Tooth LossPhase 4NCT03911336
Harnessing Chronomodulation to Enhance Osteogenesis
A Phase 4 study testing Group A - test:Tooth extraction and intake of NSAID and a non-NSAID in people with Tooth Loss, run by University of Iowa.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 85 yearsHealthy volunteers can take part
- Conditions the study is for
- Tooth Loss
- What is being tested?
- Group A - test:Tooth extraction and intake of NSAID and a non-NSAID
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Jan 2023to 1 Jan 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Tooth Loss
- Being tested
- Group A - test:Tooth extraction and intake of NSAID and a non-NSAID, Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAID, Group C - Control 2: tooth extraction and intake of a Non-Nsaid
- Keywords
- Chronotherapy, Chronomodulation, Osteogenesis, NSAID
- Medical subject headings
- Tooth Loss
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Group A - test:Tooth extraction and intake of NSAID and a non-NSAIDDrug
Also called Ketoprofen ER 50 mg and Acetaminophen/Paracetamol 500 mg
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.
Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAIDDrug
Also called Acetaminophen/Paracetamol 500 mg and Ketoprofen ER 50 mg
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.
Group C - Control 2: tooth extraction and intake of a Non-NsaidDrug
Also called Acetaminophen/Paracetamol 500 mg
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Group C - Control 2: tooth extraction and intake of a Non-Nsaid |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6 weeks after extraction
Secondary outcomes (14)
µCT analysis
Characteristics of mineralized tissue evaluated via μCT analysis.
Measured: 6 weeks post-extraction
Alveolar bone variations
Bone linear and volumetric dimensional changes between visits 2 and 4 via DICOM data analysis.
Measured: Baseline to 6 weeks post-extraction
Alveolar ridge contour variations
Alveolar ridge contour variations from visits 2 to visit 5 via STL data analysis.
Measured: Baseline to 6 weeks post-extraction
Implant insertion torque
Implant insertion torque at visit 4, expressed in N/cm
Measured: 6 weeks post-extraction
Serum CRP
Serum CRP assessment using circulating blood samples obtained at visits 2 and 4
Measured: Baseline
Serum CRP
Serum CRP assessment using circulating blood samples obtained at visits 2 and 4
Measured: 6 weeks post-extraction
Wound Healing Index (WHI)
WHI assessment at visit 3
Measured: 1 week post-extraction
Wound Healing Index (WHI)
WHI assessment at visit 4
Measured: 6 weeks post-extraction
Wound Healing Index (WHI)
WHI assessment at visit 5
Measured: 8 weeks post-extraction
Patient Reported Outcome Measures (PROMS)
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
Measured: Baseline
Patient Reported Outcome Measures (PROMS)
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
Measured: Day 1 post-extraction
Patient Reported Outcome Measures (PROMS)
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
Measured: Day 2 post-extraction
Patient Reported Outcome Measures (PROMS)
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
Measured: Day 3 post-extraction
Patient Reported Outcome Measures (PROMS)
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
Measured: Day 7 post-extraction
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2019
- Study start1 Jan 2023 (estimated)
- Primary completion1 Jan 2023 (estimated)
- Study completion1 Jan 2023 (estimated)
Why it stopped: Decided not to proceed
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Tooth LossStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This study is designed as a parallel-arm, double-blinded pilot randomized controlled trial (RCT).
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Iowa
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Satheesh Elangovan, University of Iowa
- Investigators
- Satheesh Elangovan, BDS DSc DMSc, Study chair, University of Iowa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03911336
- Sponsor's protocol ID
- 201904762
- Status last verified
- Jun 2022
- First submitted
- 8 Apr 2019
- Last updated
- 21 Jun 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 25146182Elani 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.
PubMed 30075090Innominato 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.
PubMed 24915535Takahashi 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.
PubMed 18802415Giacchetti 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.
PubMed 16877722Cutolo M. Glucocorticoids and chronotherapy in rheumatoid arthritis. RMD Open. 2016 Mar 18;2(1):e000203. doi: 10.1136/rmdopen-2015-000203. eCollection 2016.
