Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose finding study to evaluate the efficacy, safety, and tolerability of three doses of ACT-128800, an oral S1P1 receptor agonist, administered for twenty-four weeks in patients with relapsing-remitting multiple sclerosis

• Register: EUCTR
• Last refreshed on: 11 March 2013
• Main ID: EUCTR2008-006786-92-SE
• Date of registration: 08/05/2009
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals Ltd
• Public title: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose finding study to evaluate the efficacy, safety, and tolerability of three doses of ACT-128800, an oral S1P1 receptor agonist, administered for twenty-four weeks in patients with relapsing-remitting multiple sclerosis
• Scientific title: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose finding study to evaluate the efficacy, safety, and tolerability of three doses of ACT-128800, an oral S1P1 receptor agonist, administered for twenty-four weeks in patients with relapsing-remitting multiple sclerosis
• Date of first enrolment: 16/07/2009
• Target sample size: 400
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-006786-92
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Bulgaria, Czech Republic, Finland, France, Hungary, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Males and females aged 18 to 55 years (inclusive).
2. Women of childbearing potential must:
• Have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.
• Agree to use two methods of contraception from the screening visit until 8 weeks after study drug discontinuation.
Of the two contraceptive methods, one must be from Group 1, and one must be from Group 2, defined as follows:
- Group 1: Oral, implantable, transdermal or injectable hormonal contraceptives, intrauterine devices, female sterilization (tubal ligation), or partner’s sterilization (vasectomy). If a hormonal contraceptive will be chosen from this group, it must have been taken for at least 1 month prior to randomization.
- Group 2: Condoms, diaphragm or cervical cap, all in combination with spermicide.
Abstention and rhythm methods are not acceptable methods of contraception.
3. Presenting with a diagnosis of RRMS as defined by the revised (2005) McDonald Diagnostic Criteria for Multiple Sclerosis (MS).
4. Ambulatory and with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5 (inclusive).
5. With at least one of the following characteristics of RRMS:
• One or more documented relapse(s) within 12 months prior to the screening visit,
• Two or more documented relapses within 24 months prior to the screening visit,
• At least one gadolinium-enhancing lesion detected on T1-weighted MRI at the Screening visit (based on central reading).
6. In a stable clinical condition:
• Without a clinical exacerbation of MS for at least 30 days prior to randomization (exacerbation of MS is defined as one or more new symptom(s), or worsening of existing symptoms, not associated with fever or infection, and lasting for at least 24 hours).
7. Signed informed consent prior to initiation of any study mandated procedure.

