Objectives
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 is divided in two groups by age due to the bimodal age distribution with more elderly than young and the treatment courses are different in terms of early crossover:
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
Trial design
A pragmatic multicenter, randomized, controlled, outcome assessor-blinded, clinical superiority trials. We have assessed the pragmatic design using PRECIS-2(26) which yielded 40 points out of possible 45 points (Fig. 1). This study furthermore collaborates with the NORCRIN Work Package 13 network.
Study setting
Sites from Denmark, Sweden and Norway have been recruited and spans from academic level I to level III trauma centers. The following is the current list of recruiting hospitals: Kolding Hospital; Hvidovre University Hospital of Copenhagen; Zealand University Hospital; Slagelse Hospital; Holbæk Hospital; New North Zealand University Hospital of Copenhagen, Odense University Hospital; Hospital of Southern Denmark; Aalborg University Hospital; Aarhus University Hospital; Herlev-Gentofte University Hospital of Copenhagen, Oslo University Hospital; Stavanger University Hospital; Østfold Hospital Trust; Sahlgrenska University Hospital; Uppsala University Hospital; Umeå University Hospital; Stockholm South General Hospital
Material
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. The overall trial flow and timeline of data collection is outlined in Fig. 2 + 3.
Inclusion criteria
1. Fracture types 12A-C (OTA/AO classification)
a. Includes extra-articular fractures with extensions to the distal- and/or proximal ends of the humerus
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
Exclusion criteria
1. Inability to give informed consent
2. Undisplaced shaft fracture (less than a cortex-wide displacement in all radiographic plane)
3. Displaced fractures of the proximal and distal humerus (more than a 1 cm or 45 degree angulation(27))
4. Vascular injury in ipsilateral arm
5. Polytrauma (defined as a trauma with one or more absolute indications for surgical intervention)
6. Pathological fracture
7. Open fracture
8. Floating elbow fractures
9. BMI > 40
10. Health conditions preventing either treatment
Primary radial nervepalsy (RNP) is not an exclusion criterion as there has not been shown benefits in recovery time with early exploration(28).
Recruitment
Patients admitted to the emergency department (ED) in any of the trial sites will be clinically examined and plain radiographs will be obtained to confirm the diagnosis. If the patient fulfills the eligibility criteria’s, they will be informed of the trial by staff and receive written information with patient participation information and “Researchers rights in a health science research project”. They will be given time to consider and will be scheduled for an appointment with research staff within 10 days. If written consent is obtained at the consultation, randomization will occur immediately after. If patients do not wish to participate in the RCT, they will be asked to consider enrollment in an observational cohort.
The informed consent gives the investigators permission to obtain information from the patients’ health records including; age, sex, height, weight, arm dominance, American Society of Anesthesiologists grade (ASA classification), UCLA activity score(29), list of current diagnosis and medication, mechanism of injury, radiographic images, previous surgery to the arm, tobacco (cigarettes, smokeless tobacco) and alcohol habits, employment and educational status. Patients will be provided with transport allowance to cover the costs for consultations at 26 weeks and 52 weeks. They further accept telephone calls if they miss follow-up visits to promote participant retention and complete follow-up.
Interim analyses
We will carry out two interim analyses after trial completion of 25% and 50% of the planned number of included patients, separately for the two age groups. We will use the O’Brian-Fleming rule(30) for determining appropriate significance levels for each analysis, which results in a significance level of 0.0006 for the first interim analysis, 0.0151 for the second interim analysis and 0.0471 for the final analysis. Interim analyses will be carried out for both the primary endpoint (DASH) and for serious complications (iatrogenic nerve injury, deep infection, major adverse cardiac events (MACE) and death) and will be conducted by one-sided tests to determine if the improvement in DASH is significantly above 25 points, respectively if the complication rate is at least 20% higher.
A Data Monitoring Committee (DMC) has been organized to monitor and evaluate the data from the interim analyses. The DMC consist of seven members in total; three members of the steering committee and four independent members including the Patient Representative (PR), an orthopedic researcher, an orthopedic surgeon and a nurse.
In the event of one group having zero complications, the significance level cannot be computed by a Chi-square test, and the DMC will have to assess the data due to a statistical variation.
In the event of a patient sustaining several complications, the most severe complication will follow the patient. The complications are ranked in a hierarchy model describing the severity and is ranked from most severe to least severe: Death, MACE, deep infection with debridement, iatrogenic nerve injury.
The interim analyses will be conducted by a biostatistician, blinded to the treatment allocation. Data will then be presented to the DMC, in means and proportions and be accompanied with confidence intervals. The DMC will have access to the data unblinded, and if at least one of those two conditions are fulfilled or a statistical variation has occurred at an interim analysis the DMC will be asked to investigate the results in detail and present their recommendation to continue or stop the trial. In the event of disagreement, the steering committee will be involved in discussing the stopping of the trial.
Furthermore, the steering committee will be monitoring recruitment and drop-out. Any modification in design and recruitment will be registered in clinicaltrials.gov.
