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Novel Parathyroid Hormone-Based Bone Graft, KUR-113, in Treatment of Acute Open Tibial Shaft Fracture

A Phase-2 Randomized Controlled Trial

Orbeanu, Valentin MD1; Haragus, Horia MD2; Crisan, Dan MD2; Cirstoiu, Catalin MD3; Ristic, Branko MD4; Jamieson, Virginia MBChB5,a

Author Information
The Journal of Bone and Joint Surgery: March 2, 2022 - Volume 104 - Issue 5 - p 441-450
doi: 10.2106/JBJS.20.02109

Abstract

Erratum

The Journal publishes corrections when they are of significance to patient care, scientific data or record-keeping, or authorship, whether that error was made by an author, editor, or staff. Errata also appear in the online version and are attached to files downloaded from jbjs.org.

In the article entitled “Novel Parathyroid Hormone-Based Bone Graft, KUR-113, in Treatment of Acute Open Tibial Shaft Fracture” (J Bone Joint Surg Am. 2022;104[5]:441-50), by Orbeanu et al., there was an error with the copyright line. Specifically, the copyright line indicated that The Journal of Bone and Joint Surgery, Incorporated held the copyright when it should have indicated that the authors hold the copyright. The publisher regrets this error.

JBJS. 104(8):e35, April 20, 2022.

Estimates place the annual number of tibial shaft fractures (TSFs) in the United States at 492,0001. Approximately 25% of these are open fractures, which generally result from high-energy trauma and tend to be associated with multiple injuries2,3. Surgical treatment of open TSFs usually comprises placement of intramedullary nails, plate osteosynthesis, or external fixation4. Common complications include delayed union, nonunion, or malunion, especially in the presence of infection at the fracture site5,6. If healing is delayed, a secondary intervention may be required to promote fracture healing. This leads to higher morbidity, reduced quality of life, and increased cost to the health-care system7. Therapeutic approaches that increase union rates and decrease infection rates are desirable for patients and payers.

Administration of parathyroid hormone (PTH) or its fragment PTH1-34 to the fracture site has been shown to increase bone mass and reduce bone loss in animal models, resulting in an overall increase in bone formation8-10. Likewise, localized prolonged plasmid gene delivery of PTH1-34 enhances tissue regeneration in bone defects11,12. In contrast, continuous systemic administration of high concentrations of PTH1-34 leads to bone resorption13. Hence, to support fracture repair and avoid bone resorption, it is essential to achieve prolonged local delivery of PTH1-34 but, at the same time, avoid continuous high systemic levels. To address this, a technology was developed that allows cross-linking of PTH1-34 to fibrin sealants and enables the local retention and enzymatic release of PTH1-34 during the early phases of bone repair. The technology consists of a 12-amino acid linker, termed the TG-hook, which contains a transglutaminase substrate and a plasmin cleavage site. The TG-hook is added at the N-terminus of PTH1-34, resulting in peptide TGplPTH1-3414,15. Upon mixing with a fibrin sealant, TGplPTH1-34 is covalently linked to fibrin by factor XIIIa as the fibrin clot forms. The gel produced can be applied into the fracture site during the polymerization process, leading to the formation of a solid fibrin-PTH1-34 clot in situ. As the clot is gradually degraded by plasmin over time, PTH1-34 is released locally, stimulating fracture healing. A single application of fibrin-PTH1-34 to a fractured bone in animal studies has been shown to be effective in promoting bone healing without raising safety concerns14,16,17.

Materials and Methods

Study Design

This was a Phase-2, prospective, randomized, controlled, open-label (dose-blinded), dose-finding, parallel-group, international multicenter study to evaluate the efficacy and safety of a single application of an investigational product, KUR-113 (I-040202), given as an adjunct to the standard of care (SoC) in open TSF as compared with SoC alone. Patients were enrolled from 34 study sites in Europe (Table I). Regulatory and Independent Ethical Committee approval was obtained for each site before initiation. All of the subjects gave written informed consent to participate. This study was registered in the EU Clinical Trials Register (2006-005093-40) and ClinicalTrials.gov (NCT00533793).

