3, 4, 9 5. The 
PI has extensively worked on oral health in CKD within the scope of her NIH/NIDCR K23 Mentored 
Patient-Oriented Research Career Development Award (K23DE018689), which has successfully 
achieved 4 major goals: 1) to assess the prevalence of periodontal infections in CKD, 2) to examine the 
impact of periodontitis on the systemic inflammatory status of CKD patients following oral interventions 
and 3) to produce pilot data on inflammation and oxidative stress and 4) to develop multidisciplinary 
partnerships securing strong recruitment strategies and effective regulatory processes.
Using the National Health and Nutrition Examination Survey (NHANES) III database, we 
demonstrated significantly higher periodontitis prevalence accentuated by racial disparities in CKD 
(Table 1)5, which exceeds 50% in ESRD6, 39-42. Despite periodontitis recognition as a critical public health 
problem (Healthy People 2020), disease awareness in CKD/ESRD populations is low43. Therefore, oral 
health promotion as well as effective treatment and prevention with focus on improving systemic 
inflammation and oxidative stress should become a priority in these populations.
Table 1: Periodontitis prevalence as stratified by race in CKD and non-CKD population (n=11,604). Data represents 
Prevalence (%) and standard deviation (SD). Notice the statistically significant difference in prevalence between CKD and 
non-CKD populations in every racial group. For the entire sample, inflation-adjusted prevalence was 35.28% in CKD (data 
not shown) (Ioannidou & Swede, 2011)
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Why is the research needed?
Within the last decades, the high inflammatory burden in ESRD has been attributed to the “uremic 
puzzle” with pieces developing and connecting in an intricate manner20 contributing to cardiovascular 
(CVD) mortality. We now know that the complexity of the “uremic puzzle” extents past the Framingham 
CVD risk factors involving systemic inflammation and oxidative stress as variables strongly associated 
with poor CVD outcomes in CKD20. Overwhelming evidence has indicated that the enzymatic activity of 
myeloperoxidase links oxidative stress and inflammation in uremia emphasizing the importance of both 
in the atherosclerotic process22. Consequently, research has focused on identifying factors contributing 
to systemic inflammation and oxidative stress at different levels. At an ethnic level, several culture- 
related dietary habits have been identified as anti-inflammatory correlating with low CVD risk26. Dialysis 
related factors such as membrane bio-incompatibility, type of access, impure dialysate have also been 
linked to systemic inflammation53. At the patient level, additional comorbid factors including bacterial 
infections, volume overload, failed transplant and depression have been implicated in the elevation of 
serum CRP 32 and were targeted in anti-inflammatory therapeutic efforts21, 32.
Table 2: Logistic regression models confirming the impact of periodontitis extent and severity on inflammation in CKD
In the same context, the American Heart Association has recognized the independent association 
between periodontitis and systemic inflammation54 as expressed by high levels of inflammatory 
biomarkers such as interleukin 6 (IL-6) and C-reactive protein (CRP)55-57. Our group and others 
produced evidence supporting the contribution of periodontitis to inflammation in CKD as measured by 
hsCRP levels7, 9, 11. As seen in Table 2 chronic periodontitis is associated with ~100% increase in the odds 
of elevated serum CRP levels in the parsimonious regression model. Moreover, the impact of 
periodontitis on serum CRP levels has been shown to be significant in ESRD with a dose-response 
association between hsCRP and periodontitis stages 58.
As confirmed by analogy59, other infections have 
shown to result in increased levels of inflammatory 
mediators in dialysis patients and to consequently 
contribute to atherosclerosis process and increased 
mortality 18, 48, 60. Therefore, the relationship between 
periodontitis and CKD is potentially bi-directional in 
nature, with CKD/ESRD not only potentiating 
periodontitis 
incidence, 
but 
periodontitis 
likely 
contributing to sustained inflammation  and poor 
outcomes in CKD/ESRD. These  observations led to 
interventional studies with a goal to assess the effect of 
oral periodontal therapy on inflammatory mediators as 
surrogate markers of CVD risk. Within the scope of the 
K award, we conducted a pilot clinical trial working 
closely with our collaborator at the University of 
Washington, Dr. Himmelfarb, and studying the effect 
of periodontal therapy on systemic inflammation and
oxidative stress in ESRD patients with periodontitis (NCT 01094639). We recruited 16 dialysis patients, 
who were randomly assigned to two arms. One arm received a single course of periodontal therapy and 
the other arm was untreated during the observation period. For both arms oral examination and blood
Figure 2: Serum hsCRP is shown to decrease in the 
intervention arm as opposed to the control within the 
2-month period (p=0.13)
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draw were performed at baseline and at the 2-month follow-up. The recruitment took place with the 
following inclusion criteria: a) older than 21 years, b) having periodontitis 61, c) non-smoker, d) no 
vascular access infection within the last month, e) no periodontal therapy within the last year. We 
quantified serum hsCRP (inflammation) and F2-isofurans (oxidative stress) as primary outcomes. Using 
general linear modeling, we found that hsCRP (Fig. 2)
and F2-isofurans (Fig.3) were reduced following 
periodontal therapy as compared to the control group 
(Ioannidou 
& 
Himmelfarb, 
unpublished 
data), 
although no statistically significant difference was 
observed due to the limited sample size. More 
specifically, the 40% reduction in hsCRP levels was 
found to be similar to the hsCRP reduction observed 
following conversion from the central venous catheter 
to fistula18. These results are in agreement with other 
reports confirming a short-term (2-month follow-up) 
positive treatment effect on the inflammatory markers 
in ESRD15, 16, 62-66. However, only one long-term 
randomized controlled trial on periodontal treatment 
effect extended to 6-months in ESRD and revealed no 
difference in inflammatory changes between the 
arms15. In a critical appraisal of the above trial, the 
main study limitation was the episodic, single 
periodontal therapy approach without any attempt for 
maintenance, as confirmed by the poor oral hygiene 
scores. Clearly, that approach was not effective enough
to promote optimal oral hygiene, and prevent recurrent periodontitis and control systemic 
inflammation 67-69. In our model, the dialysis outpatient centers could serve as an archetype for 
continuous in center oral health maintenance as shown below in our approach and recruitment strategy. 
