Clinical trial NCT00395317: Study Of SB-683699 Compared To Placebo In Subjects With Relapsing-Remitting Multiple Sclerosis (MS)
Official title: Randomised, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study to Investigate the MRI Efficacy and the Safety of Six Months Administration of SB-683699 in Subjects With Relapsing-Remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: magnetic resonance imaging
multiple sclerosis
SB-683699
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-11-02
Enrollment: 343
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: SB-683699 is an oral medication that is thought to reduce the number of active white blood cells entering the brain; these white blood cells are part of the disease process for MS. This study will look at whether different doses of SB-683699 are effective and safe in patients with relapsing remitting MS.


Eligibility criteria: Inclusion criteria:

* Written informed consent
* Males or females, aged 18 to 65, inclusive
* A diagnosis of relapsing-remitting MS \[Polman, 2005; McDonald, 2001\] with dissemination in time and space
* EDSS of between 0 and 6.0 inclusive at the Screening visit
* Occurrence of at least two relapses in previous 24 months with at least one relapse or documented evidence of gadolinium-enhancement on MRI (prior to screening) in the previous 12 months. Subject must not have had a relapse within 4 weeks prior to Screening. In addition, subjects experiencing a relapse between Screen and Visit 3 will not be eligible to be randomized.
* A minimum of five T2 lesions on brain MRI at Visit 2 as determined by the central MRI analysis reader
* A female subject is eligible to enter the study if she is:

  * Of non-childbearing potential, i.e. women who:
  * have documented evidence of tubal ligation, bilateral oophorectomy or hysterectomy; or
  * are post-menopausal, defined as at least one year without menses in the absence of hormone replacement therapy. In questionable cases, menopausal status will be confirmed by oestradiol and FSH levels consistent with menopause according to local laboratory ranges. Oestrogen-containing hormone replacement therapies are not allowed during the study.
  * Of childbearing potential, has a negative urine pregnancy test at Screening, and agrees to the consistent and correct use of one of the methods of contraception listed below. Subjects will use this contraceptive method for at least one month prior to Screening and should continue to use the same contraceptive method throughout the study until at least 3 days after the last dose of investigational product.
  * Progesterone-only oral contraceptives or implants (inserted at least one month prior to Screening, but not beyond the third successive year following insertion). Oestrogen-containing contraceptives are not allowed during the study.
  * Intra-uterine device (IUD) inserted by a qualified clinician. The IUD must have published data showing that the highest expected failure rate is less than 1% per year.
  * Spermicide in conjunction with either a diaphragm, cervical cap or condom. Male partner sterilization (vasectomy) prior to female subject's entry into the study and is the sole partner for that female subject
* In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

* Subjects receiving corticosteroids within 4 weeks of Screening for treatment of MS. If non-systemic steroids are being used for other chronic inflammatory conditions, subjects may be included at the discretion of the investigator after discussion with the GSK medical monitor
* Use of an b-interferon product, glatiramer acetate or azathioprine within 3 months of Screening, or use of Mitoxantrone within 12 months of Screening. Subjects who have received other therapies affecting the immune system (such as intravenous immunoglobulin (IVIg), cyclophosphamide, plasmapheresis, or any other immunosuppressive or immunomodulatory treatment) in the past may be included on a case by case basis after discussion with the GSK medical monitor. None of these treatments will be allowed during this study
* Previous exposure to alemtuzumab, natalizumab or firategrast administration, bone marrow transplantation or whole body irradiation
* Subjects with a cardiac pacemaker or any other type of metal implant or with any other contraindication for MRI (including known allergy to gadolinium)
* Use of 4-aminopyridine, rosiglitazone, pioglitazone or any drug that is an inhibitor of or a substrate (with a low therapeutic index) for OATP at Screening.
* Subjects with clinically significant renal laboratory values: subjects with a calculated creatinine clearance \<60ml/min (by Cockcroft and Gault) at Screening
* Subjects with local urinalysis findings of 1) proteinuria, defined as ≥1+ protein, on urine dipstick or 2) renal tubular cell casts or 3) ≥5 red blood cells / high power field will be excluded from the study if the result is still present on a repeat urinalysis during the screening period.
* Presence of clinically significant hepatic laboratory values: ALT, AST, GGT \> 2.0- times the upper limit of normal (ULN); total bilirubin \> 1.5 times the ULN at Screening
* CD4 count \<500, CD4:CD8 \<1.0 (if result still present on a repeat test during the screening period), JC viremia detected in plasma or white cells, idiopathic CD4/CD8 lymphopenia or secondary lymphopenia at Screening
* Any findings on the MRI of the brain at Visit 2 other than MS, except for benign findings that (in the opinion of the central MRI reading site and local site investigator) require no further evaluation or treatment and do not impact patient's neurological health (e.g., small arachnoid cysts, venous angiomas)
* Current or history of cancer, excluding localized non-melanoma skin cancer
* Uncontrolled or any active bacterial, viral, or fungal infection at Screening. Any previous serious infections should be discussed with the GSK medical monitor (e.g. opportunistic or atypical infections)
* History of tuberculosis (TB) or positive chest X-ray for TB at Screening (prior chest X-ray is acceptable if performed within previous 6 months)
* Known congenital or acquired immunodeficiency
* Any abnormality on 12-lead ECG at Screening which is clinically significant in the opinion of the investigator
* Subjects with positive hepatitis B surface antigen, hepatitis C antibody, or HIV tests at Screening
* Women who are lactating, pregnant (positive pregnancy test at Screening), or planning to become pregnant during the course of the study
* Recent history or suspicion of current drug abuse (including analgesic abuse) or alcohol abuse within the last 6 months prior to Screening
* Use of an investigational drug for condition other than MS within 30 days or five half-lives (whichever is longer) preceding Screening. Prior use of an investigational drug for MS should be discussed with the GSK medical monitor
* Any concurrent illness, disability or clinically significant abnormality (including laboratory tests) that may affect the interpretation of clinical efficacy or safety data or prevent the subject from safely completing the assessments required by the protocol

