Rheumatoid ArthritisPhase 1NCT00717808
Effects of Tranilast on Pharmacokinetics of Methotrexate (MTX) in Patients With Rheumatoid Arthritis (RA)
A Phase 1 study testing Tranilast in people with Rheumatoid Arthritis, run by Imperial College London.
Trial summary
The treatment of rheumatoid arthritis has improved considerably in recent years with the understanding that better outcomes can be achieved by optimising the dosage schedule of conventional drugs that suppress the inflammatory response in joints. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- Tranilast
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Sep 2008to Sep 2009
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult men and non-pregnant, non-lactating women between 18 and 75 years of age. Sexually active females must be of either non-childbearing potential or willing to comply with the contraceptive requirements.
- Body weight greater >40 kg and <120 kg with a body mass index (BMI) between 19-31 kg/m2
- Clinical history of rheumatoid arthritis as defined by ACR criteria and currently on a stable dosing regimen of methotrexate 7.5 to 25 mg once weekly, as their only DMARD (no changes in dosing regimen for 4 weeks prior to screening).
- Negative urine pregnancy test (for all women except those with documented proof of hysterectomy or bilateral oophorectomy)
- Subjects who are able and willing to give written consent
Who cannot join
- Any clinically relevant abnormality identified on the screening history, physical exam, clinical laboratory evaluations or ECG, with the exception of values related to rheumatoid arthritis.
- Estimated Glomerular Filtration rate <60mL/min.
- Significant hepatic insufficiency as defined by total bilirubin greater than 25.7umol/L or transaminase(ALT, AST) elevations greater than 2 times the upper limit of the clinical laboratory range. Also any patient with documented cirrhosis or a history consistent with a diagnosis of cirrhosis or hepatitis.
- Patients not on a stable DMARD and/or NSAID drug regimen, or expecting to remain on a stable drug regimen, as defined by starting a new drug or changing dosage within 14 days prior to administration of study medication.
- Patients taking any drugs known to be substrates of CYP2C9 or taking digoxin, or cerivastatin within 14 days prior to Session 1, or taking any drugs known to inhibit or induce CYP2C9.
- Known or suspected hypersensitivity to tranilast or to structurally similar compounds.
Show all 13Show fewer
- History of recurrent urinary tract infections or kidney stones.
- History of an acute illness within 2 weeks prior to the first dose of study medication.
- History of alcohol abuse within 2 years preceding the first dose of study medication.
- History of gout or hyperuricaemia.
- History of drug abuse within 2 years preceding the first dose of study medication.
- Use of an investigational drug within 30 days preceding the first dose of study medication.
- Donation of blood in excess of 500 mL within 56 days prior to the first dose of study medication.
About this study
Official title: A Phase 1, Blinded, Randomised, Crossover Pilot Study to Investigate the Safety, Tolerability and Pharmacokinetics of Tranilast in Patients With Rheumatoid Arthritis on Methotrexate
The treatment of rheumatoid arthritis has improved considerably in recent years with the understanding that better outcomes can be achieved by optimising the dosage schedule of conventional drugs that suppress the inflammatory response in joints. Furthermore, the development of protein based drugs that are given parenterally (i.e. by subcutaneous injection or intravenous infusion), known as biologics, have given rise to even better clinical results. However, despite this over 60% of patients with rheumatoid arthritis can still be expected to have an unacceptably high degree of disease activity and the prohibitively high cost of biologic therapy has resulted in rationing following NICE review. Therefore there is a need for more effective and less costly treatment.
The proposed study is designed to test potential drug interactions between one such candidate oral treatment, tranilast, and the gold standard therapy for rheumatoid arthritis, methotrexate, which is given as a once weekly oral, intramuscular or intradermal regimen. The drug to be tested, tranilast, an analogue of a naturally occurring molecule that regulates inflammatory responses, is currently used in the treatment of allergic inflammation and has recently been shown to be effective in an animal model of multiple sclerosis. Tranilast is an analogue of a naturally tryptophan metabolite. Laboratory studies of cell biology indicate that this molecule inhibits a number of key inflammatory pathways and the function of white blood cells that play a critical role in the inflammatory features of rheumatoid arthritis. The aim of this study is to assess whether tranilast may be useful for the treatment of RA. In an animal model of rheumatoid arthritis, initial assessment showed that prophylactic administration of tranilast interfered with the development of disease. Therapeutically, in an animal model of arthritis, tranilast was very effective, and reduced all aspects of the disease, including joint swelling, clinical score, and histological damage in a dose-dependent fashion, and reduced pain. This degree of benefit compares well with therapeutics that have been highly successful in humans, such as anti-TNF therapy. Furthermore studies at the Kennedy Institute of Rheumatology Division, Imperial College suggest that tranilast has a greater analgesic effect than the potent steroid dexamethasone at effective anti-inflammatory doses
Read the detailed description
THEORETICAL FRAMEWORK:The treatment outcomes in rheumatoid arthritis have dramatically improved with the recognition that the inflammatory component of disease needs to be suppressed optimally at every stage in its evolution. However, all existing conventional oral therapies are associated with limited efficacy and loss of effectiveness over time. Furthermore all of these therapies are associated with significant toxicity and tolerability problems. Another approach to treatment involves the use of biologic (protein based), parenterally administered therapies directed against important inflammatory molecules or cells involved in disease pathology. Despite the notable success of anti-TNF therapy, which is one of these biologics,approximately one third of patients do not respond adequately and the costs of drug production are very high.