TABLE I - List of Clinical Sites
1 Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
2 CHU de Dijon - Hôpital Général, DIJON CEDEX, France
3 Universitätsklinikum Leipzig, Leipzig, Germany
4 Berufsgenossenschaftliche Unfallklinik Ludwigshafen, Ludwigshafen, Germany
5 Klinik für Orthopädie und Unfallchirurgie, Ravensburg, Germany
6 Abteilung für Unfall- und Wiederherstellungschirurgie, Rostock, Germany
7 Trauma Hospital of Brno, Brno, Czech Republic
8 University Medical School of Pécs, Pécs, Hungary
9 Kenézy Hospital, Debrecen, Hungary
10 Jósa András County Hospital, Nyíregyháza, Debrecen, Hungary
11 Spitalul Clinic Judetean de Urgenta, Timişoara, Romania
12 Spitalul Clinic de Urgenta “Prof Dr Octavian Fodor,” Cluj Napoca, Romania
13 Spitalul de Urgenta “Bagdasar-Arseni,” Bucharest, Romania
14 Spitalul Clinic de Urgenta “Floreasca,” Bucharest, Romania
15 Institute for Orthopedic Surgery and Traumatology, Belgrade, Serbia
16 KBC Bežanijska kosa, Belgrade-Zemun, Serbia
17 Clinic for Orthopaedics and Traumatology, Kragujevac, Serbia
18 Hospital and Polyclinics Žilina, Žilina, Slovak Republic
19 Derer’s Faculty Hospital Bratislava, Bratislava, Slovak Republic
20 Faculty Hospital “F.D. Roosevelta,” Banská Bystrica, Slovak Republic
21 General Hospital “Novo Mesto,” Novo Mesto, Slovenia
22 General Hospital Izola, Izola, Slovenia
23 Turku University Central Hospital, Turku, Finland
24 Kuopio University Hospital, Kuopio, Finland
25 Oulu University Hospital, Oulu, Finland
26 Spitalul Clinic Judetean Oradea, Oradea, Romania
27 Spitalul Clinic Judetean de Urgenta Sibiu, Sibiu, Romania
28 Clinical Centre of Vojvodina, Novi Sad, Serbia
29 Institute for Orthopaedic Surgery “Banjica,” Belgrade, Serbia
30 Kaposi Mór Teaching Hospital, Kaposvár, Budapest, Hungary
31 Spitalul Universitar de Urgenţǎ Bucureşti, Bucharest, Romania
32 Károlyi Sandor Hospital, Budapest, Hungary
33 Szent János Hospital, Budapest, Hungary
34 Constanta County Clinic Emergency Hospital, Constanta, Romania

Study Population

Subjects who were able to provide informed consent in writing, were ≥18 years of age, and had an acute open TSF secondary to trauma were enrolled in the study and treated within 14 days after injury. All had been assessed by medical examination and had radiographs that indicated the need for open fracture reduction and internal fracture fixation with osteosynthesis plates or intramedullary nails.

Study Interventions

Soft-tissue management (for example, debridement, irrigation, and application of antibiotics), if medically warranted, was performed no later than 24 hours after the trauma, in accordance with local hospital practice.

Subjects were randomly assigned to the control group (SoC alone, consisting of open fracture reduction, internal fracture fixation by intramedullary nail fixation or osteosynthesis plates, and routine soft-tissue management) or to 1 of 3 KUR-113 groups receiving SoC plus a single application of 4 mL of KUR-113 containing TGplPTH1-34 in fibrin at concentrations of 0.133 mg/mL (KUR-113-low), 0.4 mg/mL (KUR-113-mid), or 1.0 mg/mL (KUR-113-high) into and around the fracture void after fixation or before definitive wound closure.

Subjects were hospitalized after surgery for as long as clinically indicated and were followed for up to 12 months postoperatively with monthly follow-up visits for the first 6 months and then at 9 and 12 months.

Secondary interventions were discouraged but permitted during the study. Patients requiring secondary intervention were included in the safety and efficacy analyses but their fracture was considered not healed.

The following co-medications were not permitted during the study: chronic use of COX-2 (cyclooxygenase-2) inhibitors (parenteral or oral for >5 consecutive days), chronic oral or parenteral use of steroids (same duration), other PTH treatment, application of bone morphogenetic proteins, and use of any form of surgical implant to promote bone healing at the fracture site.

Radiographic Assessments

Anteroposterior and lateral radiographs were obtained at every follow-up visit. All radiographs were reviewed for fracture union assessment by an independent radiology evaluation panel (IREP) for each follow-up visit. The IREP also performed additional radiographic safety assessments of ectopic bone formation, implant failure, and the presence of abnormal bone resorption at the fracture site at monthly intervals up to 6 months.