If it is observed that inclusion of patients in the two age groups is too slow, it can be decided to pool the age groups and analyze them as one total group instead. If this decision is made before the first interim analysis, above significance levels will be used for the total group. If the decision is made between the first and second interim analysis, O’Brian-Fleming significance levels for four analyses will be used, resulting in a significance level of 0.0184 for the second interim analysis and 0.0412 for the final analysis. If the decision is made after the second interim analysis, a significance level of 0.0417, corresponding to O’Brian-Fleming with five analyses, will be used for the final analysis.
Patient and public involvement
Patients were involved in the planning and development of the study protocol. A series of in-depth semi-structured interviews were conducted with the qualitative purpose of exploring the experiences acquired during the treatment course of a humeral shaft fracture. Beyond the qualitative study aim, a discussion of the most meaningful primary outcome measures was undertaken. All patients completed two questionnaires (DASH and QuickDASH) to solicit their feedback and to determine which PROM they found most appropriate when considering relevance, comprehensibility, comprehensiveness and length. The interviews further revealed complaints that were discussed with the patients and were subsequently priorities to be implemented as outcome measures of the trial.
One of the patients from the interviews accepted to be involved in the trial as the patient representative (PR). The PR is included in the steering committee and in the data monitoring committee (DMC). The study protocol was discussed with the PR in layman terms to facilitate a common understanding of the trial and to solicit feedback that could minimize patient burden and risk of missing data, as well as providing insights from a patient perspective to optimize the communication between physicians and patients during the trial course and by written information. The feedback resulted in minor revisions of words in the patient information sheet to conform with patient concerns.
Interventions
Treatment will be performed within 14 days after injury. Eligible patients will be randomly allocated to one of two treatment options.
We anticipate that surgical treatment will include plate osteosynthesis (MIPO and ORIF), intramedullary nailing (antegrade and retrograde) and external fixation. Plate and nail types, screw configurations and surgical approaches will be decided by the surgeons. The procedure will be conducted or supervised by a senior consultant.
Non-surgical treatment will include sugar tong splint, plaster splints, hanging casts, or functional bracing such as the Sarmiento brace, and will be worn until a surgeon removes it.
All patients will be advised to follow this rehabilitation protocol.
Criterias for early crossover
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:
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Unacceptable pain experienced by the patient
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Severe pain with gross instability of the fracture site assessed by:
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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.
Randomization
A computerized database software, Research Electronic Data Capture (REDCap)©(31) 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.
Protocol violation
Patients that meet any of these criteria will remain in the study and be included in the intention-to-treat analysis but omitted from a per-protocol analysis.
Participant withdrawal
If the patient withdraws the consent, patients will be included in the statistical analysis through multiple imputation, if baseline data is obtained, otherwise imputation is not possible, and the patient will be replaced to meet the calculated sample size.
Blinding
The trial will consist of several levels of blinding:
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The primary outcome will be blinded to everyone involved in the trial, apart from the patients and a central trial worker (non-physician), who will only review the questionnaire for completion in REDCap
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The statistical analysis will be conducted by a blinded biostatistician
Primary outcome measure
The primary outcome is the Disability of Arm, Shoulder and Hand (DASH) score at 52 weeks(32). The DASH score is a 30-item self-reporting patient-reported outcome measure specific for physical function and symptoms of the upper limb. Scores range from 0 (no disability) to 100 (most severe disability). The DASH score is validated for the target population(33) and has undergone cross-cultural adaptation in Danish, Swedish and Norwegian(34).
Secondary outcome measures
Secondary outcomes consist of a self-reported measure of health-related quality of life (EQ-5D-5L), complication rates, visual analogue scale (VAS) for pain from the arm, a functional outcome score (Constant Murley) and anchor-questions including clinical anchors, retrospective global transition questions and a binary repeat treatment question. Secondary outcome measures will be assessed at baseline, 3 weeks, 6 weeks, 12 weeks, 26 weeks, 52 weeks, 2 years and 5 years of the trial, Fig. 3:
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DASH score at 26 weeks (MIC(35), 7 and 10 respectively to age 18–64 and 65+)
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General health status questionnaire measured by EQ-5D-5L(36) (MIC(37), 0.074)
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Complications after treatment will be recorded and include local complications, early general complication and mortality:
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Local complications: Infection (needing antibiotic treatment with or without debridement), nerve or vascular injury, surgical revision (due to implant malpositioning, hardware failure, aseptic loosening or peri-implant fracture) and tolerance problems with brace (discomfort resulting in non-compliance of wearing the brace
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Major adverse cardiac events (MACE) including myocardial infarction, heart failure, thromboembolism, cardiomyopathy and cardiac arrythmias.
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Pain is assessed by using the visual analog scale (VAS) score. Patients are asked to assess their overall pain from the arm from 0-100 in a day (MIC(40), 16.55mm)
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Constant-Murley score(41) (MIC(35), 6.1). The subscales of strength and ROM will be depicted. ROM (flexion-extension) of the elbow will be recorded
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Clinical anchor (CA) questions presented with 5 response options (RO) and analyzed as a 5-point Likert scale:
Q: In general, would you say your health is?
