The primary objective is to assess the effects on amyloid plaque burden of administration of VX-745 for 12-weeks, as assessed by Dynamic 11C-PiB (Carbon-11 labeled Pittsburgh Compound B) PET Amyloid Scanning in patients with Mild Cogntitive…
ID
Source
Brief title
Condition
- Mental impairment disorders
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variables are:
* Change from Baseline to Week 12 within each treatment group in quantitative
relative cortical uptake of 11C-PiB as assessed by dynamic PET scanning at
baseline and at end of treatment
* Number and proportion of responders by quantitative dynamic PET scanning
within each dose group (response defined as *7% reduction in amyloid plaque
load)
Secondary outcome
The secondary efficacy variables are change from Baseline to Week 12 in
Mini-Mental State Examination (MMSE), and Wechsler Memory Scale (WMS). No
change in cognitive score is anticipated during the brief 12-week period of
treatment. Nevertheless, the cognitive assessment will be conducted to
determine whether any improvement is observed, and as part of the safety
assessment to ensure that there is no marked deterioration of performance.
In addition, MEG and resting state fMRI data will be obtained in order evaluate
for a signal of activity on synaptic function, and to obtain initial treatment
effect data to design/size future studies in which one of these measures would
be a primary efficacy measure.
Other endpoints are pharmacokinetics and safety.
Background summary
Alzheimer*s disease (AD) is a progressive brain disease that results in
impaired cognitive function, such as memory and thinking, and ultimately
impairs one*s ability to complete simple daily tasks. Available treatments
provide symptomatic relief for a period of time, but do not prevent or slow
neuronal loss and inevitable disease progression. The importance of
microglia-driven inflammation in the central nervous system of human
Alzheimer's disease, and the role of p38 MAPK in regulating microglia, have
recently been defined. VX-745 binds to the ATP binding pocket of p38 MAPK and
inhibits the kinase competitively. VX-745 nonclinical data suggest that it may
have a therapeutic effect in patients with inflammatory diseases of both the
peripheral and central nervous systems.
Study objective
The primary objective is to assess the effects on amyloid plaque burden of
administration of VX-745 for 12-weeks, as assessed by Dynamic 11C-PiB
(Carbon-11 labeled Pittsburgh Compound B) PET Amyloid Scanning in patients with
Mild Cogntitive Impairment due to Alzheimer*s Disease (*MCI due to AD*) or mild
Alzheimer*s disease (AD).
The secondary objectives are:
- To develop a PK/PD model for VX 745 and amyloid plaque burden reduction, if
an effect on amyloid plaque burden is observed.
- To obtain a preliminary evaluation of the safety and tolerability of VX-745
in patients with MCI or AD.
- To obtain data on the effects of VX-745 on synaptic function as assessed by
Magnetoencephalography (MEG) and resting state functional Magnetic Resonance
Imaging (fMRI).
Study design
This is a phase IIa, monocenter, multiple-dose, open-label study of VX-745 (40
mg or 125 mg) administered twice daily for 12 weeks in subjects with a
confirmed diagnosis of MCI or AD.
Intervention
Once eligibility is confirmed and before the first dose of VX-745, subjects
will be randomly assigned to one of two VX-745 dose groups. Investigators and
patients will be blind to the dosage strength. Dosing will start on Day 1
following completion of all Baseline procedures. During the treatment period,
subjects will return to the clinic on Days 14, 28, 56, and 84. A Follow-up
visit will be conducted 14 (±3) days following the last dose of VX-745. Dynamic
PET scanning with full quantitative analysis will be performed at baseline and
at the end of treatment.
Study burden and risks
Based on the nonclinical and clinical data available to date and the planned
safety monitoring, the overall risk-benefit balance for this trial is
considered to be acceptable.
Foreseeable benefits
The current study represents the first clinical investigation in Alzheimer's
disease of VX-745. Available treatments provide symptomatic relief for a period
of time, but do not prevent or slow neuronal loss and inevitable disease
progression. VX-745 nonclinical data suggest that it may have a therapeutic
effect in patients with inflammatory diseases of both the peripheral and
central nervous systems.
