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White Blood Cell Signaling and Defense Mechanisms in Patients With Diabetes Mellitus Type 2 and Periodontitis (DMS)

Primary Purpose

Chronic Periodontitis, Diabetes Mellitus, Type 2

Status

Unknown status

Phase

Not Applicable

Locations

Germany

Study Type

Interventional

Intervention

ADT+FD

About this trial

This is an interventional basic science trial for Chronic Periodontitis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Diabetes Mellitus, Type II
Glycated Hemoglobin ≥8.5%
Chronic Periodontitis
Patients and controls should have at least 12 natural teeth (without subgingival fillings, crowns or caries)

Exclusion Criteria:

Pregnancy
Smoking
Low Body Mass Index (BMI <18.5kg/m*m)
Severe cardiovascular disease including coronary artery disease, cerebral vascular disease, peripheral vascular disease, valvular heart disease, and congestive heart failure
Other major illnesses including cancer, liver disease, pulmonary disease, chronic infectious disease other than periodontitis (HIV, hepatitis, etc.), rheumatological disease, hematological disease, or any condition requiring hospitalization or chronic medical therapy other than diabetes.
Major psychiatric illness requiring treatment, or that might interfere with the ability to understand or cooperate with the protocol
Ongoing alcohol or drug abuse; all forms of medication or illegal substance abuse
Systemic enteral or parenteral medication, in part daily vitamin or anti-oxidative supplementation and certain calcium channel blockers (i.e. Nifedipine); but anti diabetic drugs or insulin substitution
Allergies to antibiotics or adjuvant medication / antiseptics as well as dental materials in use (including gloves) in particular those against topical antiseptic solutions i.e. chlorhexidine / N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)] or povidone iodine / 2-Pyrrolidinone, 1-ethenyl-, homopolymer, compound with iodine
Severe dental disease defined as severe dental caries, and/or severe pulpal disease requiring surgical correction, or any other mucosal or dental condition not readily treated, or requiring extensive dental, oral surgical or prosthetic treatment, or any other oral treatment which could affect the outcome of periodontal therapy or diseases or syndromes that require systemic medication.
Systemic, topical or inhaled steroid treatment for more than 30 consecutive days within 6 weeks of baseline.
Any periodontal treatment within 6 months prior to baseline
For controls: a periodontal screening index (PSI) > 1

Sites / Locations

Department of Periodontontology, ZentrumZMK

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

No Intervention

Arm Label

Antidiabetic Therapy(ADT)+Full Mouth Decontamination(FD)

Full Mouth Deconatamination(FD)

No Treatment

Arm Description

ADT: (Par-)enteral, anti-diabetic medication, diet and dietetic supervision, physiotherapy and physical exercises FD: The oral use of topical antiseptics prior and after mechanical tooth debridement, tooth as well as root surface planing and soft tissue decontamination in combination with systemic antibiotics (a combination of amoxicillin and metronidazole - if no microbial resistances were detected)

FD: The oral use of topical antiseptics prior and after mechanical tooth debridement, tooth as well as root surface planing and soft tissue decontamination in combination with systemic antibiotics (a combination of amoxicillin and metronidazole - if no microbial resistances were detected)

Healthy individuals to be monitored cross-sectional

Outcomes

Primary Outcome Measures

Change from Baseline in Clinical Attachment Level (CAL) at 6 and 12 Months

CAL: Clinically and quantitatively, level of attachment is defined as the distance in mm from the cemento-enamel junction (CEJ) of the teeth to the bases of the periodontal pockets. Attachment gain may be found during healing or periodontal treatment procedures.

Secondary Outcome Measures

Probing Pocket Depth (PPD)

PPD: also called periodontal probing depth is defined as the distance in millimeters from the gingival margin to the base of the sulcus or periodontal pocket. It is measured on six surfaces/tooth (disto-buccal, mid-buccal, mesio-buccal, disto-lingual, mid-lingual, and mesio-lingual) of all teeth present using the pressure calibrated Florida probe.

Bleeding on Probing (BOP)

BOP: will be determined by recording the presence or absence of bleeding following probing to determine pocket depth (PPD). This parameter will be expressed as % bleeding sites out of all examined sites in the dentition and will be documented with the Florida probe software.

Body Mass Index (BMI)

The body mass index will be assessed as the participants' body mass divided by the square of their height

Glycated Hemoglobin (HbA1c)

Physiological levels of blood glucose result in a normal amount of glycated hemoglobin. Treatment procedures may help to reduce plasma glucose in individuals with diabetes mellitus type 2, thus, in a timely extended fashion the fraction of glycated hemoglobin.

