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  • Research article
  • Open Access
  • Open Peer Review

Pilot randomized controlled trials in the orthopaedic surgery literature: a systematic review

  • 1,
  • 1,
  • 2,
  • 3,
  • 1,
  • 4, 5Email author,
  • 5,
  • 4, 5 and
  • 4, 5
BMC Musculoskeletal Disorders201819:412

https://doi.org/10.1186/s12891-018-2337-7

  • Received: 8 June 2018
  • Accepted: 7 November 2018
  • Published:
Open Peer Review reports

Abstract

Background

The primary objective of this systematic review is to examine the characteristics of pilot randomized controlled trials (RCTs) in the orthopaedic surgery literature, including the proportion framed as feasibility trials and those that lead to definitive RCTs. This review aim to answer the question of whether pilot RCTs lead to definitive RCTs, whilst investigating the quality, feasibility and overall publication trends of orthopaedic pilot trials.

Methods

Pilot RCTs in the orthopaedic literature were identified from three electronic databases (EMBASE, MEDLINE, and Pubmed) searched from database inception to January 2018. Search criteria included the evaluation of at least one orthopaedic surgical intervention, research on humans, and publication in English. Two reviewers independently screened the pool of pilot trials, and conducted a search for corresponding definitive trials. Screened pilot RCTs were assessed for feasibility outcomes related to efficiency, cost, and/or timeliness of a large-scale clinical trial involving a surgical intervention. The quality of the pilot and definitive trials were assessed using the Checklist to Evaluate a Report of a Non-Pharmacological Trial (CLEAR NPT).

Results

The initial search for pilot RCTs yielded 3857 titles, of which 49 articles were relevant for this review. 73.5% (36/49) of the orthopaedic pilot RCTs were framed as feasibility trials. Of these, 5 corresponding definitive trials (10.2%) were found, of which four were published and one ongoing. Based on author responses, the lack of a definitive RCT following the pilot trial was attributed to a lack of funding, inadequacies in recruitment, and belief that the pilot RCT sufficiently answered the research question.

Conclusions

Based on this systematic review, most pilot RCTs were characterized as feasibility trials. However, the majority of published pilot RCTs did not lead to definitive trials. This discrepancy was mainly attributed to poor feasibility (e.g. poor recruitment) and lack of funding for an orthopaedic surgical definitive trial. In recent years this discrepancy may be due to researchers saving on time and cost by rolling their pilot patients into the definitive RCT rather than publish a separate pilot trial.

Keywords

  • Orthopaedic
  • Surgery
  • RCT
  • Feasibility
  • Pilot study
  • Definitive trial

Background

Definitive randomized controlled trials (RCTs) exist to demonstrate unmistakable evidence of a certain inventions benefit on a patient [1]. Although they are very impactful for clinical practice are typically expensive and time-consuming [2]. Given the resources and time, investigators often conduct pilot trials designed with an aim to demonstrate the feasibility of the larger-scale definitive trial [3]. Pilot trials can identify possible challenges, predict costs, and fine-tune study design. In addition, by demonstrating feasibility, a successful pilot trial can be used to leverage momentum and definitive trial funding [2].

Effective pilot trials have a well-defined set of objectives to assess feasibility.3 Feasibility is assessed in terms of whether the intervention of interest, trial design, and protocol can be successfully implemented and completed by the researchers [3]. Feasibility can be determined at the program level, study level, and site or investigator level. Program level feasibilities include determining the prevalence of particular diseases in a particular region and include clinical and epidemiological trials [4]. Study level feasibilities are centered on assessing whether a specific clinical trial can be conducted in a country or region [3]. Site or investigator level feasibility trials focus on identifying challenges and probable solutions with respect to the investigator and clinical aspects of the trial (drug dosages, actual study population, recruitment and follow-up, usage of assessment tools, etc.) [4].

Despite the benefits of pilot trials, previous literature has demonstrated that they do not always lead to a definitive trial. In 2004, Lancaster et al reviewed four general medicine journals and three specialist journals and identified 90 pilot studies published from 2000 to 2001; of which 45 reported the intention to carry out further work [1]. However, in 2010, Arain et al. found that only eight out of the 45 were followed by a larger, definitive study [5]. The impact of pilot data and subsequent research remains to be evaluated in the orthopaedic surgical literature.

This systematic review assessed the quality of pilot RCTs and frequency of ensuing definitive RCTs in the orthopaedic surgical literature. The primary objectives of this review were to: 1) assess feasibility outcomes across pilot trials in the orthopaedic surgery literature; 2) identify the proportion of pilot trials that lead to and how they inform definitive RCTs, and 3) evaluate the quality and frequency of pilot trials over time.

Methods

Identification of RCTs

EMBASE, MEDLINE and Pubmed were searched for relevant articles published from database inception until January 25, 2018 (Additional file 1). All search results were imported into the Mendeley Reference Manager software (Elsevier Publishing, 2013) to remove all duplicate trials.

