The purpose of this study is to compare the efficacy and the safety of an experimental drug, masitinib,in combination with riluzole to placebo in combination with riluzole administered during 48 weeks to patients suffering from ALS.You will be…
ID
Source
Brief title
Condition
- Cranial nerve disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline to week 48 in Amyotrophic Lateral Sclerosis functional
rating scale (ALSFRS)-Revised
Secondary outcome
-Combined Assessment of Function and Survival (CAFS)
-Survival defined as the time from randomisation to the date of documented
death or first tracheotomy
-Time to first tracheotomy defined as the time from randomisation to the
time of the first tracheotomy
-Change of Forced V ital Capacity (FVC) from baseline to each t ime point
(week 4, 8, 12, 24, 36, 48)
-Number of failure defined as a 9-point drop in ALSFRS-R or death from
baseline
-Change from baseline to each time point (week 4, 8, 12, 24 and
36) in Amyotrophic Lateral Sclerosis
functional rating scale (ALSFRS)-Revised
- Survival rate defined as the rate of patients alive without tracheotomy
at each time point (week 12, 24,
36 and 48)
- Change in cystatin C level from baseline to each time point
- Absolute and relative change in ALSAQ- 40 at each time point
- Safety: occurrence of Adverse Events (AE), changes on clinical
examination including vital signs and
weight, ECG and laboratory exams (biochemistry, hematology and urinalysis)
Background summary
Motor neurons are nerve cells located in the brain, brainstem, and spinal cord
that serve as controlling units and vital communication links between the
nervous system and the voluntary muscles of the body. Messages from motor
neurons in the brain (called upper motor neurons) are transmitted to motor
neurons in the spinal cord (called lower motor neurons) and from them to
particular muscles.
In ALS, both the upper motor neurons and the lower motor neurons degenerate or
die, ceasing to send messages to muscles. Although the exact pathophysiological
mechanisms underlying neurodegeneration in ALS remain uncertain, a common
pathological hallmark is the presence of ubiquitin-immunoreactive cytoplasmic
inclusions in degenerating neurons, followed by a strong inflammatory reaction.
Emerging evidence suggests that neuro-inflammation may be a pathological
characteristic of ALS and could therefore represent a potential therapeutic
target for a pharmacological agent to help treat this severe disease.
Recent studies have shown inflammatory markers in affected neural tissues of
ALS patients and suggest that inflammation in ALS spinal cord and cortex is
based on innate immune responses by macrophages and mast cells and adaptive
immune responses by T cells.
Mast cell seems to play a central role in the inflammatory process in ALS.
Several researches highlight key mechanism of action of mast cells. Mast cells
infiltrate spinal cord of ALS patients. Elevated TNF alpha levels, which is
expressed through mast cells, have been reported in ALS patients and have been
shown to induce motorneuron death
Study objective
The purpose of this study is to compare the efficacy and the safety of an
experimental drug, masitinib,
in combination with riluzole to placebo in combination with riluzole
administered during 48 weeks to
patients suffering from ALS.
You will be proposed to participate in optional ancillaries studies:
- Pharmacogenomic sub-study- Specific risks associated with masitinib
If during treatment (whatever treatment you are receiving) you
present severe side effects
(decrease of white blood cells or severe skin toxicity) an additional blood
sampling of 4 ml will be
performed and sent to Institut Paoli Calmettes in Marseille, France, under
responsibility of Professor
Dubreuil. A genetic analysis will be conducted in order to better
understand why the patient is presenting those side effects.
- Pharmacokinetic sub-study
The aim of this test is to measure the concentration of riluzole
in your blood before and after
riluzole intake when masitinib is used as add-on therapy.
Study design
This is a multicenter, randomised, double-blind, placebo-controlled, parallel
groups, phase 2/3 study to compare the efficacy and safety of masitinib at 4.5
or 3 mg/kg/day in combination with riluzole as add-on therapy versus placebo in
combination with riluzole as add-on therapy in the treatment of patients
suffering from Amyotrophic Laterale Sclerosis (ALS) for 48 weeks.
