Human Dental Pulp Mesenchymal Stem Cells for the Treatment of Chronic Periodontitis Patients

Study Overview
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Brief Summary
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The primary objective:To evaluate the efficacy of different administration protocols of human dental pulp mesenchymal stem cells for the treatment of chronic periodontitis patients. The secondary objective:To evaluate the safety of different administration protocols of human dental pulp mesenchymal stem cells for the treatment of chronic periodontitis patients. The exploratory objective:To investigate the effects of human dental pulp mesenchymal stem cells on biomarkers in gingival crevicular fluid in chronic periodontitis patients.

Detailed Description
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This is a multicenter, randomized, double-blind, parallel, placebo-controlled study, including three treatment groups which are single-dose group, two-dose group (low-dose), and two-dose group (high-dose). The patients of single-dose group will receive only one dose on day 1 (D1), and the patients of two-dose groups will receive one dose on D1 and D90 respectively. 68 participants will be enrolled in each group, and be randomized (3:1) to receive human dental pulp mesenchymal stem cells (hDP-MSCs) or placebo (normal saline). Participants in the single-dose group and the two-dose group (high-dose) will receive local injection of 1.0 × 107 hDP-MSCs (0.6mL normal saline suspension) / periodontal defect site or 0.6mL normal saline / periodontal defect site, and participants in the two-dose group (low-dose) will receive local injection of 1.0 × 106 hDP-MSCs (0.6mL normal saline suspension) / periodontal defect site or 0.6mL normal saline / periodontal defect site. All participants will receive basic periodontal treatment simultaneously. Dosing interval: the dosing interval is set at 89 days, which is based on the results of preclinical trials of hDP-MSCs, the improvement of periodontitis observed on D90 after hDP-MSCs administration, and good safety profile in phase 1 clinical trial.

Official Title
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A Phase 2, Randomized, Double-blind, Parallel, Placebo-controlled Study to Evaluate Efficacy and Safety of Local Injection of Human Dental Pulp Mesenchymal Stem Cells for the Treatment of Chronic Periodontitis Patients.