Once the final pool of included pilot RCTs was determined, an additional search was conducted in the same electronic databases in an attempt to find corresponding definitive trials. If a literature search of titles was unsuccessful, other trials conducted by at least one of the authors after the pilot were considered. The secondary search was conducted using key terms used in the pilot RCT. Additionally, clinicaltrials.gov, an online database of ongoing clinical trials, was reviewed to determine if the previously identified pilot RCTs had a definitive trial in progress. Finally, if no definitive trial was found using these methods, the pilot RCT authors were contacted by email and asked whether a definitive trials was ongoing, published, or submitted for publication.

Eligibility criteria

Trails had to be defined explicitly and reported as pilot trials within the paper itself to be included in this review. Trials reported as pilot RCTs were deemed eligible for this review if they: 1) included an orthopaedic surgical intervention, 2) included a drug that was used intra-operatively at the site of surgery/fracture, or 3) evaluated the difference between two surgical interventions or surgical vs. non-surgical orthopaedic interventions. Only clinical trials in humans published in English were included. RCTs were excluded if they were: 1) non-pilot RCT designs (including small trials not reported as pilot trials) 2) trial interventions were exclusively non-surgical including physiotherapy, exercise regimens, post-operative rehabilitation, anesthesia, post-operative pain management interventions, or 3) trial interventions were surgical procedures not related to orthopaedics (e.g. oral, urology, and ocular surgeries), and 4) drugs and supplements administered orally (intravenously administered during surgery were included).

Screening

Articles were independently screened in duplicate at the title, abstract, and full-text stage by decisions were independently recorded in a spreadsheet (Microsoft Excel, 2015). In order to ensure comprehensive screening, an article was progressed to the next screening stage if at least one reviewer had noted that the article should be included, and illustrated as a flow diagram and checklist in Fig. 1 below. All disagreements were resolved by consensus during the full-text screening phase in consultation with a third senior reviewer (AD).
Fig. 1
Fig. 1

Flow diagram of the search and screening strategies to define the final pool of trails

Data abstraction

Pilot and definitive trial data, such as the country, number of patients in the RCT, orthopaedic condition being treated, orthopaedic intervention(s), controls, primary and secondary outcomes, percentage of patients that were lost to follow-up, follow-up schedule, and feasibility objectives were abstracted. In addition, for the definitive trials, any changes in interventions, controls, primary and secondary outcomes, or patient sample from the pilot trial were noted. For definitive RCTs, the time elapsed between the date of publication of the pilot and definitive trial and whether or not the sample size was calculated based on event rates from the pilot trial were determined.

Assessment of feasibility

Feasibility trials were defined as trials with a primary purpose of piloting the protocol to inform a definitive trial. In order to distinguish between pilot trials created solely for investigating the efficacy of interventions compared to feasibility trials, specific reference to feasibility objectives were evaluated. Feasibility objectives include determining the preliminary efficacy of a surgical intervention as well as the safety of the intervention, accurate event rates for a definitive sample size, the cost of a large scale clinical trial, patient recruitment rates, trial design, randomization procedure, and ability to maintain blinding.

Assessment of methodological quality

The reviewers (BD, VD, ALS, and SS) independently assessed the quality of each included pilot and definitive trial in duplicate using the Checklist to Evaluate A Report of Non-Pharmacological Trial (CLEAR NPT). The CLEARN NPT is designed for the critical appraisal of RCTs in nonpharmacological and surgical trials [6]. The original checklist was modified, where the question regarding patient adherence was omitted as all our trials evaluated a single, one-time surgical intervention. As the original checklist did not provide a scoring method, the criteria employed by Somford et al. was adopted to provide a modified CLEAR NPT (Additional file 2) [6]. The maximum CLEAR NPT score was 18, whereby a score of 0–6 indicated a low quality trial, 7–12 indicated a medium quality trial, and 13–18 indicated a high quality trial.

Statistical analysis

A kappa (κ) statistic was used to determine agreement at all stages of article screening with 95% confidence intervals (CI) [7]. An intraclass correlation coefficient (ICC) was calculated for the purpose of evaluating inter-rater reliability for the CLEAR NPT quality assessment. Agreement for both the κ and ICC was categorized as follows: > 0.90 indicated an almost perfect level of agreement, 0.80 < 0.90 strong agreement, 0.60 < 0.79 moderate agreement, 0.40 < 0.59 weak agreement, 0.21 < 0.39 minimal agreement, and 0.0 < 0.20 no agreement [8].

A t-test was performed using an online statistical calculator (Vassal Stats) to compare trial quality between pilot and definitive trials and a Pearson’s r correlation was calculated to determine if there was a relationship between number of studies and quality of pilot RCTs over time. A p-value less than 0.05 was considered significant. Descriptive statistics including means, proportions, standard deviations, and CIs are reported. A meta-analysis was not performed given the broad heterogeneity of the trial designs, interventions, and outcome measures.

