Prospective Validation Study of the CD8+TEMRA Cells As a Prognostic Biomarker of Healing Outcome After Fracture (BioBone)

In approx. 10-15% of all fracture patients, there is a prolonged healing time or even a complete absence of fracture healing (non-union). As a result, these patients require further surgical interventions, combined with renewed or prolonged hospitalisation/rehabilitation and incapacity to work. To summarise, this therefore represents a serious socio-economic problem. At present, there is no prognostic method for the early prediction of patients at risk of a disturbed healing process. However, if these patients are successfully stratified, there are already a variety of therapeutic strategies available to additionally stimulate fracture healing. Therefore, the aim is to conduct a prospective clinical study to validate CD8+ TEMRA cells as a prognostic marker of impaired fracture healing. The investigators assume that preoperative CD8+ TEMRA cell expression represents a prognostic biomarker with high diagnostic precision for differentiating between a) normal healing patients, b) delayed healing patients and c) pseudarthrosis patients. Furthermore, the sensitivity and specificity should be high enough, health-economically significant and realisable in clinical routine.

Study Overview

• Status: Recruiting
• Conditions: Femoral Neck Fractures; Femoral Shaft Fracture; Tibial Shaft Fracture; Forearm Fracture; Fracture Non Union; Distal Tibia Fracture; Fracture Healing; Femur Distal Fracture; Proximal Tibia Fracture; Humerus Shaft Fracture; Long Bone Delayed-Union Fracture; Pertrochanteric Fracture of Femur
• Intervention / Treatment: Diagnostic test: CD8+TEMRA

Detailed Description

The aim is to identify high-risk patients before the initial operation based on their immunological profile and to be able to provide them with an improved, individualised therapeutic strategy. There are already a large number of approved therapeutic options that are currently only used in revision cases because, among other things, preoperative diagnostics and prognostics are lacking. Furthermore, a sufficient preoperatively determined biomarker would form the basis for the development of new therapeutic approaches, which represent a low cost-benefit and risk-benefit ratio.

The prospective biomarker validation study is applied in a routine-adapted procedure, i.e. all visits are part of the clinical radiological and functional routine checks. Blood sampling on arrival at the hospital will be used to determine the preoperative value of CD8+TEMRA cells. The healing process will be recorded using X-ray/CT images, radiological scores and functional clinical examinations as well as the SF-36. The 1st study endpoint (delayed healing) is after 17-19 weeks postoperatively, the 2nd study endpoint (pseudarthrosis) after 34-36 weeks. The validation of the biomarker will take place in a blinded procedure, whereby the predefined threshold value of the preoperative CD8+ TEMRA cell expression will be compared with the patient's healing status.

• Study Type: Observational
• Enrollment (Estimated): 640

Contacts and Locations

• Study Contact: Name: Simon Reinke, Phd; Phone Number: +49 (0)30-450-659617; Email: simon.reinke@bih-charite.de
• Study Contact Backup: Name: Sven Geißler, Phd; Phone Number: +49(0)30450 559539; Email: sven.geissler@bih-charite.de

Study Locations

• Germany
  • Berlin, Germany, 12683
    • Recruiting
    • Unfallkrankenhaus Berlin
    • Contact: Regina Zappel, MD; Phone Number: +49 (0) 30 5681 4050; Email: kristina.zappel@ukb.de
    • Contact: Stefan Weber, MD
  • Berlin, Germany, 13353
    • Recruiting
    • Charité Universitätsmedizin Berlin, Centre for Musculoskeletal Surgery (CMSC)
    • Contact: Sven Märdian, Prof.; Phone Number: +4930450552092; Email: sven.maerdian@charite.de
    • Contact: Sven Märdian, Prof.
  • Berlin, Germany, 13585
    • Recruiting
    • Vivantes Klinikum Spandau Berlin
    • Contact: Anja Bauer, MD; Phone Number: +4930130132290; Email: anjamaria.bauer@vivantes.de
    • Contact: Philipp Schwabe, MD
  • Nordrhein-Westfalen
    • Münster, Nordrhein-Westfalen, Germany, 48149
      • Recruiting
      • Clinic for Trauma, Hand and Reconstructive Surgery University Hospital Münster (UKM)
      • Contact: Marion Laumann; Phone Number: +49251 83-51479; Email: marion.laumann@ukmuenster.de
      • Contact: Richard Stange, Prof.
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Recruiting
      • University Hospital University Centre for Orthopaedics and Trauma Surgery Dresden
      • Contact: Maik Stiehler, Prof., Phd; Phone Number: +49351 458-3777; Email: Maik.Stiehler@ukdd.de
      • Contact: Maik Stiehler, Prof., Phd
    • Leipzig, Sachsen, Germany, 04103
      • Recruiting
      • University Hospital Clinic and Polyclinic for Orthopaedics, Trauma Surgery and Plastic Surgery Leipzig
      • Contact: Georg Osterhoff, Prof; Phone Number: +49 341 97-17867; Email: georg.osterhoff@medizin.uni-leipzig.de
      • Contact: Georg Osterhoff, Prof.
  • Thüringen
    • Eisenberg, Thüringen, Germany, 07607
      • Recruiting
      • Clinic for Orthopaedics and Trauma Surgery Jena/Eisenberg
      • Contact: Georg Matziolis, Prof.; Phone Number: +4936691 81010; Email: g.matziolis@waldkliniken-eisenberg.de
      • Contact: Georg Matziolis, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

