Clinical trial NCT04574336: Scandinavian Humeral Diaphyseal Fracture Trial
Official title: Scandinavian Humeral diAphyseal Fracture Trial - A Pragmatic Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Fracture Humerus of Shaft
Keywords: Humeral shaft fracture
Diaphysis
Fracture fixation
Fracture Healing
Aged
Randomized Controlled Trial
Comparative study
Lead sponsor: Kolding Sygehus
Sponsor class: OTHER
Collaborators: name: Copenhagen University Hospital, Hvidovre
name: Zealand University Hospital
name: Oslo University Hospital
name: Helse Stavanger HF
name: Sahlgrenska University Hospital
name: Uppsala University Hospital
name: Odense University Hospital
name: Hospital of Southern Jutland
name: Slagelse Hospital
name: Aalborg University Hospital
name: University Hospital, Umeå
name: Nordsjaellands Hospital
name: Holbaek Sygehus
name: Aarhus University Hospital
name: Copenhagen University Hospital, Herlev-Gentofte
name: University Hospital Bispebjerg and Frederiksberg
name: Viborg Regional Hospital
name: Karolinska University Hospital
name: Danderyd Hospital
name: Tampere University Hospital
name: Helsinki University Central Hospital
First posted: 2020-10-05
Enrollment: 287
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This pragmatic multicenter randomized controlled trial (RCT) includes adult participants with an acute humeral shaft fracture to compare surgical fixation of humeral shaft fracture to non-surgical treatment with early identification and treatment of delayed union by a patient-reported outcome after 52 weeks. The trial population of 287 participants The trial population is divided in two age-groups due to the changes in DASH score by age. The definition of delayed union differs in the young and elderly population to consider dissimilarity in bone healing rates and the timepoint for crossover is therefor different between the groups. Participants will be randomized 1:1 between non-surgical treatment and surgical treatment. The primary outcome is the Disability of Arm, Shoulder and Hand (DASH) score at 52 weeks, and is assessor blinded. The secondary outcomes are DASH score earlier than 52 weeks, EQ-5D-5L, pain assessed by visual analogue score, Constant-Murley score including elbow range of motion and anchor-questions collected at all timepoints throughout the trial. All complications will be reported including; infection, nerve or vascular injury, surgical revisions (implant malpositioning, hardware failure, aseptic loosening and peri-implant fracture), major adverse cardiovascular events, other major adverse events and mortality. SHAFT will provide information on the effectiveness of two standard treatments for humeral shaft fractures, while taking the dilemmas within the population into account.

Detailed description: We will conduct a pragmatic multicenter, randomized, controlled, outcome assessor-blinded, clinical superiority trial. The objective is to compare surgical fixation of humeral shaft fracture to non-surgical treatment with early identification and treatment of delayed union by a patient-reported outcome after 52 weeks. .

Null-hypothesis:

The DASH score at 52 weeks after surgical treatment is not superior to non-surgical treatment with the option of early crossover surgery in patients with humeral shaft fractures

The trial population is divided in two age-groups due to the changes in DASH score by age. The definition of delayed union differs in the young and elderly population to consider dissimilarity in bone healing rates:

1. SHAFT-Y for the young with an age cut-off of 18 to 64 years. The early identification and treatment of delayed union is set to 6 to 12 weeks
2. SHAFT-E for the elder with an age cut-off +65 years. The early identification and treatment of delayed union is set to 12 to 26 weeks

Sites from Denmark, Sweden and Norway have been recruited and spans from academic level I to level III trauma centers

287 patients (n=163 for SHAFT-Y, n=124 for SHAFT-E) with a humeral shaft fracture will be equally randomized to surgical treatment or non-surgical treatment in each group.

Patients admitted to the emergency department in one of the trial sites and fulfil the eligibility criteria, will be invited to enroll into the trial. They will be given time to consider and be scheduled for a consultation with a trial worker within 10 days. If written consent is obtained at the consultation, randomization will occur immediately after.

