Safety and Efficacy Evaluation of the Ivory Dentin Graft Device
Condition: Deficiency of Alveolar Ridge (Disorder); Alveolar Bone Grafting; Mandibular Prosthesis User
Study type: Interventional

Summary: 
      Ivory Dentin Graft is at least as good as the competitor treatment group (OsteoBiol Gen Os)
      for alveolar ridge preservation following tooth extraction.

      The non-inferiority endpoints will be achieved if the competitor treatment group will not be
      statistically better than the Ivory Graft treatment.
    

Detailed description: 
      Device Description - Investigational Medicinal Product Ivory Dentin Graft is a bone graft
      material for the repair or augmentation of bone defects in dental procedures. It consists of
      sterile 300 - 900 μm porous particles of hydroxyapatite which retain the natural form of the
      source porcine dentin.

      Ivory Dentin Graft is intended to be used as a bone graft material for the repair or
      augmentation of bone defects in dental procedures.

      OsteoBiol Gen Os. - Comparator control device A natural replicate of autologous bone, Gen-Os®
      conserves the same intimate structures (matrix and porous form) and presents a highly
      osteoconductive properties. Gen-Os® is gradually resorbable and provides support in bone
      neoformation helping to preserve the original graft shape and volume.

      Study Design: The Ivory Dentin Graft study is a prospective, randomized, semi double blinded
      with blinded assessments study comparing patients grafted with Ivory Dentin Graft
      (Investigational group) and patients grafted with OsteoBiol Gen Os (comparator group) for
      alveolar ridge preservation following tooth extraction.

      Study Population and Justification: A total of 44 adult patients in 2 study groups scheduled
      to undergo at least one dental implant placement of mandibular premolar or molar are planned
      to be enrolled. The patients will be randomized into two treatment groups: One group is to be
      grafted with Ivory Dentin Graft while the second group will be grafted with OsteoBiol Gen Os,
      randomization ratio of 1:1 between the experimental and control group.

      Sample size Justification and Statistical Analysis Plan: The rationale for sample size
      calculation is based on demonstrating non-inferiority in the study primary endpoint between
      the tested and the reference treatment groups.

      The calculations assume a difference of up to 30% (percent as in unit of measure and not of
      relative difference) woven bone between the treatments, which will be considered equivalent
      (non-inferiority) and standard deviation of 32%.

      In a sample of 15 patients per group, a difference of up to 30% in the mean woven bone
      between the treatment groups will be considered equivalent with 5% significance level and 80%
      statistical power. Assuming expected dropout rate of ~30%, 44 patients (22 per group) will be
      recruited in order to ensure final sample size of 30 study completers (15 per group). All
      tests will be two-tailed, and a p value of 5% or less will be considered statistically
      significant. The data will be analysed using the R version 4.0.1 (R development Core Team.
      Vienna, Austria).

      Primary Endpoints: 95% Confidence Interval of the Differences between the treatments (Mean
      Ivory Graft - Mean Comparator) in woven bone ratio at 4 months after grafting will be
      applied. The non-inferiority endpoint will be achieved if the lower limit of the confidence
      interval will be higher than -30 (meaning that the comparator is less than 30 points better
      than Ivory Graft or not better at all).

      Secondary Endpoints: Differences in categorical secondary endpoints will be tested for
      significance using Chi-Square test or Fisher's Exact test (as appropriate) Differences in
      numeric secondary endpoints will be tested for significance using the two-sample T-test or
      Non-parametric Wilcoxon-Mann-Whitney Rank sum test for independent samples (as is
      appropriate).

      Exploratory Endpoints: Usability, defined as ease of procedure using 10-points satisfaction
      scale, will be summarized in appropriate tables by treatment.

      The percent of teeth which require additional grafting at implant placement will be
      summarized and compared using Chi-square test or Fisher's exact test (as is appropriate).

      Handling of Participant Withdrawals: Participants who leave the study prematurely will be
      replaced. A patient discontinuing the study before grafting of Ivory Dentin Graft (Visit 2)
      will be followed for safety. Each case of premature withdrawal will be properly recorded in
      the Screening Failure Log as deemed necessary.

      Patient Screening: Prior to any study-related screening procedure, delegated study team
      members will approach potentially eligible adult patients who are waiting to be scheduled for
      tooth extraction and grafting for necessary titanium implant placement. Patients who do not
      meet inclusion criteria or who are for any other reason determined to be unsuitable for
      inclusion in the study, or who decline to participate in the study, will be considered and
      recorded as "screening failure" and receive standard and appropriate treatment.

      Informed Consent: The informed consent document will be signed and dated for screening and
      enrollment and each patient consenting will be documented in the patient medical binder. The
      patient will be given a copy of the consent form together with the study doctor's letter at
      the time of enrollment. The clinician will ask the patient about his plans and his
      willingness to attend all scheduled follow-up visits.

      Randomization will be done by Castor EDC web-software. The patients will be randomized into
      two treatment groups: One group is to be grafted with Ivory Dentin Graft while the second
      group will be grafted with OsteoBiol Gen Os, randomization ratio of 1:1 between the
      experimental and control group.

      TRIAL PROCEDURES: After informed consent is obtained, a case record form including all
      aspects listed below will be recorded. Eligible patients will be enrolled into the study and
      be treated according to standard treatment protocols for tooth extraction, grafting, implant
      placement, dental biopsy and dental radiographic procedures and with the standard protocol
      for local anesthetic.

      Visit 1: Screening and Enrolment, as part of pre-operative visit (0-90 days before grafting
      procedure ) The following assessments will be performed: Demographics, Medical history, Vital
      signs, Current medications. A CT scan will be performed in order to verify patient
      eligibility and graft procedure preparation Visit 2: Randomization and extraction socket
      graft filling by Ivory Dentin Graft or Gen Os after tooth extraction.