Safety Evaluations

Vital signs, adverse events, and 12-lead electrocardiographs were assessed in accordance with the protocol. Blood concentrations of TGplPTH1-34 and its cleavage products and serum calcium were determined once daily for the first 5 days after surgery and at each subsequent follow-up visit in parallel with hematological and other clinical chemistry tests.

Quality-of-Life Assessment

Quality-of-life assessments were performed utilizing the Short Form-36 (SF-36) health survey18 and the Musculoskeletal Function Assessment19. Pain was assessed with a visual analog scale (VAS)20.

Randomization

Prior to surgery, subjects were assigned to 1 of the 4 treatment groups (KUR-113-low plus SoC, KUR-113-mid plus SoC, KUR-113-high plus SoC, or SoC alone) by a central randomization procedure. The randomization was carried out in blocks of ≥4 in a ratio of 1:1:1:1 using the random number generator algorithm of Wichmann and Hill21 as modified by McLeod22.

Subject treatment was stratified into 2 steps: first by considering the surgical technique (plate fixation versus unreamed nailing versus reamed nailing) and second according to the Gustilo-Anderson classification (I, II, or IIIa versus IIIb)23.

Blinding

As the treatment of the control group did not involve any measures other than fracture fixation and wound management, the study was deemed to be open-label. However, the investigators were blinded to the concentrations of KUR-113. The IREP was blinded to the treatment allocation and concentration of KUR-113 as the product was radiolucent on radiographs and computed tomography (CT). The patients, treating surgeons, and outcome assessors were not blinded to whether the patient underwent treatment with KUR-113 or the SoC but were blinded to the dose of KUR-113.

Study Outcomes

The primary efficacy outcome was the proportion of subjects with fracture healing at 6 months after surgery as defined by the investigator using the clinical, surgical, and radiographic criteria listed in Table II. The fracture had to meet all 3 criteria to be considered healed.

TABLE II - Fracture-Healing Criteria for Clinical Investigators
Criteria Assessment
Clinical criteria Weight-bearing, reduced pain on manual stress (according to VAS score), and walking without aid
AND
surgical criteria
Lack of need for surgical interventions on the fractured site with the intention of promoting bone healing (secondary intervention)
AND
radiographic criteria
Cortical bridging (≥1 cortex bridged), disintegration and disappearance of fracture lines, and absence of signs of complications such as infection (e.g., osteolytic lesions, periosteal reaction, or sclerotic islands) or malunion

Secondary efficacy end points were the proportion of subjects with fracture healing at 3, 9, and 12 months after surgery and the proportion of subjects with, time to, and extent of tibial union as assessed radiographically by the IREP at each of the study follow-up visits. Radiographic evidence of tibial union was determined using the criteria summarized in Table III. Fracture union was determined through consensus of 2 readers. If no consensus was reached, a third reader made a decisive evaluation of the case.

TABLE III - Radiographic Criteria* for Tibial Union Used by IREP
Criteria Description
Cortical bridging and/or disappearance of fracture lines In 3 of 4 visible cortices
AND
No signs of infection
E.g., no osteolytic lesions, periosteal reaction, or sclerotic islands
AND
No malunion
No loss of reduction or healing of bones in a faulty position compared with immediate postop. image
*As judged on anteroposterior and lateral radiographs.

Sample Size

Sample size was determined assuming healing rates of 60% in the SoC group and 85% in the KUR-113 groups, which were based on 6-month efficacy data previously obtained from a review of a similar patient population reported in the literature24. If 46 subjects per treatment group had an evaluable result, the study had approximately 87% power to show superiority of 1 of the concentrations of KUR-113 over SoC assuming a type-I error of 10%. We assumed a 10% dropout rate and planned to include 200 patients.

Statistical Analysis

All statistical analyses conducted were prespecified in statistical analysis plans completed before the end of the 6 and 12-month follow-up visits. All safety analyses were based on the safety population (subjects treated), and efficacy analyses were based on the intention-to-treat (ITT) population (subjects randomized and treated).

The likelihood-ratio chi-square test was used at the 2-sided 10% significance level to demonstrate the superiority of 1 of the 3 concentrations of KUR-113 versus SoC with respect to the proportion of subjects with a healed fracture 6 months after surgery.

Ninety percent 2-sided confidence intervals (CIs) were calculated for the difference between the healing rates for each concentration of TGplPTH1-34 in fibrin and for SoC alone using a likelihood-ratio chi-square test.