Treatment will be performed within 14 days after injury

* Surgical treatment. The specific treatment is decided by the treating surgeon/department
* Non-surgical treatment with the option of early secondary surgery from 6-12 weeks for SHAFT-Y and 12-26 weeks for SHAFT-E

Patients can be offered to undergo early crossover fixation with a surgical procedure of the surgeon's choice, if one of these criteria are met:

* Unacceptable pain experienced by the patient
* Severe pain with gross instability of the fracture site assessed by:
* Unable to en bloc elevate the arm due to clear fracture instability
* Gentle manipulation of the fracture site. Gentle manipulation should respect the risk of callus breakage
* Severe problems tolerating the brace, e.g. discomfort, skin irritation, wounds, hygiene problems.

The patients that undergo early crossover surgery will have the reason for crossover thoroughly noted. We anticipate the surgical procedures will be similar to the ones previously mentioned with the possible addition of bone graft.

A computerized database software, Research Electronic Data Capture (REDCap) will be used to generate an irreversible random allocation sequence and perform block randomization with selected block sized of 2 and 4, which will be stratified on site and age (18-64 and +65). Patients will be assigned to the trial with an allocation of 1:1 to either surgical treatment or non-surgical treatment. The trial worker acquires the allocated treatment from the central coordinator with randomization rights to REDCap. The trial worker then initiates the treatment, either by scheduling the surgery date or applying the chosen non-surgical method.

The two groups (SHAFT-Y and SHAFT-E) require individual sample size calculations. Two standard deviations (SDs) were obtained from the data of the FISH trial(13) and were separated in age groups of 18-64 years and 65 years and above. By the distribution-based approach, one half a SD corresponds to the minimal important change (MIC). The calculations are powered to detect a MIC of 7 points in the young and 10 points in the elderly group in DASH, respectively. Two independent means sample size calculation were performed. For SHAFT-Y the following data were included: Mean difference= 7.0, SD= 14.91, α= 0.05 and power= 0.8. For SHAFT-E the following data were included: Mean difference= 10.0, SD= 18.59, α= 0.05 and power= 0.8. Based on the preceding assumptions and including an attrition of 15%, the total sample size is estimated to 163 patients for SHAFT-Y and 124 patients for SHAFT-E.

Primary analysis Descriptive statistics will be used to report demographic data. Demographic data and outcome measures will be tested visually and statistically (i.e. Shapiro Wilks test). Numeric variables will be summarized by means, standard deviations and 95% confidence intervals (95% CI). Median and interquartile ranges will be used when normal distribution is not met. Categorical variables will be summarized by frequency and proportion. For group comparison with numerical data, a student's t-test will be used if data is normally distributed, otherwise a non-parametric test will be used. For categorical data a Chi-square test will be used for group comparison. An intention-to-treat (ITT) analysis of the primary outcome will be conducted by univariable linear regression, including all patients that do not meet the withdrawal criteria and will be conducted to minimize bias within results. A sensitivity analysis will test the effects of non-adherence to protocol by conducting a per-protocol analysis and includes only patients who comply with the protocol. For missing data points in an outcome measure, a multiple imputation analysis using predictive covariates (age, sex, smoking, alcohol, UCLA activity, ASA grade)(50-52) will be conducted to deal with nonresponse bias. For comparison we will carry out a sensitivity analysis excluding all the missing values.

Data will be considered statistically significant if p-values \< 0.0471.

Secondary analysis In order to validate data a linear regression analysis will be computed with DASH score as the dependent variable and treatment modality as the independent variable. Additional regression analysis will be carried out between the early crossover group and the primary treatments. A multivariate regression analysis will be conducted to adjust for potential confounders. Variables adjusted for are: age, sex, smoking, alcohol, UCLA activity, ASA grade. Furthermore, we will analyze the longitudinal observations by applying a linear mixed effects regression model, including modality and time as well as a modality-time interaction as fixed effects and a random intercept for each patient. Data will be summarized as coefficients with 95% CIs and variance will be summarized as r-squares, adjusted r-squares, predicted r-squares, standard errors. Coefficients will be considered statistically significant if p-values \< 0.05.

Outcome timepoints Subjective and objective outcome measures will be obtained at following time points: pre-injury, baseline, 6 weeks, 12 weeks, 26 weeks, 52 weeks, 2 years and 5 years.