Results

Screening

The initial screening of online databases yielded 3857 articles after the removal of 2230 duplicates. After title, abstract, and full text screening, 49 pilot RCTs were included (Fig. 1 and Additional file 3). Of these, we identified five definitive trials (one of which is still ongoing) that corresponded to the original published pilot trial. Inter-reviewer agreement was high at all stages of screening (title, κ = 0.886 (95% CI 0.878 to 0.893); abstract, κ = 0.740 (95% CI 0.693 to 0.780); and full text, κ = 0.792 (95% CI 0.737 to 0.835)).

Pilot trial characteristics

Pilot trials were commonly published from the UK and Canada (22 and 16%, respectively) (Tables 1 and 2). A total of 2117 patients were recruited across all pilot RCTs, and 5.84 ± 10.9% of patients, on average, were lost to follow up. The greatest proportion of pilot trials (59.2%, 29/49) focused on surgical fracture repair, including long bone, knee, spinal, foot and hip fractures (Fig. 2). As classified by the World Bank, 40 of the pilot trails were conducted in high-income countries, 6 were classified as middle income and 3 were classified as low income [9].
Table 1

Characteristics of the Included Pilot RCTs

Title

Country

# of patients

Condition

Type of Surgery

Control

Patient-Reported Outcomes

Clinician Reported Outcomes

Primary Outcome

Secondary Outcome

Loss to follow-up (%)

Length of follow-up

Feasibility Category

Framed as feasibility?

Definitive Trial Published?

CLEAR-NPT Score

Hamdy, R. C et al., (2009) [15]

Canada

52

Lower extremity limb lengthening and deformity correction.

Ilizarov technique

Sterile saline solution

Faces Pain Scale-revised, Adolescent Pediatric Pain Tool, Pediatric Quality of Life Inventory, Gillette Functional Assessment Questionnaire

n/a

Pain, quality of life, functional mobility

Adverse effects

3%

3 mo

Study design

Yes

Yes

17

Vaccaro, A. R et al., (2005) [16]

USA

12

Iliac crest autograft in posterolateral lumbar fusions

Op-1 putty (rhbmp-7) as an adjunct

No control group

Oswestry scale and SF-36

Radiographic

Fusion success rate

Cost effectiveness and pain

0%

24 mo

Safety & efficacy

Yes

No

11

Ekrol, I et al., (2008) [17]

UK

30

Distal radial fractures.

RhBMP-7 as an alternative to bone graft healing

No control group

n/a

Radiographic, clinical and functional outcomes

Functional outcome

Complications

0%

12 mo

Efficacy

Yes

No

18

Lerner, T et al., (2009) [18]

Germany

40

Adolescent idiopathic scoliosis.

Graft extenders in scoliosis surgery

No Control Group

VAS pain score

Biopsies

Fusion success rate

Pain

0%

48 mo

Efficacy

Yes

No

15.5

Marks, P et al., (2008) [19]

Canada

40

ACL reconstruction

Comparing the Mitek bone–tendon– bone cross pin and bioabsorbable screw

No control - comparative trial

International Knee Documentation Committee (IKDC) Knee Ligament Standard Evaluation, Mohtadi’s ACL Deficiency Quality of Life

Lateral x-Ray

Clinical outcomes

Length of surgery

20%

24 mo

Efficacy

Yes

No

16.5

Shamji, M. F et al., (2014) [20]

Canada

23

Thoracolumbar burst

Applying a brace to treat thoracolumbar bursts

No brace

VAS pain score

Radiographic, clinical & functional outcome

Average length of hospital stay & cost

Pain & adverse effects

0%

6 mo

Efficacy

Yes

No

14.5

Carson, J. L et al., (1998) [21]

UK

84

Hip fracture

Blood transfusion during hip fracture

No Control- comparative trial

Phone interviews of family or patient

Various methods to evaluate adverse effects (CT scan, ultrasound, autopsy)

Mortality & ability to walk 10 ft across a room

Functional status, residence status, in-hospital myocardial infarction,thromboembolism, stroke and pneumonia.