Source of Funding

This clinical study was funded by Kuros Biosurgery AG (a subsidiary of Kuros Biosciences AG), which is the manufacturer of KUR-113. One of the authors was an employee of Kuros at the time that the study was conducted.

Results

Study Population

A total of 215 subjects were enrolled. The Consolidated Standards of Reporting Trials (CONSORT) flow diagram is shown in Figure 1.

fig1
Fig. 1:
CONSORT flow diagram showing the numbers of patients who were enrolled, withdrew from the study, and were included in the analysis.

A total of 52 subjects were treated with the KUR-113-low dose; 50, with the KUR-113-mid dose; 48, with the KUR-113-high dose, and 51, with SoC alone. Subject demographics were similar across treatment groups (Table IV). The average age of the subjects was <50 years, with a relatively small number of subjects who were >60 years old spread across the treatment groups. The treatment groups were similar with regard to the prevalences of fracture types characterized as high energy (range among groups, 56.0% to 61.5%) and concomitant ipsilateral fibular fractures (range among groups, 82.0% to 87.5%). The most common fracture classification25 in all groups was simple (OTA/AO 42A2), which was found in 103 patients (51.5%). A slightly lower percentage of subjects in the KUR-113-mid group (7 of 50; 14.0%) had a fracture classified as complex (OTA/AO 42C2) compared with the KUR-113-low group (12 of 52; 23.1%), the KUR-113-high group (11 of 48; 22.9%), and the control group (9 of 50; 18.0%).

TABLE IV - Demographic and Baseline Characteristics
Characteristic KUR-113 SoC
0.133 mg/mL 0.4 mg/mL 1.0 mg/mL
Safety analysis population
 No. of subjects 52 50 48 51
 Age*(yr) 42.4 ± 15.5 41.9 ± 15.1 47.3 ± 16.7 45.6 ± 15.1
 Male subjects (no. [%]) 43 (82.7%) 42 (84.0%) 40 (83.3%) 42 (82.4%)
 Weight*(kg) 78.42 ± 11.99 79.56 ± 15.92 76.01 ± 12.64 77.25 ± 12.75
 Height*(cm) 176.25 ± 8.61 174.64 ± 8.54 174.15 ± 8.37 173.94 ± 9.55
 Body mass index*(kg/m 2 ) 25.19 ± 3.04 25.95 ± 4.14 25.00 ± 3.27 25.45 ± 3.04
Intention-to-treat population
 No. of subjects 52 50 48 50
 Site of TSF (no. [%])
  Left 24 (46.2%) 14 (28.0%) 21 (43.8%) 22 (44.0%)
  Right 28 (53.8%) 36 (72.0%) 27 (56.3%) 28 (56.0)
 Trauma causing TSF (no. [%])
  High energy 32 (61.5%) 28 (56.0%) 27 (56.3%) 30 (60.0%)
  Low energy 20 (38.5%) 22 (44.0%) 21 (43.8%) 20 (40.0%)
 Fracture classification (no. [%])
  Simple (OTA/AO 42A2) 21 (40.4%) 27 (54.0%) 28 (58.3%) 27 (54.0%)
  Wedge (OTA/AO 42B2) 19 (36.5%) 16 (32.0%) 9 (18.8%) 14 (28.0%)
  Complex (OTA/AO 42C2 12 (23.1%) 7 (14.0%) 11 (22.9%) 9 (18.0%)
 Concomitant ipsilateral fibular fracture (no. [%]) 43 (82.7%) 41 (82.0%) 42 (87.5%) 41 (82.0%)
 Gustilo-Anderson classification (no. [%])
  Type I 25 (48.1%) 29 (58.0%) 31 (64.6%) 29 (58.0%)
  Type II 18 (34.6%) 17 (34.0%) 12 (25.0%) 16 (32.0%)
  Type IIIa 7 (13.5%) 3 (6.0%) 5 (10.4%) 3 (6.0%)
  Type IIIb 2 (3.8%) 1 (2.0%) 0 2 (4.0%)
*Data are presented as mean ± standard deviation.

In the majority of subjects, the fracture was classified as Gustilo-Anderson Type I (114; 57%) or Type II (63; 31.5%), with similar numbers of subjects across the treatment groups. A very small number of fractures (18 of 200; 9%) were classed as Type IIIa, with a slightly higher prevalence in the KUR-113-low (7 of 52; 13.5%) and KUR-113-high (5 of 48; 10.4%) groups than in the KUR-113-mid and SoC (3 of 50; 6%) groups. The study included only 5 subjects with a Type-IIIb fracture, with 2 in the KUR-113-low, 1 in the KUR-113-mid, and 2 in the SoC group.