This causes rationing in all healthcare economies. There is therefore a need for new, safe, well tolerated and effective drugs that are cost effective. Tranilast (a tryptophan metabolite) is already licenced in Japan for the treatment for allergy. Basic science studies including those undertaken at The Kennedy Institute indicate that this drug suppresses the activity of a number of key inflammatory mediators as well as the activation of lymphocytes (white blood cells) responsible for the perpetuation of inflammation and associated tissue destruction in rheumatoid. Therefore, there was a rationale to test the effectiveness of tranilast in vivo for the treatment of arthritis. In an animal model of arthritis, tranilast effectively reduces joint swelling and read outs of pain. Since tranilast is well tolerated and safe in the licenced treatment indication in man, it is timely to test its effectiveness in rheumatoid arthritis. The majority of patients with this condition are treated with methotrexate often in combination with other anti-rheumatoid drugs. The current study is a prelude to a larger randomised controlled study investigating the efficacy of tranilast in rheumatoid arthritis.
PURPOSE:This study will evaluate the pharmacokinetics, safety and tolerability of an oral medication, tranilast, in patients with rheumatoid arthritis who are on another disease modifying medication, methotrexate.
DESIGN:The study is a randomised crossover pilot study with an optional higher dose open label phase.
METHOD:During the study the patient will either receive tranilast (300mg twice a day) or a placebo drug for a period of seven days. The patient will then have a seven day break followed by another period of seven days in which the patient will receive the other medication. They will attend the clinic on at least 6 occasions(screening, day 2,3 8 and 9 then on 5 occasions in session 2 plus a follow up session. During the study blood samples will be taken to assess safety and serum concentrations of the study drug and interactions with methotrexate.
- Conditions
- Rheumatoid Arthritis
- Being tested
- Tranilast, Placebo comparator
- Keywords
- Tranilast, Rheumatoid Arthritis, Pharmacokinetics, Methotrexate
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TranilastDrug
Also called Rizaben (Tranilast), 3',4'-dimethoxycinnamonyl anthranilic acid
Tranilast (300mg twice a day) for a period of seven days whilst taking their weekly prescribed dose of methotrexate. Followed by a 7 day washout period before starting arm 2
Placebo comparatorDrug
Also called Lactose Monohydrate
The patient will receive the placebo capsule twice a day whilst receiving their weekly dose of methotrexate
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | During the study the patient will either receive tranilast (300mg twice a day) or a placebo drug for a period of seven days. The patient will then have a seven day break followed by another period of seven days in which the patient will receive the other medication. Receives: Drug: Tranilast |
| 2 | Placebo comparator | The patient will receive the placebo twice a day for 7 days whilst taking their weekly methotrexate dose Receives: Drug: Placebo comparator |
What is being measured
The primary outcome is the main question the study is designed to answer.
Plasma pharmacokinetics of tranilast and methotrexate following multiple doses of tranilast in patients with Rheumatoid Arthritis.
Measured: Predosing on day 8 and throughout day 8 and 24 hours later on day 9 for both sessions 1 and 2
Secondary outcomes (1)
Safety and tolerability of tranilast in combination with methotrexate will also be assessed
Measured: Throughout the study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jul 2008 (estimated)
- Study startSep 2008
- Primary completionSep 2009 (estimated)
- Study completionSep 2009 (estimated)
Why it stopped: Due to unforeseen circumstances this study will not now start.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- Nuon Therapeutics, Inc.
- Responsible party
- Sponsor
- Investigators
- Peter C Taylor, PhD, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00717808
- Sponsor's protocol ID
- 112007
- Other IDs
- 2007-005357-39, REC Ref:08/H0707/2, R&D ref: TAYP2010
- Status last verified
- Sep 2011
- First submitted
- 14 Jul 2008
- Last updated
- 28 May 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM, Gupta R, Lee LY, Kidd BA, Robinson WH, Sobel RA, Selley ML, Steinman L. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 2005 Nov 4;310(5749):850-5. doi: 10.1126/science.1117634.