For anti-inflammatory strategies to be effective, they inclusively need to consider all comorbidities30, 31. 
Consequently, the scientific question in this proposal is: could systematic and repeated periodontal 
interventions modulate systemic inflammation in ESRD?
Innovation: The highly prevalent periodontal infection, although recognized as a cause of persistent 
inflammation in ESRD6 and associated with increased CVD mortality risk8, 58, its treatment and 
prevention in a constant and systematic manner has never been studied. Currently, only 11% of 
CKD/ESRD individuals have one dental visit a year43 due to low socioeconomic status and low oral 
health awareness. Therefore, well-designed interventional studies are essential for the development of 
systematic treatment and maintenance protocols in ESRD. As kidney transplant is considered highly 
preferred modality of renal replacement, infection-free oral environment is a major priority, relevant to 
the approximately 19% of dialysis patients receiving a kidney transplant within the first year of dialysis70. 
The proposed study is innovative because it is the first study to:
●
Assess the long-term effect of repeated oral health interventions on serial changes of systemic 
inflammatory and oxidative stress as well as nutritional biomarkers in ESRD patients.
●
Offer a global testing of our hypothesis by focusing on patient-reported outcomes as supported 
by US Department of Health and Human Services, Food and Drug Administration guidelines on clinical 
studies (FDA guidelines, 2009) and the NIH roadmap for re-engineering the Clinical Research 
Enterprise (2002).
●
Establish treatment protocol safety data by documenting adverse events within the observation 
period.
●
Implement a systematic oral care model not in an academic center but in the urban setting of the 
selected dialysis units, embracing population ethnic and socioeconomic diversity.
Figure 3: Plasma F2-isofuran levels are shown to 
decrease dramatically in the intervention arm from 
baseline to 2-month as compared to the control arm 
(p=0.2)
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This pioneer proposal will directly address oral preventive practices leading to an infection free 
environment and improving ESRD outcomes. If the feasibility of this model is established, then larger 
clinical trials may be developed to solidify the knowledge on effective  approaches and guidelines 
targeting persistent inflammation in ESRD.
3. Hypotheses, aims and objectives
Hypothesis:
Given the well-documented inflammatory and oxidative stress burden in ESRD and its implication 
to cardiovascular (CVD) mortality 19, current research focuses on anti-inflammatory nutritional and 
pharmacological strategies 20-23. Although results from these trials hold promise, different sources of 
inflammation such as untreated periodontitis have been recognized in ESRD limiting the magnitude of 
the effect21. Therefore, untreated periodontitis may be a forgotten comorbidity. This proposal aims to 
assess the anti-inflammatory effect of repeated and regular oral health interventions, which will target 
periodontitis in ESRD. We hypothesize that there is a difference in the response to repeated and 
ongoing vs. single periodontal interventions as measured by: a) patient-centered outcomes, b) 
inflammatory, oxidative stress and nutritional biomarkers as well as c) clinical oral outcomes. This will 
be achieved by following specific aims:
Specific aim 1: We aim to compare the difference (Δ) in patient-centered as well as clinical oral 
outcomes between ESRD subjects receiving repeated (Test group) and the standard-of-care (Control) 
periodontal therapy. For this aim, we will measure and compare patient-centered outcome (Oral Health 
Impact Profile-14 survey) reflecting patient’s perspective on oral health at baseline and 6-months. The 
clinical oral outcomes will evaluate the clinical response and effectiveness of the intervention at each 
time point.
Specific aim 2: We aim to compare the difference (Δ) in outcomes of systemic inflammation (C- 
reactive protein, Interleukin 6), oxidative stress (F2-isoprostanes, and isofurans), and nutrition 
(albumin) in the repeated vs. standard-of-care periodontal therapy in ESRD at baseline and 6-months. 
To accomplish this, we will collect blood samples from all patients at each time point. Serial changes of 
the inflammatory and oxidative stress markers will also be evaluated during the observational period 
and correlated with clinical disease markers.
The PI has extensively worked on the ESRD/CKD-periodontitis interactions and has developed strong 
partnerships with several outpatient dialysis units in two states, which will facilitate patient recruitment. 
With this study, we will change the paradigm of care in ESRD proposing a novel model of oral 
interventions. We aim to show that, as with any other therapeutic approaches, repeated (not episodic) 
oral interventions could be more effective in promoting oral health and controlling systemic 
inflammation in ESRD. This pioneer proposal will directly address oral preventive practices leading to 
an infection free oral environment and improving ESRD outcomes. If the feasibility of this model is 
established, then longitudinal studies will aim to determine the synergistic systematic treatment effect 
of multiple comorbidities including periodontitis on all cause and CVD mortality.
4. Study Design & Procedures
 Screening Procedures and who will perform them: ESRD subjects will be screened at visit 1 by a 
licensed dentist or Registered Dental Hygienist.