3%

60 days

Patient recruitment

Yes

No

16.5

Vaccaro, A. R et al., (2003) [22]

USA

12

Iliac crest autograft in posterolateral lumbar fusions

Op-1 putty (rhbmp-7) as an adjunct

No control group

n/a

Radiographic & clinical

Fusion success rate

Adverse effects

0%

24 mo

Safety & efficacy

Yes

No

13.5

Vaccaro, A. R et al., (2004) [23]

USA

36

Symptomatic degenerative spondylolisthesis

Spinal stenosis

Autograft

n/a

Radiographic & clinically

Fusion success rate

Well-being/Quality of life

5%

1 yr

Safety

Yes

No

18

Glazebrook, M et al., (2013) [24]

Canada

24

Ankle and Hindfoot Arthrodesis

B2A-Coated Ceramic Granules (Amplex) Compared to Autograft

Autograft

Computerized tomography & Ankle Osteoarthritis Scale scores

n/a

Bone healing at site of fusion

n/a

0%

12 mo

Safety & efficacy

Yes

No

17

Mauffrey, C et al., (2012) [25]

UK

24

Tibial fracture

Arthrodesis surgery

No control - comparative trial

Functional outcome questionnaire (DRI)

n/a

DRI

Olerud and Molander Ankle Score (OMAS)10 and the EuroQol EQ-5D generalized health outcome questionnaire

0%

12 mo

Efficacy

Yes

No

18

Darmanis, S et al., (2007) [26]

UK

40

Knee arthroplasty

Knee arthroplasty

No laser

Fisher’s Exact test and the Mann-Whitney U test

n/a

Fisher’s Exact test and the Mann-Whitney U test

n/a

0%

n/a

Efficacy

Yes

No

15.5

Buse, G. L et al., (2014) [27]

Canada

60

Hip fracture

Accelerated surgery

No

Functional Independence Measure & SF-36

Troponin measurement & confusion Assessment Method.

Proportion of eligible patients randomly assigned, completeness of follow-up & timelines of accelerated surgery

Major perioperative complication

0%

18 mo

Sample size

Yes

No- Ongoing Definitive Trial

15

Adolfsson, L et al., (2001) [28]

Sweden

53

Waist

Percutaneous Acutrak screw fixation.

Immobilization in a below elbow plaster cast for 10 weeks

n/a

Radiographic

Assessment of union

Failure

1%

10 wks

Efficacy

Yes

No

16.5

Kang, P et al., (2012) [29]

China

77

Femoral

Multiple drilling core decompression combined with systemic alendronate as a femoral head-preserving procedure

Multiple drilling core decompression

THA & Harris score

Radiographic

Efficacy of combined treatment

Reduction in disease progression

10%

48 mo

Safety & efficacy

Yes

No

17

Moseley, J. B et al., (1996) [30]

USA

10

knee

Arthroscapic surgery of the knee

Placebo (sterile saline)

Arthritis Impact Measurement Scale 34 and the SF-36

n/a

Evaluate the placebo effect as part of a pilot trial preceding a randomized, controlled trial of arthroscopic treatment of osteoarthritis

Ability to find and recruit eligible subjects; developing and testing measurement instruments; ability to retain patients for at least 6 months; determine feasibility of completing trial

0%

12 mo

Ability of patients to complete the trial; ability to maintain blindness

Yes

No

18

Chhabra, H. S et al., (2009) [31]

India

5

Spinal cord

Olfactory mucosal transplantation into the spinal cord

No

American Spinal Injury Association (ASIA) Impairment Scale (AIS), Spinal Cord Independence Measure, Beck Depression Inventory scores and life impact scores on International Spinal Cord Injury Scale

MRI

Autologous olfactory mucosal transplantation therapy

n/a

0%

18 mo

Safety & efficacy

Yes

No

16

Wang, Y et al., (2015) [32]

China

21

Foot

Total-contact casting (TCC)

No

Quantitive sensory Testing (temperature, pain, light touch, perception)

Radiographic

Comparing the effectiveness of arthrodesis plus TCC with TCC alone for the prevention, treatment and recurrence of midfoot ulcerations

Sample size

0%

12 mo

n/a

No

No

18

Zou, J et al., (2013) [33]

China

94

Tibial

Minimally invasivepercutaneous plate osteosynthesis

Comparative trial, control group was treated with ORIF

n/a

Radiographic

Functional status

Sample size

0%

12 mo

n/a

No

No

16.5

Zehir, S et al., (2015) [34]

Turkey

45

Clavicular

Minimally invasive plating fixation

Mini invasive plating

(DASH) Quick Disability of the Arm, Shoulder and Hand

Radiographic

Efficacy

Sample size

0%

12 mo

Efficacy

Yes

No

16.5

Pang, H. N et al., (2011) [35]

Singapore

140

Knee

Knee arthroplasty

Resection technique

Knee Society Score [20], Oxford Knee Questionnaire [36] and SF-36 Questionnaire

Radiographic

Efficacy

Unclear

0%

24 mo

Efficacy

Yes

No

18

Wondrasch, B et al., (2009) [36]

Austria

21

Femoral

Matrix associated autologous chondrocyte implantation

Delayed weightbearing

Knee Documentation Committee (IKDC), the Tegner activity scale, and the Knee Injury and Osteoarthritis Outcome Score (KOOS)

Radiological outcome was evaluated by the MOCART score and the size and amount of bone marrow edema and effusion