PubMed 16272121Inglis JJ, Criado G, Andrews M, Feldmann M, Williams RO, Selley ML. The anti-allergic drug, N-(3',4'-dimethoxycinnamonyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis. Rheumatology (Oxford). 2007 Sep;46(9):1428-32. doi: 10.1093/rheumatology/kem160. Epub 2007 Jul 21.
PubMed 17644821
Study at a glance
From the registry record, last updated by the sponsor on 28 May 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1, Blinded, Randomised, Crossover Pilot Study to Investigate the Safety, Tolerability and Pharmacokinetics of Tranilast in Patients With Rheumatoid Arthritis on Methotrexate
- ClinicalTrials.gov ID
- NCT00717808
- Acronym / sponsor ID
- 112007
- Conditions
- Rheumatoid Arthritis
- Keywords
- Tranilast, Rheumatoid Arthritis, Pharmacokinetics, Methotrexate
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Due to unforeseen circumstances this study will not now start.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- Nuon Therapeutics, Inc.
- Study start
- Sep 2008
- Primary completion
- Sep 2009 (estimated)
- Study completion
- Sep 2009 (estimated)
- First posted
- 18 Jul 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The treatment of rheumatoid arthritis has improved considerably in recent years with the understanding that better outcomes can be achieved by optimising the dosage schedule of conventional drugs that suppress the inflammatory response in joints. Furthermore, the development of protein based drugs that are given parenterally (i.e. by subcutaneous injection or intravenous infusion), known as biologics, have given rise to even better clinical results. However, despite this over 60% of patients with rheumatoid arthritis can still be expected to have an unacceptably high degree of disease activity and the prohibitively high cost of biologic therapy has resulted in rationing following NICE review. Therefore there is a need for more effective and less costly treatment.
The proposed study is designed to test potential drug interactions between one such candidate oral treatment, tranilast, and the gold standard therapy for rheumatoid arthritis, methotrexate, which is given as a once weekly oral, intramuscular or intradermal regimen. The drug to be tested, tranilast, an analogue of a naturally occurring molecule that regulates inflammatory responses, is currently used in the treatment of allergic inflammation and has recently been shown to be effective in an animal model of multiple sclerosis. Tranilast is an analogue of a naturally tryptophan metabolite. Laboratory studies of cell biology indicate that this molecule inhibits a number of key inflammatory pathways and the function of white blood cells that play a critical role in the inflammatory features of rheumatoid arthritis. The aim of this study is to assess whether tranilast may be useful for the treatment of RA. In an animal model of rheumatoid arthritis, initial assessment showed that prophylactic administration of tranilast interfered with the development of disease. Therapeutically, in an animal model of arthritis, tranilast was very effective, and reduced all aspects of the disease, including joint swelling, clinical score, and histological damage in a dose-dependent fashion, and reduced pain. This degree of benefit compares well with therapeutics that have been highly successful in humans, such as anti-TNF therapy. Furthermore studies at the Kennedy Institute of Rheumatology Division, Imperial College suggest that tranilast has a greater analgesic effect than the potent steroid dexamethasone at effective anti-inflammatory doses
Detailed description
THEORETICAL FRAMEWORK:The treatment outcomes in rheumatoid arthritis have dramatically improved with the recognition that the inflammatory component of disease needs to be suppressed optimally at every stage in its evolution. However, all existing conventional oral therapies are associated with limited efficacy and loss of effectiveness over time. Furthermore all of these therapies are associated with significant toxicity and tolerability problems. Another approach to treatment involves the use of biologic (protein based), parenterally administered therapies directed against important inflammatory molecules or cells involved in disease pathology. Despite the notable success of anti-TNF therapy, which is one of these biologics,approximately one third of patients do not respond adequately and the costs of drug production are very high.
This causes rationing in all healthcare economies. There is therefore a need for new, safe, well tolerated and effective drugs that are cost effective. Tranilast (a tryptophan metabolite) is already licenced in Japan for the treatment for allergy. Basic science studies including those undertaken at The Kennedy Institute indicate that this drug suppresses the activity of a number of key inflammatory mediators as well as the activation of lymphocytes (white blood cells) responsible for the perpetuation of inflammation and associated tissue destruction in rheumatoid. Therefore, there was a rationale to test the effectiveness of tranilast in vivo for the treatment of arthritis. In an animal model of arthritis, tranilast effectively reduces joint swelling and read outs of pain. Since tranilast is well tolerated and safe in the licenced treatment indication in man, it is timely to test its effectiveness in rheumatoid arthritis. The majority of patients with this condition are treated with methotrexate often in combination with other anti-rheumatoid drugs. The current study is a prelude to a larger randomised controlled study investigating the efficacy of tranilast in rheumatoid arthritis.
