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Trial registered on ANZCTR


Registration number
ACTRN12613000530729
Ethics application status
Approved
Date submitted
22/04/2013
Date registered
13/05/2013
Date last updated
7/04/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
PRECISE: pregabalin in addition to usual care for sciatica.
Scientific title
PRECISE, a two arm, double blind randomised controlled trial of pregabalin in addition to usual care compared to placebo with usual care for reducing leg pain in patients with sciatica.
Secondary ID [1] 282382 0
None
Universal Trial Number (UTN)
Trial acronym
PRECISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sciatica 288962 0
Condition category
Condition code
Musculoskeletal 289295 289295 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 pregabalin plus usual care.

Pregabalin is a drug to treat neuropathic pain.

Initial dose of 150mg/day, divided over 2 dosed and may be increased to a maximium dose of 600mg/day with gradual titration over a four week period. Discontinuation is to reduce the dose over >7 days.

It is administered in capsule form.

The participants will be monitored over the 8 week treatment by a study doctor period.The study doctor will amend the dosage based on the patient’s ‘adequate improvement’ to the study medicine. Adequate improvement is defined as a pain rating of 0 or 1 out of 10, for leg pain, for a minimum of 72 hours, with none or tolerable side effects. If ‘adequate improvement’ has not occurred, the study doctor may increase the study medicine dosage. If ‘adequate improvement’ is reported, the dose can remain the same until the end of the study. The maximum tolerated dose for each participant will be maintained for 4 weeks or up to ‘adequate improvement’or if achieved before the 8 week standard treatment regimen is completed, early titration down to cessation. All patients will be titrated down to cessation to complete the study treatment period.

In addition to receiving the study medicines and advice (patient reassurance, staying active and avoiding bed rest) participants will receive usual care. This can consist of physical or manual therapies and other analgesic medications (except adjuvant analgesics), if deemed appropriate by the study doctor.

The total invention time is 8 weeks. The follow up includes up to 9 participant consultations with the study doctor study to begin treatment, monitor progress and adjust the dose of the study medication. Outcomes measures will be collected at baseline and weeks 2, 4, 8, 12, 26 and 52.

Adherence will be achieved through study doctor training, participant consultations, data collected from the participant by research assistants. Procedures for monitoring adherence include Adherence to study medication will be documented through a self-reported daily medication diary and by counting the returned medicine, compared to the prescribed regimen as recorded by the study doctor. Participants will be asked to return unused medicines via a reply paid post satchel at the end of the 8-week treatment period.
Intervention code [1] 287012 0
Treatment: Drugs
Comparator / control treatment
Placebo plus usual care.

The placebo capsule consists of
lactose, maize starch, purified talc, gelatin, titanium dioxide, sodium lauryl sulfate, colloidal anhydrous silica, red iron oxide CI77491.

Its duration, control and follow up is the same as the intervention treatment of pregbalin ( as described above)
Control group
Placebo

Outcomes
Primary outcome [1] 289405 0
Average leg pain intensity over the last 24 hours measured by the numeral pain rating scale.

Timepoint [1] 289405 0
Time point: baseline, week 2, 4, 8, 12, 26, 52.
Secondary outcome [1] 302408 0
Back pain intensity using the Numerical Pain Rating Scale.
Timepoint [1] 302408 0
Time point: baseline and weeks 2, 4, 8, 12, 26 and 52.
Secondary outcome [2] 302409 0
Disability by the Roland Disability Questionnaire for Sciatica.
Timepoint [2] 302409 0
Time point: baseline and weeks 2, 4, 8, 12, 26 and 52.
Secondary outcome [3] 302410 0
Quality of Life (SF-12v2) questionnaire.
Timepoint [3] 302410 0
Time point: baseline and weeks 2, 4, 8, 12, 26 and 52.
Secondary outcome [4] 302411 0
Global Perceived Effect, which asks the participant to compare their leg pain to when this episode of sciatica first started.
Timepoint [4] 302411 0
Time point: baseline and weeks 2, 4, 8, 12, 26 and 52.
Secondary outcome [5] 302412 0
Work and health utilization questions to report the use of health services and amount of hours missed from paid employment because of sciatica.
Timepoint [5] 302412 0
Time point: baseline and weeks 4, 12, 26 and 52.