Patients enrolled will be randomised in 3 groups:
* Group 1: 127 patients will receive masitinib at 4.5 mg/kg/day + riluzole
* Group 2: 127 patients will receive masitinib at 3 mg/kg/day + riluzole
* Group 3: 127 patients will receive placebo + riluzole
Randomisation will be performed with a minimization algorithm on
(Stratification):
- ALS patients population (*Normal progressors*(progression before
randomization<1.1) VS *Faster progressors* (progression before
randomization>=1.1))
- Progression of ALSFRS-R score (point/month) from date of first symptom to
baseline (ALSFRS-R score at date of first symptom supposed to be 48) , Balanced
between treatment groups in each of ALS patients population *Normal
progressors* and *Faster progressors*
- Site of onset (Bulbar vs Others)
- ALSFRS-R score at baseline
- Age at baseline
- Region (North America and West Europe versus Est Europe versus Other
Countries)
At Week 48 patient visit, patients will be proposed to enter a double-blind
extension phase if benefit is assessed as positive by investigator as compared
to expected deterioration and if tolerability is acceptable.
Study treatment will be discontinued in case of:
- Informed consent withdrawal
- Adverse or undercurrent event considered intolerable by the patient or
incompatible with continuation
of the study according to the investigator
-Protocol violation (e.g., noncompliance with treatment administration,
prohibited treatment needed)
Intervention
NA
Study burden and risks
The patient will be regularly and medically follow up during the treatment of
48 weeks. He/she will have to visit the research location for 8 visits.
- First visit (screening visit): Before the patient can start the study, the
study doctor will check that you meet all required criteria to participate.
The patient will have a clinical examination. Different tests will be
performed including routine blood and urine tests and neurologic examination.
HIV and hepatitis B & C screening tests will be performed on your blood and a
screening for tuberculosis will be done using an intra-dermal reaction test.
Additionally you will be asked to answer a Specific Quality of Life
Questionnaire for ALS
- Baseline visit (from 1 day to 7 days after the screening visit): the study
doctor will check some criteria before you can start the study treatment.
- Following visits: 4, 8, 12, 24, 36, 48 weeks after the baseline visit.
- Final visit, 48 weeks after the baseline visit (or earlier when dropped out
before the end of the trial)
At each of these visits, the study doctor will ask you about any other
medicines that you have taken since the last visit, and how you feel.
the patient will be called weekly by the site staff during the first
two months of treatment to check his/her physical status.
Moreover, some exams will be performed. These exams can vary from a visit to
another. They include:
- Physical exam, including your height and weight.
- Vital signs: blood pressure, heart rate and temperature will be measured.
- Electrocardiogram (ECG, this is a registration of the activity of the hart)
at baseline visit and at 12, 24, 36, 48 weeks and at final visit. These exams
measure the activity of the heart and are painless.
- Chest X-ray to check the lungs at baseline and at final visit.
- A Forced Vital Capacity that is an evaluation of the vital capacity (VC)
measured when the patient is exhaling with maximal speed and effort during the
course of an examination called a spirometry and that is painless. The FVC will
be assessed at baseline and at week 4, 8, 12, 24, 36 and 48 and at the final
visit (If this is not week48).
- Blood sampling (about 2 to 4 teaspoonfuls depending on the visit,
10-20ml) and urinalysis for usual laboratory tests will be performed at
each visit.
- If the patient is a woman of child -bearing potential, a pregnancy test
will be performed at screening, baseline and at final visit. In
addition, blood (about 1 teaspoonful, 5ml) samples will be drawn at weeks 1,
2, 3, 5, 6, 7 and 10 and every 4 weeks after the start of the treatment to
check that the patient tolerates it well.
- For male patients, a spermogram will be performed (optional) in order to
assess the number of spermocytes, morphogenesis (biological process that turn
on the organism to develop the shape) and mobility: at baseline and then every
12 weeks.
- Neurologic examinations to assess the progress of your ALS using
the ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised)
and a Specific Quality of Life Questionnaire for ALS.
Risks:
SIDE EFFECTS OBSERVED IN PATIENTS TREATED WITH MASITINIB DURING STUDIES NOT
RELATED TO CANCER
Side effects that could appear after taking the treatment (masitinib) are
presented below. However, as all treatments under development, it is possible
to discover other side effects, rare and unexpected. In this case, the patient
will be notified in good time of any new information which might influence
their decision to maintain their participation in this study. To date, it is
not completely clear whether the side effects
below are due to masitinib or to the treated disease.
- Side effects reported by more than 20% of the patients: nausea, skin
toxicities and oedema (mainly eyelid and peripheral edemas).
- Side effects reported between 10-20% of the patients: vomiting, skin rash ,
and itching
- Side effects reported between 5-10% of the patients: diarrhea
asthenia gastroenteritis sinusitis abdominal pain and face edema
SPECIFIC RISKS OF TREATMENT WITH MASITINIB DURING THE FIRST 2 MONTHS OF
TREATMENT
Severe neutropenia
Severe skin toxicity
POTENTIAL RISKS ASSOCIATED WITH MASITINIB TREATMENT
Cardiac function
Reproductive organs
Renal function
Risks with pregnancy
long term risks
hepatobiliary risks
risks for the central nerveous system
RISKS RELATED TO RILUZOLE
Like all medicines, riluzole can cause side effects as described in the
prescribing information for riluzole.
