Primary objective1. To demonstrate the efficacy of at least one of three doses of ACT-128800 as compared to placebo in patients withrelapsing-remitting multiple sclerosis (RRMS) on the cumulative number of new gadolinium-enhancing lesionsper patient…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy endpoint
• 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 outcome
Secondary efficacy endpoints
• Annualized confirmed relapse rate within 24 weeks of study drug initiation.
• Time to first confirmed relapse within 24 weeks of study drug initiation.
A relapse is defined as the occurrence of an acute episode of one or more new
symptoms, or worsening of existing
symptoms of MS, not associated with fever or infection, and lasting for at
least 24 hours after a stable period of at least
30 days.
A *confirmed relapse* is a relapse accompanied by an increase from baseline of
at least 0.5 point in the EDSS score, or
one point in the score for at least one of the Functional System (FS) scores,
excluding the bowel and bladder, and mental FS. The confirmatory EDSS must be
performed within 7 days of the onset of a new symptom or worsening of an
existing
symptom of MS. Symptoms of transient neurological worsening that do not meet
the criteria for *confirmed relapse* because unaccompanied by objective
findings but still judged to constitute a relapse by the treating neurologist,
will be recorded as *unconfirmed relapse* and included in the number of total
relapses.
Only confirmed relapses are included in the secondary efficacy analyses. For
exploratory efficacy endpoints both confirmed
and total relapses are analyzed.
Exploratory efficacy endpoints
1. Other MRI-related variables:
• Cumulative number of total gadolinium-enhancing lesions (a lesion may be
counted twice on two consecutive MRI scans) per patient recorded on T1-weighted
MRI scans at Weeks 12, 16, 20, and 24
after study drug initiation.
• Number of patients with no (new and total) gadolinium-enhancing lesions on
T1-weighted MRI scans at Weeks 12, 16, 20, and 24.
• Cumulative number of (new and total) gadolinium-enhancing lesions per patient
on T1-weighted MRI scans at Weeks 4, 8, 12, 16, 20, and 24.
• Number of (new and total) gadolinium-enhancing lesions per patient on a
T1-weighted MRI scan at
Week 24.
• Number of patients with no (new or total) gadolinium-enhancing lesions on a
T1-weighted MRI
scan at Week 24.
• Total volume of (new and total) gadolinium-enhancing lesions per patient on
T1-weighted MRI scans at
Weeks 12, 16, 20, and 24.
• Cumulative number of new or enlarging lesions per patient on T2-weighted MRI
scans at Weeks 12, 16, 20,
and 24.
• Change from baseline to Week 24 in total lesion volume per patient on
T2-weighted MRI scans.
• Cumulative number of combined unique active lesions (new gadolinium-enhancing
lesions plus new or
enlarging T2 lesions without gadolinium-enhancement) per patient on MRI scans
at Weeks 12, 16, 20, and 24.
• Change from baseline to Week 24 in brain volume.
• Additional MRI parameters may be evaluated as appropriate.
2. Relapse over the 24-week treatment period:
• Annualized total relapse rate within 24 weeks of study drug initiation
• Time to first (total) relapse within 24 weeks of study drug initiation.
• Number of (confirmed and total) relapses.
• Number of patients without any (confirmed and total) relapse.
• Number of patients with a relapse requiring corticosteroid treatment.
3. Neurological assessments:
• Categorical change from baseline to Week 24 in EDSS and FS scores.
4. Ophthalmological assessments:
• Change from baseline to Week 24 of average retinal nerve fiber layer (RNFL)
thickness, central foveal
thickness and total macular volume as measured by optical coherence tomography
(OCT) at selected
centers.
• Change from baseline to Week 24 of average number of letters correctly read
in a best corrected visual acuity
test (recorded only at centers that also perform OCT).
5. Quality of life assessments:
• Change from baseline in quality of life based on the following two
questionnaires to be completed by the
patients at baseline, Week 12, and Week 24 (only in countries for which
validated translations are available):
* Multiple Sclerosis Impact Scale 29 (MSIS-29).
* Modified Fatigue Impact Scale (mFIS).
6. Additional exploratory endpoints:
• If appropriate, other exploratory endpoints derived from the clinical
database, will be analyzed based on
data-driven considerations. For safety and tolerability endpoints and
pharmacokinetic and pharmacodynamic endpoints see page 70-71 of protocol.
Background summary
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.
Study objective
Primary objective
1. 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.
Secondary objectives
1. To evaluate the effects of ACT-128800 on the annualized
confirmed relapse rate within 24 weeks of study drug
initiation.
2. To evaluate the effects of ACT-128800 on time to first
confirmed relapse within 24 weeks of study drug initiation.
3. To evaluate the safety and tolerability of ACT-128800.
Study design
Prospective, multicenter, multinational, randomized, double-blind,
placebo-controlled, four-arm, parallel group, dose-finding, Phase 2b
superiority study.
Intervention
One capsule of ACT-128800, administered orally in the morning with or without
breakfast (preferably always in the
same way and at approximately the same time).
• Group I: 10 mg for 24 weeks until EOT
• Group II: 10 mg from Day 1 to Day 7, 20 mg from Day 8 until EOT
• Group III: 10 mg from Day 1 to Day 7, 20 mg from Day 8 to Day 14, 40 mg from
Day 15 until EOT
One capsule of matching placebo, administered orally in the morning with or
without breakfast (preferably always in the
same way and at approximately the same time).
• Group IV: placebo for 24 weeks until EOT.
Study burden and risks
Hospital visits x13
Bloodsample x11 (average of 8 ml blood taken)
Physica examination x12
MRI x8
Chest X-ray x2
ECG x 31
Pulmonary function test x 10
Ophthalmological Assessment x 5
Questionnaire x3
Echocardiography x3 (in selected centers)
24-hour Holter ECG x5
Headache, dizziness, fatigue, a transient drop in heart rate after
administration of the first dose of ACT-128800, asymptomatic, intermittent
AV-block second degree Mobitz type I/Wenckebach after administration of first
dose of 10 mg ACT-128800, QT prolongation after administration of first dose of
10 mg ACT-128800. A reduction in FEV1 (observed with the 40 mg dose) has been
reported in previous clinical trials with ACT-128800. Due to immunosuppression
in general there may be an increased risk of opportunistic infections and skin
cancers. However, this has not been seen in previous clinical trials with
ACT-128800.
389 Chiswick High Road
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389 Chiswick High Road
W4 4AL London
GB
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Age
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.
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 QTprolonging
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 (NYHA Class III or IV).
• History or presence of rhythm disorders (e.g., sino-atrial heart block, sick sinus syndrome,
second or third-degree atrioventricular (AV) block, symptomatic bradycardia, atrial flutter or atrial
fibrillation) or ongoing anti-arrhythmic therapy.
• 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2008-006786-92-NL |
CCMO | NL27374.003.09 |