Efficacy Assessment

The proportion of subjects with fracture healing at 6 months (primary efficacy end point) was greater in the KUR-113-mid group (37 of 46; 80.4%) than in the KUR-113-low group (34 of 45; 75.6%), KUR-113-high group (27 of 39; 69.2%), or SoC group (31 of 48; 64.6%) (Table V). The difference in the proportion of subjects with fracture healing between the KUR-113-mid and SoC groups was significant based on the likelihood-ratio chi-square test with a 2-sided 10% significance level (p = 0.084). The same result was achieved in the per-protocol analysis.

TABLE V - Investigator’s Healing Assessment at 6 Months Postoperatively (Primary Efficacy End Point in Intention-to-Treat Analysis Set)*
KUR-113 SoC
0.133 mg/mL 0.4 mg/mL 1.0 mg/mL
n/N 34/45 37/46 27/39 31/48
% 75.6% 80.4% 69.2% 64.6%
90% CI for proportion 64.1%-85.0% 69.7%-88.8% 56.4%-80.3% 52.8%-75.2%
2-sided p value vs. SoC 0.247 0.084 NA§
*If secondary interventions at the fracture site were needed at any time with the intention to promoting bone healing, the bone was regarded as “not healed.”
CI based on the likelihood-ratio chi-square test.
Only calculated if 0.133 mg/mL versus SoC was not significant at 10% significance level; otherwise NA (not applicable).
§Only calculated if 0.133 mg/mL versus SoC and 0.4 mg/mL versus SoC were not significant at 10% significance level; otherwise NA.

At 9 and 12 months, more subjects in each of the KUR-113 groups had healing than in the SoC group (Table VI).

TABLE VI - Summary of Secondary Efficacy End Points
KUR-113 SoC
0.133 mg/mL 0.4 mg/mL 1.0 mg/mL
Fracture-healing—investigator assessment*(n/N [%])
 9 months 37/41 (90.2%) 36/43 (83.7%) 34/40 (85.0%) 32/44 (72.7%)
 12 months 39/42 (92.9%) 38/43 (88.4%) 37/40 (92.5%) 34/46 (73.9%)
Secondary intervention*(n/N [%])
 6 months 2/45 (4.4%) 2/46 (4.3%) 3/39 (7.7%) 6/48 (12.5%)
 12 months 3/44 (6.8%) 4/46 (8.7%) 3/40 (7.5%) 9/47 (19.1%)
Radiographic evidence of tibial union—IREP assessment (n/N [%])
 6 months 25/44 (56.8%) 22/45 (48.9%) 23/39 (59.0%) 21/47 (44.7%)
 9 months 31/40 (77.5%) 33/41 (80.5%) 32/40 (80.0%) 32/42 (76.2%)
 12 months 39/42 (92.9%) 38/42 (90.5%) 37/39 (94.9%) 40/44 (90.9%)
Time to fracture healing(mo) 7.07 ± 2.99 7.13 ± 2.74 7.38 ± 2.70 7.72 ± 2.58
*Fracture-healing and secondary intervention were assessed by the clinical investigators.
If secondary interventions at the fracture site were needed at any time with the intention to promoting bone healing, the bone was regarded as “not healed.”
Data are presented as mean ± standard deviation. Only subjects whose fracture was “healed” within 12 months were included in this analysis. If secondary interventions at the fracture site were needed at any time with the intention to promoting bone healing, the bone was regarded as “not healed.”

Within 6 months after surgery, the number of subjects who had secondary surgical interventions to promote fracture healing was lower in each of the KUR-113 groups compared with the SoC group (6 of 48: 12.5%), with the lowest proportion in the KUR-113-mid group (2 of 46; 4.3%) (Table VI). All of the fractures with secondary surgical intervention were considered not healed for the statistical analysis.

By 12 months, the proportion of secondary interventions in the SoC group (19.1%) was higher than that in all KUR-113 groups (range, 6.8% to 8.7%) (Table VI).

There was a lack of concordance between the IREP readers regarding radiographic evidence of tibial union at the 6-month time point, with approximately 50% of the radiographs requiring adjudication. Concordance between readers improved at the 9 and 12-month time points. At 12 months, tibial union was observed radiographically in the majority of patients in the KUR-113 groups (range among groups, 90.5% to 94.9%) and the SoC group (90.9%).

