A Double-Blind, Placebo-Controlled, Randomized, Parallel Group, 12-Month Safety and Efficacy Trial of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Behavioral Variant Frontotemporal Dementia (bvFTD)

Onset of bvFTD typically occurs sometime in the 50s, though it can occur as
early as age 20 or as late as age 80. Diagnosis of bvFTD is primarily on the
basis of clinical signs and symptoms, informed by imaging of selected regions
of the brain. Character change and disordered social
conduct are the dominant features initially and throughout the disease course.
Instrumental functions of perception, spatial skills, praxis and memory are
intact or relatively well preserved. LMTM delivers the active moiety, MT,
following dissociation of the counter ions. The proposed primary mechanism
through which MT acts to ameliorate and prevent the pathology which underlies
bvFTD is through the dissolution of tau aggregates and prevention of tau
aggregation through dissolution of early tau oligomers in the brain and by
inhibition of TDP-43 protein aggregation, most likely by binding to and
disrupting TDP-43 dimers and oligomers and thereby inhibiting fibril formation.
Nonclinical and clinical evidence supports the further study of LMTM in
subjects with bvFTD.

Primary:
To demonstrate the efficacy of LMTM as assessed by the change from Baseline on:
* Addenbrooke*s Cognitive Examination Revised (ACE-R)
* Symptomatic effect as reflected by the Functional Activities Questionnaire
(FAQ)
* Disease-modifying effect based on reduction in decline in whole brain volume
(WBV), using change from Baseline as measured by the Brain
Boundary Shift Integral (BBSI) by MRI imaging


Secondary:
To evaluate the effect of LMTM as measured by the following additional global,
disease severity, and motor impairment scales:
* Modified Alzheimer's Disease Cooperative Study * Clinical Global Impression
of Change (Modified ADCS-CGIC) * independently rated
* Frontotemporal Dementia Rating Scale (FRS)
* Unified Parkinson's Disease Rating Scale (UPDRS Parts II and III)
- To evaluate the safety and tolerability of LMTM


Exploratory:
4. To evaluate an early effect on ADCS-CGIC (after 8 weeks of treatment)
5. To evaluate the effect of LMTM on the Mini-Mental Status Examination (MMSE)
6. To determine the effect of LMTM on bvFTD by showing retardation of the
expected decline in whole brain volume

Multinational, randomized, placebo-controlled, double-blind, parallel-group,
52-week, outpatient study with seven post-baseline on-treatment visits planned
and an off-treatment follow-up visit for subjects who either discontinue early
or complete treatment but chose not to enter a separate open-label extension
study. Unscheduled visits and housing may be occur as needed for assessment.

Subjects will be randomized 1:1 (stratified by country) to one of the following
oral treatment groups:
* LMTM 200 mg/day group: LMTM 100 mg twice daily (b.i.d.) (one 100-mg tablet in
the morning and one 100-mg tablet in the evening) [n=90]
* Placebo group: Placebo twice daily (b.i.d.) (one LMTM 4-mg tablet in the
morning and one LMTM 4-mg tablet in the evening) [n=90]
The placebo group will receive low dose LMTM as a urinary and fecal colorant to
maintain blinding. All tablets are of matching appearance.

We hope that the treatments will improve the patient's symptoms and that he
will feel better. However this cannot be guaranteed. He will be helping to test
a treatment that could help people suffering from bvFTD in the future.

The patients will have to give up some of their time and will need to visit the
clinic a total of 10 times over a period of approximately 62 weeks (15 months).
Study visits could last for several hours up to an entire day. The study staff
will also communicate with the patient and carer via telephone several times
throughout the study. This may be inconvenient. The patient and his carer will
also have to answer some personal questions.
The trial medication will cause urine and/or bowel movements to turn blue. This
can be an inconvenience and may become a problem if the patient is unable to
control when he goes to the toilet. In this case, his/her clothes may become
stained. If this happens, the study doctor or nurse will tell the patient and
his/her carer the best way to remove the stains. The patient will also be
provided with an information leaflet to describe this. Also, the inside of the
patient*s mouth or teeth will become stained if the tablets are bitten or
chewed. This should not happen if the trial medication is taken as directed.
The patient may feel some discomfort and have some bruising as a result of
giving blood samples during the trial.
Patients who are covered by private medical insurance should check with their
company whether participation in this trial will affect their medical insurance.
Patients may have side effects while on the trial. Everyone taking part in the
trial will be watched carefully for any side effects. To find out about any
side effects, trial team will need to ask the patient and his/her carer some
personal questions. Some of these questions may be uncomfortable for him to
answer but it is important that he answers these as honestly as possible.
Patients will need to have 4 MRI scans. This means that they will have to lie
still in an enclosed space for up to 20 minutes. Some people with
claustrophobia may not be able to tolerate this. Some MRI scanners make a loud
noise when they are working. This test will use a Gadolinium contrast agent to
help detect any problems in the brain. The patient will be injected with this
agent before the test starts. The study doctor may also decide this agent is
not right for the patient. Gadolinium contrast agent must not be used in people
who are hypersensitive (allergic) to medicines containing gadolinium. It must
not be used in patients who have poor kidney function due to a risk of a
condition called nephrogenic systemic fibrosis (NSF). NSF causes thickening of
the skin and connective tissues. If the patient is allergic or it is not right
for him, the MRI scan may be done without contrast. The contrast agent used in
this study is approved by the European Medicines Agency and the United States
Food and Drug Administration. There is a chance that the study doctor will find
something abnormal on the brain scan that is not related to this research. If
this happens, the study doctor will inform the patient of these findings.