University Hospital UniversityCentre for Orthopaedics and Trauma Surgery Dresden Charité Universitätsmedizin Berlin Centre for Musculoskeletal Surgery Clinic for Orthopaedics and Trauma Surgery Jena/Eisenberg Clinic Trauma Hospital Berlin Berlin Vivantes Hospital Spandau Berlin Clinic University Hospital Clinic and Polyclinic for Orthopaedics, Trauma Surgery and Plastic Surgery Leipzig

Description

Inclusion Criteria:

• male or female subjects
• subjects > 18 to 80 years of age at the time of screening
• closed fractures
• fractures of the humerus-shaft, forearm-shaft, femur and tibia
• Subjects suffering monotrauma or comparable with monotrauma, due to comparable post-surgery mobilisation
• osteosynthesis
• subject has signed an informed consent form
• legal capacity

Exclusion Criteria:

• cancer related fractures
• periprosthetic fractures
• known active Hepatitis B virus or Hepatitis C virus infection at screening
• known human immunodeficiency virus (HIV) infection, severe uncontrolled inflammatory disease or severe uncontrolled autoimmune disease (e.g., ulcerative colitis, Crohn's disease
• active malignancy or history of malignancy within 5 years prior to screening
• known diagnosis of moderate to severe dementia based on subject's medical history or severe psychiatric disorder
• known history of drug or alcohol abuse in the past 12 months, based on self-report or medical record
• history of autologous/allogeneic bone marrow (BM) or solid organ transplantation
• exposure to allogeneic cell-based therapy in the past or exposure to autologous cell therapy in the last 12 months before screening
• pregnancy
• subject is currently enrolled in an investigational device or drug trial, or has not yet completed a period of at least 30 days since ending other investigational device or drug trial(s).
• subject is detained or institutionalized under a court order or administrative order
• in the opinion of the investigator, the subject is unsuitable for participating in the study (patient compliance).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
fracture cohort; Humerus fracture, forearm fracture, femoral fracture. tibia fracture	Diagnostic test: CD8+TEMRA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical assessement of the fracture consolidation at first study endpoint based on radiological images	Clinical assessement of the fracture consolidation (yes/no) based on radiological images at primary end point	From surgery to 19 weeks post surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical assessement of the fracture consolidation at second study endpoint based on radiological images	fracture consolidation (yes/no) after 36 weeks post surgery based on radiological images.	From surgery to 36 weeks post surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to work	Period of return to work in days	From surgery to 1 year post surgery
Proportion of subjects with an additional intervention independent of a surgical or non-surgical treatment to foster the fracture healing process	Number of surgically invasive and non-invasive measures	From surgery to 1 year post surgery
Duration of Physiotherapy	Duration of physiotherapy sessions (units) done with a professional post-surgery.	From surgery to 1 year post surgery
Weight bearing and fracture healing	Time to complete full weight bearing post surgery (weeks).	From surgery to 1 year post surgery
Rehabilitation and fracture healing	Proportion of subjects with inpatient or day-care rehabilitation post surgery.	From surgery to 1 year post surgery
Infection rate	Proportion of subjects with postoperative infections	From surgery to 1 year post surgery

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Jena University Hospital; Beckman Coulter, Inc.; University Hospital Dresden; Unfallkrankenhaus Berlin; Leipzig University Hospital; Federal Ministry of Education and Reserach (BMBF); Vivantes Klinikum Spandau; Universitaetsklinikum Muenster
• Investigators: Principal Investigator: Simon Reinke, Phd, Charité Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT)

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: October 17, 2024
• First Submitted That Met QC Criteria: October 23, 2024
• First Posted (Actual): October 26, 2024

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: prognosis; T cells; Immune system; radiology; long bone fracture; prognostic biomarker; impaired fracture healing; fracture non-union; bone fracture healing
• Additional Relevant MeSH Terms: Wounds and Injuries; Leg Injuries; Hip Injuries; Hip Fractures; Fractures, Bone; Fractures, Ununited; Femoral Fractures; Tibial Fractures; Femoral Neck Fractures
• Other Study ID Numbers: 01EK1514; DRKS00010872 (Other Identifier: german clinical trials register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: For data protection reasons, no individual participant data will be shared

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