Conditions
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Periodontitis

Intervention / Treatment
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* Drug: Human Dental Fulp Stem Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: 1)18 to 65 years old (including threshold), unlimited gender; 2)Radiological examination of the periodontal defect site shows angular bone defect; 3)The probing depth (PD) at the periodontal defect site is 4 to 8 mm at baseline; 4)Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures; 5)Voluntarily participate in the clinical study, understand and sign the informed consent; Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Participants with severe periodontal diseases (alveolar bone resorption exceeds two-thirds of the tooth root length) which affect the investigator's judgment; The grade of studied tooth looseness ≥ grade 3 at baseline (only buccolingual movement is defined as grade 1; buccolingual and mesiodistal movement is grade 2; vertical loosening is grade 3); The studied tooth with occlusal trauma which affect the investigator's judgment; Participants with surgical treatment of previous periodontal defect sites and adjacent periodontal tissues; Participants with non-steroid anti-inflammatory drug, steroid hormone therapy, and/or other hormone (except topical hormones) treatment within past 3 months of the screening visit, and/or previous use of bisphosphonates; Participants with severe systemic infection within past 3 months of the screening visit, or antibiotics treatment within past 72h of the screening visit; Participants with uncontrolled hypertension within 1 month before screening (defined as sitting systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg after receiving the optimal antihypertensive therapy); Participants with severe or uncontrolled diseases in any system (cardiac, hepatic, renal, respiratory, hematologic, endocrine, nervous, or psychiatric); Participants are known to be allergic to any materials that may be used during surgery (allergy-prone constitution or history of allergy to blood products); Any of the following abnormalities in clinical laboratory tests at screening: ALT > 3 ULN, total bilirubin > 1.5 ULN, serum creatinine > 1.5 ULN, international normalized ratio (INR) ≥ 1.5 ULN or activated partial thromboplastin time (APTT) ≥ 1.5 ULN (except for patients receiving anticoagulation therapy), Hb < 80 g/L, or PLT < 75.0×109/L; Positive result for any of the following tests at screening: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab), or Treponema pallidum antibody (TP-Ab); Females who are pregnant or breastfeeding; Participants and their partners who plan to conceive or do not agree to use the effective non-pharmacological method of contraceptive during the trial from screening visit to 6 months after the end of the trial; Participants participated in other clinical studies within past 3 months of the screening visit; Participants with a history of smoking addiction within past 12 months of the screening visit (the number of cigarettes smoked per day ≥ 10); Other circumstances deemed inappropriate by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multicenter, randomized, double-blind, parallel, placebo-controlled study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single-dose group<br>Human Dental Fulp Stem Cells Injection: 1X 10^7 cells/periodontaldefect site. | Drug: Human Dental Fulp Stem Cells<br>* Investigational drugs: Based on the initial periodontal treatment (supragingival cleansing, subgingival scaling and root planning), human pulp stem cell injections will be given for a single or two local injection<br>* Other names: Initial periodontal therapy;|
| Experimental: two-dose group (low-dose)<br>Human Dental Pulp Stem Cells Injection: 1X 10^6 cells/periodontaldefect site. Continuous administration twice, with an interval of 89 days between each administration. | Drug: Human Dental Fulp Stem Cells<br>* Investigational drugs: Based on the initial periodontal treatment (supragingival cleansing, subgingival scaling and root planning), human pulp stem cell injections will be given for a single or two local injection<br>* Other names: Initial periodontal therapy;|
| Experimental: two-dose group (high-dose)<br>Human Dental Pulp Stem Cells Injection: 1X 10^7 cells/periodontaldefect site. Continuous administration twice, with an interval of 89 days between each administration. | Drug: Human Dental Fulp Stem Cells<br>* Investigational drugs: Based on the initial periodontal treatment (supragingival cleansing, subgingival scaling and root planning), human pulp stem cell injections will be given for a single or two local injection<br>* Other names: Initial periodontal therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in height of the periodontal bone defect | Changes from baseline in height of the periodontal bone defect which will be examined by CBCT at D90±7 and D180±14 (primary efficacy endpoint) | at baseline, 90 days, 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in respiration rate of Vital Signs | Respiratory rate, in beats per minute | within 180 days after administration | 
| Changes from baseline in heart rate of Vital Signs | Heart rate in beats per minute | within 180 days after administration | 
| Changes from baseline in blood pressure of Vital Signs | Blood pressure in mmHg, both systolic and diastolic blood pressure will be measured. | within 180 days after administration | 
| Changes from baseline in body temperature of Vital Signs | Body temperature in Celsius degree | within 180 days after administration | 
| Changes from baseline in red blood cell count of Laboratory Examination | Red blood cell count in whole blood is reported in the form of number | within 180 days after administration | 
| Changes from baseline in white blood cell count of Laboratory Examination | White blood cell count in whole blood is reported in the form of number | within 180 days after administration | 
| Changes from baseline in neutrophil count of Laboratory Examination | Neutrophil count in whole blood is reported in the form of number | within 180 days after administration | 
| Changes from baseline in lymphocyte count of Laboratory Examination | Lymphocyte count in whole blood is reported in the form of number | within 180 days after administration | 
| Changes from baseline in platelet count of Laboratory Examination | Platelet count in whole blood is reported in the form of number | within 180 days after administration | 
| Changes from baseline in hemoglobin of Laboratory Examination | Changes of hemoglobin concentration（g/dL）in whole blood will be recorded. | within 180 days after administration | 
| Changes from baseline in PT of Laboratory Examination | Prothrombin time (PT) is a screening test for exogenous coagulation factors | within 180 days after administration | 
| Changes from baseline in INR of Laboratory Examination | International standardized ratio (INR) is calculated from prothrombin time and international sensitivity index (ISI) of the reagent. | within 180 days after administration | 
| Changes from baseline in APTT of Laboratory Examination | Activated partial thromboplastin time (APTT) is a screening test for endogenous coagulation factors | within 180 days after administration | 