Risks and side effects for LMTM include those which are:
Likely:
* Stomach irritation and upsets that can include loose stools or diarrhoea,
nausea, retching, or vomiting
* Urinary problems that can include discomfort and pain when urinating, and the
need to urinate more frequently or more urgently
Less Likely:
* Dizziness and falls
* Skin rashes
* Anaemia: this can cause tiredness, weakness, and shortness of breath. The
patient*s blood will be checked for this side effect when blood samples are
taken at trial visits.
* Other changes in the patient*s blood cells may be seen, for example, changes
in the number of white blood cells.
The patient*s blood will be checked for this when blood samples are taken at
trial visits.
Rare but serious:
* There is a small risk that the trial medication LMTM may cause
methaemoglobinaemia. MetHb levels will be measured at each visit during the
course of the trial. Other changes to the blood may also occur and these will
be checked for when blood samples are taken at trial visits.
* There is a small risk that taking LMTM may cause a change in the way the
patient*s liver works. The patient*s blood will be checked for this side effect
when blood samples are taken at trial visits to catch early signs.
* Anaphylaxis has been reported for treatment with a similar medication.
* There is some information to suggest that LMTM may cause serotonin toxicity.
This could happen when LMTM is taken at the same time as medicines used to
treat depression or with some other medicines. Common symptoms of serotonin
syndrome include increased temperature and heart rate, shivering, sweating and
dilated pupils. The trial doctor will tell the patient if he/she is taking one
of these medicines and he/she will be monitored for signs of serotonin toxicity
* There is some information from studies in animals to suggest that LMTM may
cause heart damage. Although the risk of damage to the heart is very small, and
is not expected to be seen, it is a possibility. The heart will be checked for
any damage with an ECG at each visit.
* Certain drugs that work in the brain can increase the risk of suicidal
thoughts or actions. Because LMTM falls into this category of drug, the trial
doctor will watch for new or sudden changes in mood, behaviour, actions, and
will ask about feelings and thoughts at each trial visit, including thoughts
about killing oneself.
Other possible side effects may include: headaches, traces of blood and protein
in urine samples (this finding will be investigated if it is found, urine
samples will be checked for this), pain around the chest area (however in cases
where this has been found it has been described as muscular pain and not in
relation to any pain connected with the heart), weakness, itching, slight
change in sense of taste, or the patient may become flushed.
There is some information to suggest that LMTM may cause increased
photosensitivity (or sun sensitivity) of the patient*s skin, however this has
only been reported when MT has been delivered to the body through the veins
using a needle rather than taken by mouth.
In laboratory studies on cells, a drug similar to LMTM damaged genetic material
in these cells. In studies with living animals, the same damage was not seen.
Based on these studies, there may be a risk of damage to genetic material in
cells in the body when LMTM is given to humans. Some mice and rats developed
cancers after receiving a drug similar to LMTM for a long period of time. Some
of these were in numbers that are higher than expected. Based on these studies,
there may also be a higher risk of cancer when LMTM is given to humans.
There may also be side effects of the medicine that are as yet unknown:
* In a small number of patients who took part in other studies for Alzheimer's
disease, a small amount of bleeding and/or swelling of the brain was seen. This
bleeding or swelling was temporary. There is a chance that this might happen to
the patient while he is in this study. If this happens, he may become confused
or think less clearly, see or hear things that are not there, have a headache,
have trouble walking, vomit or have an upset stomach. The study doctor will
look at the MRI scans for any signs of any bleeding or swelling in the brain.
If the study doctor sees any bleeding or swelling in the brain, the patient
will be taken out of the study.
* Laboratory studies of cells showed that LMTM may damage genetic material.
This type of damage was not seen in studies with living animals. Based on these
studies, there may be a risk of damage to genetic material in cells in the body
when LMTM is given to humans.
* Some types of cancers were seen more often in mice and rats after they
received doses of the study medicine for a long time. Based on these studies,
LMTM might increase the chance of getting certain types of cancer when given to
humans.

There is not enough information available about whether the trial medication
causes harm to the unborn child.
Therefore:
A female patient will be excluded from the trial if she is pregnant,
breastfeeding or if she plans to become pregnant during the trial. If she could
become pregnant, she will be asked to have a pregnancy test before taking part
in the trial and again at every other visit. This will involve providing a
blood sample. If she could become pregnant she must also agree to use a
reliable form of contraception during the trial, e.g. combined oral
contraceptive pill, injectables, intrauterine device (IUD), foams, jellies,
diaphragm not having sexual intercourse or having a vasectomised partner. The
trial doctor will discuss with her what methods of contraception are
appropriate and acceptable to use while she is in the trial. If she becomes
pregnant during the course of the trial, she should tell the trial doctor
immediately so he/she can help her decide what to do. The trial doctor would
discuss referral for specialist counselling on the possible risks.
A male patient should use condoms during the trial and for an additional 4 days
after treatment has finished.