The mean time to fracture healing based on radiographs was shorter in all 3 KUR-113 groups (range among groups, 7.07 to 7.38 months) than in the SoC group (7.72 months) within 12 months after the surgery, although the differences among treatment groups did not achieve significance (p = 0.603). The time to tibial union based on radiographs is presented in Figure 2.

fig2
Fig. 2:
Time to radiographic evidence of tibial union as assessed by the independent radiographic expert panel in the intention-to-treat (ITT) population. SoC = standard of care.

Safety Evaluation

Two subjects (1 in the KUR-113-low group and 1 in the SoC group) died during the study. The causes of death were renal failure and sudden death, respectively. These were considered to be unrelated to the study medication and study procedure by the investigators.

The most frequently reported adverse event was procedural pain, reported by 102 (68.0%) subjects who received KUR-113 and 39 (76.5%) subjects who received SoC alone. Over the same period, 13 subjects (8.7%) who received KUR-113 reported a total of 17 serious adverse events and 9 (17.6%) who received SoC alone reported a total of 10; most of these events were moderate or severe. Two subjects who received the low concentration of KUR-113 experienced infections (Klebsiella infection and wound infection), one of which was considered related to the procedure to apply the KUR-113 (not the actual product itself) and the other, to the surgery at the fracture site. Two subjects in the control group experienced wound dehiscence and fracture nonunion, with both considered related to the surgery at the fracture site.

The profile of adverse events and serious adverse events in the KUR-113 groups was similar to that in the control group and was typical for the study population.

Additional safety assessments performed by the IREP revealed no evidence of ectopic bone formation or abnormal bone resorption at the fracture site in any of the treatment groups.

The PTH1-34 plasma concentrations in the SoC group were low or below the limit of detection, indicating that standard treatment of TSFs does not have an effect on plasma PTH1-34 levels. Systemic exposure to PTH1-34 or TGplPTH1-34 was observed in all KUR-113-treated patients, with a tmax of around 1 to 2 hours and the levels returning to baseline at around 120 hours after the KUR-113 application.

Isolated increases in serum calcium above the reference range were observed in all of the treatment groups including the SoC group. There was no clinically relevant increase in serum calcium in any of the KUR-113 treatment groups. In addition, there was no relationship between serum TGplPTH1-34 or its cleavage products and serum calcium.

There were no clinically relevant abnormalities in serum calcium or other safety parameters.

Quality of Life

There were no notable differences between groups with respect to SF-36 parameters (Table VII).