Recruitment Strategy: As a result of the K23 award, the PI has developed a strong multidisciplinary 
research team that successfully partnered with several dialysis outpatient units in Connecticut and 
Massachusetts. This resulted in a community-based network among the Principal Investigator, the study 
coordinator, calibrated dental providers, nephrologists, nurses, and dieticians in the units. Moreover, 
we have developed a recruitment strategy involving an active and close collaboration with the unit 
stakeholders (nephrologist, nurse manager and dietician) in order to achieve higher study acceptance 
rates 71. Physical limitations and fatigue, which may prevent this population from independent everyday 
transportation,  have  been  identified  as  major  barriers  for  research  study  participation  in  this
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population72. Hence, to overcome these obstacles, we have developed a community-based model, which 
has been effective with the retention and adherence rates. Based on this model, we will utilize mobile 
dental units, which facilitate examinations and periodontal therapy in the dialysis units using the 
isolation rooms to secure privacy and confidentiality. We systematically review our recruitment and 
retention rates as well as feedback from patients in the team’s monthly meetings.
ESRD patients will be recruited at the Dialysis Units of the University of Connecticut Health Center, and 
the DCI Unit in Manchester, CT. The recruitment strategy includes study fliers posted in different 
locations including UCONN Health Nephrology and Dental Clinics and Dialysis Outpatient Units as well 
as DCI Unit in Manchester, CT. The PI has included Dr. Trivedi (UCONN Health and DCI Units) as a Co- 
Investigator in the study. All recruitment strategies and material will be approved by UCONN 
Institutional Review Board (IRB). Once UCONN Health IRB is approved, while DCI will follow a separate 
IRB process utilizing UCONN IRB approved consent forms.
Patient selection will be based upon administrative patient list review and/or study flyer. In case 
administrative list review is employed, medical record review will be performed by the dialysis unit 
director in each unit with the utilization of our screening form. The nephrologist/dialysis unit director 
will then review the proposed selection list based on clinical judgment and the pre-screening criteria. 
We have also developed recruitment tools (Pre-screening Form, study brochures), which are practical 
and easy to implement in order to assist the nephrologist and dialysis personnel during the pre- 
screening process. Once the pre-screening process is completed, the ESRD subjects will contact the study 
coordinator for screening appointment. After an explanation of the study, the overall risk/benefits 
analysis, written consent will be sought from each of the participants. Following consent, patients will 
receive a brief oral exam to establish eligibility based on the Screening Form. Dental sessions will be 
scheduled based on patient choice but preferably prior dialysis session to minimize patient fatigue.
Our team has an extensive experience with the dental management of ESRD patients. Our protocol has 
derived from a close collaboration between the dental and renal teams.
●
Prior to entering the study and any oral intervention, ESRD patient with recent complete blood count 
is cleared by the nephrologist.
●
Prior and during the dental procedures, vital signs are monitored as a standard of care in dialysis.
●
Since several drug metabolism and elimination takes place in the kidney, and for protocol adhesion, 
only analgesics such as acetaminophen and anti-inflammatory drugs such as aspirin will be 
prescribed and “realistically dosed”, resulting to either a dose reduction or prolongation of the dosing 
interval. If any other anti-inflammatory medication is needed, the patient will be excluded from the 
study (as per exclusion criteria)
●
There is no evidence-based recommendation on the use of prophylactic antibiotics in the dental 
management of ESRD patients due to the lack of data on the duration and effects of transient 
bacteremia post dental intervention. Our preliminary study, which was conducted without 
antibiotics, had in no adverse events to report. Transient bacteremia has been shown to resolve in less 
than 20min in systemically healthy individuals (Lockhart et al., 2008). Antibiotic overutilization and 
misuse result in selection of resistant microorganisms and reduced antibiotic efficacy. Therefore, in 
our study we plan to use antibiotics wisely only if recommended by the primary nephrologist for high- 
risk patients.
Methods
Study design and Subject selection: The proposed study will be a two parallel arm feasibility clinical trial 
that will recruit 72 ESRD subjects with periodontitis in a model of computerized block randomization, 
which will facilitate recruitment in each outpatient dialysis unit. Blocks will be determined as per 2x2x2 
a priori categorization of age, race and gender. More specifically, the participants in 2 dialysis units 
(UCONN Dialysis/ DCI and DCI Manchester) will be randomly assigned to the study arms using a 
computer randomization program. As a result, once sequences are determined by the statistician, they 
will be concealed in opaque envelops and opened prior to the first recruitment in the unit. This study 
will include participants treated with dialysis 3 times a week. Out of 900 ESRD patients in recruitment 
sites, we estimated approximately 450 patients with periodontitis. Individuals will be included in the
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study if they are older than 21 years old; if they are ESRD on dialysis; if they have chronic periodontitis 
as defined before 61; if life expectancy is more than 1 year; if they have can provide consent form. 
Individuals will be excluded from the study if they had periodontal treatment within a year prior to the 
study initiation; if they have AIDS, or active malignancy; if they poorly adhere to dialysis protocol; in 
anticipation for kidney transplant during study period; if they are pregnant; if they have dementia; if 
they take anti-inflammatory medication, except aspirin≤325mg/d; if they use temporary catheter for 
dialysis access.
Population: This trial will recruit ESRD adult patients with periodontitis fulfilling the eligibility criteria 
below.
Inclusion criteria: Individuals will be included in the study if they are older than 21 years old; if they are 
ESRD on dialysis; if they have a minimum of 12 teeth; if they have chronic periodontitis as defined by 
the presence of at least two sites with CAL≥4mm or at least two sites with PD≥5mm not on the same 
tooth[26]; if they have no history of periodontal treatment within a year; if life expectancy is more than 
one year; or if they have can provide consent form.
