A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial with an Open-label Extension Phase to Evaluate the Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults with Chronic Immune Thrombocytopenia (Idiopathic Thrombocytopenic Purpura).

Thrombocytopenia is the presence of relatively low numbers of platelets in the
blood, and in severe cases can be associated with significant morbidity and
mortality. ITP is one of the numerous disease-related thrombocytopenias and
there are estimated to be approximately 50,000 individuals with chronic ITP
(cITP) in Europe. People with cITP often bleed from small blood vessels,
resulting in bruising, nosebleeds or, more rarely, fatal bleeds, in particular
intracranial bleeds.
E5501 monomaleate is an orally administered, small molecule c-Mpl agonist that
mimics the biological effects of TPO in vitro and in vivo. TPO is the principal
physiologic regulator of platelet production and exerts its effect on
megakaryocytopoiesis and thrombocytopoiesis via binding and activation of the
c-Mpl receptor, which is expressed on hematopoietic stem cells, on cells of the
megakaryocytic lineage, and on platelets. Like TPO, E5501 also binds to the
human c-Mpl receptor and affects signal transduction through the induction of
downstream signaling, thereby enhancing human megakaryocytic proliferation and
differentiation.
E5501 is a small molecule that can be administered orally, and thus presents
neither the clinical/safety risks associated with parenteral agents nor the
immunogenic risks of recombinant proteins and peptide -based products. E5501
has increased platelet production in normal healthy subjects both in single-
and multiple-dose oral administration, and has demonstrated superior efficacy
in cITP subjects compared with placebo, as measured by platelet response on Day
28, as well as a favorable safety profile (protocol 6.1.2.2).
This is a Phase 3 multicenter, randomized, double-blind, parallel group and
placebo-controlled trial with an open-label extension phase that will further
evaluate the efficacy of oral E5501 (in addition to standard of care) versus
placebo in raising and maintaining platelet counts within 6 months from the
start of dosing, and the safety of E5501 over a long-term 2.5-year treatment
period in adult subjects with cITP. This study has been designed to provide the
best possible efficacy and safety evidence for E5501 in the treatment of cITP
subjects in order to gain regulatory approval to make E5501 available for
clinical use worldwide.

Core Study:
Primary objective:
• To demonstrate that the efficacy of E5501 (in addition to standard of care)
is superior to placebo (in addition to standard of care) for the treatment of
adult subjects with chronic immune thrombocytopenia (idiopathic
thrombocytopenic purpura) (ITP) as measured by durable platelet response.

Secondary objectives:
• To demonstrate that the efficacy of E5501 (in addition to standard of care)
is superior to the efficacy of placebo (in addition to standard of care) as
measured by platelet response rate at Day 8
• To demonstrate that the efficacy of E5501 (in addition to standard of care)
is superior to the efficacy of placebo (in addition to standard of care) as
measured by an alternate durable response
• To demonstrate that the efficacy of E5501 (in addition to standard of care)
is superior to the efficacy of placebo (in addition to standard of care) as
measured by the proportion of subjects with reduction in concomitant ITP
medication use
• To evaluate the safety of E5501 compared with placebo

Additional Objectives:
• To evaluate the efficacy of E5501 (in addition to standard of care) is
superior to the efficacy of placebo (in addition to standard of care) with
regard to bleeding minimization and use of rescue therapy
• To evaluate the population pharmacokinetic/pharmacodynamics (PK/PD) of plasma
E5501 exposure and effect on platelet counts

Extension Phase:
Primary Objective:
• To evaluate the safety and tolerability of long-term therapy with E5501 in
subjects with chronic ITP (cITP)

Secondary Objectives:
• To demonstrate the effectiveness of long-term therapy with E5501 as measured
by platelet response, bleeding, and the use of rescue therapy
• To assess the reduction in use of steroids and concomitant ITP medication in
subjects receiving E5501

This study is a multicenter, multinational, randomized, double-blind,
placebo-controlled, parallel-group study of E5501 in men and women >= 18 years
who have cITP. Approximately 84 subjects who meet all the eligibility
requirements will be randomized into the study. Splenectomized subjects must
make up at least 35% of the study population, therefore, when enrollment of
nonsplenectomized subjects reaches 65%, enrollment of those subjects will be
stopped. The Screening Visit and Day 1 Baseline/Randomization Visit platelet
counts will be averaged to obtain the baseline platelet count value. The two
samples must be obtained >= 48 hours and <= 2 weeks apart and the results must be
available prior to randomization.

