| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsing-remitting multiple scelorsis |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • 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. |
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| E.2.2 | Secondary objectives of the trial |
• 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. |
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| 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 |
Ancillary studies included in this protocol, but only implemented at selected sites:
- Exploration of echocardiographic parameters
- Exploration of ophtalmological parameters by Optical Coherence Tomography (OCT)
Additional ancillary studies may be conducted under dedicated sub-study protocols submitted and implemented only at selected sites.
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| E.3 | Principal 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.
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| E.4 | Principal 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 β-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 findings at screening or within the previous 3 months, suggestive of active or latent tuberculosis or absence of a negative test result for tuberculosis at screening based on an interferon gamma release assay.
15. Abnormal liver function tests as defined by elevations of ALT/SGPT or AST/SGOT > 2-fold the upper limit of the normal range (ULN) or total bilirubin > 1.5-fold ULN.
16. Any of the following abnormal laboratory values:
• White blood cell (WBC) count < 3,500/μL
• Hemoglobin (Hb) < 10 g/dL
• Lymphocyte count < 1,000/μL
• Platelets < 100,000/μL
17. Known allergy to any of the study drug excipients.
18. Any other clinically relevant medical or surgical condition, which, in the opinion of the investigator, would put the patient at risk by participating in the study.
19. Patients who are confined by order of either judicial or administrative authorities.
20. Patients unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits or known likelihood of not completing the study including mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study.
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| E.5 End points |
| E.5.1 | 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.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| dose finding, Tolerability |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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