Full Information

NCT ID

NCT01848379

First Posted

April 29, 2013

Last Updated

June 30, 2017

Sponsor

Zentrum fuer Zahn-, Mund- und Kieferheilkunde

1. Study Identification

Unique Protocol Identification Number

NCT01848379

Brief Title

White Blood Cell Signaling and Defense Mechanisms in Patients With Diabetes Mellitus Type 2 and Periodontitis

Acronym

DMS

Official Title

Human Polymorphonuclear Neutrophil (PMN) Cytosolic Signaling and Effector Functions in Patients With Diabetes Mellitus Type 2 and Periodontitis

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Unknown status

Study Start Date

January 2012 (undefined)

Primary Completion Date

December 2017 (Anticipated)

Study Completion Date

December 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Zentrum fuer Zahn-, Mund- und Kieferheilkunde

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

White blood cell membrane and surface structures are affected by the metabolic disorders and complications found in diabetes mellitus. Therefore, cellular activation, signal propagation, intracellular signaling as well as bactericidal effector functions are altered. When diabetic symptoms are corrected by the systemic intervention and treatment of the patients (Anti-diabetic Therapy/ADT, i.e. anti-diabetic medication, diet and dietetic supervision, physiotherapy and physical exercises), white blood cell functions will then normalize and reach the functionality comparable to those cells derived from healthy subjects. Gum diseases like periodontitis have long been associated with and termed complications of uncontrolled diabetes mellitus. Vice versa, after diabetic conditions are corrected, periodontitis treatment will be proven effective, when oral hygiene regimen, full mouth decontamination (FD, i.e. the oral use of topical antiseptics prior and after professional mechanical tooth cleaning, tooth as well as root surface planing, polishing as well as gum and soft tissue decontamination in combination with systemic antibiotics) are performed. To reinforce gum healing, reinfection prevention (RP) as well as supportive periodontal therapy (SPT) will be administered by dental professionals on an individual basis and a detailed schedule. If periodontal pockets critical for participant's self care are not eliminated by FD including RP and SPT, and niches >5mm after 6 month persist, patients are informed and offered surgical intervention as indicated for gum disease elimination. Dental follow up exams will be offered to all participants.

Detailed Description

Specific Aims To investigate if cytosolic Ca2+- ( delta[Ca2+]i) and pH (delta_pHi) signaling responses and bactericidal effector functions of PMN dependent upon the status of diabetic control and are reduced or increased when compared to age and gender matched controls To determine the biochemical basis for diabetic PMN alteration of motility as well as bactericidal functions: production of superoxide and release of elastase, respectively To characterize the molecular basis of the observed alterations in the regulation of cytosolic calcium (delta[Ca2+]i) and pH (delta_pHi) exhibited by diabetic PMN To investigate if the pre-activated state and altered bactericidal functionality of diabetic PMN are reversed when the patients' glycemic control is normalized, blood glucose levels as well as periodontal disease are corrected To evaluate, if systemic and periodontal intervention can lead to clinical attachment gain in patients with diabetes mellitus type 2

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Periodontitis, Diabetes Mellitus, Type 2

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Antidiabetic Therapy(ADT)+Full Mouth Decontamination(FD)

Arm Type

Experimental

Arm Description

Arm Title

Full Mouth Deconatamination(FD)

Arm Type

Active Comparator

Arm Description

Arm Title

No Treatment

Arm Type

No Intervention

Arm Description

Healthy individuals to be monitored cross-sectional

Intervention Type

Procedure

Intervention Name(s)

ADT+FD

Other Intervention Name(s)

Anti-diabetic Treatment and Full Mouth Decontamination

Intervention Type

Procedure

Intervention Name(s)

Other Intervention Name(s)

Full Mouth Decontamination

Primary Outcome Measure Information:

Title

Change from Baseline in Clinical Attachment Level (CAL) at 6 and 12 Months

Description

Time Frame

0, 6 and 12 months

Secondary Outcome Measure Information:

Title

Probing Pocket Depth (PPD)

Description

Time Frame

0, 6 and 12 months

Title

Bleeding on Probing (BOP)

Description

Time Frame

0, 6 and 12 months

Title

Body Mass Index (BMI)

Description

The body mass index will be assessed as the participants' body mass divided by the square of their height

Time Frame

-3 weeks; 0, 6 and 12 months

Title

Glycated Hemoglobin (HbA1c)

Description

Time Frame

-3 weeks; 0, 6 and 12 months

Other Pre-specified Outcome Measures:

Title

Neutrophil Cytoplasmic Calcium Concentration ([Ca2+]i)

Description

[Ca2+]i: ex vivo 2nd messenger cytoplasmic calcium concentration resembles a key parameter for chemoattractive or phagocytic PMN-receptor activation.