Exclusion criteria: Individuals will be excluded from the study if they had periodontal treatment within 
a year prior to the study initiation; if they have HIV/AIDS, or active malignancy; if they poorly adhere 
to dialysis treatment; in anticipation for kidney transplant during study period; if they are pregnant; if 
they have dementia; if they take anti-inflammatory medication, except aspirin≤325mg/d; or if they use 
temporary catheter for dialysis access.
 Subject characteristics and justifications:
o
Age: 21 years of age or older
o
Ethnicity: Please see NIH enrollment data in the grant application
o
Gender: Same as above
o
Vulnerable Population NA
o
Other characteristics - (e.g. vulnerable populations; primary language etc.): NA
Intervention: The Test arm will receive treatment and maintenance sessions. Briefly, treatment sessions 
will include oral hygiene behavioral modification and scaling and root planning (removing the bacterial 
biofilm and calculus below the gum line) in order to eliminate etiologic factors and control periodontal 
inflammation. More specifically, the behavioral interventions will include oral hygiene instructions with 
specific techniques of tooth brushing and flossing demonstrated on typodont. In order to standardize 
the oral hygiene session (intervention fidelity), the providers will be trained to follow specific oral 
hygiene guidelines with re-calibration on the protocol procedures every 3 months to maintain study 
quality control. Once the treatment sessions are completed, the patients will enter the maintenance 
phase and will be followed for 6 months. In this phase, the patients will receive systematic supportive 
periodontal treatment (tooth cleanings above the gum line with re-enforcement of oral hygiene). 
Outcomes will be assessed at 2-, 4-, and 6-months.
Control: The Control arm will receive only a single session of treatment without maintenance sessions 
(see visit Table in Human Subject Protection section). Outcomes will be assessed at 2-, 4-, and 6-months. 
Dental Treatment Needs: Throughout the course of the study, additional dental needs for both Arms 
(Test and Control) will be addressed with immediate referral to the Advanced General Dentistry 
Program at the UCONN Health or the subject’s own general dentist.
Strategies to Improve Adherence: We systematically review our recruitment and retention rates as well 
as feedback from patients in the team’s bi-weekly meetings. For treatment fidelity, the study staff will be 
trained to follow an oral hygiene script and guidelines followed by re-calibration on the protocol 
procedures every three months to maintain study quality control. The OHIP-14 will be filled during oral 
hygiene session in an interactive interview form following provider training on the questionnaire 
administration to control for treatment fidelity.
Outcomes and Rationale:
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1) Inflammatory Markers (Primary Outcomes) and Oxidative Stress Markers (Secondary outcomes): 
We aim to measure serum CRP (primary outcome) as a biomarker of inflammation as well as IL-6, F2 
isofurans and F2 isoprostanes as markers of oxidative stress linked to atherosclerosis and poor CVD in 
ESRD22. A single serum CRP elevated measure has been shown to predict poor outcomes and sudden 
death in ESRD75. Additional studies showed that IL-6 has been determined as a direct promoter of 
atherosclerosis and protein energy wasting through mechanisms of vascular calcification, muscle 
catabolism and cell aging 32 predicting poor outcomes in ESRD75. In addition to testing the primary 
and secondary outcomes at baseline and 6-month, we will compare serial changes of the biomarkers 
throughout the study period at 2- and 4-month time points. Moreover, we will also measure F2 
isoprostanes and isofurans, which are chemically stable, precise and easily detectable markers of lipid 
peroxidation76 associated with poor outcomes in ESRD.20
2) Patient-centered outcome (Secondary outcome): Given the wide recognition of patient-centered 
outcome research by the Agency for Healthcare Research and Quality (AHRQ) and the NIH 77, the 
validated OHIP-14 (true outcome) will evaluate patient’s perception of oral status change 78 and 
predictably assess periodontal treatment effect on oral health quality of life 79, 80. Oral health perception 
has been determined fair to poor in groups of ESRD patients 81. The oral health related quality of life will 
be assessed with the OHIP-14 questionnaire 82. The response codes for the items in this tool are based on 
a five-point scale, ranging from “never” to “all the time”.
3) Clinical Periodontal Parameters (Secondary Outcomes): The baseline full mouth periodontal 
examination will include missing teeth, probing depth (PD), bleeding on probing (BOP), clinical 
attachment loss (CAL), and plaque score (PS) at six sites on all teeth. BOP is an indicator of gingival 
(gum) inflammation and presence of active disease 83. Periodontal parameters will be measured at 
baseline, at 2-, 4- and 6-months. Changes in probing depth (ΔPD) and BOP (ΔBOP) will be considered 
as the clinical outcome of treatment effectiveness and clinical response.
4) Nutrition Biomarkers: Serum albumin levels have been widely associated with malnutrition and 
mortality in ESRD 84. We will use albumin levels less than 3.6g/dL as cutoff for malnutrition 85, 86. As 
serum albumin has been associated with poor oral health status (Ioannidou et a. 2013), we will assess 
changes in these biomarkers as a result oral intervention.
5) Adverse Event Frequency (Secondary outcome): For this outcome, pain, swelling, number of 
analgesics used (continuous) and presence of oral ulcers (dichotomous) will be recorded. More 
specifically, pain and swelling will be measured by ordinal scale (10cm horizontal Visual Analogue Scale, 
VAS).