No single platelet count should be > 35 x 109/L. Subjects will be centrally
stratified at time of randomization by splenectomy status and baseline platelet
count (<=15 x 109/L or >15 to <30 x 109/L), and use of concomitant ITP
medication (i.e., yes or no for the use of concomitant TP medication) at
baseline, and will be randomized by an Interactive Voice and Web Response
System (IxRS) to receive either E5501 or placebo in a 2:1 ratio in double-blind
fashion. Subjects will receive blinded therapy at a starting dose of 20 mg
E5501 or placebo once daily. Subjects will be allowed to have their dose
titrated up (maximum dose 40 mg for E5501 or matching placebo) or down (minimum
dose 5 mg for E5501 or matching placebo) in accordance with their
individual responses to study drug; a placebo titration will be used to
maintain the blind. The overall goal of any dose modification will be to
maintain the
peripheral platelet count at levels >= 50 × 109/L and <= 150 × 109/L, and to
decrease the need for ITP-directed concomitant medications, if possible.

The study will consist of three phases: Prerandomization, Randomization (Core
study), and the Extension. The Prerandomization Phase will have one Screening
Period (up to 4 weeks).

The Randomization Phase (Core Study) will have six periods: Baseline
/Randomization (1 day), Titration (6 weeks), Concomitant ITP Medication
Reduction (12 weeks), Maintenance (8 weeks including the End-of-Treatment [EOT]
Visit [Visit 22]), Dose-tapering (up to 4 weeks), and Follow-up (30 days).
Dose-tapering and Follow-up are required only for those subjects not continuing
into the Extension Phase.
The Extension Phase will consist of four periods: Conversion (6 weeks),
Maintenance Period/Concomitant ITP Medication Reduction Period (90 weeks),
Dose-tapering (up to 4 weeks), and Follow up (30 days).

Prerandomization Phase
Screening Period (Visit 1): During this period, subjects will be assessed for
eligibility and have a platelet count performed.
The Screening Visit and Day 1 Baseline/Randomization Visit platelet counts will
be averaged to obtain the baseline platelet count value. The two samples
must be obtained >= 48 hours and <= 2 weeks apart and the results must be
available prior to randomization. Therefore, an additional screening platelet
count may be required due to issues with scheduling. If an additional platelet
count is taken, an average of the last two platelet counts of >= 48 hours apart
needs to be < 30 x 109/L for eligibility.

Core Study
Randomization Phase
Baseline/Randomization Period (Visit 2): During this period, baseline
assessments, including platelet count and randomization will be performed.
Blinded study drug administration will be started.

Titration Period (Visits 3 to 7): During this period, titration of study drug
from the initial starting dose will be performed in accordance with
protocol-specified titration guidelines in order to find the minimum dose
required to maintain platelet counts of >= 50 × 109/L and <= 150 × 109/L. No down
titration of
concomitant ITP medication will be permitted during this period (except for
reasons of subject safety). Subjects will return on Days 5, 8, 14, 21 and 28
during this period.

Concomitant ITP Medication Reduction Period (Visits 8 to 13): During this
period, downward titration of concomitant ITP medication will be permitted in
accordance with the Concomitant ITP Downward Titration Guidelines. Additional
study drug dose adjustments before and after the ITP concomitant
downward titration may be needed. Subjects will return every 2 weeks during
this period.

Maintenance Period (Visits 14 to 22): Subjects will continue treatment in order
to maintain platelet counts of >= 50 × 109/L and <= 150 × 109/L. Study drug
dose adjustments will be made in accordance with titration guidelines. No down
titration of concomitant ITP medication will be permitted during this
period unless there is a safety concern. Subjects will return weekly for visits.
At the EOT Visit, subjects will have the choice to enter the Extension Phase
and receive open-label E5501 therapy. Subjects who are unable or unwilling to
continue in the Extension Phase of the study will enter the Dose-tapering and
Follow-up Periods.
Subjects who require study drug dose adjustments, who undergo concomitant ITP
medication reduction or who receive rescue therapy during the periods of
Concomitant Medication Reduction and Maintenance are required to return for
weekly visits for 3 consecutive weeks.