Efficacy

n/a

0%

24 mo

Efficacy

Yes

No

14

De Sèze, M. P et al., (2011) [11]

France

28

ankle

ankle foot orthosis

Standard ankle-foot orthosis

Pain evaluation on an analogical visual scale

n/a

Gain ratio at day 30

 

0%

 

Efficacy

Yes

No

16

Kraus, V. B et al., (2012) [37]

USA

11

Knee

ACL

Placebo (sterile saline)

Standardized Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire

n/a

Efficacy

Sample size

0%

1 mo

Efficacy

Yes

No

16

Flow Investigators (2011) [38]

Canada

111

General open fractures

Fracture healing

Saline

SF-12 and EQ-5D, respectively (12-item questionnaire that measures health-related quality of life in 8 domains)

n/a

Reoperation rates

Infection & wound healing problems

11%

12 mo

Efficacy & large scale trial

Yes

Yes

18

Lindsey, R. W et al., (2006) [39]

USA

10

General long bone fractures

Grafting long bone fractures

No

n/a

Radiographic

Effectiveness of a composite graft consisting of demineralized bone matrix (DBM) putty enriched with aspirated bone marrow

Sample size

0%

24 mo

Efficacy

Yes

No

16

Costa, M. L et al., (2003) [40]

UK

28

Achilles tendon

Achilles tendon ruptures

Serial plaster casting

n/a

Ultrasound

Safety

Sample size

29%

12 mo

Safety

Yes

Yes

18

Mahowald, M. L et al., (2009) [41]

USA

11

Advanced rheumatoid arthritis and osteoarthritis

IA-BONT/A

Saline Placebo

Patient global assessment of change was measured with a validated 7-point verbal descriptor scale & WOMAC

n/a

Efficacy and safety of IA-BoNT/

Decreases in pain and functional improvement

13%

1 mo

Safety & efficacy

Yes

No

12

Paterson, K et al., (2013) [42]

Australia

37

Knee

PA-PRP

Hyaluronic acid

VAS pain score

n/a

Recruitment and safety data

Symptomatic and functional changes following treatment

17%

4 and 12 wks

Efficacy

Yes

No

18

Zehir, S et al., (2014) [43]

Turkey

64

Distal radius fractures

Sonoma Wrx

Standard volar locking plate fixation

n/a

Radiographic

Reliability and efficacy

Complication prevention

0%

12–13 mo

Efficacy

Yes

No

13.5

Hey, H et al., (2013) [44]

Singapore

7

Spinal

Hybrid surgery

Anterior cervical discectomy and fusion + artificial disc replacement

Complications and functional scores (VAS, NDI, EQ-5D health score and index)

n/a

Clinical differences between three groups

n/a

0%

2 wks

Safety & efficacy

Yes

No

10.5

Kuo, L. C et al., (2013) [45]

Taiwan

22

Radial

Early digit mobilization

Home programmes

Manual Ability Measure-36 (MAM-36) to assess their self-awareness of manual abilities

Radiographic

Differences in functional outcome

n/a

0%

12 wks

Efficacy & cost

Yes

No

18

Abbott, A et al., (2013) [46]

Sweden

17

Cervical

With post-operative cervical collar usage

Without post-operative cervical collar usage

Falls Efficacy Scale (patients measuring completing tasks without falling)

Radiographic

Sample size feasibility

Physical, functional, and quality of life-related outcomes

45%

6 wks

Cost & sample size

Yes

No

12

McMorland, G et al., (2010) [47]

Canada

120

SCIATICA

Surgical microdiskectomy

Standardized chiropractic spinal manipulation

McGill Pain Questionnaire, Aberdeen Back Pain Scale, and Roland-Morris Disability Index)

n/a

Recruitment and randomization process, choice of outcome measures, and effect size for definitive trial

Compare the clinical efficacy

0%

1 yr

Sample size patient recruitment randomization

Yes

No

18

Ringel, F et al., (2012) [48]

Germany

60

Spinal

Robot-assisted (RO) implantation

Freehand (FH) conventional technique

n/a

CT scan

Evaluate accuracy of techniques

n/a

0%

No follow up

Efficacy

Yes

No

16

Boonen, S et al., (2002) [49]

Belgium

33

Proximal Femoral Fracture

Administration of rhIGF-I/IGFBP-3

Placebo

Kerr-Atkins score for pain and function

Radiographic

Pain and function

Musculoskeletal effects

0%

6 mo

Safety

Yes

No

17

Griffin, D et al., (2014) [50]

UK

151

Calcaneal fractures

Surgery by open reduction and internal fixation

Non-operative treatment

Kerr-Atkins calcaneal fracture score

Radiographic

Pain and function

Complications

5%

24 mo

 

No

No

18

Guo, Q et al., (2013) [51]

