Primary objective: Study Part 1 : Single Ascending Dose: • To determine the clinical and biological safety and tolerability of oxathridine after an oral increasing single dose administration oxathridine in healthy male subjects. Study Part 2 : Proof…
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Study Part 1 : Single Ascending Dose Part.
The safety tolerability criteria include the following analysis:
• Adverse and unexpected events, emergent or not, reported during the study
course (frequency, severity, relationship to study drug, incidence and
occurrence) and up to one month after the last dose taken.
• Change of vital signs parameters (heart rate, blood pressure, respiratory
rate, and body temperature) from baseline values.
• Physical examination: abnormalities in each system class and change from
baseline
• Laboratory abnormalities and change from baseline.
• ECG parameters performed at each predetermined time point during the study
days; change from baseline.
• 48-hour ECG Holter recording, significant change from baseline.
Study Part 2 : Proof Of Concept Part.
• Polysomnography in comparison with placebo and active control.
Secondary outcome
Study Part 1 : Single Ascending Dose Part.
The following pharmacokinetic parameters will be assessed:
• Serum levels and urine levels of oxathridine and of its major inactive
methylated metabolite (BP1.5658).
• Time to reach the maximum serum concentration (Tmax).
• Maximum serum concentration (Cmax).
• Area under the serum concentration-time curve (AUCt) for the last sampling
time and area under the serum concentration-time curve from time zero to time
of infinity (AUC0-*).
• Terminal half-life (T1/2β).
• Amount of oxathridine and of its major inactive methylated metabolite
(BP1.5658) excreted in urine (Ae and fe).
• Renal clearance (CLr)
• Apparent volume of distribution in steady state(Vss) and in the terminal
elimination phase (Vz)
The following pharmacodynamic tests will be performed :
• Saccadic eye movements
• Smooth pursuit eye movements
• Body sway
• Visual analogue scales (VAS) according to Bond and Lader
• Visual analogue scales (VAS) Bowdle
• Visual Verbal Learning Test
• EEG
• Sustained Attention to Response Task (SART)
• Leeds Sleep Evaluation Questionnaire (LSEQ).
Background summary
Activators of the histamine H3receptor (H3R) inhibit the release of endogenous
histamine from its stores in the brain or the gastrointestinal tract. They
represent potentially important drugs for the treatment of a variety of
disorders in the Central Nervous System (CNS) such as sleep or neuropsychiatric
disorders as well as in peripheral tissues such as gastrointestinal or
cardiovascular system.
Oxathridine (BP1.5375) is a partial agonist of the H3R, a NME (New Molecular
Entity) developed by Bioprojet that lacks activity on other histamine receptor
(HR) subtypes or on a large amount of other receptors. Preclinical data in rats
and cats suggest that oxathridine increases deep sleep and reduces Rapid Eye
Movement(REM) sleep. In addition, it also increases deep sleep when a zolpidem
treatment is stopped as compared to a direct zolpidem weaning which is
characterized by a large reduction in deep sleep (oxathridine IB draft).
Oxathridine also displays anxiolytic activity. No clinical studies with
oxathridine have been conducted so far. This study aims to assess the
tolerability, safety pharmacokinetics and some pharmacodynamic parameters of
oxathridine in humans.
Diphenhydramine is a first-generation H1 receptor antagonists mainly used to
treat allergies. Like most other first-generation antihistamines, the drug also
has a powerful hypnotic effect, and for this reason it is often used as a
non-prescription sleep aid. In this study, diphenhydramine is used as a
positive control.
Study objective
Primary objective:
Study Part 1 : Single Ascending Dose:
• To determine the clinical and biological safety and tolerability of
oxathridine after an oral increasing single dose administration oxathridine in
healthy male subjects.
Study Part 2 : Proof of Concept:
• To determine whether an oxathridine single oral dose induced an effect on
polysomnography in healthy male subjects compared to diphenhydramine 50 mg and
matching placebo.
Secondary objectives:
Study Part 1 : Single Ascending Dose:
• To assess the pharmacokinetic parameters of oxathridine and its main
metabolite BP1.5658 by measuring serum and urine levels,
• To explore possible pharmacodynamic effects of oxathridine on different
pharmacodynamic tests (psychometric tests and EEG),
• To select three doses of oxathridine to be studied in study part 2 taking
into account the tolerability, safety, pharmacokinetics and pharmacodynamics,
• To determine oxathridine*s safety margin.