Dose-tapering Period (Visits 23 to 26): Subjects who do not continue into the
Extension Phase will be required to attend weekly visits at which the study
drug will be down-titrated one dose level per week until the study drug is
discontinued. This will be done in a blinded fashion with placebo substitution
occurring as required, and will take up to 4 weeks to get all subjects off
study drug. During the Dose-tapering Period, subsequent up-titration or
addition of concomitant ITP medication should be considered, at the
investigator*s discretion. Once the dose-tapering of study drug is completed,
subjects will
enter the Follow-up Period.

Follow-up Period (Visit 27 to 30): Subjects will be followed for 30 days after
the last dose taken in the Dose-tapering Period. Subjects will return every
week for visits during this period and will have their final evaluations on the
last day of the Follow-up Period.

Extension Phase
Subjects who meet all the eligibility requirements for the Extension Phase and
who are willing and able, will enter the Extension Phase. Subjects who
discontinue the Core Study early because of lack of treatment effect (see Study
Drug Discontinuation) will still be eligible to continue into the Extension
Phase. Subjects entering directly into the Extension Phase will not enter the
Dose-tapering and Follow-up Periods of the Core Study.

Conversion Period: (Visits E1 to E8): This period will consist of E1 Visit (Day
1 Visit of the Extension Phase), E2 Visit (Day 5 Visit of the Extension
Phase), E3 Visit (Day 8 Visit of the Extension Phase), and then 5 weekly visits
thereafter. The E1 Visit will be performed on the same day as the EOT Visit of
the Core Study. No washout is required between the Core and the Extension
Phases. Subject eligibility for the Extension Phase will be determined at the
E1 visit. The results of the EOT assessments will be used for the E1 Visit and
serve as a baseline for the Extension Phase. Open-label E5501 therapy will be
dispensed at the E1 Visit and should be started on the next day as the subject
would have received the last dose of blinded therapy at EOT Visit of the Core
Study for PK assessment.
During the Conversion Period of the Extension Phase, all subjects and
investigators will remain blinded to the treatment received in the Core Study.
Subjects entering the Extension Phase will receive a starting dose 20 mg of
open-label E5501. Titration of E5501 will be performed in accordance with the
protocol-specified titration guidelines. No down titration of concomitant ITP
medication will be permitted during this period unless there is a safety
concern.

Maintenance Period/Concomitant ITP Medication Reduction Period (Visits E9 to
E31): Titration of open-label E5501 treatment will be performed in accordance
with E5501 dose adjustment guidance in order to find the minimum dose required
to maintain platelet counts of >= 50 × 109/L and <= 150 ×
109/L. Downward titration of concomitant ITP medication will also be permitted
during this period of the Extension Phase. Concomitant ITP
Downward Titration Guidelines will be specified by the protocol. Subjects will
return after 2 weeks for the Visit E9. Thereafter, the subjects will
return for monthly visits during this period, unless they require E5501 dose
adjustments and/or concomitant ITP medication downward titration. Affected
subjects will be required to return to undergo 3 consecutive weekly visits.
Unplanned visits may be scheduled at any time for subjects who require urgent
correction of platelet counts, E5501 dose adjustment, or for other reasons at
the investigator*s discretion.

Dose-tapering Period (Visits E32 to E35): Dose tapering of E5501 treatment will
be performed in all subjects who have either completed the Extension
Phase of the study (2 years total duration) or who discontinue early from any
phase. Subjects will be required to attend up to 4 weekly visits for
down titration of the dose of E5501 at 10 mg per week until the 10 mg dose is
reached, followed by 1 week of treatment at 5 mg, before reaching 0 mg.
During the Dose-tapering Period, subsequent up-titration or addition of
concomitant ITP medication should be considered, at the investigator*s
discretion. Once the dose tapering of the study drug has finished, subjects
will enter the Follow-up Period.

Follow-up Period (Visits E36 to E39): Subjects will be followed for 30 days
after the last dose of the Dose-tapering Period. Subjects will return every
week for visits and will have their final evaluations on the last day of the
Follow-up Period.

