Condition category
Musculoskeletal Diseases
Date applied
25/10/2013
Date assigned
25/10/2013
Last edited
02/09/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Miss Lema Vernon

ORCID ID

Contact details

Chapel Allerton Hospital
Chapeltown Road
Leeds
LS7 4SA
United Kingdom
-
l.p.vernon@leeds.ac.uk

Additional identifiers

EudraCT number

2013-001689-41

ClinicalTrials.gov number

Protocol/serial number

15495

Study information

Scientific title

Pain Reduction with Oral Methotrexate in knee Osteoarthritis: a pragmatic phase III trial of Treatment Effectiveness

Acronym

PROMOTE

Study hypothesis

Osteoarthritis (OA) is the most prevalent form of arthritis and is an increasingly common problem in our aging society. In the UK an estimated 8.5 million people are affected by OA, causing an enormous burden to health authorities, as well as considerable pain and disability to these individuals. A recent study by Arthritis Care reported that 81% of people with OA experience constant pain and 72% have important related conditions, such as hypertension or depression.

Current treatments for knee OA are limited as they often only work for short periods and are not effective for all patients. As a result people with OA often live with severe pain and have significant difficulty in carrying out their normal day-to-day activities. There is therefore an urgent need to find new and better ways to manage pain for people with OA. Methotrexate has been used very successfully to treat inflammation in rheumatoid arthritis; it is now the commonest drug used to treat that type of arthritis. Recent studies suggest that inflammation is also important in OA, and that by reducing inflammation, pain will also be reduced. We believe that methotrexate may be an effective treatment for reducing inflammation in knee OA and that this reduction in inflammation will lead to a reduction in pain.

Ethics approval

13/YH/0279; First MREC approval date 23/09/2013

Study design

Randomised interventional treatment trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Topic: Primary Care Research Network for England; Subtopic: Not Assigned; Disease: All Diseases

Intervention

Patients will be randomised on a 1:1 basis to the intervention (Methotrexate, up to 25 mg per week) or placebo, used in combination with drugs licensed for use in pain management of OA

Follow Up Length: 13 months

Intervention type

Drug

Phase

Phase III

Drug names

Methotrexate

Primary outcome measures

Average overall knee pain severity over the 1-week period prior to measurement; Timepoint(s): 6 months

Secondary outcome measures

Added 25/08/2016:
Clinical endpoints:
1. Patient-reported knee pain
2. Disease activity and knee function
3. Pain in other joints
4. Number of withdrawals due to total knee replacement in the signal knee
Measured at baseline, 3, 6, 9 and 12 months

Quality of life endpoints:
1. Quality of life
2. Anxiety and depression
Measured at baseline, 6 and 12 months

Resource use endpoints:
1. Health service resource utilisation
2. Imaging/MRI endpoints (MRI sub study)
3. Synovitis and cartilage scores
Measured at baseline, 6 and 12 months

Overall trial start date

01/01/2014

Overall trial end date

31/07/2018

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 25/08/2016:
1. Fulfil clinical American College of Rheumatology (ACR) Criteria for knee OA
2. Knee pain on most days in the last 3 months
3. Insufficient pain relief from, inability to tolerate, or contra-indication to oral and/or topical Non-steroidal anti-inflammatory drugs (NSAIDs) and/or opioids and/or Paracetamol. Moderate to severe pain of the signal knee as defined by a score of ≥40mm on a Visual analogue scale (VAS) (0-100mm) using the question “On average, how would you rate your knee pain during the last 3 months?”
4. Knee pain is the predominant pain condition
5. Patient able to identify a ‘signal’ painful knee (either the most painful knee or selected from equally painful knees)
6. A radiograph (X-Ray) of the signal knee within the last 2 years, with changes consistent with tibio-femoral OA
7. No change in the average weekly dose of oral/topical analgesics (including NSAIDs and Paracetamol) for at least 4 weeks
8. Has used chondroitin or glucosamine for at least 3 months with no change to the average weekly dose, is not using, or is willing to stop using if recently started
9. All male and female participants biologically capable of having children must agree to use a reliable method of contraception for the duration of the study and 24 weeks after the end of the study period. Acceptable methods of contraception are surgical sterilisation, oral, implantable or injectable hormonal methods, intrauterine devices or barrier contraceptives. If female and have potential for child bearing then a negative pregnancy test must be performed prior to starting treatment
10. The patient must be able to adhere to the study visit schedule and other protocol requirements
11. The patient must be capable of giving informed consent and the consent must be obtained prior to any screening procedures
12. All patients must have had a chest radiograph (X-Ray) within the last 6 months
13. Aged ≥ 18 years

Previous inclusion criteria:
1. Fulfil clinical ACR Criteria for knee OA.
2. Knee pain on most days in the last 3 months.
3. Insufficient pain relief from, inability to tolerate, or contra-indication to oral and/or topical NSAIDs and/or opioids. Moderate to severe pain of the signal knee as defined by a score of ≥40mm on a VAS (0-100mm) using the question “On average, how would you rate your knee pain during the last 3 months?”.
4. Knee pain is the predominant pain condition.
5. Patient able to identify a ‘signal’ painful knee (either the most painful knee or selected from equally painful knees).
6. A previous radiograph (X-Ray) of the signal knee with changes consistent with tibiofemoral OA.
7. No change in the average weekly dose of oral/topical analgesics (including NSAIDs) for at least 4 weeks.
8. Has used chondroitin or glucosamine for at least 3 months with no change to the average weekly dose, is not using or is willing to stop using if recently started.
9. Men and women must use adequate birth control measures (e.g. abstinence, oral contraceptives, Intra-uterine device, barrier method with spermicide, or surgical sterilisation) for the duration of the study and should continue such precautions for 6 months after receiving the last dose of MTX. If female and have potential for child bearing then a negative pregnancy test must be performed prior to starting treatment.
10. The patient must be able to adhere to the study visit schedule and other protocol requirements.
11. The patient must be capable of giving informed consent and the consent must be obtained prior to any screening procedures.
12. All patients must have had a chest radiograph (X-Ray) within the last 6 months.
13. Target Gender: Male & Female ; Lower Age Limit 18 years

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

UK Sample Size: 160

Participant exclusion criteria

Current exclusion criteria as of 25/08/2016:
1. The presence of any inflammatory arthritis (e.g. gout, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, seronegative spondylarthropathy, previous diagnosis of pseudogout in target joint with proven crystals on joint aspiration or elevated CRP at time of knee arthritis flare) or fibromyalgia.
2. Use of intra-articular (IA) hyaluronic acid in the signal knee within the 4 months preceding enrolment in the study.
3. Use of IA, IM or oral corticosteroids in the 3 months preceding enrolment.
4. Use of other anti-synovial agents (e.g. hydroxychloroquine or sulphasalazine) in the 2 months preceding the study.
5. Significant knee injury or any knee surgery within the 6 months preceding enrolment in the study.
6. A history of partial or complete joint replacement surgery in the signal knee at any time, listed for knee surgery, or anticipating knee surgery during the study period.
7. Commencement of physiotherapy or non-pharmacological knee OA treatment in the 2 months preceding the study.
8. The presence of non-OA causes of pain in the signal knee e.g. referred hip pain, osteonecrosis.
9. Women who are pregnant, breast-feeding, or men or women planning pregnancy within 18 months after screening (i.e. approximately 6 months following last study medications).
10. Use of any investigational (unlicensed) drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
11. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral disease, or active current infection.
12. Uncontrolled disease states, such as moderate/severe asthma, Chronic Obstructive Pulmonary Disease (COPD) or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids, or recurrent infections.
13. Unwilling to keep alcohol intake to below the recommended maximum daily limit during the trial (2 units per day for women, 3 units per day for men).
14. Planned need for live vaccination during 12 months of study (e.g. for foreign travel) with exception of Zostavax® which is permissible.
15. Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period.
16. Melanoma, squamous cell carcinoma or non-skin cancer in the past 3 years.
17. Intolerance to lactose.
18. Significant haematological or biochemical abnormality
18.1. Haemoglobin =<8.5 g/dL
18.2. WCC =<3.5 x 109/L
18.3. Neutrophils =<1.5 x 109/L
18.4. Platelets =<100 x 109/L
18.5. ALT >2 times ULN for the laboratory conducting the test.
18.6. Creatinine > 1.5 times ULN for the laboratory conducting the test
18.7. eGFR <30ml/minute

Subjects with the following contra-indications to MRI scanning will not be included in the MRI substudy but may still be enrolled into the main study:
1. Pacemakers
2. Surgical clips within the head
3. Certain inner ear implants
4. Neuro-electrical stimulators
5. Metal fragments within the eye or head

Previous exclusion criteria:
1. The presence of any inflammatory arthritis (e.g. gout, reactive arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, seronegative spondylarthropathy) or fibromyalgia.
2. Use of intra-articular (IA) hyaluronic acid in the signal knee within the 4 months preceding enrolment in the study.
3. Use of IA, IM or oral corticosteroids in the 3 months preceding enrolment.
4. Use of other anti-synovial agents (e.g. hydroxychloroquine or sulphasalazine) in the 2 months preceding the study.
5. Significant knee injury or any knee surgery within the 6 months preceding enrolment in the study.
6. A history of partial or complete joint replacement surgery in the signal knee at any time, listed for knee surgery or anticipating knee surgery during the study period.
7. Commencement of physiotherapy or non-pharmacological knee OA treatment in the 2 months preceding the study.
8. The presence of non-OA causes of pain in the signal knee e.g. referred hip pain, osteonecrosis.
9. Women who are pregnant, breast-feeding, or men or women planning pregnancy within 18 months after screening (i.e. approximately 6 months following last study medications).
10. Use of any investigational (unlicensed) drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
11. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease.
12. Uncontrolled disease states, such as moderate/severe asthma, COPD or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids, or recurrent infections.
13. Intake of alcohol above the recommended government guidelines (2 units per day for women, 3 units per day for men).
14. Planned need for live vaccination during 12 months of study (e.g. for foreign travel) or lack of immunity to chicken pox.
15. Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period.
16. Melanoma or non-skin cancer in the past 3 years.
17. Intolerance to lactose.
18. Significant haematological or biochemical abnormality
18.1. Haemoglobin =<8.5 g/dL
18.2. WCC =<3.5 x 109/L
18.3. Neutrophils =<1.5 x 109/L
18.4. Platelets =<100 x 109/L
18.5. ALT >2 times ULN for the laboratory conducting the test.
18.6. Creatinine > 1.5 times ULN for the laboratory conducting the test
18.7. eGFR <30ml/minute

Subjects with the following contra-indications to MRI scanning will not be included in the MRI substudy but may still be enrolled into the main study:
1. Pacemakers
2. Surgical clips within the head
3. Certain inner ear implants
4. Neuro-electrical stimulators
5. Metal fragments within the eye or head

Recruitment start date

01/05/2014

Recruitment end date

31/08/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Leeds Teaching Hospitals Trust
Chapel Allerton Hospital Chapeltown Road
Leeds
LS7 4SA
United Kingdom

Trial participating centre

Aintree University Hospital NHS Trust
Longmoor Lane
Liverpool
L9 7AL
United Kingdom

Trial participating centre

Staffordshire and Stoke-on-Trent Partnership NHS Trust
Haywood Hospital High Lane Burslem
Stoke-On-Trent
ST6 7AG
United Kingdom

Trial participating centre

Northumbria Healthcare NHS Foundation Trust
Rake Lane
North Shields
NE29 8NH
United Kingdom

Trial participating centre

NHS Fife
Victoria Hospital Hayfield Road
Kirkcaldy
KY2 5AH
United Kingdom

Trial participating centre

Cannock Chase Hospital
Brunswick Road
Cannock
WS11 5XY
United Kingdom

Trial participating centre

New Cross Hospital
Wolverhampton Road
Wolverhampton
WV10 0QP
United Kingdom

Trial participating centre

Guys and St Thomas’s
Guy's Hospital Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

King's College Hospital
King's College London Suite 3, Golden Jubilee Wing King’s College Hospital Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Ashford & St Peter’s Hospitals NHS Foundation Trust
Guildford Road
Chertsey
KT16 0PZ
United Kingdom

Trial participating centre

NIHR Wellcome Trust Southampton Clinical Research Facility
Southampton Centre for Biomedical Research C Level West Wing Mailpoint 218 Southampton General Hospital Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Harrogate and District NHS Foundation Trust
Lancaster Park Road Harrogate
York
HG2 7SX
United Kingdom

Trial participating centre

York Teaching Hospital NHS Foundation Trust
Wigginton Road
York
YO31 8HE
United Kingdom

Trial participating centre

Salford Royal NHS Foundation Trust
Stott Lane
Salford
M6 8HD
United Kingdom

Trial participating centre

Oxford University Hospitals NHS Foundation Trust
Nuffield Orthopaedic Centre Windmill Road Headington
Oxford
OX3 7HE
United Kingdom

Trial participating centre

West Suffolk NHS Foundation Trust
Hardwick Lane
Bury St Edmunds
IP33 2QZ
United Kingdom

Sponsor information

Organisation

University of Leeds (UK)

Sponsor details

Faculty Research Office
Room 10.110
Level 10 Worsley Building
Clarendon Way
Leeds
LS2 9NL
United Kingdom

Sponsor type

University/education

Website

http://www.leeds.ac.uk/

Funders

Funder type

Charity

Funder name

Arthritis Research UK (UK)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

To be confirmed at a later date

Intention to publish date

31/07/2019

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2015 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/25872649

Publication citations

Additional files

Editorial Notes

25/08/2016: the overall trial end date was changed from 30/06/2015 to 31/07/2018.