Study Part 2 : Proof of Concept:
• To select an active and safe dose range of oxathridine to pursue further drug
development.
Study design
First-time-in-man, Phase I/IIa single centre study, with 2 parts :
Study Part 1 : Double-blind, randomized, placebo controlled, parallel groups,
single ascending dose (range 0.5 mg to 100 mg) study (6 active; 2 placebo), in
6 groups of 8 healthy male subjects each (plus 2 optional groups of 8
subjects).
Study Part 2 : Five way, double-blind, placebo and positive controlled,
cross-over proof of concept study evaluating the effect of 3 different
oxathridine doses on polysomnography (PSG) in 10 healthy male subjects.
Intervention
NA
Study burden and risks
During the screening, clinical significant abnormalities may be found
De study days can be quite intensive: CNS-test battery, bloodsamping, ECG, EEG,
PSG, bloodpressure measurements, etc
De studiedagen zijn intensief: CNS-batterij, bloedafnames, ECG, EEG,
bloeddrukmetingen etc.
As oxathridine is for the first time administered in humans, there are not any
previously known side effects. This means that there is a small chance of
unexpected adverse events. Medications similar to the study drug have been
known to have side effects that could be expected with this type of medication
such as: dizziness, somnolence or sleepiness, headache, drowsiness. At higher
doses in animals, oxathridine caused abnormalities in the heart rate.
The most frequent adverse events of diphenhydramine are drowsiness, sleepiness,
dry mouth, increased heart rate, blurred vision, nausea, vomiting, diarrhea,
allergic reactions, low blood pressure, Jaundice.
Some people that decide to participate in the trial may experience side effects
such as headache, nausea, dizziness due to the fact that during the study blood
samples are taken and that you are not allowed to drink coffee for some days.
Rue Rameau 9
Paris 75002
FR
Rue Rameau 9
Paris 75002
FR
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure.
2. Healthy male subjects aged between 18 and 45 years (inclusive).
3. Subjects with a body weight of at least 50 kg and a body mass index (BMI) between 18.0 and 28.0 kg/m2 (both inclusive).
4. Healthy subjects, based on history, physical examination, complete laboratory evaluation, and 12-lead ECG.
5. Normal arterial blood pressure (BP) and pulse rate or, if abnormal, considered not clinically significant by the investigator. Normal BP to be [100-140] mmHg systolic and [45-90] mmHg diastolic. Normal pulse rate to be [40-90] bpm after 5 minutes rest in lying position.
6. Ability to communicate well with the investigator in the local language, and to understand and comply with the requirements of the study.
Exclusion criteria
1.Subject with a history of cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic, haematological, neurological, psychiatric, systemic, or infectious disease, or any other condition which, in the opinion of the investigator, would jeopardize the safety of the subject, or impact the validity of the study results.
2. Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
3. Haematology, clinical chemistry, and urinalysis results deviating from the normal range to a clinically relevant extent at screening.
4. Clinically significant findings on physical examination at screening.
5. 12-lead electrocardiogram (ECG) with clinically relevant abnormalities in supine position at screening.
6. Positive results from urine drug screen at screening.
7. Veins unsuitable for i.v. puncture on either arm (e.g., veins that are difficult to locate, access or puncture, or veins with a tendency for rupture during or after puncture).
8. Treatment with any prescribed medications (including vaccines) or over-the-counter (OTC) medications (including herbal medicines such as St John*s Wort) within 2 weeks prior to the (first) scheduled administration of study drug, except paracetamol (maximum 1 g/day).
9. Treatment with another investigational drug within 3 months prior to screening or having participated in more than four investigational drug studies within 1 year prior to screening.
10. History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
11. History or clinical evidence of any disease, and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs.
12. Have undergone surgery or have donated an amount equal or more than 500 mL blood, or 300 mL of plasma, within 3 months prior to screening.
13. Positive results from any of the hepatitis serology tests (HBsAg, anti-HCV), at screening.
14. Positive results from the HIV 1 or/and 2 serology at screening.
15. History of allergy to diphenhydramine or antihistaminic drugs.
16. Smoking more than 5 cigarettes per day.
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 | EUCTR2013-000697-30-NL |
| CCMO | NL44541.056.13 |