Study Drug Dose Adjustment Guidelines
To minimize the risk of developing thrombocytosis, dose adjustment of the study
drug will target maintaining the platelet count of >= 50 × 109/L and
<= 150 × 109/L. Study drug dose adjustment for the Core Study must follow the
dose adjustment guidelines defined below.
Investigators must consider dose titration in accordance with a subject*s
platelet count every 2 weeks (as most subjects take approximately 10 to 14 days
to demonstrate the full effect of study drug on platelet count). However, dose
titration may be performed weekly for subjects with platelet counts
< 50 × 109/L or > 250 × 109/L.
The proposed dose adjustment guidelines should be adhered to with the exception
of the following clinical scenarios:
• If a subject has recently received rescue therapy and the subject*s platelet
count is expected to rise, making upward dose titration of the study drug
inappropriate or;
• If a subject*s platelet count has risen as a result of receiving rescue
therapy and this rise in platelet count is transient and expected to fall,
making downward dose titration of the study drug inappropriate
• If a subject*s study drug is stopped due to elevated platelet counts (i.e.,
platelet count >250 × 109/L) the investigator can choose not to place the
subject onto the same dose of study drug that originally this high rise in
platelet count. This is to avoid large fluctuations in platelet counts.
• If a subject*s platelet count is >= 50 × 109/L and <= 150 × 109/L and the
investigator would like to down-titrate the subject*s concomitant ITP
medication, the subject*s study drug can be up titrated.

A maximum dose of 40 mg E5501 will be permitted for upward titration and a
minimum dose level titration of 5 mg E5501 will be permitted for downward
titration. If the platelet count remains > 250 × 109/L after 3 consecutive
weeks, the subject*s concomitant ITP medication should, if possible, be down
titrated provided a) the subject is in the concomitant ITP medication reduction
period of the Core Study (i.e., Visits 8 to 13) or b) maintenance
period/concomitant ITP medication reduction period of the Extension Phase
(i.e., Visits E9 to E31). Otherwise, the subject should be discontinued.

E5501 dose adjustment in the Extension Phase of the study are identical to
those of the Core Study but will be performed with open-label E5501 as
defined by E5501 dose adjustment guidance for the Extension Phase

Study Drug Discontinuation
In both the Core Study and the Extension Phase, study drug may be permanently
discontinued at discretion of the investigator due to safety reasons or as
follows:
• Due to lack of treatment effect defined as:
o Platelet count remains < 30 × 109/L more than 3 weeks at the maximum dose
(subjects can be discontinued after 7 days of therapy at the maximum dose if
they have dangerously low platelet counts in the opinion of the investigator) or
o Subjects who require rescue therapy more than three times or continuous
rescue therapy for more than 3 weeks (Core Study only)
• Treatment with some ITP therapies/procedures, such as vinca alkaloids,
cyclophosphamide, rituximab, splenectomy, and other TPO-receptor agonists
(eltrombopag, romiplostim)
• Excessive platelet count responses (>250 × 109/L) after more than 3 weeks at
the minimum dose and the subject is unable to down titrate concomitant ITP
medication
• Subjects with elevated fasting gastrin-17 greater than 5 times upper limit of
normal (ULN) will be requested to undergo an endoscopy and will be discontinued.
• Subjects with two consecutive elevated fasting gastrin-17 greater than 2.5
times ULN who, in the opinion of the gastric biomarker expert review committee,
require discontinuation due to gastric safety concerns
• Subjects with significant gastric atrophy (OLGA staging >=II)

Concomitant ITP Medication Downward Titration Guidelines
Those subjects receiving concomitant ITP medication when entering the study may
have this medication down-titrated and ultimately eliminated. This can
only occur during the Concomitant ITP Medication Reduction Period (Visits 8 to
13) of the Core Study and Maintenance Period/Concomitant ITP Medication
Reduction Period of the Extension Phase (Visits E9 to E31).
Concomitant ITP medication downward titration can be implemented at the
discretion of the investigator. Downward titration of concomitant ITP
medication can only be considered if the subject*s platelet count remains>= 150
× 109/L. The downward titration of concomitant ITP medication will be
made as an alternative to downward titration of E5501 (i.e., instead of
titrating down E5501, the concomitant ITP medication will be down-titrated). Any
down titration of ITP medication should occur in a controlled manner in order
to prevent an excessive and unsafe drop in the subject*s platelet count.

