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Trial registered on ANZCTR


Registration number
ACTRN12619001376134
Ethics application status
Approved
Date submitted
18/09/2019
Date registered
9/10/2019
Date last updated
9/10/2019
Date data sharing statement initially provided
9/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Impact of NSAIDs on delayed fracture healing
Scientific title
Feasibility of prescribing non-steroidal anti-inflammatory drugs following surgical repair of long bone fracture healing: A placebo-controlled pilot RCT
Secondary ID [1] 298862 0
none
Universal Trial Number (UTN)
U1111-1237-6869
Trial acronym
NODelay (Impact of NSAIDS On Delayed fracture healing)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tibial shaft fracture 313350 0
Femoral shaft fracture 313354 0
Condition category
Condition code
Injuries and Accidents 311790 311790 0 0
Fractures

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BRIEF NAME: Non-steroidal anti-inflammatory drugs (NSAIDs)

WHY: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed following musculoskeletal injuries and fractures as an effective method of pain relief, and are thought to offer a safer alternative to prescription opioids which are associated with an epidemic of abuse and secondary harm. However, there is some evidence that NSAIDs may impair bone formation, and therefore impact upon fracture healing, creating delayed union or non-union. Recent high-quality systematic reviews on the association between NSAID use and fracture non-union have concluded that, owing to a lack of clear evidence for impaired bone healing due to NSAID use, randomised controlled trials (RCTs) and high-quality prospective cohort studies are still needed. Given the frequency and use of NSAIDs, it is essential that we have solid evidence to inform clinical guidelines on the use of safe and appropriate analgesia to improve patient care. In order to conduct a large multi-site RCT to draw more definitive conclusions about the effects of NSAIDs on bone healing, it is important to firstly ascertain the safety and feasibility of conducting such a study via a pilot RCT. Therefore, the aims of this study are:
1. To determine the feasibility of using a prescribed treatment regime of NSAIDs versus a placebo in people with tibial shaft or femoral shaft limb fractures; and
2. To inform the design of a definitive multi-site trial that aims to determine the effect of NSAIDs on rates of non-union in people with tibial or femoral shaft limb fractures

WHAT:
NSAID: Parecoxib
- Dose: 40mg
- Frequency/Duration: Single dose, intra-operative
- Mode: intravenous

NSAID: Celecoxib
- Dose: 200mg
- Frequency/Duration: twice daily, commencing 24 hours after surgery and in the two weeks post-surgery
- Mode: Oral

Procedure:
Participants in the intervention group will receive standard care* plus intervention NSAIDs (parecoxib and celecoxib). Parecoxib will be intravenously administered to patients peri-operatively. Celecoxib will be prescribed to be taken twice daily, 24 hours after surgery for a duration of 2 weeks.

*According to local analgesic ladder. This includes regular paracetamol, regular and as required opioid, and if necessary, other non-opioids (e.g. gabapentinoids, clonidine) or Acute Pain Service consultation in those with difficult pain control.

WHO:
Randomisation and preparation of study drugs will be prepared by the Clinical Trials Pharmacists at the Alfred Pharmacy Department. Upon receipt of a completed clinical trials prescription by an authorised study prescriber, designated research personal will collect the study drug from Clinical Trials and deliver to the appropriate location, theatres or ward. Receipt and dispensing of study drugs will occur per Clinical Trials Pharmacy procedures.

ADHERENCE:
• Patient adherence will be determined in the two weeks post-surgery. Participants will complete a daily medication diary, and participate in a face-to-face or telephone call follow-up at two weeks, where participants will be asked questions about medication adherence and any barriers to medication adherence.
• Physician adherence will be determined by reviewing the medications prescribed in the first three days post-surgery. Anaesthetic charts, preoperative medication orders, post-operative orders, medication administration records, medication reconciliation forms, and discharge summaries are potential sources for information. A pharmacist working on the orthopaedic ward will conduct the medication monitoring. The type of information collected will be informed by the Alfred Health Guidelines for Pharmacological Management of Acute Pain in Adults and include; name/type of drug, dosage, route of administration, date and time(s) of administration, length of exposure (in-hospital) and details of treatment and any co-morbidities.
Additionally, participants will be provided with a letter to give to their GP to inform them about their participation in the study. The GP will be asked to refrain from prescribing any non-steroidal anti-inflammatory medications during the first two weeks following surgery.
Intervention code [1] 314787 0
Treatment: Drugs
Comparator / control treatment
In the control group, an intravenous and oral placebo will be administered.

WHAT:
Sodium chloride 0.9%
- Frequency/Duration: Single dose, intra-operative
- Mode: intravenous

Microcrystalline cellulose USP
- Frequency/Duration: twice daily, commencing 24 hours after surgery and in the two weeks post-surgery
- Mode: Oral

Procedure:
Participants in the control group will receive standard care* plus placebo. Sodium chloride will be intravenously administered to patients peri-operatively. Microcrystalline cellulose USP will be prescribed to be taken twice daily, commencing 24 hours after surgery for a duration of 2 weeks.

*According to local analgesic ladder. This includes regular paracetamol, regular and as required opioid, and if necessary, other non-opioids (e.g. gabapentinoids, clonidine) or Acute Pain Service consultation in those with difficult pain control.