Time Frame

-3, 0 and 2 weeks; 6 and 12 months

Title

Neutrophil Cytoplasmic pH (pHi)

Description

pHi: ex vivo liganded neutrophil receptors initiate a series of signals, resulting in phagocytosis of an entity and release of the phagocyte granules' contents as well as oxidative products. The specific mechanisms by which these effector functions occur depend upon the receptor involved among [Ca2+]i is changes of pHi.

Time Frame

-3, 0 and 2 weeks; 6 and 12 months

Title

Release of Reactive Oxygen Species (ROS)

Description

ROS: these NADPH products are predominantly found within phagolysosomal compartments of the neutrophils. During phagocytosis, neutrophils may release ROS resulting in collateral tissue damage. The reactivity of ROS release will be assessed ex vivo after activation of chemoattractant as well as phagocytic receptors of the cells.

Time Frame

-3, 0 and 2 weeks; 6 and 12 months

Title

Release of Neutrophil Elastase (EA)

Description

EA: residing in the azurophilic granules of the neutrophils, elastase is activated after phagolysosomal fusion; thence, in proximity to the engulfed entities it unfolds bactericidal activity by degrading valine-rich proteins. The elastolytic activity will be assessed ex vivo after chemoattractant as well as phagocytic activation of the neutrophils' receptors.

Time Frame

-3, 0 and 2 weeks; 6 and 12 months

Title

Gingival Crevicular Fluid (GCF)

Description

GCF: a quantitative and qualitative assessment of the serum like exudate in the gingival crevice will be performed.

Time Frame

-3 and 0 weeks

Title

Global Luminol Dependent Chemiluminescence of Stimulated Neutrophils (CLt)

Description

The detection of total ROS will be performed ex vivo with a kinetic chemiluminescence assay after receptor activation of neutrophils.

Time Frame

0 weeks

Title

Extracellular Luminol Dependent Chemiluminescence of Stimulated Neutrophils (CLex)

Description

The detection of extracellular ROS will be performed ex vivo with a kinetic chemiluminescence assay after receptor activation of neutrophils.

Time Frame

0 weeks

Title

Cellular Immune responses

Description

Analyses of leukocyte subsets, i.e. T-lymphocytes from the peripheral venous blood samples

Time Frame

0, 6 and 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diabetes Mellitus, Type II Glycated Hemoglobin ≥8.5% Chronic Periodontitis Patients and controls should have at least 12 natural teeth (without subgingival fillings, crowns or caries) Exclusion Criteria: Pregnancy Smoking Low Body Mass Index (BMI <18.5kg/m*m) Severe cardiovascular disease including coronary artery disease, cerebral vascular disease, peripheral vascular disease, valvular heart disease, and congestive heart failure Other major illnesses including cancer, liver disease, pulmonary disease, chronic infectious disease other than periodontitis (HIV, hepatitis, etc.), rheumatological disease, hematological disease, or any condition requiring hospitalization or chronic medical therapy other than diabetes. Major psychiatric illness requiring treatment, or that might interfere with the ability to understand or cooperate with the protocol Ongoing alcohol or drug abuse; all forms of medication or illegal substance abuse Systemic enteral or parenteral medication, in part daily vitamin or anti-oxidative supplementation and certain calcium channel blockers (i.e. Nifedipine); but anti diabetic drugs or insulin substitution Allergies to antibiotics or adjuvant medication / antiseptics as well as dental materials in use (including gloves) in particular those against topical antiseptic solutions i.e. chlorhexidine / N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)] or povidone iodine / 2-Pyrrolidinone, 1-ethenyl-, homopolymer, compound with iodine Severe dental disease defined as severe dental caries, and/or severe pulpal disease requiring surgical correction, or any other mucosal or dental condition not readily treated, or requiring extensive dental, oral surgical or prosthetic treatment, or any other oral treatment which could affect the outcome of periodontal therapy or diseases or syndromes that require systemic medication. Systemic, topical or inhaled steroid treatment for more than 30 consecutive days within 6 weeks of baseline. Any periodontal treatment within 6 months prior to baseline For controls: a periodontal screening index (PSI) > 1

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jens Martin Herrmann, Dr.

Organizational Affiliation

Department of Periodontology, ZentrumZMK

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Periodontontology, ZentrumZMK

City

Giessen

ZIP/Postal Code

35392

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

31912903

Citation

Herrmann JM, Sonnenschein SK, Groeger SE, Ewald N, Arneth B, Meyle J. Refractory neutrophil activation in type 2 diabetics with chronic periodontitis. J Periodontal Res. 2020 Apr;55(2):315-323. doi: 10.1111/jre.12717. Epub 2020 Jan 8.

Results Reference

derived

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White Blood Cell Signaling and Defense Mechanisms in Patients With Diabetes Mellitus Type 2 and Periodontitis

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