China

90

Intertrochanteric fractures

Percutaneous compression plate

Proximal femoral nail anti-rotation

n/a

Radiographic

Clinical effectiveness

Complications

0%

2 yrs

 

No

No

16.5

Storey, P et al., (2013) [52]

UK

49

Carpal Tunnel

C-Trac splints

Conventional resting splint

n/a

Radiographic

Levine questionnaire scores

Grip, pinch and sensation scores

0%

1 yr

 

No

No

14

Zhang, Y. Z et al., (2011) [53]

China

22

Abnormalities with hip joint

Navigation template implantation

Conventional THA

n/a

CT scan

Unclear

Unclear

0%

12 to 18 mo

 

No

No

13

Nejrup, K et al., (2008) [54]

Denmark

43

Knee osteoarthritis

Gold implantation

Sham implantation

WOMAC, Knee Society Clinical Rating System

Radiographic

Knee pain, stiffness and function

Time from implant until effect and migration potential of implanted gold beads.

7%

0, 6 and 12 mo

 

No

No

18

Eskander, M. B. F et al., (1997) [55]

UK

44

Femoral neck fractures

Enoxaparin

Application of intermittent calf compression garments

n/a

CT scan

Unclear

Unclear

0%

6 wks

 

No

No

16.5

Jordan, R et al., (2014) [56]

UK

24

Tibial plateau fractures

Balloon osteoplasty

Traditional methods

Oxford Knee score and SF12 questionnaire at 3, 6 and 12 month

CT scan

Quality of reduction based on the post-operative CT scan

Surgical complication & patient satisfaction

Not stated

3, 6 and 12 mo

 

No

No

18

Kearney, R. S et al., (2011) [57]

UK

52

Achilles tendon rupture

Surgical repair

Non-surgical repair

Disability rating index EQ-5D, Achilles Total Rupture Score

n/a

Estimate of effect size for the functional outcome

Assess the use of a comprehensive cohort research design

10%

2 wks, 6 wks, 3 mo, 6 mo & 9 mo

Study design

Yes

No

10

Sabeti, M et al., (2014) [58]

Austria

20

Calcific rotator cuff tendinitis

Intraoperative ultrasound

Needling and palpating techniques

n/a

Radiographic

Notable potential clinical differences between the two groups

Clinical improvement using ultrasound

10%

2 and 6 wks and the 9 mo

 

No

No

13

Dutton, T et al., (2012) [59]

UK

48

Knee fractures

Retransfusion drain

No drain

n/a

Measure of transfusion rate

Which patients benefit most from drains

n/a

0%

No follow up

 

No

No

12.5

Sardar, Z et al., (2015) [60]

Canada

24

Spinal fracture

B2A peptide–enhanced ceramic granules (Prefix)

Autogenous iliac crest bone graft (ICBG)

n/a

Radiographic

Safety and efficacy

Fusion rate

0%

6 wks, 3, 6, and 12 mo after surgery.

 

No

No

14.5

Capa-Grasa, A et al., (2014) [61]

Spain

40

Carpal Tunnel

Ultra-MIS

Mini-open Carpal Tunnel Release

Quick-DASH questionnaire

n/a

Safety and efficacy

Recruitment rates, compliance, completion, treatment blinding, personnel resources and sample size calculation

0%

3 mo

Safety, sample size & cost

Yes

Yes

17

Okcu, G et al., (2013) [62]

Turkey

40

Reverse obliquity fractures of the proximal femur

Long nail implant

Standard nail implant

n/a

Radiographic

Reoperation (fixation failure), 1 year mortality rate, function and mobility & union rate

Implant success

18%

12 to 20 mo

 

No

No

16

Table 2

Characteristics of Included Definitive trials

Pilot RCT Author

Definitive RCT Author

Country of Publication

Number. Of Patients

Change in Condition/Intervention

Primary Outcomes

Secondary Outcomes

Loss to Follow up (%)

Were Pilot Patients rolled into the definitive sample size?

Was the sample size calculation based on data from the pilot?

Number of months between publication of pilot trial and definitive trial

CLEAR NPT score:

Buse G. et al. (2014) [27]

Manach, Y. L. et al.,(ongoing) [63]

Canada

1200 (still recruiting)

No change

Major perioperative complication

Mortality, myocardial infarction, cardiac revascularization procedure

0.00

Unclear

Yes

68 (projeted end date July 2018)

18

Hamdy, R. C. et al. (2009) [15]

Hamdy, R. C. et al. (2016) [64]

Canada

125

No change

Quality of life (questionaires, filled out by parents and children) 4 PedsQL scales.

n/a

4.00

Unclear

No

78

18

Flow Investigators (2011) [38]

Bhandari M. et al. (2015) [65]

Canada

2551

No change

Reoperation, to treat an infection at the operative site or contiguous to it, manage a wound-healing problem or promote bone healing.

