Harnessing Chronomodulation to Enhance Osteogenesis

June 17, 2022 updated by: Satheesh Elangovan, University of Iowa

Harnessing Chronomodulation to Enhance Osteogenesis - A Pilot Randomized Controlled Trial -

Chronotherapy is an emerging field in biomedicine that leverages on fine-tuning the timing of drug delivery to obtain a therapeutic effect. Dr. Tamimi and his team have successfully harnessed chronotherapy using NSAIDs to enhance bone healing in a murine fracture model. Unpublished findings revealed that mice receiving carprofen for 3 days post-fracture exclusively during activity hours exhibited superior bone healing outcomes in comparison to specimens that received the same drug during resting hours.

This is a 3-arm RCT aimed at evaluating the effect of different chronotherapeutic NSAID regimens on intraoral bone healing in humans using an extraction socket healing model in the context of an early implant placement protocol.

The primary aim is to elucidate whether there are differences in osteogenesis and in the characteristics of the newly formed bone between patients following different post-operative NSAID chronotherapeutic protocols. Secondary endpoints of interest include assessment of alveolar bone and soft tissue dimensional changes between pre- and post-extraction, implant insertion torque, serum CRP levels, wound healing index and patient-reported discomfort at different time points.

If proven beneficial, the proposed chronotherapeutic approach could be readily implemented in clinical practice as a standalone therapy or as a valuable complement to existing standard-of-care protocols, due to its simplicity, safety and cost-effectiveness.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Enrolled subjects will be randomly assigned to one of three groups (n=12 per group):

Group A (Test) - Tooth extraction and intake of an NSAID (i.e. Ketoprofen ER 50 mg) at 8 AM and a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 2 PM and 8 PM for a 3-day period, starting at 2 PM on the day of the extraction.

Group B (Control 1) - Tooth extraction and intake of an NSAID (i.e. Ketoprofen ER 50 mg) at 8 PM and a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 8 AM and 2 PM for a 3-day period, starting at 2 PM on the day of the extraction.

Group C (Control 2) - Tooth extraction and intake of a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 8AM, 2 PM and 8 PM for a 3-day period, starting at 2 PM on the day of the extraction.

VISIT 1 - Screening Referred or self-referred subjects that appear to meet all the eligibility criteria upon phone pre-screening will be invited to an in-person screening visit at the UICOD. The study purpose, duration, potential risks and expected benefits will be explained in detail to the subjects, as part of the consenting process. All screened subjects will be provided with hard copies of the study timeline and the signed consent form. Upon medical and dental history review, as well as site-specific clinical and radiographic evaluation, eligible subjects interested in participating in the study will be scheduled for Visit 2. Intraoral photographs of the site of interest will be taken. Additionally, a cone-beam computed tomography (CBCT) scan will be obtained and interpreted to evaluate the study site, prior to the baseline intervention.

VISIT 2 - Tooth Extraction (Baseline Intervention) Medical and dental history will be reviewed and updated, if necessary. Subsequently, subjects will be asked to sign the surgical procedure consent form. Prior to tooth extraction, an intraoral scan of the area of interest will be obtained using a digital scanner (e.g. Planmeca Emerald S). Likewise, a blood sample (~ 4.5 cc) will be collected for serum C-reactive protein (CRP) analysis. Following administration of local infiltrative anesthesia, the study tooth will be extracted in a minimally traumatic fashion, avoiding flap reflection. Following tooth extraction, the socket walls will be carefully inspected for the existence of dehiscences or fenestrations. Sites presenting a bony defect affecting >20% of the total wall height will be excluded. Site will be sealed using a collagen matrix (Mucograft Seal, Geistlich Pharma) stabilized with simple interrupted sutures. The intervention will be documented using intraoral photography.

Upon completion of the intervention, subjects will be randomly assigned to one of the study groups and provided with detailed written and verbal post-operative instructions, including a drug diary specific to the group that they are allocated in and a visual analog scale (VAS) to record their perceived discomfort at day 0, 1, 2, 3 and 7 after the intervention.

VISIT 3 - Postoperative Evaluation Any medical or dental history changes, or adverse events will be recorded. Sutures will be removed. An intraoral scan and photographs of the site will be obtained. Visual assessment of the healing status will be made using a wound healing index (WHI). Biofilm on the adjacent teeth will be removed and home care instructions will be revisited.

VISIT 4 - Implant Placement At the beginning of this visit, a second segmental CBCT scan will be obtained, using the same settings employed at baseline. CBCT images will be employed to evaluate ridge dimensional changes compared to baseline, as well as bone availability for dental implant placement. Any medical or dental history changes, or adverse events will be recorded. A blood sample (~ 4.5 cc) and an intraoral scan will be obtained. Assessment of the healing status will be made using the aforementioned WHI. After administering local infiltrative anesthesia, patients will undergo implant insertion, according to the early implant placement protocol.10 Following full-thickness flap elevation, a bone core biopsy of the study site will be obtained using a trephine drill of 2.5 mm in diameter or wider. The bone core will be immediately submerged in a solution of 10% neutral buffered formalin (NBF) for microCT (µCT) and histological analyses.