      The designated randomization groups (Ivory Dentin Group and Gen Os) will be:

        1. Recorded in the patient CRF

        2. A sticker of the used study item and the used package will be achived in the patient
           binder- this will be used as source to verify correct allocation.

      All patients will be operated by study delegated physicians using the same method.

      Socket debridement and cleaning: After exposure of the defect the sounding walls should be
      debrided by surgical curette and all granulation tissue removed.

      The extraction site will be graft filled either using Ivory Dentin Graft or OsteoBiol Gen-Os
      according to the respective Instructions for Use using either vial or syringe applicators
      with dental membrane. Only the graft performing sub-investigator and the study coordinator
      will be un-blinded to the patient allocation. All efforts and measures would be taken by the
      study team to keep the patient and blinded assessors blinded of allocation- semi double
      blinded study.

      Periapical x-ray imaging will be performed on each enrolled patient once completing the graft
      filling in order to validate the bone grafting procedure.

      The following assessments will be performed following the procedure:

        1. Extraction socket grafting Physician usability Form

        2. Study Patient Discharge form. Patients will be monitored for short-term follow-up (1
           week, 1 and 4 months following their extraction socket grafting procedure) and for
           long-term follow-up and will be evaluated for their medical and dental conditions.
           Implantation of titanium implants will be conducted 4 months following the grafting
           procedure at grafted site of each enrolled patient.

      Short-term Visit 3: Follow up 1 week following grafting procedure The patient will be asked
      to report any dental complication- all will be investigated by the sub-investigator using
      Visit 3 safety Follow Up Form. In addition, vital signs will be taken by study investigator.

      Visit 4: Follow up 1 month following grafting procedure The patient will be asked to report
      any dental complication- all will be investigated by the sub-investigator using Visit 4
      safety Follow Up Form. In addition, vital signs will be taken by study investigator.

      A Computerized Tomography (CT) will be performed prior to visit 5 Visit 5: Follow up 4 months
      following grafting procedure and dental Implant placement (Short-term Termination visit)

      Prior to the procedure, the patient will be asked to report any dental complication. The
      following assessments will be conducted during the visit:

        1. Vital Signs

        2. Implant placement Physician usability Form

        3. Study Patient Discharge form.

        4. Short-term termination visit The alveolar bone strength (torque measurement) will be
           measured by torque measurement.

      Adequacy of bone graft (need for additional grafting at implant placement) will be evaluated
      by the study investigator based on the clinical examination, torque measurement and CT scan,
      and will be specified and justified in the Case Report Form.

      Un-scheduled visit: The study investigator will instruct the patient to immediately contact
      the study team in case of: Implant failure, loose graft particles, loss of grafting material,
      graft site infection, insufficient healing of graft site, excessive bleeding and wound
      dehiscence. The patient must call the study nurse to schedule an un-scheduled visit which may
      only be performed by the principal Investigator.

      Post-Market Clinical Follow-up: Patients will be monitored also for long-term follow-up (6
      and 10 months, 2.5 and 5 years following their extraction socket grafting procedure) and will
      be evaluated by the study nurse for their medical and dental conditions.

      Data Monitoring and Quality Control:The investigator, through an appointed Clinical Research
      Associate (CRA), will be responsible for implementing and maintaining quality assurance and
      quality control systems with written Standard Of Procedures to ensure that trials are
      conducted and data are generated, documented (recorded), and reported in compliance with the
      protocol, GCP, and the applicable regulatory requirement(s), including ISO 14155.

      The investigator will be responsible for ensuring direct access to all trial related sites,
      source data/documents, and reports for the purpose of monitoring and auditing by the
      hospital, and inspection by Israeli regulatory authorities.

      Quality control should be applied to each stage of data handling to ensure that all data are
      reliable and have been processed correctly.

      The study CRA will verify that (a) The rights and well-being of human patients are protected,
      (b) The reported trial data are accurate, complete, and verifiable from source documents and
      (c) The conduct of the trial is in compliance with the currently approved
      protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s) (including
      ISO 14155). The full responsibilities of the trial monitor appear in full in the ICH-GCP. The
      monitor(s) should follow Ivory Graft (or their CRO representative) written for monitoring the
      specific trial. The monitor will submit a written report after each trial-site visit or
      trial-related communication. A report should include the date, site, name of the monitor, and
      name of the investigator or other individual(s) contacted. A report should include a summary
      of what the monitor reviewed and the monitor's statements concerning the significant
      findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or
      actions recommended to secure compliance.

      To ensure compliance of this investigator initiated trial with current national regulations
      and the ICH guidelines, data generated by this study will be available for inspection upon
      request by representatives of the local health authorities- IRB or the national authorities -
      MOH, or any entity providing support for this trial. Routine monitoring or audit activities
      for this study will be conducted by authorized representatives. The general scope of such
      visits would be to inspect study data (regulatory requirements), source documentation and CRF
      completion in accordance with current GCP, the ICH guidelines and the respective local and
      national government regulations and guidelines.
    

Intervention name(s): Graft Matrix
Intervention type(s): Device
Intervention description(s): Both Graft matrix products are supplied sterile, for single use only and packed in vials or a syringe-like applicator. All products consist of the same bone graft particles with the only variants being due to different amounts per package or different containers.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The Ivory Dentin Graft study is a prospective, randomized, semi double blinded with blinded assessments study comparing patients grafted with Ivory Dentin Graft (study arm) and patients grafted with OsteoBiol Gen Os (control arm) for alveolar ridge preservation following tooth extraction.
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Dental Instruments; Dental Technology