TABLE VII - Quality-of-Life Outcomes
KUR-113* SoC*
0.133 mg/mL 0.4 mg/mL 1.0 mg/mL
SF-36 health survey
 Physical functioning
  Postop. hospitalization 47, 25.29 ± 13.04 (19.15) 49, 22.47 ± 9.42 (19.15) 43, 23.81 ± 10.88 (21.26) 49, 27.23 ± 14.18 (19.15)
  6 months 44, 45.40 ± 11.12 (49.46) 45, 44.87 ± 12.69 (50.72) 38, 41.53 ± 12.87 (45.46) 48, 41.78 ± 11.71 (41.25)
  12 months 40, 50.92 ± 7.36 (53.88) 42, 50.08 ± 12.64 (57.03) 37, 48.44 ± 10.34 (52.82) 44, 47.23 ± 11.63 (53.88)
 Role-physical
  Postop. hospitalization 45, 29.21 ± 13.60 (22.57) 48, 27.26 ± 12.00 (25.02) 42, 27.64 ± 12.40 (21.34) 48, 32.33 ± 13.09 (31.14)
  6 months 45, 43.57 ± 11.24 (47.06) 45, 42.76 ± 12.74 (44.61) 39, 41.91 ± 11.22 (42.16) 48, 41.55 ± 11.15 (42.16)
  12 months 40, 47.79 ± 9.75 (47.06) 42, 48.81 ± 11.88 (56.85) 37, 46.40 ± 10.67 (49.51) 44, 47.34 ± 10.41 (49.51)
 Bodily pain
  Postop. hospitalization 47, 35.97 ± 11.57 (37.18) 48, 36.16 ± 11.21 (32.96) 43, 34.71 ± 10.80 (32.96) 48, 38.39 ± 13.02 (37.18)
  6 months 45, 49.51 ± 9.57 (51.13) 45, 50.43 ± 11.65 (51.13) 39, 50.05 ± 11.13 (51.13) 47, 50.29 ± 9.57 (51.13)
  12 months 40, 53.32 ± 9.62 (55.36) 42, 55.03 ± 10.40 (62.12) 37, 54.04 ± 9.83 (62.12) 44, 52.29 ± 9.78 (51.13)
 General health
  Postop. hospitalization 46, 45.75 ± 8.69 (44.83) 48, 45.69 ± 9.73 (46.50) 42, 46.27 ± 9.63 (45.78) 46, 46.48 ± 9.62 (46.98)
  6 months 45, 49.90 ± 9.51 (49.60) 45, 51.11 ± 9.75 (52.93) 39, 50.75 ± 10.07 (48.17) 47, 49.88 ± 9.37 (50.55)
  12 months 39, 51.23 ± 10.08 (52.93) 40, 53.06 ± 9.65 (54.36) 37, 50.45 ± 11.62 (52.93) 44, 50.61 ± 10.25 (51.74)
 Vitality
  Postop. hospitalization 47, 49.39 ± 11.31 (45.85) 48, 47.34 ± 8.99 (45.85) 42, 46.19 ± 12.05 (45.85) 49, 49.54 ± 11.05 (48.97)
  6 months 45, 56.11 ± 10.00 (58.33) 45, 54.84 ± 10.62 (58.33) 37, 56.39 ± 10.52 (58.33) 47, 56.08 ± 9.11 (58.33)
  12 months 40, 58.39 ± 9.67 (58.33) 42, 60.19 ± 10.37 (61.46) 37, 57.74 ± 10.00 (58.33) 44, 57.48 ± 10.63 (58.33)
 Social functioning
  Postop. hospitalization 47, 34.69 ± 13.95 (35.03) 48, 31.17 ± 12.53 (29.58) 43, 31.99 ± 15.21 (29.58) 49, 38.48 ± 12.87 (40.49)
  6 months 45, 47.40 ± 10.03 (51.40) 45, 46.91 ± 10.35 (51.40) 39, 46.78 ± 11.23 (51.40) 48, 45.15 ± 8.93 (45.94)
  12 months 40, 50.03 ± 9.05 (56.85) 42, 48.28 ± 12.64 (56.85) 37, 49.92 ± 9.06 (56.85) 44, 49.91 ± 8.01 (51.40)
 Role-emotional
  Postop. hospitalization 45, 34.80 ± 17.16 (32.56) 48, 33.45 ± 17.70 (38.39) 42, 34.31 ± 16.59 (32.56) 47, 33.47 ± 17.12 (32.56)
  6 months 44, 44.39 ± 13.20 (46.16) 45, 41.80 ± 14.53 (44.22) 38, 44.73 ± 13.01 (46.16) 48, 42.39 ± 13.23 (44.22)
  12 months 39, 45.11 ± 14.45 (55.88) 41, 46.21 ± 13.04 (55.88) 40, 41.59 ± 12.74 (42.27) 41, 42.61 ± 13.24 (44.22)
 Mental health
  Postop. hospitalization 47, 44.98 ± 11.60 (45.31) 48, 41.97 ± 11.28 (44.38) 41, 39.91 ± 12.97 (35.93) 48, 43.73 ± 10.33 (44.38)
  6 months 45, 51.51 ± 10.04 (55.64) 45, 49.15 ± 11.40 (50.01) 37, 51.99 ± 10.04 (52.82) 47, 48.57 ± 9.84 (50.01)
  12 months 40, 51.29 ± 9.37 (52.82) 42, 52.74 ± 11.10 (55.64) 37, 49.63 ± 10.97 (52.82) 44, 50.25 ± 11.53 (52.82)
Reported health transition
 Postop. hospitalization 48, 4.13 ± 0.82 (4.00) 49, 3.96 ± 0.93 (4.00) 43, 3.86 ± 0.99 (4.00) 49, 3.61 ± 1.06 (4.00)
 6 months 44, 3.30 ± 0.76 (3.00) 45, 3.18 ± 0.98 (3.00) 39, 3.26 ± 0.94 (3.00) 47, 3.23 ± 0.94 (3.00)
 12 months 40, 2.35 ± 1.00 (2.50) 41, 2.49 ± 1.16 (3.00) 36, 2.28 ± 1.11 (2.00) 43, 2.53 ± 1.05 (3.00)
Musculoskeletal Function Assessment
 Postop. hospitalization 48, 49.4 ± 13.7 (49.5) 49, 52.0 ± 14.0 (53.0) 44, 47.2 ± 16.5 (50.5) 49, 46.1 ± 17.1 (46.0)
 6 months 45, 19.1 ± 16.8 (16.0) 45, 21.0 ± 20.5 (13.0) 39, 22.9 ± 19.0 (17.0) 48, 22.0 ± 16.2 (18.0)
 12 months 41, 14.9 ± 13.9 (13.0) 42, 15.2 ± 18.3 (7.5) 39, 18.5 ± 17.6 (13.0) 45, 17.9 ± 17.1 (11.0)
Visual analog scale
 Postop. hospitalization 48, 47.4 ± 32.6 (45.0) 49, 56.3 ± 40.4 (56.0) 44, 52.3 ± 38.1 (44.0) 47, 46.3 ± 36.1 (51.0)
 6 months 45, 11.7 ± 18.8 (2.0) 44, 11.3 ± 20.4 (3.5) 38, 10.5 ± 16.9 (3.5) 48, 9.3 ± 15.6 (3.5)
 12 months 39, 8.8 ± 16.3 (2.0) 42, 10.7 ± 18.4 (2.0) 37, 8.1 ± 16.5 (2.0) 43, 10.6 ± 20.5 (2.0)
Weeks until return to work 21, 25.99 ± 12.81 (22.29) 25, 22.14 ± 8.94 (23.00) 14, 28.56 ± 13.08 (27.79) 24, 24.25 ± 11.11 (24.00)
*Data are presented as number of patients, mean ± standard deviation (median).
Only subjects who returned to work at any time within 12 months after surgery are included in this analysis.

