The objectives of this study are to assess the efficacy, safety, and tolerability of a once daily oral dose of laquinimod (0.6 or 1.5 mg) compared to placebo in PPMS patients.
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Brain atrophy (BA), as defined by Percentage in Brain Volume Change (PBVC) from
baseline to week 48.
Secondary outcome
* Time to confirmed disability progression (CDP), defined as increase in EDSS
of *1 point from baseline EDSS if EDSS at entry is *5.0, or increase of *0.5
points if EDSS at entry is *5.5. This increase should be confirmed after at
least 12 weeks. Progression cannot be confirmed during a relapse, although
relapses are rare in PPMS.
* Time to CDP as measured by 2 types of events for each individual (progression
cannot be confirmed during a relapse):
- An increase from baseline in EDSS score (*1 point from baseline EDSS if EDSS
at entry is *5.0, or increase of *0.5 point if EDSS at entry is *5.5),
confirmed after at least 12 weeks, or
- An increase of at least 20% from baseline in T25FW score, confirmed after at
least 12 weeks
* The number of new T2 brain lesions at week 48.
* Change from baseline to week 48 in the BICAMS score.
Background summary
Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disorder
of the central nervous system (CNS), characterized by inflammation and
demyelination, as well as oligodendrocyte and neuron dysfunction.
Approximately 15% of MS patients develop a sustained deterioration of
neurological function without distinct exacerbations from the onset; this MS
phenotype is known as primary progressive multiple sclerosis (PPMS). At
diagnosis, approximately 85% of patients have relapsing remitting multiple
sclerosis (RRMS), characterized by recurrent acute exacerbations of
neurological dysfunction (relapses), followed
by recovery. Over time, the majority of patients with RRMS will develop
secondary progressive multiple sclerosis (SPMS), in which a less acute
inflammatory and more neurodegenerative course of the disease takes over. SPMS
develops with progression in disability independent of
relapses which usually have subsided. The diagnosis of the transition into this
SPMS phase of the disease is usually made retrospectively.
Progressive MS subtypes, such as PPMS and SPMS, typically feature gait
dysfunction due to steadily worsening spastic paraparesis, progressive urinary
symptoms, and gradual cognitive decline. The disease mechanisms driving
progressive MS remain unresolved, and
there is currently no animal model available that accurately reproduces this
phenomenon.
Therapeutic options for progressive MS are currently limited to symptomatic
treatments and physiotherapy; in this context, a therapy which is effective in
limiting the neurodegenerative process and associated disability accumulation
would address a major unmet medical need in the treatment of MS.
The investigational medicinal product (IMP), laquinimod is a novel chemical
compound is an innovative oral immunomodulator, currently undergoing a third
Phase 3 study of its development for RRMS. Its emerging clinical and magnetic
resonance imaging (MRI) efficacy profile, supported by extensive pre-clinical
evidence, suggests a direct protective effect in the CNS, largely independent
of its peripheral anti-inflammatory effects, supporting the evaluation of
laquinimod*s efficacy in progressive MS.
Study objective
The objectives of this study are to assess the efficacy, safety, and
tolerability of a once daily oral dose of laquinimod (0.6 or 1.5 mg) compared
to placebo in PPMS patients.
Study design
Duration of Participation: The study will include screening up to 6 weeks and 2
parts: Part A (core study) and Part B (data analysis).
Part A will last at least 48 weeks, and individual patients will experience
variable treatment durations, depending on the order of enrollment.
Once the last ongoing patient completes the week 48 visit, the sponsor will
declare end of Part A and begin performing study analyses.
In Part B, patients will continue their randomly assigned blinded treatments
with visits every 12 weeks until the completion visit. After up to
approximately 24 weeks of Part B, or once data analysis has been completed and
the extension study design has been finalized, patients will be invited to the
clinic for the completion visit and will be offered the opportunity to continue
into an extension study.
General Design and Methodology: This is a multinational, multicenter,
randomized, double blind, parallel group, placebo controlled study, to evaluate
the efficacy, safety, and tolerability of daily oral administration of
laquinimod (0.6 or 1.5 mg) in PPMS patients.
Eligible patients will be randomized in a 1:1:1 ratio into one of the following
treatment arms:
1. Laquinimod 0.6 mg daily
2. Laquinimod 1.5 mg daily
3. Daily placebo
A capped randomization procedure will be employed to ensure that the number of
EDSS 6.0 and 6.5 patients will be no more than 20% of all enrolled patients.
Patients will have the following study visits: screening visit ( 6 weeks),
baseline visit (week 0), weeks 4, 8, 12, 24, 36, 48, and every 12 weeks until
study completion or early termination (ET).
Intervention
* 0.6 mg arm: 1 capsule containing 0.6 mg laquinimod and the other 2 containing
placebo, to be administered orally once daily.