Concomitant ITP Medication Downward Titration Guidelines are detailed below:
• Concomitant ITP medication downward titration should not take place at a rate
faster than once (one time) every 14 days.
• If a subject has two or more concomitant ITP medications, only one medication
can be down-titrated at a time.
• It is preferable that a concomitant ITP medication is eliminated prior to the
down titration of a second concomitant ITP medication, unless the
investigator considers it beneficial for the subject to continue to receive
low-dose steroids.
• Each titration step cannot be larger than 25% to 50% of the original
concomitant ITP medication dose unless the subject is receiving a low
dose of the concomitant ITP medication being down-titrated.

Permitted Concomitant Therapy
Permitted ITP concomitant background therapies are as follows:
• Corticosteroids and/or azathioprine must be taken at a stable dose for 4
weeks before randomization.
• Mycophenolate mofetil (MMF) or danazol must be taken at a stable dose for at
least 12 weeks before randomization
• Cyclosporine A (CsA) due to the fact that it is a P-glycoprotein-mediated
transport (PgP) inhibitor should be avoided unless deemed medically
necessary. If deemed medically necessary, then CsA must be taken at a stable
dose for at least 12 weeks before randomization

At the discretion of the investigator, subjects will be allowed to use aspirin,
other salicylates or approved adenosine diphosphate (ADP) receptor antagonists
(e.g., clopidogrel, prasugrel) during the study once their platelet count has
risen, at the discretion of the investigator.

Subjects treated with proton pump inhibitors (PPIs) and H2 antagonist therapy
must be receiving a stable dose for at least 6 weeks prior to randomization or
treatment with these therapies must have been completed at least 2 weeks prior
to randomization.

E5501 is a substrate and an inhibitor of PgP. Co-administration with strong
inhibitors of PgP should be avoided unless deemed medically necessary. If a
strong P-gP inhibitor is to be added to E5501 therapy or if the dose of a
concomitantly-administered strong P-gP inhibitor
is altered, platelet counts should be monitored weekly for the next 3 weeks as
a dose adjustment of E5501 may be required. If E5501 is
administered with any concomitant medications which are substrates of PgP,
clinical signs of toxicity or blood levels (if available) of these concomitant
medications need to be assessed.

Rescue therapy
Subjects will be allowed to receive rescue therapy at the discretion of the
investigator or subinvestigator based on their clinical assessment. Rescue
therapy should be considered if there is an urgent need to increase platelet
count for example:
• Life-threatening thrombocytopenia, such as a platelet count < 10 x 109/L
• Clinical signs or symptoms suggesting potential bleed( i.e., wet purpura)
• Major bleed
Rescue therapy will be defined as:
• The addition of any new ITP medication or medication to treat
thrombocytopenia (for example):
o Corticosteroids
o Intravenous immunoglobulin (IVIg) therapy
o Anti-D therapy
o MMF
o Azathioprine
o Danazol
o Dapsone
o CsA (Due to the fact that CsA is a PgP inhibitor, it should be avoided unless
deemed medically necessary and/or no other suitable alternative treatment
options are available.)
o Platelet transfusion
• Any increase in baseline dose of a concomitant ITP medication

TPO agonists are not allowed as rescue therapy.

Prohibited Concomitant Therapy
Platelet transfusion is prohibited within 7 days before the first dose of study
drug. Antifibrinolytic agents (aprotinin, tranexamic acid, and aminocaproic
acid) and recombinant activated factor VII are prohibited during the treatment
phase of the study. Heparin, warfarin, factor Xa inhibitors, direct thrombin
inhibitors, fresh frozen plasma and cryoprecipitate, chronic antiplatelet
therapy (>4 weeks) with aspirin, clopidogrel, prasugrel, ticlopidine, or
glycoprotein IIb/IIIa antagonists (e.g., tirofiban) are prohibited during the
treatment phase of the study. However, a short-term use of aspirin, other
salicylates or ADP receptor antagonists are only permitted if the platelet
count has risen and the investigator judges that subjects are at risk for
thromboembolism. The use of nonsteroidal anti-inflammatory drugs other than
aspirin for more 7 days per month is prohibited.
Some ITP therapies/procedures, such as vinca alkaloids, cyclophosphamide,
rituximab, splenectomy, and other TPO receptor agonists (eltrombopag,
romiplostim) are prohibited during the treatment phase due to the long-term
effects of these treatments, safety profile, and potential to confound efficacy
results. Subjects requiring these therapies will be discontinued from the study.