Discussion

In this study, the use of KUR-113 resulted in a statistically significant improvement in fracture healing at 6 months (the primary end point), as determined by investigator assessment using radiographic and clinical criteria, as compared with SoC. Over the 12-month postoperative period, the KUR-113 groups had fewer secondary interventions to promote fracture healing than the patients treated with SoC alone. There were no significant safety concerns following the use of KUR-113.

The primary efficacy end point in this study was designed to reflect clinical practice, in which the surgeon determines overall fracture healing based on clinical and radiographic assessments. Investigator assessment of healing in this study could be criticized as being biased, given that the same surgeon performed the surgery and the assessments. To address this, future trials should include a blinded clinical assessor.

A 6-month time point was chosen to evaluate if KUR-113 as adjunctive therapy to SoC reduces the time to healing compared with SoC alone. Using a 12-month end point, at which radiographic evidence of union would be present in nearly all subjects, would have reduced the opportunity to determine whether addition of KUR-113 can decrease the time to fracture healing. The healing rate of the SoC group is comparable with the rates observed in other open-TSF studies24,26. At 6 months postoperatively, a significant improvement of healing was observed in the KUR-113-mid group (80.4%) compared with the SoC group (64.6%). This difference in healing rates is considered clinically meaningful.

As expected, the tibial union rate as seen on radiographs at 12 months in the SoC group was comparable with that in the KUR-113 groups. However, it was achieved with the need for many more secondary interventions in the SoC group, indicating increased morbidity as well as cost for care in this group.

Use of radiographs to determine union at 6 months proved challenging as documented by the high level of disagreement between the 2 IREP readers. Using a different radiology scoring system such as the modified Radiographic Union Scale for Tibial Fractures (mRUST)27 combined with clinical scores should be a consideration for future studies. Nevertheless, union rates determined with radiographs alone lagged significantly behind clinical healing rates.

Stratification into Gustilo-Anderson Types I, II, and IIIa versus Type IIIb was considered by the investigators to be the most practical way of conducting the study. Type-I and Type-II injuries were the most common injuries, found in 177 (89%) of the 200 patients and spread evenly across the treatment groups. There were too few patients with Type IIIa or IIIb to perform a meaningful analysis.

The adverse events observed in this study along with the laboratory data reflected a typical trauma population. There were no specific safety concerns for the use of KUR-113 in this patient population.

Conclusions

Administration of KUR-113 as adjunctive therapy with SoC in patients with an open TSF may improve fracture healing. This topic warrants further research.

Data Sharing

A data-sharing statement is provided with the online version of the article (https://links.lww.com/JBJS/G858).

Note: Dr. Yue Wu of Niche Science and Technology, Ltd. provided medical writing support during the development of this manuscript; these services were funded by Kuros Biosurgery AG, a subsidiary of Kuros Biosciences AG.

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