Eligibility criteria: 1. Fracture types 12A-C (OTA/AO classification)

   a. Includes minimal displaced extra-articular fracture extensions to the proximal humerus (less than a 1 cm or 45 degree angulation)
2. Treatment within 14 days from trauma
3. Age 18-64 years for SHAFT-Y and ≥65 years for SHAFT-E
4. Patients must understand the information given and be able to read and speak Danish, Swedish or Norwegian to complete the study paperwork

All fracture extensions involving the distal humerus and displaced fracture extensions involving the proximal humerus will not be included. Isolated fractures to the proximal or the distal end of the humerus are not eligible for screening. The proximal and distal end segments of the humerus are defined by squares of which the sides are the widest length of the epiphysis/metaphysis in question on the anterior-posterior view.

Exclusion criteria

1. Inability to give informed consent
2. Undisplaced shaft fracture (less than a cortex-wide displacement in all radiographic plane)
3. Vascular injury in ipsilateral arm
4. Polytrauma (defined as a trauma with one or more concurrent fractures to the upper extremities or other trauma absolute indications for surgical intervention)
5. Pathological fracture
6. Open fracture
7. BMI \> 40
8. Health conditions preventing either treatment

Primary outcomes:
measure: Disabilities of the Arm, Shoulder and Hand (DASH) score
timeFrame: 52 weeks
Secondary outcomes:
measure: EuroQol-5 Domain (EQ-5D-5L)
timeFrame: Pre-Injury, 6 weeks, 12 weeks, 26 weeks, 52 weeks
measure: Rate of complications
timeFrame: Up to 52 weeks
measure: Visual Analogue Scale (VAS)
timeFrame: Baseline, 6 weeks, 12 weeks, 26 weeks, 52 weeks
measure: Anchor question
timeFrame: 6 weeks, 12 weeks, 26 weeks, 52 weeks
measure: Constant-Murley score
timeFrame: 6 weeks, 12 weeks, 26 weeks, 52 weeks
measure: Elbow range of motion
timeFrame: 6 weeks, 12 weeks, 26 weeks, 52 weeks
measure: Disabilities of the Arm, Shoulder and Hand (DASH) score
timeFrame: Pre-injury, 6 weeks, 12 weeks, 26 weeks
Other outcomes:
measure: Disabilities of the Arm, Shoulder and Hand (DASH) score
timeFrame: 2 years, 5 years
measure: EuroQol-5 Domain (EQ-5D-5L)
timeFrame: 2 years, 5 years
measure: Radiological measurements
timeFrame: Baseline, 6 weeks, 12 weeks, 26 weeks, 52 weeks
measure: Fracture instability
timeFrame: 6 weeks, 12 weeks
measure: Nonunion
timeFrame: Up to 52 weeks
measure: Return to work
timeFrame: Up to 52 weeks
Locations:
city: Aabenraa
country: Denmark
facility: Aabenraa Hospital
city: Aarhus
country: Denmark
facility: Aarhus Hospital
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Copenhagen
country: Denmark
facility: Hvidovre Hospital
city: Esbjerg
country: Denmark
facility: Esbjerg Hospital
city: Farsø
country: Denmark
facility: Aalborg-Farsø Hospital
city: Gentofte
country: Denmark
facility: Herlev-Gentofte Hospital
city: Hillerød
country: Denmark
facility: New North Zealand Hospital
city: Holbæk
country: Denmark
facility: Holbæk Hospital
city: Kolding
country: Denmark
facility: Kolding Hospital
city: Køge
country: Denmark
facility: Zealand University
city: Odense
country: Denmark
facility: Odense Hospital
city: Slagelse
country: Denmark
facility: Slagelse Hospital
city: Viborg
country: Denmark
facility: Viborg Regional Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital (Ullevål)
city: Stavanger
country: Norway
facility: Stanvanger University Hospital
city: Stockholm
country: Sweden
facility: Danderyd University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Umeå
country: Sweden
facility: Umeå University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Hospital Lillebaelt
name: Bjarke Viberg, MD, PhD
role: STUDY_CHAIR
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