* 1.5 mg arm: 3 capsules containing 0.5 mg laquinimod to be administered orally
once daily.
* Placebo arm: 3 capsules containing placebo to be administered orally once
daily.
Study burden and risks
Very common side effects included headache, abdominal pain, back and neck pain
that were generally mild, and occurred during the first 3 months after start of
laquinimod. Increased white blood cells, decreased platelet count that were
mild and with no symptoms were also noted. An uncommon but important side
effect was appendicitis.
Treatment with laquinimod may be associated with some abnormalities in certain
blood results that are generally mild and not accompanied by symptoms,
including:
* Increased liver enzymes (AST, ALT and GGT); This increase, which typically
occured within 6 months after start of laquinimod, was generally mild, with no
symptoms and was reversible with no need to stop the drug.
* Hematological changes such as: decreased hemoglobin level or anemia. This
decrease, which generally occured early after starting of laquinimod, was
generally mild, with no symptoms and temporary. There was no need to stop
Laquinimod or introduce any other treatment.
* Mildly increased white blood cell count and mildly decreased platelet count
with no symptoms.
* Elevation of blood C-reactive protein and elevation of blood fibrinogen
levels.
Deaths
To date, one death case (suicide) was considered by the investigator to be
possibly related to laquinimod.
Experience with higher doses
Higher doses of laquinimod were studied in a small study in MS patients for a
short treatment duration of 4 weeks (doses starting at 0.9 mg and gradually
going up to 2.7 mg, inclusive, each dose given to 12 patients). In this study,
no safety concern was noted up to a laquinimod dose of 2.7 mg. However, there
was a suggestion that higher doses of laquinimod might be associated with
elevation of CRP in the blood with no symptoms.
The current study (and an additional study in patients with Huntington Disease)
will evaluate the 1.5 mg dose in a larger number of patients and for longer
treatment duration for the first time
A list of side effects that have been associated with laquinimod is provided
below:
Very common side effects (affect more than 1 user in 10)
- Headache
- Back and neck pain
- Abdominal pain
- Increased white blood cell count
- Decreased platelet count
Common side effects (affect 1 to 10 users in 100)
- Decrease in level of hemoglobin
- Anxiety
- Bronchospasm
- Coughing
- Constipation
- Bloated abdomen
- Nausea and vomiting
- Toothache
- Joint pain
- Menstruation problems and uterine bleeding
- Swelling of limbs
- Urinary tract infection
- Skin infections
- Abnormalities of certain blood test results:
* Increased (above normal) blood fibrinogen
* Increased blood C-reactive protein
* Increased blood amylase
* Increased liver enzymes
Uncommon side effects (affect 1 to 10 users in 1,000)
- Appendicitis
- Dry mouth
- Boils
- Inflammation of bursa (small fluid-filled sac)
- Urgent need to urinate
- Asthma
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Listed location countries
Age
Inclusion criteria
1. Patients must have a confirmed and documented PPMS diagnosis as
defined by the current valid McDonald criteria
2. Baseline magnetic resonance imaging (MRI) showing lesions
consistent with PPMS in either or both brain and spinal cord
3. Patients must have an Expanded Disability Status Scale (EDSS) score
of 3 to 6.5, inclusive, at both screening and baseline visits
4. Documented evidence of clinical disability progression in the 2 years
prior to screening.
5. Functional System Score (FSS) of > or equal 2 for the pyramidal
system or gait impairment due to lower extremity dysfunction
6. Patients must be between 25 to 55 years of age, inclusive
7. Women of child-bearing potential must practice an acceptable method
of birth control for 30 days before taking the study drug, and 2
acceptable methods of birth control during all study duration and until
30 days after the last dose of treatment is administered.
8. Patients must sign and date a written informed consent prior to
entering the study.
9. Patients must be willing and able to comply with the protocol
requirements for the duration of the study.
Exclusion criteria
1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
2. Progressive neurological disorder other than PPMS.
3. Any MRI record showing presence of cervical cord compression.
4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
5. Relevant history of vitamin B12 deficiency.
6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.
8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-* (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
11. Prior use of monoclonal antibodies ever, except for:
a. natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)
b. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/*L
12. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.
13. Previous use of laquinimod.
14. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
16. Previous total body irradiation or total lymphoid irradiation.
17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
18. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
20. Use of inducers of CYP3A4 within 2 weeks prior to baseline.
21. Pregnancy or breastfeeding.
22. Serum levels *3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
23. Serum direct bilirubin which is *2×ULN at screening.
24. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.
25. A known history of hypersensitivity to gadolinium (Gd).
26. Glomerular filtration rate (GFR) less than or equal to 60 mL/min at screening visit.
27. Inability to successfully undergo MRI scanning, including claustrophobia.
28. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
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 | EUCTR2014-001579-30-NL |
| ClinicalTrials.gov | NCT02284568 |
| CCMO | NL50594.029.14 |