n/a

0.00

No

No

51

18

Costa, M. et al. (2003) [40]

Costa, M. et al. (2006) [66]

UK

48

No change

Time taken to return to normal activities, as reported by the patient

Complication rate in the treatment group

10.40

No

Yes

26

18

Capa-Grasa. et al. (2014) [61]

Rojo-Manaute, J. et al. (2016) [67]

Spain

92

No change

To compare the clinical outcomes of two surgical outcomes with primary carpal tunnel syndrome.

n/a

0.00

No

Yes

4

18

Fig. 2
Fig. 2

Frequency of various types of pilot RCT interventions in each intervention category

Primary and secondary outcomes of the pilot trials were divided into physician-reported and patient-reported outcomes. 65.3% (32/49) of all pilot RCTs used radiographic analysis, such as x-rays, MRIs, ultrasounds and CT scans. Patient-reported outcomes were recorded through self-reporting or interview style questionnaires. Questionnaires addressed outcomes such as quality of life, pain, function/independence, and emotional health. Of the pilot trials, 67.3% (33/49) made use of patient-reported questionnaires as tools for monitoring trial outcomes.

Overall, 73.5% (36/49) of the pilot RCTs found in the orthopaedic surgery literature were framed as feasibility trials (Table 1). The two most commonly explored feasibility objectives were safety and efficacy of an orthopaedic surgical intervention (Fig. 3). 26.5% (13/49) of pilot RCTs explored more than one feasibility objective. The pilot trials CLEAR NPT rating varied from 10 to 18. Only 3 of the 5 definitive RCTs included in this review determined their sample size based on their corresponding pilot trial. None of the definitive RCTs enrolled the pilot patients into the definitive trial. Additionally, 22.4% (11/49) of the pilot trials listed the efficacy/effectiveness of the surgical intervention as a primary outcome. Of these, only one led to a definitive trial.
Fig. 3
Fig. 3

Number of RCTs that define each of these feasibility objectives in their pilot RCT

Definitive trial characteristics

Of the 49 identified pilot RCTs, five (10.2%) corresponding definitive RCTs were found (Table 2). On average, definitive trials were published at a mean of 4.25 years (3–7 years) after the pilot trial. The sample size of the pilot trial was 7.2% of the definitive trials. The total number of patients recruited to definitive RCTs was 4016, with one trial still recruiting participants (Table 2). Only one of these definitive trials was ongoing according to clinicaltrials.gov (31). Authors from 17 pilot trials (34.7%) responded to our email confirming that a definitive trial had not been published. Of these, 8 authors cited the following reasons for not conducting a definitive RCT: a lack of funding (12.5%), inability to meet recruitment targets (12.5%), preliminary efficacy of the intervention was not demonstrated (25.0%), the pilot study was thought to yield reliable results therefore eliminating the need for further investigation (50.0%).

Trial quality

There was no correlation (r = − 0.1508, p = 0.5655) between number of studies and quality of pilot RCTs over time (Table 3). The overall quality of the pilot RCTs was relatively high (mean CLEAR NPT score 15.9 ± 1.53). Based on the CLEAR NPT scale, the highest quality pilot RCTs involved the treatment of arthrodesis and repair of knee fractures. All of the definitive RCTs were given a score of 18 and were therefore 2.6 points higher on the CLEAR NPT scale than their corresponding pilot trials (p < 0.01). The agreement among reviewers for the quality assessment was very high (ICC = 0.969 (95% CI 0.948 to 0.982)).
Table 3

Number and average quality of pilot RCTs over time of publication

Year

Number of Trials

Mean Clear NPT Score

1996

1

18.0

1997

1

16.5

1998

1

16.5

2001

1

16.5

2002

1

17.0

2003

3

16.5

2005

1

11.0

2006

1

16.0

2007

1

15.5

2008

3

17.5

2009

5

14.9

2010

2

17.0

2011

5

15.0

2012

4

15.9

2013

10

15.3

2014

6

15.7

2015

3

16.3

2016

0

n/a

2017

0

n/a

2018

0

n/a

Discussion

Results from this systematic review demonstrate that the majority of orthopaedic surgical pilot RCTs were framed as feasibility trials, and that the pilot trials mostly evaluated site or investigator level feasibility. As expected, the quality of the corresponding definitive RCTs was higher than their respective pilot trial. Despite the majority (87%) of pilot RCTs being conducted in the high-income countries, the majority of the included pilot trials however, did not lead to a definitive RCT. In these cases, reasons cited included: a lack of funding, inadequate sample sizes, and that research questions were sufficiently answered in the pilot phase.

