Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000683639
Ethics application status
Approved
Date submitted
21/06/2014
Date registered
27/06/2014
Date last updated
14/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Nortriptyline in knee arthritis
Scientific title
A randomised placebo controlled trial of nortriptyline for pain in knee osteoarthritis
Secondary ID [1] 284851 0
Nil known.
Universal Trial Number (UTN)
U1111-1158-3131
Trial acronym
NortIKA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoarthritis 292246 0
Condition category
Condition code
Musculoskeletal 292585 292585 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Nortriptyline as 25mg capsules. Dose adjusted during 8 week dose-finding period according to participant response from starting dose of 25mg daily to maximum potential dose of 100mg daily. During the dose-finding period each participant will be contacted fortnightly by the research nurse to make dose adjustments. This period will then be followed by a 6 week steady dosing period. Participants will be asked to complete medication diaries to assess adherence.
Intervention code [1] 289647 0
Treatment: Drugs
Comparator / control treatment
Placebo capsules containing non-active ingredients only.
Control group
Placebo

Outcomes
Primary outcome [1] 292442 0
Difference between active treatment and placebo arms in mean pain score at 14 weeks, measured using the WOMAC pain subscale and adjusted for pain score at baseline.
Timepoint [1] 292442 0
14 weeks.
Secondary outcome [1] 308952 0
Physical function using the WOMAC function subscale.
Timepoint [1] 308952 0
14 weeks.
Secondary outcome [2] 308953 0
Participant-rated global assessment using a visual analogue scale.
Timepoint [2] 308953 0
14 weeks.
Secondary outcome [3] 308954 0
Difference in the proportion of participants reporting a treatment effect, defined according to the Osteoarthritis Research Society International set of responder criteria.
Timepoint [3] 308954 0
14 weeks.
Secondary outcome [4] 308955 0
Quality of life using the Medical Outcomes Study (MOS) 36-Item Short Form Survey Instrument and scored according to the simpler RAND scoring instructions.
Timepoint [4] 308955 0
14 weeks.
Secondary outcome [5] 308956 0
Participant-recorded NSAID and other analgesic use in the final 2 weeks of the study period.
Timepoint [5] 308956 0
14 weeks.
Secondary outcome [6] 308957 0
Adverse events using the Common Terminology Criteria for Adverse Events. Tricyclic adverse effects will be specifically measured using the Antidepressant Side-Effect Checklist.
Timepoint [6] 308957 0
14 weeks.

Eligibility
Key inclusion criteria
1. Primary knee OA defined according to American College of Rheumatology (ACR) classification criteria (knee pain plus 3 of: age >50 years, stiffness <30 mins, crepitus, bony tenderness, bony enlargement, no palpable warmth).
2. Pain severity of >=20 points on the Western Ontario and McMaster Universities (WOMAC) numerical rating scale (range 0 to 50 points) at the study knee.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
01. Prior joint replacement surgery on the study knee
02. Intra-articular steroid injection within the previous 3 months
03. Secondary OA (OA due to inflammatory arthritis [eg gout, rheumatoid arthritis, juvenile arthritis], septic arthritis or trauma)
04. Known hypersensitivity to nortriptyline or history of adverse reaction to any tricyclic antidepressant
05. Current use of nortriptyline or other antidepressants, or amiodarone
06. Within 6 months of myocardial infarction
07. Heart block
08. Postural hypotension
09. Pregnancy
10. Hyperthyroidism or phaeochromocytoma under current investigation or treatment
11. History of epilepsy or other seizure
12. History of bipolar disorder or manic episode
13. History of increased intra-ocular pressure or history of angle-closure glaucoma
14. Chronic constipation
15. Urinary retention

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)
Upon providing informed consent, each participant will be assigned a unique sequentially-numbered study identifier according to the order in which he or she is enrolled in the trial. The participant will then complete the baseline assessment and anthropometric measures, before the research nurse dispenses the study medication. The study medication (nortriptyline or identical placebo) will be packaged in identical containers. Each container will be pre-labelled (by the pharmacist contracted to provide the study medication) with a study identifier according to randomisation schedule. The contracted pharmacist will have no contact with the participants, nor will he be able to influence treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to receive nortriptyline or placebo at a 1:1 ratio using a computer generated randomisation schedule with permuted blocks of random size. The randomisation schedule will not be stratified as the risk of important imbalances in prognostic factors is small for a trial of this size.
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 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The minimum important clinical difference for a reduction in pain measure using the WOMAC osteoarthritis index has been determined to be about 10% of the scale maximum, or a total difference of five points on the WOMAC pain numerical rating scale (range 0 to 50). A sample size of 85 per group will give at least 90% power at a significance level of 0.05 to detect a difference in treatment effect of five points between the nortriptyline and placebo groups. The sample size was calculated using a pooled standard deviation ten points estimated from previous studies, and conservatively assuming no correlation between baseline and follow-up scores. This sample size also allows for detection of the minimum important clinical difference in the proportion of participants responding to treatment according to the OMERACT-OARSI criteria. The sample size will be inflated to 100 participants per group (200 in total) to account for a possible 15% loss-to-follow-up.