Implant site preparation and placement will be conducted according to the manufacturer's recommendations (SLActive Bone Level - Straumann AG). Implant insertion torque will be recorded. Intraoral periapical radiographs will be obtained, as necessary, in order to assess implant placement location. Following final implant placement and cover screw delivery, simultaneous buccal contour augmentation will be performed via guided bone regeneration (GBR) using a dual bone graft. This graft composite will consist of an initial layer of locally harvested autogenous bone to cover the exposed implant surface, combined with a superficial layer of deproteinized bovine bone particles (DBBM; BioOss granules 0.25 - 1.0 mm, Geistlich Pharma), which will be subsequently covered with a native porcine collagen membrane (Bio-Gide; Geistlich Pharma). All procedures will be executed according to a two-stage (submerged) approach. Therefore, tension-free primary soft tissue closure will be attained. The procedure will be documented with intraoral photographs. All subjects will be provided with detailed written and verbal post-operative instructions. They will be instructed to avoid any disturbance in the surgical area for two weeks. Patients will be asked to use a mouthwash containing 0.12% of chlorhexidine gluconate twice a day, thirty seconds at a time, avoiding any eating or drinking for 30 minutes after rinsing, starting 48 hours after the baseline intervention. Post-operative medications (e.g. antibiotics, anti-inflammatory drugs and analgesics) will be prescribed on an individual basis.

VISIT 5 - Postoperative Evaluation (Final Study Visit) This visit will be scheduled at approximately two weeks after implant placement. Any medical or dental history changes, or adverse events will be recorded. Intraoral photographs of the site of interest, will be obtained. Assessment of the healing status will be made using the aforementioned WHI. All remaining sutures will be removed. Biofilm on the adjacent teeth will be removed and home care instructions will be revisited. Upon completion of this final study visit, the patient will be entered in a regular patient care routine, including scheduling of a future visit for implant uncovering in no less than 4 months and later referral to the restorative dentist, in order to complete tooth replacement therapy.

Study Type

Interventional

Phase

  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Adult (18 years or older) males or females with an ASA status of I or II and adequate physical and mental health to undergo study-related procedures
  • In need of extraction of a maxillary incisor, maxillary or mandibular canine, or maxillary or mandibular premolar and successive tooth replacement therapy according an early implant placement protocol10
  • Extractions socket walls must be intact or have no more than one bony wall dehiscence or fenestration extending no more than 20% of the total bony wall height
  • Subjects must have read, understood and signed the informed consent form

Exclusion Criteria:

  • Acute infection associated with the tooth to be extracted or with adjacent teeth
  • Known allergies or medical contraindications to any of the study-related drugs and biologic materials
  • Sleeping disorders or jet lagged from a recent trip or working in night shift jobs
  • History of significant heart, stomach, liver, kidney, blood, immune system disease, or other organ impairment or systemic diseases or disorders that may prevent undergoing the proposed treatment and/or may significantly affect bone healing (e.g. uncontrolled diabetes, thyroid disorders or Paget's disease)
  • Current smokers or former smokers who quit less than 12 months prior to the initiation of the study
  • Subjects taking any medication or supplement known to influence bone metabolism, such as IV bisphosphonates, long-term history of oral bisphosphonates or chronic intake of glucocorticoids
  • Regular or within 7 days of baseline intake of any anti-inflammatory and/or analgesic drugs
  • Need of oral or intravenous sedation
  • Pregnant women or nursing mothers
  • History of recreational drug abuse and/or heavy alcohol use
  • History of lack of compliance with dental visits or unwilling to return for the required number of visits