Eligibility
Key inclusion criteria
Eligible participants will meet all of the following criteria:

Radiating pain into one leg below the knee.

Nerve root/spinal nerve involvement evidenced by at least one of the following clinical features:
a) Myotomal weakness,
b) Dermatomal sensory deficits,
c) Diminished reflexes,
d) Leg pain radiating in a dermatomal distribution.

Leg pain severe enough to cause at least moderate pain or moderate interference with normal work or daily activities over the last week (measured by adaptations of items 7 and 8 in the SF-36 questionnaire).

Pain duration of current episode of at least 1 week and up to 1 year.

Age 18 years and over.

Sufficient understanding of the English language or interpretation assistance available to complete the study treatment and assessments.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they meet any of the following criteria:

Known or suspected serious spinal pathology (e.g. cauda equina syndrome, spinal fracture).

Pregnant or breastfeeding women, and males or females planning conception during the 8 week treatment period.

Scheduled or being considered for spinal surgery or interventional procedures for sciatica during the 8 week treatment period.

Contraindications to pregabalin (known allergy to pregabalin or significant renal impairment. Pregabalin is predominantly renally excreted, so patients with an estimated creatinine clearance of < 60 ml/min will be excluded).

Already taking an anticonvulsant medication, a medication for neuropathic pain, a tricyclic antidepressant or a sedative and unable to cease the medication.

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)
Participants will be recruited from patients in the community who consult a study general practitioner (GP) or medical specialist (e.g. orthopaedic surgeon, neurosurgeon, neurologist or rheumatologist). Other sources will be patients seeking care from physiotherapists and chiropractors, or patients who respond to a community advertisement. Potential participants are then referred to a study GP to complete screening and enrolment.

Allocating treatment- the study medication (pregabalin or placebo) will be prepared by the study pharmacy according to a randomisation schedule generated a priori, then sealed and supplied to the recruiting doctor (blinded). The doctor will provide each eligible and consenting participant with a sealed study medication pack, thus randomising them to either the treatment or control group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A researcher not involved in participant recruitment or data collection will generate a randomisation schedule a priori using a computer derived random number sequence. Study medication will be prepared according to the randomisation schedule by the study pharmacy, then sealed and supplied to the study doctors. Upon recruitment, the doctor (blinded) will provide the medication pack to the participant (blinded), thus randomising the participant to one of two groups: pregabalin with usual care or placebo with usual care. Placebo capsules will have an identical appearance to the active pregabalin capsules. The randomisation process will ensure concealed allocation and blinding of the doctor, participant and outcome assessor.
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 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Treatment effectiveness analyses will be blinded and by intention-to-treat. A two-tailed p-value of < 0.05 will be considered statistically significant. Longitudinal linear models including all post-baseline measurements available will be used to assess the effect of treatment group on the primary and secondary outcomes with the baseline measurement and symptom duration as covariates. In case of significant missing data, sensitivity analyses will be conducted using multiple imputation, where reasonable. A secondary analysis will assess the presence of neuropathic pain features, measured by the PainDETECT questionnaire at baseline, as a modifier of treatment effects.

Economic evaluation will be conducted in two ways. Firstly a cost-effectiveness study using leg pain intensity as a measure of effectiveness and secondly a cost-utility analysis where health state utilities (quality-adjusted life-years or QALY) will be based on measures obtained from the SF-12 and transformed into utilities via the SF-6D algorithm. The primary analysis will be conducted from the health sector’s perspective, where healthcare services will be valued at standard rates published by the Australian Government (e.g. the Medical Benefits Scheme standard fees, the Pharmaceutical Benefits Scheme costs). Private non-medical healthcare services (e.g. physiotherapy) will be valued at standard rates published by the relevant professional body or third party payer. An additional analysis will entail a societal perspective in which costs associated with the use of community services (e.g. community hydrotherapy classes) and work absenteeism due to sciatica will be included. Costs of community services will be based on the self-reported costs. Costs of absenteeism from paid employment will be estimated by the number of days absent from work multiplied by the average wage rate. Sensitivity analysis will test uncertainty in key parameters such as the selection of cost weights and statistical variation in quality of life scores.

