Esteridone Protocol Synopsis of a Phase I Clinical Trial
Research Applications in Clinical Pharmacology
July 27, 2015
Kristin Zhong
Title
A Placebo-Controlled, Randomized, Open-Label Study to Investigate the
Pharmacokinetics, Side Effect Profile and Efficacy of Esteridone in Patients with
Mania and a Diagnosis of Bipolar I Disorder
Study Site
The Ohio State University
OSU Pharmacokinetics and Pharmacodynamics Unit
333 W. 10th Avenue
Columbus, OH 43210
Phone: (614) 292-1597
Fax: (614) 292-7232
Objectives
The objectives of the study are to evaluate the pharmacokinetics such as drug
absorption, distribution, metabolism, and excretion along with safety and
efficacy of esteridone in patients who have mania and a diagnosis of bipolar I
disorder
Esteridone’s activity is primarily due to the parent drug instead of any major
metabolites. Elimination of esteridone is done mainly by the hepatic system and
there is a mean half-life of 5 hours. Steady state concentrations are reached
within one to two days of dosing. The mean apparent systemic clearance is 9
ml/min/kg. Esteridone is likely to interfere with the metabolism of drugs
metabolized by the cytochrome P450 enzymes. Esteridone is well absorbed after
orally ingested and it reaches peak plasma concentration in 5-7 hours. The
absorption of esteridone is increased 1.5-fold in the presence of food.
Esteridone has a mean apparent volume of distribution of 1.7 L/kg. Esteridone is
bound by greater than 99% to plasma proteins, predominately with albumin. The
possibility of drug interactions is not a cause for concern due to displacement.
Esteridone is almost completely metabolized after oral administration with a
small amount excreted in the urine or feces unchanged.
Summary of PreClinical Data
Study Design
The study design is a placebo-controlled, randomized, open-label study in
patients with bipolar disorder. The study drug esteridone, is an atypical
antipsychotic. Patients will receive a daily 200 mg oral dose of esteridone every
day.
There will be a screening period with specific criteria which need to be met
before they can be admitted into the OSU Pharmacokinetics and
Pharmacodynamics Unit. The screening criteria includes testing on blood glucose
levels, urine sampling, and testing of vital signs. There will be a complete
physical exam performed by a general medicine medical doctor. A full medical
history will be recorded which includes any previous and current medications.
There will be a psychiatrist to do an assessment on the bipolar disorder of the
subjects.
There will be randomization of the subjects into a placebo group or study drug
group. The pharmacokinetics of esteridone will be assessed through blood and
urine sampling. Side-effect profile will be assessed by a psychiatrist. Efficacy will
be assessed through the Young Mania Rating Scale and the Positive and Negative
Syndrome Scale.
Study Schedule
The study will last for 60 days at one facility. There will be mandatory
appointments to see physicians twice every two weeks. The subjects will be
residing in the facility for the entire period. There will be 50 subjects.
Study Therapeutic Esteridone is a new atypical antipsychotic with indications for schizophrenia,
bipolar disorder mania, mixed episodes and depression, and as an adjunctive to
an antidepressant for major depression. It will be administered orally at 200 mg
per day. There will be a need to slowly titrate up to that point at the beginning.
Study Population
25 subjects each of men and women who are actively showing signs of mania
with their bipolar I disorder diagnosis.
Eligibility Criteria
Inclusion Criteria:
1. Subject has met the diagnosis of bipolar I disorder from a psychiatrist.
2. They are actively experiencing mania pertaining to their bipolar I disorder
diagnosis.
3. Aged from 18 to 50 years of age.
Exclusion Criteria:
1. Must have no co-morbidity with bipolar I disorder either physical or
psychiatric ailments.
2. Pregnant women.
3. Must not be sexually active if they are women.
4. Must abstain from drinking alcohol.
5. Must abstain from doing illegal drugs.
6. No mixed episodes along with mania.
Study End Points
Pharmacokinetics of esteridone
Side-effect profile of esteridone
Efficacy of esteridone
Evaluation of End
Points
Pharmacokinetics of esteridone:
The following will be assessed from esteridone, absorption, distribution,
metabolism, and excretion. For absorption, the pharmacokinetics parameters
include dose, dosing interval, Cmax, absorption rate constant, and
bioavailability. For distribution, the pharmacokinetics parameters includes
volume of distribution, and concentration. For metabolism, elimination half-life,
elimination rate constant, and area under the curve. For excretion, clearance.
Side-effect profile of esteridone:
Adverse events were observed and recorded. Physical examinations along with
blood tests and urine tests are to be done. Vital signs along with
electrocardiograms will be measured. Other clinical laboratory tests will be
performed to measure the side-effect profile of esteridone.
Efficacy of esteridone:
The efficacy of esteridone will be based on the reduction of manic symptoms of
the subjects who all have bipolar I disorder. This will be measured using the
Young Mania Rating Scale which is an assessment test for mania in bipolar I
disorder. The Positive and Negative Syndrome Scale will also be used to assess
for mania.
Procedures
SCREENING PERIOD (Days -10 to -1)
Patients will need to read and be able to comprehend an informed consent form
to be sent for approval to an IRB. They must sign the informed consent form in
order to participate in the study.
There will be a complete medical exam and health history assessment. All
previous and current concomitant medications will be noted. Blood tests, urine
testing, and other clinical laboratory tests will be performed. Vital signs will be
recorded as well.
TREATMENT PERIOD (Days 1 to 60)
Day 0
Baseline assessments will be made such as vital signs, blood tests, urine tests,
and other clinical laboratory tests.
Days 1-60
Every day there will be an oral administration of 200 mg of esteridone for the
subjects in the treatment group. For the placebo group they will receive a sugar
pill with no therapeutic properties. During days 1-10 there will be a slow titration
up to 200 mg for the subjects to better tolerate the drug.
Estimated Blood
Loss
FOLLOW-UP PERIOD (Days 61 to 70)
Significant adverse events will be monitored for and recorded if they indeed do
happen. If they do occur, a physician will decide whether the subject should
immediately curtail esteridone and forcibly drop out of the study.
Screening Period
Days -10 to -1
50ml (hematology and chemistry)
Treatment Period
Days 1 to 60
200ml (hematology and chemistry)
Follow-up Period
Days 61 to 70
60ml (hematology and chemistry)
Unscheduled
30ml
The estimated blood loss was up to 340ml.