An open-label study of leukocyte counts in the cerebrospinal fluid and blood of subjects with relapsing forms of multiple sclerosis following treatment with firategrast

• Register: EUCTR
• Last refreshed on: 28 October 2013
• Main ID: EUCTR2006-007057-42-BE
• Date of registration: 14/02/2007
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: An open-label study of leukocyte counts in the cerebrospinal fluid and blood of subjects with relapsing forms of multiple sclerosis following treatment with firategrast
• Scientific title: An open-label study of leukocyte counts in the cerebrospinal fluid and blood of subjects with relapsing forms of multiple sclerosis following treatment with firategrast
• Date of first enrolment: 29/05/2007
• Target sample size: 45
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-007057-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:

Countries of recruitment

Belgium, Czech Republic, Denmark, Sweden

Key inclusion & exclusion criteria

Inclusion criteria:
2. Male or female, age 18 to 65.
3. A diagnosis of a relapsing form of MS [As per McDonald, 2001; Polman, 2005], with dissemination in time and space.
4. Expanded Disability Status Scale (EDSS) score of between 0 and 6.5 inclusive.
5. Occurrence of at least one clinical attack in the previous 24 months, but not within the 4 weeks prior to Screening or prior to the Baseline Visit.
6. A minimum of two T2 lesions on brain MRI at Screening, as determined by the central MRI analysis reader.
7. A female subject is eligible to enter the study if she is:
a. Of non-childbearing potential OR
b. Of childbearing potential, has a negative urine pregnancy test at Screening and Baseline, and agrees to consistent and correct use the method of contraception as per the protocol
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Subjects receiving corticosteroids within 4 weeks of Screening for treatment of MS.
2. Use of a beta-interferon product, glatiramer acetate or azathioprine within 3 months of Screening, or use of Mitoxantrone within 12 months of Screening.
3. Previous exposure to alemtuzumab, natalizumab or firategrast administration, bone marrow transplantation or whole body irradiation.
4. Subjects with a cardiac pacemaker or any other type of metal implant or with any other contraindication for MRI.
5. Use of 4-aminopyridine, rosiglitazone, pioglitazone or any drug that is an inhibitor of or a substrate (with a low therapeutic index) for Organic Anion Transporter Protein (OATP).
6. Subjects with clinically significant renal laboratory values: subjects with a calculated creatinine clearance <60ml/min (by Cockcroft and Gault) at Screening.
7. Subjects with local urinalysis findings of 1) proteinuria, defined as greater than or equal to 1+ protein on urine dipstick or 2) renal tubular cell casts or 3) greater than or equal to 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 Phase.
8. Presence of clinically significant hepatic laboratory values: ALT, AST, GGT > 2 times the upper limit of the reference range; total bilirubin > 1.5 the upper limit of the normal range.
9. CD4 count < 500, CD4:CD8 < 1.0, JCV viremia in plasma or white cells, idiopathic CD4/CD8 lymphopenia or secondary lymphopenia at Screening.
10. Any findings at Screening on the MRI of the brain other than MS, except for benign findings.
11. Uncontrolled or any active bacterial, viral, or fungal infection.
12. History of tuberculosis (TB) or positive chest X-ray for TB at Screening.
13. Known congenital or acquired immunodeficiency.
14. Current or history of cancer, excluding localized non-melanoma skin cancer.
15. Any abnormality on 12-lead Electrocardiogram (ECG) at Screening.
16. Positive hepatitis B surface antigen, hepatitis C antibody or HIV tests at Screening.
21. Contraindications to lumbar puncture.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

relapsing forms of multiple sclerosis
MedDRA version: 9.1 Level: LLT Classification code 10063399 Term: Relapsing-remitting multiple sclerosis
MedDRA version: 9.1 Level: LLT Classification code 10063400 Term: Secondary progressive multiple sclerosis

Intervention(s)

Product Name: firategrast (USAN approved name)
Product Code: SB-683699
Pharmaceutical Form: Tablet
CAS Number: 402567-16-2
Current Sponsor code: SB-683699
Other descriptive name: firategrast (USAN approved name)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-

Primary Outcome(s)

Primary end point(s): The primary outcome measures are the number and change in number of total leukocytes, total lymphocytes and lymphocyte subsets (CD4+ and CD8+ T-lymphocytes, CD19+ B-lymphocytes, CD34+ early hematopoietic progenitor cells) and the CD4:CD8 ratio in the CSF and/or blood. The time points of interest for all of the above endpoints are Baseline, Treatment Week 4 (CD34+ early hematopoietic progenitor cells in blood only), Treatment Week 24 (End-of-Treatment) and Core Follow-up Weeks 28 and 36.
Safety and tolerability will be monitored through regular assessment of vital signs, clinical laboratory data, adverse events (AEs), clinical examination (including relapse and Expanded Disability Status Scale (EDSS) score), Magnetic Resonance Imaging (MRI) analysis for MS progression (gadolinium-enhancing lesions) and for PML and presence of JC virus in plasma and buffy coat. This study and study A4M105038 (Phase 2 efficacy study) will be conducted under the auspices of an Independent Data Monitoring Committee (IDMC), and safety data from this study will be reviewed by the IDMC on an ongoing basis.
Plasma and CSF levels of firategrast will be measured at selected visits.

Main Objective: The primary aims of this study are 1) to determine, for a sample of subjects with relapsing forms of MS, the number and change from baseline in the number of leukocytes and the CD4:CD8 ratio in the CSF and blood up to the completion of 24-weeks of dosing with firategrast and 2) to assess the number and change from the end of treatment (and baseline) in the number of leukocytes and the CD4:CD8 ratio in the CSF and blood in the 12-week period following treatment with firategrast. These objectives will be assessed through the use of descriptive statistics only.

Secondary Objective: • To determine the number and change in number of total leukocytes, total lymphocytes and lymphocyte subsets and the CD4:CD8 ratio in the CSF and blood during and after treatment with firategrast.
Lymphocyte subsets:
T-lymphocytes: CD4+, CD8+
B-lymphocytes: CD19+
• To examine blood for mobilization of CD34+ early hematopoietic progenitor cells from the bone marrow during and after treatment with firategrast.
• To explore the relationship between changes in the number of leukocytes in the CSF and blood.
• To explore the relationship between systemic exposure to firategrast and the metabolite, GW786375X, and changes in leukocyte counts in the CSF and blood.
• To determine firategrast and GW786375X levels in CSF.
• To explore potential relationships between genetic variants and response to firategrast, pharmacokinetic endpoints and bilirubin levels.
• To investigate the safety and tolerability of up to six months' administration of firategrast.

Secondary ID(s)

A4M108119