We have calculated the required sample size using a standard algorithm. The primary outcome is leg pain at week 8. A sample size of 204 participants (102 per group) will provide 90% power to detect a difference of 1.5 out of 10 units of leg pain on the Numerical Pain Rating Scale, assuming a standard deviation of 2.5, a two-tailed alpha of 0.05, and allowing for 10% of dropouts and 20% non-compliance. There is no robust evidence for the smallest worthwhile effect in pain reduction in sciatica. We have based the sample size calculation on a between-group difference of 1.5/10 in leg pain from previous trials of pregabalin for neuropathic pain. The sample size also has 90% power to detect a difference of 3 out of 23 at week 8 on our key secondary outcome, the Roland Disability Questionnaire for Sciatica. This is based on the between-group difference (3/23) and standard deviation from one of our previous sciatica trials (4/23) and the same assumptions taken for the primary outcome calculation.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 8068 0
2093 - Balgowlah
Recruitment postcode(s) [2] 8069 0
2200 - Bankstown
Recruitment postcode(s) [3] 8070 0
2119 - Beecroft
Recruitment postcode(s) [4] 8071 0
2153 - Bella Vista
Recruitment postcode(s) [5] 8072 0
2148 - Blacktown
Recruitment postcode(s) [6] 8073 0
2134 - Burwood
Recruitment postcode(s) [7] 8074 0
2570 - Camden
Recruitment postcode(s) [8] 8075 0
2560 - Campbelltown
Recruitment postcode(s) [9] 8076 0
2166 - Canley Heights
Recruitment postcode(s) [10] 8077 0
2230 - Cronulla
Recruitment postcode(s) [11] 8078 0
2099 - Dee Why
Recruitment postcode(s) [12] 8079 0
2113 - East Ryde
Recruitment postcode(s) [13] 8080 0
2233 - Engadine
Recruitment postcode(s) [14] 8081 0
2759 - Erskine Park
Recruitment postcode(s) [15] 8082 0
2768 - Glenwood
Recruitment postcode(s) [16] 8083 0
2077 - Hornsby
Recruitment postcode(s) [17] 8084 0
2220 - Hurstville
Recruitment postcode(s) [18] 8085 0
2066 - Lane Cove
Recruitment postcode(s) [19] 8086 0
2070 - Lindfield
Recruitment postcode(s) [20] 8087 0
2035 - Maroubra
Recruitment postcode(s) [21] 8088 0
2204 - Marrickville
Recruitment postcode(s) [22] 8089 0
2160 - Merrylands
Recruitment postcode(s) [23] 8090 0
2137 - Mortlake
Recruitment postcode(s) [24] 8091 0
2152 - Northmead
Recruitment postcode(s) [25] 8092 0
2021 - Paddington
Recruitment postcode(s) [26] 8093 0
2124 - Parramatta
Recruitment postcode(s) [27] 8094 0
2120 - Pennant Hills
Recruitment postcode(s) [28] 8095 0
2750 - Penrith
Recruitment postcode(s) [29] 8096 0
2011 - Potts Point
Recruitment postcode(s) [30] 8097 0
2009 - Pyrmont
Recruitment postcode(s) [31] 8098 0
2031 - Randwick
Recruitment postcode(s) [32] 8099 0
2143 - Regents Park
Recruitment postcode(s) [33] 8100 0
2216 - Rockdale
Recruitment postcode(s) [34] 8101 0
2560 - Rosemeadow
Recruitment postcode(s) [35] 8102 0
2039 - Rozelle
Recruitment postcode(s) [36] 8103 0
2112 - Ryde
Recruitment postcode(s) [37] 8104 0
2000 - Sydney
Recruitment postcode(s) [38] 8105 0
2573 - Tahmoor
Recruitment postcode(s) [39] 8106 0
2084 - Terrey Hills
Recruitment postcode(s) [40] 8107 0
2570 - The Oaks
Recruitment postcode(s) [41] 8108 0
2146 - Toongabbie
Recruitment postcode(s) [42] 8109 0
2017 - Waterloo
Recruitment postcode(s) [43] 8110 0
2145 - Wentworthville
Recruitment postcode(s) [44] 8111 0
2153 - Winston Hills
Recruitment postcode(s) [45] 8112 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 287154 0
Government body
Name [1] 287154 0
National Health and Medical Research Council (NHMRC).
Address [1] 287154 0
Level 1, 16 Marcus Clarke St,
Canberra, NSW, 2601, Australia.
Country [1] 287154 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The George Institute for Global Health
Address
PO Box M201
Missenden Rd, NSW 2050.
Country
Australia
Secondary sponsor category [1] 285919 0
University
Name [1] 285919 0
Sydney Medical School, University of Sydney.
Address [1] 285919 0
Edward Ford Building,
University of Sydney,
Cnr Physics Rd & Fisher Rd,
Camperdown, NSW, 2006.
Country [1] 285919 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289151 0
University of Sydney Research Ethics Committee
Ethics committee address [1] 289151 0
Level 6 Jane Foss Russell Building-G02,
The University of Sydney, NSW, 2006, Australia.
Ethics committee country [1] 289151 0
Australia
Date submitted for ethics approval [1] 289151 0
Approval date [1] 289151 0
07/11/2012
Ethics approval number [1] 289151 0