Hematology Tests
When a hematology test is required, two blood samples will be collected; one
for central laboratory analysis and one for local laboratory analysis. The
local laboratory hematology test result will be sent directly to the
investigators and will be used for: qualifying a subject*s entry into the
study; study drug and concomitant ITP medication dose titration, and clinical
assessment.
Only platelet count data from local laboratories will be collected and entered
into the CRF for analysis. All other hematological parameters will be collected
and loaded into the database for analysis according to results derived from the
designated central laboratory.

Bone marrow evaluation
Bone marrow evaluations will be divided into three categories: those required
for eligibility, those required during the study, and those required due to the
subject agreeing to enroll into the optional bone marrow evaluations:
1. Bone marrow evaluations will be required for eligibility in the following
situation:
Subjects who have never initially responded (platelet count > 50 × 109/L) to a
previous ITP therapy and who don*t have a bone marrow examination (biopsy or
aspirate) consistent with ITP within the last 3 years before randomization.
2. Bone marrow biopsies will be required during the study in the following
situation:
Subjects who have a WBC differential and the subsequent peripheral blood smear
confirming the presence of immature or dysplastic cells at
either the Baseline Visit or during the study.
3. Optional bone marrow biopsies:
Optional bone marrow biopsies will be requested from all subjects. These
evaluations should be strongly encouraged to allow the assessment of bone
marrow safety of E5501. For those subjects who consent to undergo these
optional bone marrow evaluations, bone marrow biopsies will be performed as
follows:
For subjects who do enter the Extension Phase:
• At Visit 2 (Baseline/Randomization Visi
• At Visit E13 (6 month visit of the Extension Phase) or on exit from the study
(whichever occurs first)
For subjects who do not enter the Extension Phase:
• At Visit 2 (Baseline/Randomization Visit)
• At Visit 22 (EOT Visit of the Core Study) or on exit from thestudy (whichever
occurs first)

If a subject has had a bone marrow biopsy within 6 months prior to
randomization (including during screening) and has not received any subsequent
TPO agonists, this bone marrow biopsy may be considered as a valid baseline
(i.e., the Visit 2 (Baseline/Randomization Visit), providing the
bone marrow specimen is available for re-examination, if required. If no
previous bone marrow evaluation is available, a bone marrow biopsy should be
performed at
Visit 2 (Baseline/Randomization Visit) as detailed above.

Subjects unwilling to consent to the optional bone marrow biopsies will still
be eligible for enrollment.

A central laboratory will be used for all bone marrow evaluations. Collagen and
reticulin will be measured. The modified Bauermeister scale will be used
to grade the severity of marrow fibrosis.

Endoscopy
All endoscopy assessments will only be considered if clinically appropriate, as
assessed by the treating physician and endoscopist (i.e., there is no excessive
risk of the subject bleeding, in particular, subjects will only be requested to
undergo endoscopies if their platelet counts are >50 x 109/L).

