Clinical Trials Register

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

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2013-001689-41

A.3

Full title of the trial

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

A.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

PROMOTE

A.4.1

Sponsor's protocol code number

RR11/9858

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Leeds
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Leeds
B.5.2	Functional name of contact point	Sarah Hogg
B.5.3	Address:
B.5.3.1	Street Address	LIRMM, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road,
B.5.3.2	Town/ city	Leeds
B.5.3.3	Post code	LS7 4SA
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01133924990
B.5.5	Fax number	01133924991
B.5.6	E-mail	s.f.hogg@leeds.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Methotrexate
D.2.1.1.2	Name of the Marketing Authorisation holder	EMEA licensed brand to be used
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Methotrexate
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	methotrexate sodium
D.3.9.1	CAS number	59-05-2
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Knee osteoarthritis

E.1.1.1

Medical condition in easily understood language

Pain in knee joints

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10031161
E.1.2	Term	Osteoarthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10023476
E.1.2	Term	Knee osteoarthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10031166
E.1.2	Term	Osteoarthritis knees
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10031165
E.1.2	Term	Osteoarthritis knee
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary objectives of the trial

The secondary objective is to determine whether methotrexate is a cost effective treatment for knee OA.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full 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.3

Principal 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.4

Principal 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.5.1

Primary 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.5.1.1

Timepoint(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.5.2

Secondary 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.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1