Similar to other fields of medicine, the majority of orthopaedic surgical pilot trials were not followed by a definitive trial. Arain et al. reviewed seven medical journals, including four general medicine journals (British Medical Journal, Lancet, the New England Journal of Medicine and the Journal of American Medical Association) and three specialist journals (British Journal of Surgery, British Journal of Cancer, British Journal of Obstetrics and Gynecology) to identify 54 pilot studies [5]. The authors reported a very low number of follow up studies, wherein only 14.8% (8/54) pilot studies yielded published definitive studies. Additionally, a systematic review published in 2017 by Kaur et al., looked at the quality of pilot studies within the Clinical Rehabilitation journal over the past 30 years, and they concluded that only 12% of their pilot studies led to a definitive trial [10].

The limited number of published pilot trials and corresponding definitive trials may be attributed to numerous factors. Firstly, the pilot may have demonstrated that a definitive trial was not feasible based on criteria established a priori (e.g. ability to recruit patients). However, we would expect that in some of these cases, researchers would amend their trial design, interventions, and outcomes to ensure feasibility in the definitive trial. Secondly, if found to be feasible, investigators may refrain from publishing their pilot trial and instead, roll the pilot patients into the definitive RCT to help save on time and costs. Trial methods papers and online registries are often used to first describe these trials. Thirdly, based on author responses in this review, definitive trials may not be feasible due to a lack of funding. In one case, the authors noted that their research question was answered by the pilot trial [11]. However, the published pilot did not provide a sample size calculation, and therefore, we cannot determine if the statistical power threshold was met for the primary outcome [12].

The majority of the orthopaedic surgical pilot trials found in this review posited feasibility objectives and were of relatively high quality. The first published pilot surgical trial was found in 1996, and since then, there has been an increase in the number of pilot RCTs published over time, with a relatively constant quality of trials up until 2013, with a decline in publications up until 2016. From 2016 to the end of our search in 2018, there were no orthopaedic surgical pilot RCTs published. This may be due to a more recent trend of trialists to roll their pilot patients into a definitive trial to save on costs and maximize recruitment. There may also be a lag in pilot publications in the past 3 years.

Strengths and limitations

Strengths of this review include a broad systematic search and high agreement at all stages of screening and quality assessment. The main limitation is the minimal data available regarding the reasons why pilot trials have not led to definitive RCTs. There was a lack of response from authors, limiting further insight into barriers to definitive trials. Within the past 5 years, 13 of the 49 pilot RCTs and 4 of the 5 definitive trials were published. Thus, the inclusion of more recent pilot RCTs may be a limitation, as their current definitive trials may be underway, and/or not yet published. This potential source of bias was mitigated by searching the clinical trial registry, clinicaltrials.gov, for any records of ongoing definitive RCTs.

This review includes the use of the CLEAR NPT checklist to evaluate each pilot trial. Specifically within orthopedic literature, the quality of reporting RCTs using the CLEAR NPT is suboptimal, and that there is a need for improved surgical reporting [13]. However, in comparison to the CONSORT statement, the CLEAR NPT scale proves to be more useful in its analysis in interventions that require technical skill, with unique considerations in both conducting and reporting trials [14]. In this review, to account for methodological considerations, a modified CLEAR NPT scale was used instead to increase reliability and remove the necessity of including the Cochrane Risk of Bias Tool. The CLEAR NPT scale was modified, tested and optimized for orthopaedic trials, which was the focus of this paper.

Conclusion

While the majority of pilot RCTs found in the surgical orthopaedic literature are framed as feasibility trials, most did not lead to definitive trials. The reported reasons include: minimal funding, the inability to recruit an adequate sample size and that the research questions were sufficiently answered in the pilot phase. Although, most pilot RCTs did not result in a definitive trial, this does not diminish the value of the pilot trial in determining feasibility.

Abbreviations

CI: 

Confidence intervals

CLEAR NPT: 

Checklist to Evaluate A Report of Non-Pharmacological Trial

ICC: 

Intraclass correlation coefficient

n/a: 

Not applicable

RCT: 

Randomized controlled trial

Declarations

Acknowledgements

The authors would like to thank Ajaykumar Shanmugaraj for his assistance with the article’s submission.

Funding

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article, found in the Additional file.

Authors’ contributions

BD, VD, SS, AS and AS all contributed to paper screening, data abstraction, data validation, and writing of the paper. NS, AD, SS, and MB contributed to study design, manuscript revision, study supervision, and have critically reviewed all content during the preparation of the final paper. All authors have made substantial contributions to the paper, including study conduct, manuscript drafting, have given final approval for this version to be published, and have agreed to be accountable for all aspects of the work.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
(2)
Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
(3)
Faculty of Medicine, University of Toronto, Toronto, ON, Canada
(4)
Department of Health Research Methods, Evidence, and Impact (HEI), Division of Orthopaedic Surgery, McMaster University, Hamilton, ON, Canada
(5)
Department of Surgery, Division of Orthopaedic Surgery, McMaster University, Hamilton, ON, Canada

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Copyright

© The Author(s). 2018

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