Study Procedures and who will perform them:
Pre-screen Phase:
The nephrologist will review the potential subject’s medical record to determine patient eligibility based 
on the criteria of the Nephrologist Pre-screen Form questions. The nephrologist will present the study to 
the potential subject and provide DCRC study contact information. If the potential subject is interested 
in participating, they will call the DCRC. At the time of the phone call from the pre-screened potential 
subject, the DCRC study staff will read the telephone script and collect name and scheduled dialysis 
treatment dates and times in order to schedule visit 1.
Visit 1: ESRD subjects will be consented in the dialysis outpatient units. Following the consent, the 
medical history will be reviewed and vital signs will be tested. During the screening process, brief 
periodontal examination will be performed to clear the periodontal inclusion criteria.
Visit 2 (Baseline): Full mouth periodontal examination will include: numbers of missing teeth, pocket 
depth (PD), clinical attachment level (CAL), plaque score (PS), bleeding on probing (BOP). In the same 
visit the OHIP-14 will be contacted in an interactive form to the both arms. Blood sample (6.5ml) will be 
collected for baseline inflammatory, oxidative stress and nutritional markers for both arms.
Visits 3-4 (Day 0): Full mouth scaling/root planning (Deep cleaning below the gum line) under local 
anesthesia will  be  performed  to  remove etiologic factors  of  the  disease  in both  arms  in  one  or  2 
appointments. At the end of the visit, both groups will receive oral hygiene instructions.
*After Visits 3-4 test and control arm visits numbers change.
Test arm: (see time table Test arm, pg.14)
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Visit 5; Test (1-month post-Day 0): Oral hygiene reinforcement and behavioral modification only for the 
Test arm.
Visit 6; Test (2-month post-Day 0): Full mouth periodontal examination including oral hygiene 
assessment will be performed. Both arms will receive the OHIP-14. Blood samples (6.5ml) will be 
collected for inflammatory, oxidative stress and nutritional markers for both arms. Only in the test arm, 
the subject  will  receive supportive  periodontal treatment including supragingival  debridement and 
mechanical instrumentation (tooth cleaning) and oral hygiene reinforcement. Any remaining pockets will 
be treated with limited deep cleaning with local anesthesia. The control arm will receive no intervention. 
Visit 7; Test (3-month post-Day 0): Oral hygiene reinforcement and behavioral modification only for the 
Test arm.
Visit 8; Test (4-month interval post-Day 0): Full mouth periodontal examination including oral hygiene 
assessment will be performed. Both arms will receive the OHIP-14. Blood samples (6.5ml) will be 
collected for inflammatory, oxidative stress and nutritional markers for both arms. Only in the test arm, 
the subject  will  receive supportive  periodontal treatment including supragingival  debridement and 
mechanical instrumentation (tooth cleaning) and oral hygiene reinforcement. Any remaining pockets will 
be treated with limited deep cleaning with local anesthesia. The control arm will receive no intervention. 
Visit 9; Test (5-month post-Day 0): Oral hygiene reinforcement and behavioral modification only for the 
Test arm.
Visit 10; Test (6-month post-Day 0): Full mouth periodontal examination including oral hygiene 
assessment will be performed. Both arms will receive the OHIP-14. Blood samples (6.5ml) will be 
collected for inflammatory, oxidative stress and nutritional markers for both arms. At the end of the study 
both arms will receive supportive periodontal treatment including supragingival debridement and 
mechanical instrumentation (tooth cleaning) and oral hygiene reinforcement. Any remaining pockets will 
be treated with limited deep cleaning with local anesthesia.
Control arm: (see time table control arm, pg. 15)
Visit 5; Control (2-month post-Day 0): Full mouth periodontal examination including oral hygiene 
assessment will be performed. Both arms will receive the OHIP-14. Blood samples (6.5ml) will be 
collected for inflammatory, oxidative stress and nutritional markers for both arms.
Visit 6; Control (4-month interval post-Day 0): Full mouth periodontal examination including oral 
hygiene assessment will be performed. Both arms will receive the OHIP-14. Blood samples (6.5ml) will 
be collected for inflammatory, oxidative stress and nutritional markers for both arms.
Visit 7; Control (6-month post-Day 0): Full mouth periodontal examination including oral hygiene 
assessment will be performed. Both arms will receive the OHIP-14. Blood samples (6.5ml) will be 
collected for inflammatory, oxidative stress and nutritional markers for both arms. At the end of the study 
both arms will receive supportive periodontal treatment including supragingival debridement and 
mechanical instrumentation (tooth cleaning) and oral hygiene reinforcement. Any remaining pockets will 
be treated with limited deep cleaning with local anesthesia.
Power Analysis: For power analysis, we assumed a Type I error rate α=0.05 and a Type II error, β =0.20 
(1-β=0.80)[36]. Based on the preliminary data analysis of independent CRP changes, and after adjusting 
for time effect, we accepted a medium effect size (d = 0.67). Hence, within the pilot grant limitations, we 
calculated a sample size of 28 per arm. Given a reported 30% attrition rate in ESRD research, we aim to 
enroll up to 36 per arm. More importantly, pilot data from this trial will enable calculation of appropriate 
effect estimate and power analysis of a future large trial.
Therefore the sample size targets 72 enrolled participants with a ceiling of 90.
 Explain on what basis it is reasonable to assume that the sample size will be obtained: The PI has 
an established collaboration with several dialysis units in CT and MA. Therefore, we have an 
available pool of 900 ESRD subjects to be screened for a recruitment goal of 72. This is a very 
realist and predictable recruitment.