PubMed 27042335Okazaki 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.
PubMed 29038345Swanson 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.
PubMed 29229227Dallmann 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.
PubMed 27066876Chappuis 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.
PubMed 29073362
Study at a glance
From the registry record, last updated by the sponsor on 21 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Harnessing Chronomodulation to Enhance Osteogenesis - A Pilot Randomized Controlled Trial -
- ClinicalTrials.gov ID
- NCT03911336
- Acronym / sponsor ID
- 201904762
- Conditions
- Tooth Loss
- Keywords
- Chronotherapy, Chronomodulation, Osteogenesis, NSAID
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Decided not to proceed
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of IowaUniversity, hospital or other
- Study start
- 1 Jan 2023 (estimated)
- Primary completion
- 1 Jan 2023 (estimated)
- Study completion
- 1 Jan 2023 (estimated)
- First posted
- 11 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 3
- Model description
- This study is designed as a parallel-arm, double-blinded pilot randomized controlled trial (RCT).
| Arm | Type | Receives |
|---|---|---|
| Group A - test | Experimental | Drug: Group A - test:Tooth extraction and intake of NSAID and a non-NSAIDGroup 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. |
| Group B - Control 1 | Active comparator | Drug: Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAIDGroup 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. |
| Group C - Control 2 | Active comparator | Drug: Group C - Control 2: tooth extraction and intake of a Non-NsaidGroup 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. |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Group A - test:Tooth extraction and intake of NSAID and a non-NSAIDAlso: Ketoprofen ER 50 mg and Acetaminophen/Paracetamol 500 mgTooth 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 |
| Group B - Control 1: tooth extraction and intake of NSAID and a non-NSAIDAlso: Acetaminophen/Paracetamol 500 mg and Ketoprofen ER 50 mgTooth 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 |
| Group C - Control 2: tooth extraction and intake of a Non-NsaidAlso: Acetaminophen/Paracetamol 500 mgTooth 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 |
Primary outcome
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.
14 secondary outcomes
µCT analysis
Time frame: 6 weeks post-extraction
Alveolar bone variations
Time frame: Baseline to 6 weeks post-extraction
Alveolar ridge contour variations
Time frame: Baseline to 6 weeks post-extraction
Implant insertion torque
Time frame: 6 weeks post-extraction
Serum CRP
Time frame: Baseline
Serum CRP
Time frame: 6 weeks post-extraction
Wound Healing Index (WHI)
Time frame: 1 week post-extraction
Wound Healing Index (WHI)
Time frame: 6 weeks post-extraction
Wound Healing Index (WHI)
Time frame: 8 weeks post-extraction
Patient Reported Outcome Measures (PROMS)
Time frame: Baseline
Patient Reported Outcome Measures (PROMS)
Time frame: Day 1 post-extraction
Patient Reported Outcome Measures (PROMS)
Time frame: Day 2 post-extraction
Patient Reported Outcome Measures (PROMS)
Time frame: Day 3 post-extraction
Patient Reported Outcome Measures (PROMS)
Time frame: Day 7 post-extraction
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jun 2022.
- Background: PubMed 25146182Slade 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.
- Background: PubMed 30075090Elani 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.
- Background: PubMed 24915535Innominato 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.
- Background: PubMed 18802415Takahashi 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.
- Background: PubMed 16877722Giacchetti 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.
- Background: PubMed 27042335Cutolo M. Glucocorticoids and chronotherapy in rheumatoid arthritis. RMD Open. 2016 Mar 18;2(1):e000203. doi: 10.1136/rmdopen-2015-000203. eCollection 2016.
- Background: PubMed 29038345Okazaki 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.
- Background: PubMed 29229227Swanson 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.
- Background: PubMed 27066876Dallmann 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.
- Background: PubMed 29073362Chappuis 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Satheesh Elangovan, BDS DSc DMSc study chair
University of Iowa
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Group A - test:Tooth extraction and intake of NSAID and a non-NSAID in people with Tooth Loss, run by University of Iowa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 21 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
proportion (%) of mineralized tissue (time frame: 6 weeks after extraction). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03911336, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2022.