Patients in the placebo group will receive adequate pain relief by either increasing the dose of analgesics or changing the combination of analgesics according to the analgesic ladder.
Control group
Placebo

Outcomes
Primary outcome [1] 320468 0
Patient Adherence will be determined via:
- Daily medication diary
- Follow-up interview where participants will be asked questions about medication adherence, any barriers to medication adherence, and satisfaction with care
- Retention rates of recruitment
Timepoint [1] 320468 0
- Medication diary to be completed daily for two weeks post-surgery
- Follow-up interview at two weeks post-surgery
Primary outcome [2] 320486 0
Physician Adherence will be determined via:
- Drug monitoring chart (which includes name/type of drug, dosage, route of administration, date and time(s) of administration, length of exposure (in-hospital) and details of treatment and any co-morbidities)
Timepoint [2] 320486 0
First three days post-surgery
Secondary outcome [1] 371725 0
Adverse Events/Complications will be determined via:
- Daily diary of side-effects
- Follow-up interview where participants will be asked questions about adverse events/complications
Examples of possible side-effects of analgesic medications include: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty urinating, retching/vomiting, skin rash, hallucinations, and gastrointestinal upset
Timepoint [1] 371725 0
Follow-up interview at two weeks post-surgery
Secondary outcome [2] 371779 0
Pain Severity determined via:
- Daily pain diary (pain rated on Numeric Rating Scale)
Timepoint [2] 371779 0
Pain diary to be completed daily for two weeks post-surgery

Eligibility
Key inclusion criteria
Participants will be eligible if they meet the following inclusion criteria:
- at least one tibial or femoral shaft fracture managed with either intramedullary nailing or plating
- an acute hospital length of stay>24 hours at The Alfred Hospital
- aged 18-65 years.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they present with:
- a pathological fracture related to metastatic disease, severe traumatic brain injury and/or spinal cord injury (recovery trajectory varies significantly from the majority of participants)
- less than conversational-level English (inability to engage in interviewing)
- multiple major fractures (bilateral tibia and/or femur; unilateral tibia and femur)
- a Glomerular Filtration Rate (GFR) below 60 mL/ min/1.73m2 or any contraindications to NSAID use (for example: known hypersensitivity including asthma/urticarial/allergic type reactions, allergy to sulphonamides, unstable ischaemic heart disease or thrombus or myocardial infarction or stroke within 3 months, active peptic ulceration or gastrointestinal bleeding, congestive heart failure NYHA II-IV, severe hepatic impairment – (Child-Pugh score greater or equal to 10).
- opioid and benzodiazepine addiction or opioid tolerance, and other regular illicit drug use or problematic alcohol use

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomisation sequence will be randomly generated by a computer.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Given that the study is a small pilot study aimed at determining the safety, feasibility and adherence of prescribing NSAID’s to this specific population, the results will be presented in the form of a descriptive analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/10/2019
Actual
Date of last participant enrolment
Anticipated
15/10/2020
Actual
Date of last data collection
Anticipated
15/02/2021
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 14017 0
The Alfred - Prahran
Recruitment postcode(s) [1] 26806 0
3004 - Prahran

Funding & Sponsors
Funding source category [1] 303078 0
University
Name [1] 303078 0
Monash University Department of Epidemiology and Preventive Medicine
Country [1] 303078 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Monash University
School of Public Health and Preventive Medicine
553 St Kilda Rd
MELBOURNE VIC 3004
Australia
Country
Australia
Secondary sponsor category [1] 303064 0
Hospital
Name [1] 303064 0
The Alfred
Address [1] 303064 0
55 Commercial Rd
Melbourne VIC 3004
Country [1] 303064 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303626 0
Alfred Health - Alfred Hospital Human Research Ethics Committee
Ethics committee address [1] 303626 0
55 Commercial Rd
Melbourne VIC 3004
Ethics committee country [1] 303626 0
Australia
Date submitted for ethics approval [1] 303626 0
10/12/2018
Approval date [1] 303626 0
20/03/2019
Ethics approval number [1] 303626 0
664/18

Summary
Brief summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed following musculoskeletal injuries and fractures as an effective method of pain relief. However, there is inconclusive evidence that these NSAIDs may impair bone formation, and therefore impact upon fracture healing, creating delayed union or non-union. It is essential that we have solid evidence to inform clinical guidelines on the use of safe and appropriate analgesia to improve patient care. In order to conduct a large multi-site randomised-controlled trial (RCT) to draw more definitive conclusions about the effects of NSAIDs on bone healing, it is important to firstly ascertain the safety and feasibility of conducting such a study via a pilot RCT. Therefore, the aim of the current study is to determine the feasibility of using a prescribed treatment regime of NSAIDs versus a placebo in people with tibial shaft or femoral shaft limb fractures, and is expected to inform the design of a large multi-site trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94310 0
Prof Peter Cameron
Address 94310 0
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
Level 3 553 St Kilda Rd
Melbourne, VIC 3004
Country 94310 0
Australia
Phone 94310 0
+61039903096
Fax 94310 0
Email 94310 0
[email protected]
Contact person for public queries
Name 94311 0
Peter Cameron
Address 94311 0
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
Level 3 553 St Kilda Rd
Melbourne, VIC 3004
Country 94311 0
Australia
Phone 94311 0
+61039903096
Fax 94311 0
Email 94311 0
[email protected]
Contact person for scientific queries
Name 94312 0
Peter Cameron
Address 94312 0
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
Level 3 553 St Kilda Rd
Melbourne, VIC 3004
Country 94312 0
Australia
Phone 94312 0
+61039903096
Fax 94312 0
Email 94312 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be shared as this had not been outlined in the protocol approved by the ethics committee. The data from this feasibility trial will be used to inform the design and implementation of a larger multi-site RCT.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3564Study protocol  [email protected]
3566Ethical approval  [email protected]



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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