RO: Excellent, Very good, Good, Fair, Poor
Q: How would you describe the results of the (operation / non-surgical treatment)?
RO: Excellent, Very good, Good, Fair, Poor
Q: How would you describe the function of your upper arm?
RO: Excellent, Very good, Good, Fair, Poor
Q: How would you describe the pain from your upper arm?
RO: None, Mild, Moderate, Severe, Extreme
Q: Overall, how would you describe your general health now, compared to after the (operation / non-surgical treatment)?
RO: Much worse, A little Worse, About the same, A little better, Much better
Q: Overall, how would you describe your upper arm now, compared to after the (operation / non-surgical treatment)?
RO: Much worse, A little Worse, About the same, A little better, Much better
Q: How would you describe the change in physical function in your upper arm since after the (operation/ non-surgical treatment)?
RO: Much worse, A little Worse, About the same, A little better, Much better
Q: How would you describe the change in pain from your upper arm since after the (operation/ non-surgical treatment)?
RO: Much worse, A little Worse, About the same, A little better, Much better
Q: With the knowledge and experience you have gained of the treatment; would you then choose the same treatment again for a similar fracture?
RO: Yes, No
The DASH, EQ-5D-5L and CA questions will be sent by email or mail and patients are asked to complete the questionnaires before visits. The questionnaires will be reviewed for missing data by a trial worker and patients will be assisted with completing the questionnaires if any data is missing, without interference from the medical staff. The trial worker collects the questionnaires before consultation with the physician. The physician then collects the additional outcome measures at the consultation and enters data directly into REDCap.
Explorative outcome measures
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DASH score at all time points (pre-injury, 6 weeks, 12 weeks, 104 weeks, 260 weeks)
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Fracture type measured by the AO-classification and the location of the fracture
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Surgical procedure recorded as treatment modalities and subdivided in procedures and device/implant use
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Radiological variables measured as degree of displacement, angulation, comminution, callus formation and visibility of fracture line
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Gross instability of the fracture site is assessed by a physician through gentle manipulation. This is first tested at 6 weeks follow-up for SHAFT-Y and 12 weeks for SHAFT-E
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Return to work will be assessed by direct questioning at clinical visits. Five answers will be available: Unemployed, not returned, partially returned, fully returned and retired. If patients are still on sick leave they have ‘not returned’. If they are back at work but not in full capacity as prior to the fracture, they are ‘partially returned’; if they have returned as prior to the fracture they are ‘fully returned’; and if the patients are a pensioner, they are “retired”
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Mechanism of injury measured as low-energy fractures e.g. fall from own height and high-energy fractures e.g. fall from heights, sports, motor vehicle accidents and other miscellaneous accidents
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Nonunion is defined as gross mobility at the fracture site after 12 weeks for SHAFT-Y and 26 weeks for SHAFT-E. Pain from the fracture site will also be noted to determine if the nonunion is symptomatic or asymptomatic. Radiological assessment of type of nonunion will also be assessed
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QALY-based cost analysis
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Successful primary treatment vs early crossover surgery
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Length of rehabilitation
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Level of activity by the UCLA activity score(42)
Other outcome measures
Any ancillary outcome measure or analysis will be reported.
Statistical analysis plan
Hypothesis
The null-hypothesis is:
Sample size
The two groups (SHAFT-Y and SHAFT-E) require individual sample size calculations due to our presumption that these groups cannot be compared in DASH scores. Based on the following assumptions, the total sample size is estimated to 163 patients for SHAFT-Y and 124 patients for SHAFT-E. The calculations are powered to detect a minimal important change (MIC) of 7 points in the young and 10 points in the elderly group in DASH, respectively. The MIC is determined on a population with the average age of 59 years(35). Our SHAFT-E will have a considerably higher average age; thus we assume a higher MIC is needed for this group. Two standard deviations were obtained from the data of the FISH trial(11) and were separated in age groups of 18–64 years and 65 years and above. The standard deviations 14.91 and 18.59, respectively. We used an α-level of 0.05, a power of 0.80 and the allowance of attrition is set to 15%.
Patients will be included consecutively to an observational group until the sample size for the RCT is completed. The trial management committee can decide to pool data from both RCTs (SHAFT-Y, SHAFT-E) if recruitment is prolonged.
Statistical methods
The data will be analyzed using computerized statistical software and all data will be entered into REDCap.
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 (sex, smoking, alcohol, UCLA activity, ASA score)(43–45) 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 re-ensure the validity of 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: sex, smoking, alcohol, UCLA activity, ASA score. 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.
Observational cohort
An observational cohort will be established and followed simultaneously with the RCT. Choice of treatment will be based on local decisions. Outcome measures, data collection and statistical plan will be similar. Follow-up can vary depending on each case, but all patients will be invited to follow the same timeline as the RCT.
The observational cohort will be subdivided into two groups of populations when statistical analysis will be conducted.
1) Patients who fulfil all eligibility criteria but decline randomization
2) Patients who fulfill all inclusion criteria but presents one or more exclusion criteria