The study doctor will inform the patient about these potential side effects. If
the patient experience any of these, tell your doctor immediately.
RISKS RELATED TO STUDY PROCEDURES
Other risks or discomforts you may experience during this study include pain,
risk of bleeding and/or bruising at the blood puncture site.
The risk associated with radiation exposure from having a chest X-ray is
minimal.
If the patient has any doubt or if the patient has side effects during the
study, the patient has to contact the study doctor that will provide the
patient with additional information.
Avenue George V 3
Parijs 75008
FR
Avenue George V 3
Parijs 75008
FR
Listed location countries
Age
Inclusion criteria
1. Female or male patient aged between 18 and 75 years of age, with a
weight > 50 kg and BMI between 18 and 35 kg/m².
2. Familial or sporadic ALS
3. Patient diagnosed with laboratory supported, clinically probable or
definite ALS according to the World Federation of Neurology Revised El
Escorial criteria (Brooks, 1994)
4. Disease duration from symptoms onset no longer than 36 months at
the screening visit
5. Patient treated with a stable dose of riluzole (100 mg/day) for at
least 30 days prior to screening
6. Patient with a FVC (Forced Vital Capacity) equal to or more than 60%
predicted normal value for gender, height, and age at the screening visit
7. Patient with life expectancy >= 6 months
8. Patient with adequate organ function at screening and baseline:
• Absolute Neutrophils Count (ANC) >= 2 x 109/L
• Hemoglobin >= 10 g/dL
• Platelets (PTL) >= 100 x 109/L
• AST/ALT <= 3 ULN
• Bilirubin <= 1.5 ULN
• Albuminemia > 1 x LLN
• Creatinine clearance > 60 mL/min (Cockcroft and Gault formula)
• Proteinuria < 30 mg/dL (1+) on dipstick; in case of the proteinuria >=
1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours
9. Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception are explained in the protocol (v4.0 dd16-Mar-2015) on page 5.
10. Male patients must use medically acceptable methods of contraception if your female partner is pregnant, from the time of the first administration of the study drug until three months following administration of the last dose of study drug. Acceptable methods are explained in the protocol on page 5.
Male patients must use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable methods are explained in the protocol on page 5.
11. Female patient of childbearing potential must have a negative
pregnancy test at screening and baseline
12. Patient able and willing to comply with study procedures as per
protocol
13. Patient able to understand, and willing to sign, and date the written
informed consent form at screening visit prior to any protocol-specific
procedures
14. Patient able to understand, and willing to follow the safety
procedures mentioned on the patient card in case of signs or symptoms
of severe neutropenia or severe cutaneous toxicity, during the first two
months of treatment
Exclusion criteria
1. Patient with history of hematologic, hepatic, respiratory disorder
that is clinically significant for his/her participation in the study
2. Patient who underwent tracheotomy and /or gastrostomy
3. Patient with a diagnosis of cancer or evidence of continued disease
within five years before starting study treatment
4. Patient with significant sensory abnormalities, dementia, other
neurologic diseases, uncompensated medical illness and psychiatric
illness
5. Patient who have participated in a clinical trial within 3 months prior
to screening
6. Pregnant, or nursing female patient
7. Patient with a known diagnosis of human immunodeficiency virus
(HIV) infection
8. Patient with known hepatitis B, hepatitis C or tuberculosis
9. Patient with any severe and/or uncontrolled medical condition
10. Patient having cardiac disorders defined by at least one of the
following conditions:
• Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia,
ventricular fibrillation, resuscitated sudden death)
• Patient with cardiac failure class III or IV of the NYHA classification
• Patient with severe conduction disorders which are not prevented by
permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
• Syncope without known aetiology within 3 months
• Uncontrolled severe hypertension, according to the judgment of the
investigator, or symptomatic hypertension
11. Patient with history of poor compliance or history of drug/alcohol
abuse, or excessive alcohol beverage consumption that would interfere
with the ability to comply with the study protocol, or current or past
psychiatric disease that might interfere with the ability to comply with
the study protocol or give informed consent;12. Patient treated with any investigational agent within 3 months prior
to screening
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 | EUCTR2010-024423-24-NL |
| CCMO | NL50742.041.14 |