Primary outcomes:
measure: Cumulative number of new gadolinium-enhancing lesions on monthly MRI scans during the Treatment Phase
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Cumulative volume of new gadolinium-enhancing lesions on monthly MRI scans
timeFrame: Baseline and 24 weeks
measure: Cumulative number of persistent gadolinium-enhancing lesions on monthly MRI scans
timeFrame: Baseline and 24 weeks
measure: Cumulative number of total enhancing lesions on monthly MRI scans: the sum of new and persistent gadolinium-enhancing lesions
timeFrame: Baseline and 24 weeks
measure: Cumulative number of new T1 hypointense lesions on MRI scans
timeFrame: Baseline and 24 weeks
measure: Cumulative number of new/newly enlarging T2 lesions on MRI scans
timeFrame: Baseline and 24 weeks
measure: Relapses Occurring during the On-Treatment Phase
timeFrame: Baseline and 24 weeks
measure: Change from Baseline in Expanded Disability Status Scale (EDSS) scores
timeFrame: Baseline and 24 weeks
measure: Change from Baseline in Multiple Sclerosis Functional Composite (MSFC)scores
timeFrame: Baseline and 24 weeks
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Woodville
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Fitzroy
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Parkville
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Graz
country: Austria
facility: GSK Investigational Site
city: Innsbruck
country: Austria
facility: GSK Investigational Site
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Gatineau
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Greenfield Park
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Turku
country: Finland
facility: GSK Investigational Site
city: Clermont Ferrand
country: France
facility: GSK Investigational Site
city: Dijon
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Marseille
country: France
facility: GSK Investigational Site
city: Nantes
country: France
facility: GSK Investigational Site
city: Rennes Cedex 9
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Neuburg / Donau
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Herborn
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Rostock
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Achim
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Bad Honnef
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Bielefeld
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Dueren
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Chieti
country: Italy
facility: GSK Investigational Site
state: Abruzzo
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Gallarate
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Siena
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Breda
country: Netherlands
facility: GSK Investigational Site
city: Den Bosch
country: Netherlands
facility: GSK Investigational Site
city: Eindhoven
country: Netherlands
facility: GSK Investigational Site
city: Nieuwegein
country: Netherlands
facility: GSK Investigational Site
city: Sittard-geleen
country: Netherlands
facility: GSK Investigational Site
city: Venray
country: Netherlands
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Christchurch
country: New Zealand
facility: GSK Investigational Site
city: Wellington
country: New Zealand
facility: GSK Investigational Site
city: Bergen
country: Norway
facility: GSK Investigational Site
city: Drammen
country: Norway
facility: GSK Investigational Site
city: Hamar
country: Norway
facility: GSK Investigational Site
city: Sandnes
country: Norway
facility: GSK Investigational Site
city: Skien
country: Norway
facility: GSK Investigational Site
city: Gdansk
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Warsaw
country: Poland
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St.-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St.-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Barakaldo (Vizcaya)
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: San Sebastián
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Romford
country: United Kingdom
facility: GSK Investigational Site
state: Essex
city: Hartshill, Stoke-on-Trent
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: GSK Investigational Site
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Miller DH, Weber T, Grove R, Wardell C, Horrigan J, Graff O, Atkinson G, Dua P, Yousry T, Macmanus D, Montalban X. Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012 Feb;11(2):131-9. doi: 10.1016/S1474-4422(11)70299-X. Epub 2012 Jan 5.