Harnessing Chronomodulation to Enhance Osteogenesis

NCT03911336 | Withdrawn Phase 4

• 1 other identifier: 201904762
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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 Unpublished findings revealed that mice receiving carprofen for 3 days post-fracture exclusively during activity hours exhibited superior bone healing outcomes in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

Conditions

Tooth Loss

Keywords

Chronotherapy; Chronomodulation; Osteogenesis; NSAID

Outcome Measures

Primary Outcomes (1)

• proportion (%) of mineralized tissue

  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 Outcomes (14)

• µCT analysis

  6 weeks post-extraction

• Alveolar bone variations

  Baseline to 6 weeks post-extraction

• Alveolar ridge contour variations

  Baseline to 6 weeks post-extraction

• Implant insertion torque

  6 weeks post-extraction

• Serum CRP

  Baseline

Study Arms (3)

Group A - test

EXPERIMENTAL

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

Group B - Control 1

ACTIVE COMPARATOR

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

Group C - Control 2

ACTIVE COMPARATOR

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

Interventions

Group A - test:Tooth extraction and intake of NSAID and a non-NSAID DRUG

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.

Also known as: Ketoprofen ER 50 mg and Acetaminophen/Paracetamol 500 mg

Group A - test

Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAID DRUG

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.

Also known as: Acetaminophen/Paracetamol 500 mg and Ketoprofen ER 50 mg

Group B - Control 1

Group C - Control 2: tooth extraction and intake of a Non-Nsaid DRUG

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.

Also known as: Acetaminophen/Paracetamol 500 mg

Group C - Control 2

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Iowa: lead

Related Publications (10)

• Slade GD, Akinkugbe AA, Sanders AE. Projections of U.S. Edentulism prevalence following 5 decades of decline. J Dent Res. 2014 Oct;93(10):959-65. doi: 10.1177/0022034514546165. Epub 2014 Aug 21.

  PMID: 25146182 BACKGROUND

• Elani HW, Starr JR, Da Silva JD, Gallucci GO. Trends in Dental Implant Use in the U.S., 1999-2016, and Projections to 2026. J Dent Res. 2018 Dec;97(13):1424-1430. doi: 10.1177/0022034518792567. Epub 2018 Aug 3.

  PMID: 30075090 BACKGROUND

• Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Levi FA. The circadian timing system in clinical oncology. Ann Med. 2014 Jun;46(4):191-207. doi: 10.3109/07853890.2014.916990.

  PMID: 24915535 BACKGROUND

• Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008 Oct;9(10):764-75. doi: 10.1038/nrg2430.

  PMID: 18802415 BACKGROUND

• Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Levi F; European Organisation for Research and Treatment of Cancer Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. doi: 10.1200/JCO.2006.06.1440.

  PMID: 16877722 BACKGROUND

• Cutolo M. Glucocorticoids and chronotherapy in rheumatoid arthritis. RMD Open. 2016 Mar 18;2(1):e000203. doi: 10.1136/rmdopen-2015-000203. eCollection 2016.

  PMID: 27042335 BACKGROUND

• Okazaki F, Matsunaga N, Hamamura K, Suzuki K, Nakao T, Okazaki H, Kutsukake M, Fukumori S, Tsuji Y, To H. Administering xCT Inhibitors Based on Circadian Clock Improves Antitumor Effects. Cancer Res. 2017 Dec 1;77(23):6603-6613. doi: 10.1158/0008-5472.CAN-17-0720. Epub 2017 Oct 16.

  PMID: 29038345 BACKGROUND

• Swanson CM, Kohrt WM, Buxton OM, Everson CA, Wright KP Jr, Orwoll ES, Shea SA. The importance of the circadian system & sleep for bone health. Metabolism. 2018 Jul;84:28-43. doi: 10.1016/j.metabol.2017.12.002. Epub 2017 Dec 9.

  PMID: 29229227 BACKGROUND

• Dallmann R, Okyar A, Levi F. Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy. Trends Mol Med. 2016 May;22(5):430-445. doi: 10.1016/j.molmed.2016.03.004. Epub 2016 Apr 5.

  PMID: 27066876 BACKGROUND

• Chappuis V, Rahman L, Buser R, Janner SFM, Belser UC, Buser D. Effectiveness of Contour Augmentation with Guided Bone Regeneration: 10-Year Results. J Dent Res. 2018 Mar;97(3):266-274. doi: 10.1177/0022034517737755. Epub 2017 Oct 26.

  PMID: 29073362 BACKGROUND

MeSH Terms

Conditions

Tooth Loss

Interventions

Ketoprofen; Acetaminophen

Condition Hierarchy (Ancestors)

Periodontal Diseases; Mouth Diseases; Stomatognathic Diseases; Tooth Diseases

Intervention Hierarchy (Ancestors)

Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Acetanilides; Anilides; Amides; Aniline Compounds; Amines

Study Officials

• Satheesh Elangovan, BDS DSc DMSc

  University of Iowa

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This study is designed as a parallel-arm, double-blinded pilot randomized controlled trial (RCT).

Study Record Dates

• First Submitted: April 8, 2019
• First Posted: April 11, 2019
• Study Start: January 1, 2023
• Primary Completion: January 1, 2023
• Study Completion: January 1, 2023
• Last Updated: June 21, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share