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Harnessing Chronomodulation to Enhance Osteogenesis

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ClinicalTrials.gov Identifier: NCT03911336
Recruitment Status : Suspended (Decided not to proceed)
First Posted : April 11, 2019
Last Update Posted : June 14, 2021
Sponsor:
Information provided by (Responsible Party):
Satheesh Elangovan, University of Iowa

Brief Summary:

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 Unpublished findings revealed that mice receiving carprofen for 3 days post-fracture exclusively during activity hours exhibited superior bone healing outcomes in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.


Condition or disease Intervention/treatment Phase
Tooth Loss Drug: Group A - test:Tooth extraction and intake of NSAID and a non-NSAID Drug: Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAID Drug: Group C - Control 2: tooth extraction and intake of a Non-Nsaid Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is designed as a parallel-arm, double-blinded pilot randomized controlled trial (RCT).
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description:

Participants, Surgeon and Assessors collecting the data and conducting the appropriate statistical analyses for all outcomes in the study will be blinded.

All surgical procedures will be scheduled between 8 and 10 AM and performed by the same blinded clinician to maintain a consistent therapeutic approach for all subjects.

Primary Purpose: Treatment
Official Title: Harnessing Chronomodulation to Enhance Osteogenesis - A Pilot Randomized Controlled Trial -
Estimated Study Start Date : January 1, 2023
Estimated Primary Completion Date : January 1, 2023
Estimated Study Completion Date : January 1, 2023

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: Acetaminophen/Paracetamol 500 mg




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. µCT analysis [ Time Frame: 6 weeks post-extraction ]
    Characteristics of mineralized tissue evaluated via μCT analysis.

  2. 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.

  3. 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.

  4. Implant insertion torque [ Time Frame: 6 weeks post-extraction ]
    Implant insertion torque at visit 4, expressed in N/cm

  5. Serum CRP [ Time Frame: Baseline ]
    Serum CRP assessment using circulating blood samples obtained at visits 2 and 4

  6. Serum CRP [ Time Frame: 6 weeks post-extraction ]
    Serum CRP assessment using circulating blood samples obtained at visits 2 and 4

  7. Wound Healing Index (WHI) [ Time Frame: 1 week post-extraction ]
    WHI assessment at visit 3

  8. Wound Healing Index (WHI) [ Time Frame: 6 weeks post-extraction ]
    WHI assessment at visit 4

  9. Wound Healing Index (WHI) [ Time Frame: 8 weeks post-extraction ]
    WHI assessment at visit 5

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03911336


Sponsors and Collaborators
University of Iowa
Investigators
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Study Chair: Satheesh Elangovan, BDS DSc DMSc University of Iowa
Publications:

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Responsible Party: Satheesh Elangovan, Principal Investigator, University of Iowa
ClinicalTrials.gov Identifier: NCT03911336    
Other Study ID Numbers: 201904762
First Posted: April 11, 2019    Key Record Dates
Last Update Posted: June 14, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Satheesh Elangovan, University of Iowa:
Chronotherapy
Chronomodulation
Osteogenesis
NSAID
Additional relevant MeSH terms:
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Tooth Loss
Periodontal Diseases
Mouth Diseases
Stomatognathic Diseases
Tooth Diseases
Acetaminophen
Anti-Inflammatory Agents, Non-Steroidal
Ketoprofen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action