Summary
Brief summary
Patients with sciatica experience low back pain, with pain radiating into the leg and possible neurological deficits. Sciatica is associated with substantial pain and chronic disability. The lack of evidence supporting effective treatments for sciatica makes clinical management difficult.

The aim of the study is to determine the efficacy and cost effectiveness of adding pregabalin to usual care for reducing leg pain intensity in patients with sciatica.

PRECISE is a prospectively registered, double blind, randomized placebo controlled trial of pregabalin, in addition to usual care in people with sciatica. Participants will be recruited from patients in the community who consult a study general practitioner (GP) or medical specialist (e.g. orthopaedic surgeon, neurosurgeon, neurologist or rheumatologist) with moderate to severe sciatica. GPs and specialists will be recruited from the Sydney metropolitan area (Australia). Other referral sources include physiotherapists and chiropractors that may identify potential participants and then refer the patient to a study GP. Participant inclusion criteria include low back pain that radiates below the knee, neurological compromise, interference with normal daily activities and pain duration of 1 week to 1 year. Participants will not be eligible if they are scheduled for spinal surgery, have known serious pathology, are pregnant, have contraindications to pregabalin or taking certain prescribed medicines. Participants will be randomised to receive either pregabalin with usual care (n=102) or the placebo with usual care (n=102) for 8 weeks. The medicine dosage will be titrated up to the participant’s optimal dose, to a maximum 600 mg per day. Usual care, if deemed appropriate by the study doctor may include analgesic medication or physical and manual therapy. Participants, doctors and researchers collecting participant data will be blinded. The primary outcome is leg pain. Secondary outcomes include back pain, disability and quality of life. Treatment effectiveness analysis will be blinded and by intention-to-treat. A p-value of < 0.05 will be considered statistically significant. A parallel economic evaluation will be conducted from the societal perspective.
Trial website
Trial related presentations / publications
Mathieson S, Maher CG, McLachlan AJ, Latimer J, Koes BW, Hancock MJ, Harris I,
Day RO, Billot L, Pik J, Jan S, Lin CC. Trial of Pregabalin for Acute and Chronic
Sciatica. N Engl J Med. 2017 Mar 23;376(12):1111-1120. doi:10.1056/NEJMoa1614292. PubMed PMID: 28328324.
Public notes

Contacts
Principal investigator
Name 39490 0
Dr Chung-Wei Christine LIN
Address 39490 0
The George Institute for Global Health,
PO Box M201,
Missenden Rd, NSW 2050.
Country 39490 0
Australia
Phone 39490 0
+612 8238 2437
Fax 39490 0
+612 9657 0301
Email 39490 0
clin@georgeinstitute.org.au
Contact person for public queries
Name 39491 0
Ms Stephanie MATHIESON
Address 39491 0
The George Institute for Global Health,
PO Box M201,
Missenden Rd, NSW 2050.
Country 39491 0
Australia
Phone 39491 0
+612 9657 0300
Fax 39491 0
+612 9657 0301
Email 39491 0
smathieson@georgeinstitute.org.au
Contact person for scientific queries
Name 39492 0
Dr Chung-Wei Christine LIN
Address 39492 0
The George Institute for Global Health,
PO Box M201,
Missenden Rd, NSW 2050.
Country 39492 0
Australia
Phone 39492 0
+612 8238 2437
Fax 39492 0
+612 9657 0301
Email 39492 0
clin@georgeinstitute.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary