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    Summary
    EudraCT Number:2013-001689-41
    Sponsor's Protocol Code Number:RR11/9858
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-10-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2013-001689-41
    A.3Full title of the trial
    Pain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Does methotrexate provide effective pain relief for people with knee osteoarthritis?
    A.3.2Name or abbreviated title of the trial where available
    PROMOTE
    A.4.1Sponsor's protocol code numberRR11/9858
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Leeds
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Leeds
    B.5.2Functional name of contact pointSarah Hogg
    B.5.3 Address:
    B.5.3.1Street AddressLIRMM, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road,
    B.5.3.2Town/ cityLeeds
    B.5.3.3Post codeLS7 4SA
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01133924990
    B.5.5Fax number01133924991
    B.5.6E-mails.f.hogg@leeds.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Methotrexate
    D.2.1.1.2Name of the Marketing Authorisation holderEMEA licensed brand to be used
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMethotrexate
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmethotrexate sodium
    D.3.9.1CAS number 59-05-2
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Knee osteoarthritis
    E.1.1.1Medical condition in easily understood language
    Pain in knee joints
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10031161
    E.1.2Term Osteoarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10023476
    E.1.2Term Knee osteoarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10031166
    E.1.2Term Osteoarthritis knees
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10031165
    E.1.2Term Osteoarthritis knee
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to determine whether methotrexate is an effective treatment for relieving pain in knee OA.
    E.2.2Secondary objectives of the trial
    The secondary objective is to determine whether methotrexate is a cost effective treatment for knee OA.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    MRI sub study: The objective of the MRI substudy is to examine whether methotrexate reduces inflammation within the osteoarthritic knee joint and if this is related to symptom change and is a predictor of response. MRI of the signal knee will be performed at baseline and six months (24 weeks). Participation in the MRI substudy is optional.
    Biological sub study: The objective of the biological substudy is to analyse markers of inflammation in the blood to determine which markers/genes are important in osteoarthritis and the response to treatment. Biological samples (blood and urine) will be taken at baseline and six months (24 weeks). Participation in the biological substudy is optional.
    E.3Principal inclusion criteria
    Patients to be included must meet the following 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 radiograph (X-Ray) of the signal knee within the last 2 years 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. All male and female subjects 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
    E.4Principal exclusion criteria
    Patients will be excluded from this study for any of the following reasons:
    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, 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
    a. Haemoglobin =<8.5 g/dL
    b. WCC =<3.5 x 109/L
    c. Neutrophils =<1.5 x 109/L
    d. Platelets =<100 x 109/L
    e. ALT >2 times ULN for the laboratory conducting the test.
    f. Creatinine > 1.5 times ULN for the laboratory conducting the test
    g. 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:
    • Pacemakers
    • Surgical clips within the head
    • Certain inner ear implants
    • Neuro-electrical stimulators
    • Metal fragments within the eye or head
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will be change in knee pain between baseline and 6 months (24 weeks). This will be measured using an 11 point numerical rating scale (NRS) with the anchor questions ‘On average, how would you rate your overall knee pain severity over the last week (7 days)', at 6 months (24 weeks) after the start of treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months (24 weeks)
    n.b. “Month” will be the label used on all follow-up CRF’s, and is defined as a period of 4 weeks for the purposes of the PROMOTE Trial.
    E.5.2Secondary end point(s)
    Clinical endpoints (at 0, 3, 6, 9, 12 months)
    • Patient reported knee pain
    • Disease activity and knee function
    • Pain in other joints;

    Quality of life endpoints (at 0, 6, 12 months)
    • Quality of life
    • Anxiety and depression

    Resource use endpoints (at 0, 6, 9, 12 months)
    • Health service resource utilisation

    Imaging/MRI endpoints (MRI substudy at 0 and 6 months)
    • Synovitis and cartilage scores
    E.5.2.1Timepoint(s) of evaluation of this end point
    0, 3, 6, 9, 12 months as stated above.
    n.b. “Month” will be the label used on all follow-up CRF’s, and is defined as a period of 4 weeks for the purposes of the PROMOTE Trial.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned17
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state160
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the trial, participants will be return to the care of their General Practitioner to determine appropriate long-term therapy as per clinical need.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation West Yorkshire CLRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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