Data analysis will be performed on an intention to treat basis. All statistical tests will be two-sided and a level of significance (alpha) of = 0.05 set for all confidence intervals and p values. The mean and standard deviation of participants’ WOMAC pain score at 14 weeks follow-up, and change between baseline and 14 weeks, will be calculated for each treatment group. The primary outcome of the study will be the size of the treatment effect (mean difference in pain between treatment groups at 14 weeks adjusting for differences at baseline), which will be determined using linear regression modelling including treatment group as fixed effect and baseline pain scores as a covariate. A secondary analysis of this primary outcome will be conducted using multivariable linear regression, adjusting for pre-randomisation variables reasonably expected to predict a favourable outcome (duration of disease, medication use at baseline, and use of assistive devices), and participants’ use of other analgesics (paracetamol, NSAIDs, and opiates) in the 2 final weeks of the study period (weeks 12-14). Secondary continuous outcome measures (WOMAC function and stiffness, patient global assessment, and quality of life measures) will be analysed in a similar manner.

As secondary analysis, patients will be dichotomised according to the OMERACT-OARSI set of responder criteria, defined as a high improvement in pain or function, or a moderate improvement in at least two of pain, function, or patient’s global assessment. Incident rates will be calculated for this and other binary outcomes (including use of other pain medications, adverse events, and tricyclic side effects and compared using chi-square or Fisher exact tests. Generalised linear regression models will be used to calculate absolute and relative differences in risk between treatment groups with 95% confidence intervals, adjusting for other variables as appropriate. Self-reported treatment dosage over the past two weeks will be summarised for each follow-up, as will the number of participants discontinuing treatment and reasons for doing so. The incidence of all suspect serious treatment reactions will be presented in line with the CONSORT 2010 recommendations.

Participants who are missing outcome data will be included in the analysis using modern multiple imputation methods. To determine the robustness of results per protocol analysis will be performed, excluding participants with major protocol violations such as cross-over treatments, withdrawals and loss-to-follow-up. The dose-response rate will be investigated by entering final dose achieved as a predictor in regression models.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/02/2015
Actual
3/03/2015
Date of last participant enrolment
Anticipated
1/02/2017
Actual
31/10/2017
Date of last data collection
Anticipated
Actual
8/02/2018
Sample size
Target
200
Accrual to date
Final
205
Recruitment outside Australia
Country [1] 6171 0
New Zealand
State/province [1] 6171 0

Funding & Sponsors
Funding source category [1] 289460 0
Government body
Name [1] 289460 0
Health Research Council of New Zealand
Country [1] 289460 0
New Zealand
Primary sponsor type
Individual
Name
Dr Ben Hudson
Address
Department of General Practice
University of Otago
PO Box 4345
Christchurch 8140
New Zealand
Country
New Zealand
Secondary sponsor category [1] 288147 0
None
Name [1] 288147 0
Address [1] 288147 0
Country [1] 288147 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292008 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 292008 0
Ethics committee country [1] 292008 0
New Zealand
Date submitted for ethics approval [1] 292008 0
27/08/2014
Approval date [1] 292008 0
15/09/2014
Ethics approval number [1] 292008 0
14/NTA/139

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49386 0
Dr Ben Hudson
Address 49386 0
Department of General Practice
University of Otago
Christchurch
PO Box 4345, Christchurch 8140
Country 49386 0
New Zealand
Phone 49386 0
+64 27 3481122
Fax 49386 0
+64 3 3643637
Email 49386 0
ben.hudson@otago.ac.nz
Contact person for public queries
Name 49387 0
Ben Hudson
Address 49387 0
Department of General Practice
University of Otago
Christchurch
PO Box 4345, Christchurch 8140
Country 49387 0
New Zealand
Phone 49387 0
+64 27 3481122
Fax 49387 0
+64 3 3643637
Email 49387 0
ben.hudson@otago.ac.nz
Contact person for scientific queries
Name 49388 0
Ben Hudson
Address 49388 0
Department of General Practice
University of Otago
Christchurch
PO Box 4345, Christchurch 8140
Country 49388 0
New Zealand
Phone 49388 0
+64 27 3481122
Fax 49388 0
+64 3 3643637
Email 49388 0
ben.hudson@otago.ac.nz

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseNortriptyline in knee osteoarthritis (NortIKA Study): Study protocol for a randomised controlled trial.2015https://dx.doi.org/10.1186/s13063-015-0961-1
N.B. These documents automatically identified may not have been verified by the study sponsor.