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Recruitment and Consent Procedures: Patient recruitment was initiated on November 7th, 2017 with 
expected enrollment completion in April 2019. The trial is currently recruiting patients at UCONN 
Dialysis/DCI and DCI Manchester. The recruitment strategy includes study fliers posted in different 
locations including UCONN Health Nephrology, Dental Clinics and Dialysis Outpatient Units. All 
recruitment strategies and material were approved by UCONN Institutional Review Board (IRB) and DCI 
ARO. Figure 2 represents study flow chart.
The initial patient selection is based upon administrative and medical record review by the nurse manager 
with the utilization of the study’s pre-screening form. The nephrologist reviews the patient selection and, 
based on clinical judgment and the pre-screening criteria makes the recommendation. We have also 
developed recruitment tools (pre-screening forms, study brochures), which are practical and easy to 
implement in order to assist the nephrologist and dialysis personnel during the pre-screening process. 
Once the pre-screening process is completed and the patient agrees to be approached, the study 
coordinator meets with the ESRD patient to present the study, the overall risk/benefits analysis, written 
consent is sought from each of the participants. The consent process may be extended to more than one 
meeting given the patient’s level of fatigue [37].
Randomization and Allocation: The study follows a block randomization scheme. Blocks will be 
determined as per 2X2X2 a priori categorization of age, race and gender. More specifically, the 
participants in two dialysis units (UCONN Dialysis/DCI and DCI Manchester) will be randomly assigned 
to the study arms using a computer randomization program supervised by the study’s biostatistician. 
Once sequences are determined, they remained concealed in opaque envelopes and opened prior to 
enrollment in the unit by the study coordinator.
Examiner calibration: The calibrated dental hygienist practices under the supervision of the Principle 
Investigator (PI). Following the calibration process, there was an agreement within ±1mm of 96%.
Blinding: At 6-month visit, the final assessment will be conducted by the PI, who will be blinded to the 
study arm.
Methods of Data Collection and Types of Data to be collected (may refer to attached surveys/ forms etc.) 
Medical data collection: Once enrollment is completed, demographic, anthropometric, medical history 
data will be collected using a standardized data extraction form at baseline. The biochemical data will 
include serum albumin, dialysis adequacy (Kt/V), vitamin D levels. Potential confounders will include 
race, history and duration of diabetes, diabetic control, smoking history, history of CVD, body mass 
index (BMI), history of peripheral arterial disease and comorbid conditions. Additionally, in order to 
assess the magnitude of comorbidities, we will use the Charlson Comorbidity Score, which has been 
validated in ESRD and found appropriate to assess comorbidity prognostic impact74. Biochemical data 
will be examined at every study time point to assess medical changes.
Periodontal Data: Full mouth periodontal examination will include: numbers of missing teeth, pocket 
depth (PD), clinical attachment level (CAL), plaque score (PS), bleeding on probing (BOP). PS (O’Leary) 
is a dichotomous measure with the use of disclosing solution at six sites of all teeth. Pocket depth (PD) is 
the distance from the gingival margin to the base of the pocket is measured in mm. Bleeding on Probing 
(BOP) is scored after probing depth measurements are taken. Clinical attachment level (CAL) represents 
the distance from the cemento-enamel junction to the base of the pocket in mm. For all measures, six 
sites around each tooth will be examined: mesial-buccal, buccal, distal-buccal, distal-lingual, lingual and 
mesial-lingual.
Blood Collection and Analyses: Blood samples will be drawn prior to dialysis session at each 
participating dialysis unit. Samples will be centrifuged at 3000rpm for 15 minutes and then transported 
on ice. Samples will be coded and stored at -70°C. IL-6 and hsCRP levels will analyzed in dublicate by 
ELISA with kits from BioSource International (Carmillo, CA) and Diagnostic Systems Laboratories 
(Webster, TX). Oxidative stress markers will be quantified by simultaneous measurements of F2- 
isoprostane and isofuran concentrations with gas chromatography as described before 23. Serum 
albumin will be measured by enhanced chemiluminescence immunoassay on Roche Modular Analyzer 
(Roche Diagnostics, Indianapolis, IN).
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Statistical methods: All analyses will follow the intent-to-treat principle. Given an attrition of rate of 
approximately 30% in the dialysis population, missing data will likely be from different sources (e. g., 
failure to complete questionnaire, study dropout, death). We will, therefore, utilize the multiple 
imputation algorithms of the IBM SPSS Missing Values 22 software[39, 40] to impute missing data. Data 
will be screened as recommended[41]. Standard diagnostic procedures will examine whether multivariate 
outliers exist, as well test for deviations from normality and linearity among dependent measures. When 
continuous measures are skewed, linear transformation will be attempted in order to preserve the 
inherent power of the continuous metric[42]. Descriptive analysis for all four time points will be including 
continuous measures with means, medians and standard deviations. Given OHIP-14 responses are 
ordinal, we will calculate the responses based on the “simple count”, score frequencies as used before[43] 
and analyzed with non-parametric methods. Spearman correlation analysis will be used to test 
associations between clinical parameters and patient’s oral health perception. In order to assess the effect 
of the confounding factors on oral response, univariate model will correlate PD and CAL changes with 
the baseline  parameters, demographic, socioeconomic status variables, as well as diabetic control, 
dialysis adequacy and vintage, vitamin D levels.
Exploratory univariate analysis and test statistics will be conducted to examine variable distribution. 
Outliers defined as more than two standard deviations from the mean will be detected. All biomarker 
variables will be tested for normality and logarithmically transformed if not normal. All analyses will
include means and standard deviations for continuous variables and percentages for categorical 
variables. For skewed variables, analyses will show median and interquartile ranges. CRP and IL-6 
changes (ΔCRP and ΔIL6) will be the dependent variables for hypothesis testing between the two arms. 