Possible side effects of the study drug
The medicinal product being studied is called VX-745. This study may cause the
following side effects:
- headache
- common cold
- gastroenteritis (inflammation of the stomach and the small intestine)
- diarrhea
- dizziness
- sleeplessness/ insomnia
- dyspnea (breathlessness)
- myalgia (muscle pain)
- abdominal pain
- elevations in liver enzymes, markers of potential injury to the liver
- reduction of fever and inflammation, which may mask the signs of infection
- pharyngitis (inflammation of the throat) and rhinitis (inflammation of the
mucous membrane inside the nose).
Known risks of study procedures
* Blood samples: it can be painful when blood is taken. Some people become
dizzy or faint when blood is collected. Some may also develop an infection
(rare), bleeding, redness or bruising at the site at which the blood is taken.
* ECG: the plasters that are used can cause skin irritation.
* MEG: there are very few know risks of MEG (magnetoencephalography). Sitting
inside the machine can feel constraining or frightening to someone who is prone
to such feelings, but unlike a MRI machine a MEG machine is not built as a
tunnel and this risk is rare. There are is also a theoretical risk of leakage
of the fluid that is used to cool the magnets inside the machine, but there are
safeguards built into the machine to prevent injury.
* PET scan: subjects will be exposed to a small amount of radioactivity from
the tracer for the PET scan. The risk of the radiation dose from this study is
considered small. Although this radiation dose is considered to be acceptable
by current guidelines, the effect of radiation adds up over the lifetime. Any
increase in the amount of radiation received above natural background radiation
carries with it a risk of later developing serious and possibly fatal
conditions, including cancer. It is also possible, although very unlikely, to
have an allergic reaction to the radioactive substance used for this scan. Some
people have pain, redness, or swelling at the injection site.
* MRI scan: there are no known side effects of exposure to the powerful
magnetic field used by MRI scanners. There are strict safety regulations in
place before an MRI scan is performed.
Risks to the unborn child
If the patient is a man with a female partner who can become pregnant, he will
be asked to use at least one of the following contraceptive methods from before
first dose on Day 1 through 7 days following the last dose of study drug:
complete abstinence, sterilization, or condom use.
A woman cannot be in this study if she is pregnant, planning to become pregnant
during the study or nursing a child. If the patient is a woman and can still
become pregnant, she will be asked to use at least one of the following
contraceptive methods from before first dose on Day 1 through 7 days following
the last dose of study drug: complete abstinence, birth control pill (or
contraceptive injection), intrauterine device, or condom use.
Risk from radiation
X-rays or radiation from radioactive materials can damage genes. This damage of
genes can lead to cancer or a congenital defect. In the above mentioned
radiation, there will be no other side effects of radiation than redness of the
skin or hair loss.
For further information about risks and side effects, please refer to the
patient information leaflet.
Patients will be monitored for safety throughout the study. Unforeseen/unwanted
events will be taken care of by the study staff at all sites, which are
experienced in handling patients with AD and in conducting similar clinical
trials.
11 Channing Street
Cambridge MA 02138
US
11 Channing Street
Cambridge MA 02138
US
Listed location countries
Age
Inclusion criteria
1. Men and women age 60-85 years.;2. Willing and able to provide informed consent.;3. Confirmed diagnosis of mild cognitive impairment due to Alzheimer*s disease (MCI due to AD) or mild AD.;4. Mini-Mental State Examination (MMSE) score ranging from 20 to 28, inclusive.;5. Evidence of amyloid pathology by Amyloid PET scan determined by visual inspection (any method) by an experienced nuclear medicine physician.;6. If the patient is taking drug for AD (e.g.; donepezil or memantine), he has been on a stable dose for at least 3 months.;7. Dutch-speaking.;8. Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments
Exclusion criteria
1. Evidence of neurodegenerative disease other than AD (including but not limited to vascular dementia, dementia with Lewy bodies, and Parkinson*s disease).;2. Subject has any concurrent medical or psychiatric condition that, in the opinion of the investigator, would compromise his/her ability to comply with the study requirements.;3. History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.;4. Significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude treatment with p38 MAP kinase inhibitor and/or assessment of drug safety and efficacy.;5. History of an allergic reaction of any severity to 11PiB injection.;6. Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of the investigation drug, whichever is longer, before enrollment in this study.;7. Male subjects with female partners of child-bearing potential who are unwilling or unable to adhere to contraception requirements.;8. Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingo-oophorectomy.;9. Positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the trial.;10. Contraindications (e.g. pacemaker, vascular stent or stent graft) to MRI testing.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002855-25-NL |
| CCMO | NL50211.029.14 |