| Changes from baseline in total bilirubin of Laboratory Examination | Changes of total bilirubin concentration (μmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in direct bilirubin of Laboratory Examination | Changes of direct bilirubin concentration (μmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in ALT of Laboratory Examination | Changes of ALT concentration (U/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in AST of Laboratory Examination | Changes of AST concentration (U/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in total protein of Laboratory Examination | Changes of total protein concentration (g/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in albumin of Laboratory Examination | Changes of albumin concentration (g/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in total bile acid of Laboratory Examination | Changes of total bile acid concentration (μmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in urea of Laboratory Examination | Changes of urea concentration (mmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in creatinine of Laboratory Examination | Changes of creatinine concentration (μmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in uric acid of Laboratory Examination | Changes of uric acid concentration (μmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in glucose of Laboratory Examination | Changes of glucose concentration (mmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in potassium of Laboratory Examination | Changes of potassium concentration (mmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in sodium of Laboratory Examination | Changes of sodium concentration (mmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in chlorine of Laboratory Examination | Changes of chlorine concentration (mmol/L) in serum will be recorded | within 180 days after administration | 
| Changes from baseline in Detection of infectious diseases of Laboratory Examination | It refers to infectious diseases screening | within 180 days after administration | 
| Changes from baseline in IgA of Laboratory Examination | Changes of IgA concentration （g/L）in serum will be recorded | within 180 days after administration | 
| Changes from baseline in IgG of Laboratory Examination | Changes of IgG concentration （g/L）in serum will be recorded | within 180 days after administration | 
| Changes from baseline in IgM of Laboratory Examination | Changes of IgM concentration （g/L）in serum will be recorded | within 180 days after administration | 
| Changes from baseline in total IgE of Laboratory Examination | Changes of total IgE concentration （g/L）in serum will be recorded | within 180 days after administration | 
| Changes from baseline in Pregnancy test of Laboratory Examination | Pregnancy test will be tested in female subjects | within 180 days after administration | 
| Changes from baseline in urine specific gravity of Laboratory Examination | Changes of urine specific gravity will be recorded | within 180 days after administration | 
| Changes from baseline in urine pH of Laboratory Examination | Changes of urine pH value will be recorded | within 180 days after administration | 
| Changes from baseline in urine glucose of Laboratory Examination | Changes of urine glucose will be examined by qualitative test (positive or negative) | within 180 days after administration | 
| Changes from baseline in urine protein of Laboratory Examination | Changes of urine protein will be examined by qualitative test (positive or negative) | within 180 days after administration | 
| Changes from baseline in urine ketone body of Laboratory Examination | Changes of urine ketone body will be examined by qualitative test (positive or negative) | within 180 days after administration | 
| Changes from baseline in urine white blood cell of Laboratory Examination | Changes of white blood cell in urine will be examined by qualitative test (positive or negative) | within 180 days after administration | 
| Changes from baseline in urine bilirubin of Laboratory Examination | Changes of urine bilirubin will be examined by qualitative test (positive or negative) | within 180 days after administration | 
| Changes from baseline in urine occult blood of Laboratory Examination | Changes of urine occult blood will be examined by qualitative test (positive or negative) | within 180 days after administration | 
| Changes from baseline in ECG PR interval | The cardiac rhythm is showed in 12 Leads Ambulatory Electrocardiogram in the form of continuous curve. Changes of this continuous curve will be recorded. | within 180 days after administration | 
| Changes from baseline in ECG QRS interval | The cardiac rhythm is showed in 12 Leads Ambulatory Electrocardiogram in the form of continuous curve. Changes of this continuous curve will be recorded. | within 180 days after administration | 
| Changes from baseline in ECG RR interval | The cardiac rhythm is showed in 12 Leads Ambulatory Electrocardiogram in the form of continuous curve. Changes of this continuous curve will be recorded. | within 180 days after administration | 
| Changes from baseline in ECG QT interval | The cardiac rhythm is showed in 12 Leads Ambulatory Electrocardiogram in the form of continuous curve. Changes of this continuous curve will be recorded. | within 180 days after administration | 
| Incidence of Treatment-Emergent Adverse Event | Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events during the study period, and the severity of adverse events is determined according to the NCI CTCAE version 5.0 | within 180 days after administration | 
| Change from baseline in Clinical Attachment Level (AL) | Clinical Attachment Level (AL) may be assessed to the nearest millimeter by means of a graduated probe and expressed as the distance in millimeters from the CEJ to the bottom of the probeable gingival/periodontal pocket | at baseline, 90 days, 180 days | 
| Change from baseline in Tooth Mobility (TM) | The continuous loss of the supporting tissues during periodontal disease progression may result in increased tooth mobility, which is divided into 3 degree: I°, II°, and III°. Changes from baseline in tooth mobility will be recorded | at baseline, 90 days, 180 days | 
| Change from baseline in Probing Depth (PD) | The probing depth is the distance from the gingival margin to the bottom of the gingival sulcus/pocket, is measured to the nearest millimeter by means of periodontal probe | at baseline, 90 days, 180 days | 
| Change from baseline in Gingival recession （GR） | Exposure of the tooth through apical migration of the gingiva is called gingival recession. Recorded as the distance in millimeters from the CEJ to the gingival margin | at baseline, 90 days, 180 days | 
| Change from baseline in Probing bleeding on probing (BOP) | A periodontal probe is inserted to the bottom of the gingival/periodontal pocket applying light force and is moved gently along the tooth (root) surface. If bleeding is provoked by this examination, the site examined is considered bleeding on probing-positive and, hence, inflamed. Probing Bleeding Index is divided into 5 grades: 0, 1, 2, 3 and 4. | at baseline, 90 days, 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Dental Pulp Stem Cell