We will use a 3-level (time, subject, and cluster) hierarchical linear modeling technique[44] in the 
analysis of the data. The intercept (as a more robust indicator of initial baseline status) and slope (as an 
indicator for change, modeled as linear) are created for each subject. Predictors of inflammatory 
response will be assessed at subject level as well as subject nested within arm/recruitment site level. 
Additional secondary analyses will assess changes in the nutritional markers. The HLM will isolate 
predictors of inflammatory and oxidative stress response based on clinical phenotype, medical 
confounders, and cluster data.
Retention efforts: Physical limitations and fatigue, which may prevent this population from independent 
everyday transportation, have been identified as major reasons for research study participation in this 
population [38]. Hence, to overcome these difficulties, we have developed a community-based model, 
which has been effective with the retention and adherence rates. Based on this model, we will utilize a 
mobile dental unit that facilitates examinations and periodontal therapy in the isolation room of each 
hemodialysis unit. The isolation room secures privacy for both patient and provider. We systematically 
review our recruitment and retention rates as well as feedback from patients in the team’s monthly 
meetings.
DATA AND SAFETY MONITORING PLAN
We have a Data and Safety Monitoring Plan in place, which will be submitted and approved by the IRB. 
Based on this plan, the data will be reviewed annually. Given that the clinical protocol procedures in the 
proposed study are standard of care procedures with minimal/slight increase over minimal risk, the 
individuals performing the safety monitoring will be the PI, the study coordinator, an institutional 
colleague, who is not involved in the study, and the IRB.
The data used for safety monitoring will be data related to:
1.
Serious adverse events,
2.
Dropout rates and reasons for the dropouts,
3.
Enrollment numbers,
4.
Analysis of outcome data and its relationship to potential changes in study design,
5.
Protocol deviations
6.
Un-blinded data
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During the course of the study, a copy/summary of the monitor reports and/or minutes will be submitted 
to the IRB, Clinical Research Center (CRC) and NIH. The PI will evaluate the adverse events and 
determine whether the adverse events affect the risk/benefit ratio of the study and if modifications in the 
protocol and/or consent form are needed. In case of adverse events, the PI will report them to IRB, CRC, 
and NIH.
Protection of Confidentiality: The study will be conducted under the supervision of the PI, the co- 
Investigators and the collaborators. Best medical practices will followed during all procedures. All dialysis 
units are staffed with qualified and licensed personnel prepared to address emergencies. Further, 
nephrologist/attending is present at the dialysis units to clear the patient’s medical status. During the 
course of the study, a copy/summary of the monitor reports and/or minutes will be submitted to the IRB, 
Clinical Research Center (CRC) and NIH. The PI will evaluate the adverse events and determine whether 
the adverse events affect the risk/benefit ratio of the study and if modifications in the protocol and/or 
consent form are needed. In case of adverse events, the PI will report them to IRB, CRC, and NIH. Study 
data will be maintained in a separate research record. All materials and data will be coded with number 
combinations. The code linking the study data to identifiers will be in the PI’s computer protected by 
password. All study records will be coded in a locked cabinet in a secure area accessible only to research 
staff. A copy of the consent will be placed in the dialysis unit medical record. All electronic records (e.g. 
database, spreadsheets) will be password protected. Any computer hosting such files will have password
protection to prevent access by unauthorized users. Access to study data will be restricted to the PI and 
Co-Is as well as the study key personnel. Data that will be shared with others will be coded to 
confidentiality protection.
Study Management: At the study initiation meeting, a delegation of responsibilities was carried out 
according to which, each investigator, and study personnel agreed to their assigned roles. The study PI 
has been in charge of the execution of this plan. Roles were assigned as justified in the research grant 
proposal. At the end of the initiation meeting, a study flow sheet was developed with all study procedures 
and practices. The flow sheet follows the study clinical schema as presented above. The flow sheet 
guarantees that all study activities are completed in the specific time points as described in the research 
strategy and the endpoints and outcomes are reached.
The study coordinator has been in charge of the regulatory management of the study, which includes the 
development of the regulatory binder with all essential documents. The regulatory binder includes study 
protocol, the study personnel human subject training log, the delegation of responsibilities form, the pre- 
screening and screening forms, consent forms, HIPAA forms, serious adverse events list, protocol 
deviation reports, and IRB approvals. The study subject chart contains all information about each study 
visit dated appropriately and precisely as well as a note declaring the procedures completed per visit. The 
pre-screening form is part of the chart. De-identified subjects that fail pre-screening are also maintained 
in a separate file. The study coordinator maintains a master subject log list, where all visits of all subjects 
are securely listed. This list guarantees accurate scheduling based on study time points.
The PI and the study coordinator are in charge for reporting the adverse events and also the follow up 
visit with the subject. Further, any protocol deviation is documented and reported. All laboratory 
assessments are maintained in a log list with specimen numbers and dates. An important part of the study 
is the quality management plan, which ensures study quality and adherence to the protocol standards. 
To achieve this, we have established an extensive monitoring plan to secure the study design, and achieve 
the endpoints and outcomes. Weekly study team communication and meetings are scheduled to prevent 
any misunderstandings or protocol gaps. The meetings help the team resolve problems and move to 
corrective actions at once before they become an established pattern. Every three months, the study 
subject charts are audited internally. To ensure the presence of consent form, pre-screen and screening 
form, lab requests, data collection forms, missed appointments and notes. Further, the electronic data 
files and all data variables are crosschecked with the source original data. The subject ID will be also 
crosschecked. Missing data will be left blank. Merging files of laboratory and clinical variables will be 
performed carefully based on ID variable.