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A - test
Group A (Test) - Tooth extraction and intake of an NSAID (i.e. Ketoprofen ER 50 mg) at 8 AM and a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 2 PM and 8 PM for a 3-day period, starting the regime at 2 PM on the day of the extraction.
Drug: Group A - test:Tooth extraction and intake of NSAID and a non-NSAID
Tooth extraction and intake of an NSAID (i.e. Ketoprofen ER 50 mg) at 8 AM and a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 2 PM and 8 PM for a 3-day period, starting the regime at 2 PM on the day of the extraction.
Other Names:
  • Ketoprofen ER 50 mg and Acetaminophen/Paracetamol 500 mg
Active Comparator: Group B - Control 1
Group B (Control 1) - Tooth extraction and intake of an NSAID (i.e. Ketoprofen ER 50 mg) at 8 PM and a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 8 AM and 2 PM for a 3- day period, starting the regime at 2 PM on the day of the extraction.
Drug: Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAID
Tooth extraction and intake of an NSAID (i.e. Ketoprofen ER 50 mg) at 8 PM and a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 8 AM and 2 PM for a 3-day period, starting the regime at 2 PM on the day of the extraction.
Other Names:
  • Acetaminophen/Paracetamol 500 mg and Ketoprofen ER 50 mg
Active Comparator: Group C - Control 2
Group C (Control 2) - Tooth extraction and intake of a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 8AM, 2 PM and 8 PM for a 3-day period, starting the regime at 2 PM on the day of the extraction.
Drug: Group C - Control 2: tooth extraction and intake of a Non-Nsaid
Tooth extraction and intake of a non-NSAID (i.e. Acetaminophen / Paracetamol 500 mg) at 8AM, 2 PM and 8 PM for a 3-day period, starting the regime at 2 PM on the day of the extraction.
Other Names:
  • Acetaminophen/Paracetamol 500 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
proportion (%) of mineralized tissue
Time Frame: 6 weeks after extraction
proportion (%) of mineralized tissue present in the bone core samples obtained at the time of implant placement, approximately 6 weeks after tooth extraction. This will be evaluated via histomorphometric analysis.
6 weeks after extraction

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
µCT analysis
Time Frame: 6 weeks post-extraction
Characteristics of mineralized tissue evaluated via μCT analysis.
6 weeks post-extraction
Alveolar bone variations
Time Frame: Baseline to 6 weeks post-extraction
Bone linear and volumetric dimensional changes between visits 2 and 4 via DICOM data analysis.
Baseline to 6 weeks post-extraction
Alveolar ridge contour variations
Time Frame: Baseline to 6 weeks post-extraction
Alveolar ridge contour variations from visits 2 to visit 5 via STL data analysis.
Baseline to 6 weeks post-extraction
Implant insertion torque
Time Frame: 6 weeks post-extraction
Implant insertion torque at visit 4, expressed in N/cm
6 weeks post-extraction
Serum CRP
Time Frame: Baseline
Serum CRP assessment using circulating blood samples obtained at visits 2 and 4
Baseline
Serum CRP
Time Frame: 6 weeks post-extraction
Serum CRP assessment using circulating blood samples obtained at visits 2 and 4
6 weeks post-extraction
Wound Healing Index (WHI)
Time Frame: 1 week post-extraction
WHI assessment at visit 3
1 week post-extraction
Wound Healing Index (WHI)
Time Frame: 6 weeks post-extraction
WHI assessment at visit 4
6 weeks post-extraction
Wound Healing Index (WHI)
Time Frame: 8 weeks post-extraction
WHI assessment at visit 5
8 weeks post-extraction
Patient Reported Outcome Measures (PROMS)
Time Frame: Baseline
Self-perceived discomfort measured using a 10-point Visual Analog Scale (1 [lower discomfort] to 10 [higher discomfort]) at day 0, 1, 2, 3 and 7 after tooth extraction
Baseline
Patient Reported Outcome Measures (PROMS)
Time Frame: Day 1 post-extraction
Self-perceived discomfort measured using a 10-point Visual Analog Scale (1 [lower discomfort] to 10 [higher discomfort]) at day 0, 1, 2, 3 and 7 after tooth extraction
Day 1 post-extraction
Patient Reported Outcome Measures (PROMS)
Time Frame: Day 2 post-extraction
Self-perceived discomfort measured using a 10-point Visual Analog Scale (1 [lower discomfort] to 10 [higher discomfort]) at day 0, 1, 2, 3 and 7 after tooth extraction
Day 2 post-extraction
Patient Reported Outcome Measures (PROMS)
Time Frame: Day 3 post-extraction
Self-perceived discomfort measured using a 10-point Visual Analog Scale (1 [lower discomfort] to 10 [higher discomfort]) at day 0, 1, 2, 3 and 7 after tooth extraction
Day 3 post-extraction
Patient Reported Outcome Measures (PROMS)
Time Frame: Day 7 post-extraction
Self-perceived discomfort measured using a 10-point Visual Analog Scale (1 [lower discomfort] to 10 [higher discomfort]) at day 0, 1, 2, 3 and 7 after tooth extraction
Day 7 post-extraction

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Iowa

Investigators

  • Study Chair: Satheesh Elangovan, BDS DSc DMSc, University of Iowa

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

January 1, 2023

Primary Completion (Anticipated)

January 1, 2023

Study Completion (Anticipated)

January 1, 2023

Study Registration Dates

First Submitted

April 8, 2019

First Submitted That Met QC Criteria

April 8, 2019

First Posted (Actual)

April 11, 2019

Study Record Updates

Last Update Posted (Actual)

June 21, 2022

Last Update Submitted That Met QC Criteria

June 17, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201904762

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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