PURPOSE:This study will evaluate the pharmacokinetics, safety and tolerability of an oral medication, tranilast, in patients with rheumatoid arthritis who are on another disease modifying medication, methotrexate.
DESIGN:The study is a randomised crossover pilot study with an optional higher dose open label phase.
METHOD:During the study the patient will either receive tranilast (300mg twice a day) or a placebo drug for a period of seven days. The patient will then have a seven day break followed by another period of seven days in which the patient will receive the other medication. They will attend the clinic on at least 6 occasions(screening, day 2,3 8 and 9 then on 5 occasions in session 2 plus a follow up session. During the study blood samples will be taken to assess safety and serum concentrations of the study drug and interactions with methotrexate.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: TranilastDuring the study the patient will either receive tranilast (300mg twice a day) or a placebo drug for a period of seven days. The patient will then have a seven day break followed by another period of seven days in which the patient will receive the other medication. |
| 2 | Placebo comparator | Drug: Placebo comparatorThe patient will receive the placebo twice a day for 7 days whilst taking their weekly methotrexate dose |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Adult men and non-pregnant, non-lactating women between 18 and 75 years of age. Sexually active females must be of either non-childbearing potential or willing to comply with the contraceptive requirements.
- Body weight greater >40 kg and <120 kg with a body mass index (BMI) between 19-31 kg/m2
- Clinical history of rheumatoid arthritis as defined by ACR criteria and currently on a stable dosing regimen of methotrexate 7.5 to 25 mg once weekly, as their only DMARD (no changes in dosing regimen for 4 weeks prior to screening).
- Negative urine pregnancy test (for all women except those with documented proof of hysterectomy or bilateral oophorectomy)
- Subjects who are able and willing to give written consent
Key exclusion criteria (13 listed)
- Any clinically relevant abnormality identified on the screening history, physical exam, clinical laboratory evaluations or ECG, with the exception of values related to rheumatoid arthritis.
- Estimated Glomerular Filtration rate <60mL/min.
- Significant hepatic insufficiency as defined by total bilirubin greater than 25.7umol/L or transaminase(ALT, AST) elevations greater than 2 times the upper limit of the clinical laboratory range. Also any patient with documented cirrhosis or a history consistent with a diagnosis of cirrhosis or hepatitis.
- Patients not on a stable DMARD and/or NSAID drug regimen, or expecting to remain on a stable drug regimen, as defined by starting a new drug or changing dosage within 14 days prior to administration of study medication.
- Patients taking any drugs known to be substrates of CYP2C9 or taking digoxin, or cerivastatin within 14 days prior to Session 1, or taking any drugs known to inhibit or induce CYP2C9.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TranilastAlso: Rizaben (Tranilast), 3',4'-dimethoxycinnamonyl anthranilic acidTranilast (300mg twice a day) for a period of seven days whilst taking their weekly prescribed dose of methotrexate. Followed by a 7 day washout period before starting arm 2 | Drug | 1 |
| Placebo comparatorAlso: Lactose MonohydrateThe patient will receive the placebo capsule twice a day whilst receiving their weekly dose of methotrexate | Drug | 2 |
Primary outcome
Plasma pharmacokinetics of tranilast and methotrexate following multiple doses of tranilast in patients with Rheumatoid Arthritis.
Time frame: Predosing on day 8 and throughout day 8 and 24 hours later on day 9 for both sessions 1 and 2
1 secondary outcome
Safety and tolerability of tranilast in combination with methotrexate will also be assessed
Time frame: Throughout the study
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 May 2015.
- Background: PubMed 16272121Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM, Gupta R, Lee LY, Kidd BA, Robinson WH, Sobel RA, Selley ML, Steinman L. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 2005 Nov 4;310(5749):850-5. doi: 10.1126/science.1117634.
- Background: PubMed 17644821Inglis JJ, Criado G, Andrews M, Feldmann M, Williams RO, Selley ML. The anti-allergic drug, N-(3',4'-dimethoxycinnamonyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis. Rheumatology (Oxford). 2007 Sep;46(9):1428-32. doi: 10.1093/rheumatology/kem160. Epub 2007 Jul 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter C Taylor, PhD principal investigator
Imperial College London
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tranilast in people with Rheumatoid Arthritis, run by Imperial College London.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 28 May 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Plasma pharmacokinetics of tranilast and methotrexate following multiple doses of tranilast in patients with Rheumatoid Arthritis. (time frame: Predosing on day 8 and throughout day 8 and 24 hours later on day 9 for both sessions 1 and 2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00717808, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 May 2015.