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Study Rigor and Transparency: The proposed trial follows a rigorous and transparent study design 
as requiring by the NIH capturing elements of trail design, pre-specified eligibility criteria, pre-specified 
primary and secondary outcomes, detailed intervention description to allow replication, intervention 
random allocation and concealment, blinding in outcome assessment, appropriate sample size 
calculations, explanation of interim analysis, as per CONSORT Guidelines[45, 46]. The proposed 
methods secures a robust and unbiased analysis as expected in a randomized controlled trial (RCT) and 
will ensure reproducibility of the experimental design[47]. With these efforts, we acknowledge the 
importance of research transparency through updated trial status, result and data reporting on 
Clinicaltrials.gov, as expected[48].
Timetable: Test Arm
Intervention
Visit 1
Visit 2
Baseline
Visit 3-4
Day 0
Visit 5
1-month
Visit 6
2-month
Visit 7
3-month
Visit 8
4-month
Visit 9
5-month
Visit 10
6-month
Consent Form
x
Medical History 
Review/Vitals
x
Periodontal 
Screening
x
Full mouth 
periodontal exam
x
x
x
x
OHIP-14
x
x
x
x
Periodontal 
Therapy (Deep 
periodontal 
cleaning)
x
Oral hygiene/ 
Behavioral 
modification
x
x
x
x
x
x
x
Maintenance
(Tooth Cleaning)
x
x
x
Inflammatory 
Markers 
(CRP, IL-6)
x
x
x
x
Oxidative 
stress 
(F2 isoprostanes, 
isofurans)
x
x
x
x
Nutritional 
Markers 
(Albumin)
x
x
x
x
Control Arm (The shaded columns symbolize absence of study activities)
Intervention
Visit 1
Visit 2
Baseline
Visit 3-4
Day 0
1-month
Visit 5
2-month
3-month
Visit 6
4-month
5-month
Visit 7
6-month
Consent Form
x
Medical History
x
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Review/Vitals
Periodontal 
Screening
x
Full mouth 
periodontal exam
x
x
x
x
OHIP-14
x
x
x
x
Periodontal 
Therapy (Deep 
periodontal 
cleaning)
x
Oral hygiene/ 
Behavioral 
modification
x
x
Maintenance
(Tooth Cleaning)
x
Inflammatory 
Markers 
(CRP, IL-6)
x
x
x
x
Oxidative 
stress 
(F2 isoprostanes, 
isofurans)
x
x
x
x
Nutritional 
Markers 
(Albumin)
x
x
x
x
Standard Protocol timepoints and items based on SPIRIT guidelines.
STUDY PERIOD
Enrollment 
Baseline
Post-allocation
Close-out
TIMEPOINT**
-t2
t0
t1
t2
t3
t4
t5
t6
X
X
X
Nephrology Pre- 
screening
Informed Consent 
Periodontal Screening
Allocation
X
INTERVENTIONS:
Arm 1: Repeated 
Interventions + 
Behavioral Modification 
Arm 2: 
Control/Standard of 
Care
X
X
X
ASSESSMENTS:
Demographic Data 
Biochemical Data
X
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X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inflammatory Markers
Oxidative Stress 
Markers
Nutritional Markers 
OHIP-14
Periodontal Parameters
Adverse Events
X
[Provide a detailed timetable scheduling all aspects of the research. This will include data collection (e.g. time taken to 
administer questionnaires, complete interviews, abstract data from charts), analyze data, write reports etc. You may reference 
an attached flow diagram, including expected start and completion dates, and/or describe the time table here]:

Expected Start Date: May 2016 
General Time Table:
6-months: Complete the regulatory requirements, present the protocol in our recruitment sites and 
start recruitment.
12-months: Complete recruitment and treatment of 20 patients-Collect and transfer blood samples to 
the lab.
18-months: Complete recruitment and treatment of 20 patients-collect and transfer blood samples to 
the lab.
24-months: Complete follow-ups, perform biomarker lab analyses, compile and analyze data.

Expected Completion Date: November 2018
6. Budget / resources: [You need to think about what you will need for your research and whether those resources 
are available to you. The IRB will want to know that you have thought carefully about what resources are needed and from 
where you expect to obtain these, and whether or not a budget workbook needs to be completed. Some types of research are 
more resource intensive/expensive than others and you will have to consider this when deciding upon your research 
method.]: The NIH budget is attached.
7. Dissemination [Describe how you intend to disseminate the results of your research, e.g. dissertation, presentation, 
web site, journal article.]: The results of this research project will be presented in national and 
international meetings as well as in a form of peer-review journal article as expected by NIH.
8. References / Literature Review:
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Pihlstrom
BL,
Michalowicz
BS,
Johnson
NW.
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Ioannidou E, Hall Y, Swede H, Himmelfarb J. Periodontitis associated with chronic kidney 
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Kshirsagar AV, Moss KL, Elter JR, et al. Periodontal disease is associated with renal insufficiency 
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Fisher MA, Taylor GW, Papapanou PN, Rahman M, Debanne SM. Clinical and serologic markers 
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Kshirsagar AV, Craig RG, Moss KL, et al. Periodontal disease adversely affects the survival of 
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Fisher MA, Taylor GW, Shelton BJ, et al. Periodontal disease and other nontraditional risk factors 
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Fisher MA, Taylor GW, West BT, McCarthy ET. Bidirectional relationship between chronic kidney 
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