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. Breast feeding women.
2. A diagnosis of MS categorized as primary progressive or secondary progressive or progressive relapsing.
3. Treatment with
Within 30 days prior to randomization:
• Systemic corticosteroids or adrenocorticotropic hormone (ACTH)
• Treatment with ß-blockers, diltiazem, verapamil, or digoxin or QT-prolonging drugs (as listed in Appendix 9), for any indication
Within 3 months prior to randomization:
• Interferon or glatiramer acetate
• Systemic immunosuppressive treatment (e.g., cyclosporine, sirolimus, mycophenolic acid)
• Vaccination with live vaccines
• Plasma exchange (plasmapheresis, cytapheresis)
• Treatment with an investigational drug (within 3 months or 5 half-lives of the drug, whichever is longer), except biological agents (see below)
Within 6 months prior to randomization:
• Azathioprine or methotrexate
• Natalizumab (or previous failure to natalizumab)
• Intravenous immunoglobulin
• Non-lymphocyte-depleting biologic agents (e.g., daclizumab)
At any time prior to randomization:
• Cyclophosphamide, mitoxantrone, or cladribine
• Lymphocyte-depleting biologic agents such as alemtuzumab or rituximab
4. Patient currently treated for an autoimmune disorder other than MS.
5. Contraindications for MRI such as:
• Pacemaker, any metallic implants such as artificial heart valves, aneurysm/vessel clips and any metallic material in high-risk areas
• Known allergy to any gadolinium contrast agent
• Severe renal insufficiency defined as a creatinine clearance < 30 mL/min according to the Cockroft-Gault formula
• Claustrophobia
6. Ongoing bacterial, viral or fungal infection (with the exception of onychomycosis and dermatomycosis), positive hepatitis B surface antigen or hepatitis C antibody tests.
7. Congenital or acquired severe immunodeficiency or known human immunodeficiency virus (HIV) infection.
8. Negative antibody test for varicella-zoster virus at screening.
9. History or presence of malignancy (except for surgically excised basal or squamous cell skin lesions), lymphoproliferative disease, or history of total lymphoid irradiation or bone marrow transplantation.
10. Poorly controlled type I or type II diabetes.
11. Macular edema or diabetic retinopathy (as confirmed within 30 days prior to randomization).
12. History of clinically significant drug or alcohol abuse.
13. Any of the following cardiovascular conditions:
• Resting heart rate (HR) < 55 bpm, as measured by the pre-randomization ECG on Visit 3 (Day 1).
• History or presence of ischemic heart disease.
• History of or current valvular heart disease.
• History of or current heart failure
• History or presence of rhythm disorders (e.g., sino atrial heart block, sick sinus syndrome, second or third-degree atrioventricular (AV) block, ventricular arrhythmias, symptomatic bradycardia, atrial flutter or atrial fibrillation) or ongoing anti-arrhythmic therapy.
• QTc > 470 msec (females) and QTc > 450 msec (males) in any of the ECGs performed at Screening, Baseline, or Day 1 prior to randomization.
• History of syncope.
• Uncontrolled arterial hypertension.
14. Any of the following pulmonary conditions:
• Moderate or severe bronchial asthma or chronic obstructive pulmonary disease (COPD) stage II–IV, i.e., forced expiratory volume in 1 second (FEV1) < 70% of forced vital capacity (FVC), i.e., FEV1/FVC ratio < 0.7.
• History of pulmonary fibrosis (scarring of the lung), pulmonary Langerhans’cell histiocytosis.
• History of tuberculosis, chest X-ray findin

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

Health Condition(s) or Problem(s) studied

relapsing-remitting multiple scelorsis
MedDRA version: 9.1 Level: LLT Classification code 10063399 Term: Relapsing-remitting multiple sclerosis

Intervention(s)

Product Name: ACT-128800
Product Code: ACT-128800
Pharmaceutical Form: Capsule, hard
Current Sponsor code: ACT-128800
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: ACT-128800
Product Code: ACT-128800
Pharmaceutical Form: Capsule, hard
Current Sponsor code: ACT-128800
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: ACT-128800
Product Code: ACT-128800
Pharmaceutical Form: Capsule, hard
Current Sponsor code: ACT-128800
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: • To evaluate the effects of ACT-128800 on the annualized confirmed relapse rate within 24 weeks of study drug initiation.
• To evaluate the effects of ACT-128800 on time to first confirmed relapse within 24 weeks of study drug initiation.
• To evaluate the safety and tolerability of ACT-128800.

Main Objective: • To demonstrate the efficacy of at least one of three doses of ACT-128800 as compared to placebo in patients with relapsing-remitting multiple sclerosis (RRMS) on the cumulative number of new gadolinium-enhancing lesions per patient, recorded on T1-weighted MRI scans at Weeks 12, 16, 20, and 24 after study drug initiation.

Primary end point(s): • Cumulative number of new gadolinium-enhancing lesions per patient recorded on T1-weighted MRI scans at Weeks 12, 16, 20, and 24 after study drug initiation.

This endpoint is derived by summing the observed numbers of new gadolinium-enhancing lesions on MRI scans at Weeks 12, 16, 20, and 24. A reduction from 8 to 4 (50% decrease compared to placebo) in the mean cumulative number of the lesions is to be detected.

Secondary ID(s)

2008-006786-92-CZ

AC-058B201