Patients will be subjected to the following interventions/procedures and
defined behavioural rules (for a schedule of procedures at each site visit:
please see protocol tables 5 & 6):
> oral intake of study medication (once daily, with food): tablets with 5mg,
10mg, 20mg or 40mg of either E5501 or placebo in a flexidose design. E5501 will
be started at a dose of 20mg, with dose titration down to 5mg or up to 40mg as
per specified guidelines (protocol 8.4.5 and table2).
> physical examinations
> measurement of vital signs
> blood sample collection (including an optional pharmacogenomic (PG) sample,
for which there is a seperate patient information leaflet and consent form):
for certain visits, patients will be asked to be fasting and to not smoke in
the 12 hours prior to collection.
> pregnancy tests (blood and urine)
> collection of urine samples
> electrocardiogram (ECG)
> questionaires (EQ-5D, SF-36, TSQM)
> bone marrow biopsy (if patient has never responded to previous treatment for
ITP, or is aged 60 years and older, and has not had a bone marrow biopsy within
past 3 years to confirm they have ITP AND/OR if the blood samples taken at any
point during the study show that levels of blood cells are abnormal)
> optional bone marrow biopsy, for which there is a separate patient
information leaflet and consent form.
> possibly an endoscopy, if the results from the fasting blood samples suggest
that further testing is necessary.
> patients will be asked to attend all scheduled study visits, to take the
study medication as instructed (once daily, with food), to inform their study
doctor if they missed any doses or took more tablets than supposed to, to
return all study medication boxes (even if empty) given at each visit and to
bring their study drug to every study visit.
> patients will be asked to report all side effects, symptoms and medical
problems.
> patients will be asked not to take certain drugs, to inform the study team of
any changes in their medication and to consult their study team before taking
any over the counter medicines/vitamins/supplements/herbals and prescription
drugs or alternative procedures.
> female patients must agree to use an effective method of contraception 30
days before, during the entire study period and for 30 days after their
participation in the study. If they become pregnant during the course of the
study, the patient must tell her study doctor immediately and she and her
unborn baby will be followed to term.

Burden:
The study procedures that will be performed are listed in K2 "Interventions".
The duration of treatment for each subject is 26 weeks for the randomized
treatment period and 104 weeks (2 years) for the extension period.

Side effects and risks:
The side effects most commonly reported in previous research studies of E5501
were:
-headache
-fatigue
-excessive platelet count increase
-nausea
-vomiting
-dizziness
-drowsiness/sleepiness
-reoccurrence of a low level of platelets in the blood upon stopping E5501
-minor bleeding events (e.g. nose bleeds, bleeding gums, bruising)
-common cold
-joint pains
-collection of fluid in feet and legs
-Back pain
-increased gas in stomach or intestines
-stomach pain

Because of the way E5501 works there is a potential risk for developing blood
clots or blockage of blood vessels in the body. The patient will be closely
monitored for any signs of clotting or high levels of platelets in the blood.
If platelet counts increase, the study doctor will stop study drug, and may
prescribe aspirin if he/she believes the patient may be at risk for clotting.
If the patient is unable to take aspirin, an alternative anti-platelet drug
such as clopidogrel, may be prescribed. By giving aspirin or alternative
anti-platelet drugs, this should reduce the patient's risk of developing blood
clots or blocked blood vessels.

E5501, like other medications that increase platelet count, may cause changes
in the bone marrow. These changes may cause the bone marrow to make fewer than
normal cells or to make abnormal cells. These blood cell problems may be life
threatening. These changes were seen with other medications after long-term
use (> 6 months) although rare cases were reported after 1 months use. These
bone marrow changes were generally reversible when the medication stopped. The
patient's blood counts will be monitored throughout the study.

E5501 is not for use in people with blood cancer or a precancerous condition
called myelodysplastic syndrome (MDS). E5501 may worsen this cancer or
condition.

In laboratory studies, an increase in the cells of the stomach lining
(hyperplasia), as well as tumours (known as carcinoids) was seen in rats, mice
and monkeys. These findings were observed at higher doses than the doses used
in this study; however, because the risk in humans is unknown, a blood test
will be performed at different time points during the study, to monitor for
potential changes in the stomach lining.

Discomforts that may be casued by the study procedures while the patient is on
this study are also listed in the patient information form.

Benefits:
E5501 has increased platelet production in normal healthy subjects both in
single- and multiple-dose oral administration, and has demonstrated superior
efficacy in cITP subjects compared with placebo, as measured by platelet
response on Day 28, as well as a favorable safety profile (protocol 6.1.2.2).
Thus, treatment with E5501 in this study is expected to increase the durable
platelet response in adult subjects with cITP with superior efficacy compared
to placebo (in addition to standard care) and thereby improve the patients'
medical condition. However, it cannot be guaranteed that the patient will
benefit from this study.
The information gathered from this study may also help treat future patients
with thrombocytopenia.