Primary Objectives:* To determine the safety and tolerability of ENA-001 in healthy subjects after low and high doses of ENA-001 under hypoxic and hypercapnic conditions in conjunction with low and high doses of propofol.* To determine the…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
Safety will be evaluated based on reported adverse events, physical
examinations, vital signs, 12-lead ECGs, clinical laboratory test results and
Columbia-Suicide Severity Rating Scale (C-SSRS) responses.
Other parameters may be collected or derived with equipment used by the study
center but will not be captured in the CRF. Values will be listed with
descriptive statistics.
Pharmacodynamic endpoints
Included will be Hypoxic sensitivity (*Ventilation/*Saturation), tidal volume
(VT), respiratory rate (breaths/min), minute ventilation (VE), end-tidal CO2
(mmHg), and transcutaneous hemoglobin saturation (SpO2 in %), arterial blood
gases, BIS, and hemodynamic parameters from arterial line monitoring.
Secondary outcome
Pharmacodynamic endpoints
Included will be Hypoxic sensitivity (*Ventilation/*Saturation), tidal volume
(VT), respiratory rate (breaths/min), minute ventilation (VE), end-tidal CO2
(mmHg), and transcutaneous hemoglobin saturation (SpO2 in %), arterial blood
gases, BIS, and hemodynamic parameters from arterial line monitoring.
Blood Pressure and cardiac output will be recorded using arterial lines
connected to continuous monitors and mean obtained at pre-specified time
points. Time point specific and summarized results will be listed with
descriptive statistics.
Pharmacokinetic endpoints
PK parameters will include, but will not be limited to, Cmax, Css, AUC; AUCinf,
and Tmax, and if possible, t* for ENA-001, and potentially propofol.
PK/PD endpoints
EC50 and Emax for ENA-001 effects on ventilatory measurements as determined by
PK/PD models may be determined.
Background summary
Interference with normal respiratory control is a common iatrogenic event in
the peri-procedural setting. Interference with ventilatory control can be the
result of a procedure (e.g., colonoscopy; surgery), drug treatment (e.g.,
anesthetic, benzodiazepine, opioid), disease (e.g., central/sleep apnea) or
combinations of these factors. In the post-procedural setting, it is not
possible to predict the onset, duration, or severity of deleterious respiratory
events due to a number of contributing factors, including differing drug
sensitivity and pharmacokinetics, occult pulmonary and central nervous system
(CNS) dysfunction, environmental activity level, and concomitant medications.
Respiration is controlled largely in the brainstem with input from the cortex
and peripheral nerves. Chemoreceptors exist in both the brainstem and
peripheral nerves that are sensitive to oxygen tension, carbon dioxide tension,
pH, and other chemical stimuli. The primary peripheral sensors for hypoxia are
the type I glomus cells in the carotid body at the bifurcation of the internal
and external carotid arteries. Activation of several ion channels (e.g., BK,
TASK-1, and TASK-3) in the glomus cells/carotid body leads to stimulation of
the respiratory control arc (carotid body through carotid sinus nerve to
brainstem nucleus tractus solitarius (NTS). The NTS integrates signals from the
peripheral sensors (e.g., carotid and aortic body chemoreceptors, and airway
mechanoreceptors) providing feedback loop control of central respiratory drive.
ENA-001 is intended to be a first in class, fast acting, and short-duration
intravenous agent acting partially through the BK(Ca2+) (Maxi K channels) in
the carotid body to stimulate respiration and increase minute ventilation by
primarily increasing tidal volume and secondarily through minor increases in
the respiratory rate. ENA-001 is being developed as an intravenous therapeutic
agent for short to intermediate term use to stimulate ventilation for treatment
of respiratory depression in post-operative patients while not acting through
antagonism of mu-opioid receptors and not being a CNS stimulant.
Two common uses for short acting anesthetics in the hospital are: sedation
facilitating diagnostic or therapeutic procedures (e.g., cardioversion,
colonoscopy); and surgical interventions under general anesthesia. This study
is designed to further evaluate the potential of ENA-001 on ventilation during
anesthetics. Among short acting anesthetic agents, propofol is used widely by
both anesthesiologists and proceduralists. Accompanying the benefits of
propofol during procedures are undesired ventilatory effects with reduced
respiratory drive and diminished neuromuscular tone in the upper airways.
Previous studies with this compound (Roozekrans, 2014), confirmed the
stimulatory effects on respiratory function under hypercapnic ventilatory
conditions and with co-administration of an opioid. This study aims to evaluate
the ventilatory response after ENA-001 administration under hypercapnic and
hypoxic ventilatory conditions and with co-administration of propofol. This
design will lead to knowledge regarding the ventilatory response after propofol
administration under different ventilatory conditions.
Study objective
Primary Objectives:
* To determine the safety and tolerability of ENA-001 in healthy subjects after
low and high doses of ENA-001 under hypoxic and hypercapnic conditions in
conjunction with low and high doses of propofol.
* To determine the ventilatory response (minute ventilation) of low and high
doses of ENA-001 under hypoxic and hypercapnic conditions in conjunction with
low and high doses of propofol. The hypoxic response will be assessed by
calculation the Hypoxic Ventilatory Sensitivity. (*Ventilation/*Saturation =
Hypoxic Sensitivity in L/min per % desaturation).
Secondary Objectives:
* To determine the cardiovascular response of low and high doses of ENA-001
during hypoxic and hypercapnic conditions in conjunction with low and high
doses of propofol.
* To determine the ventilatory response (minute ventilation) of low and high
doses of ENA 001 after previous treatment with low and high doses of propofol
under normocapnic and mild hypercapnic conditions during normoxia.
* To determine the PK parameters of ENA-001 and propofol in healthy volunteers.
Study design
Subjects will be initially screened up to 6 weeks prior to randomization.
Following successful initial medical screening at CHDR, they will be scheduled
for the study and receive a randomization number.
Subjects will then undergo 3 separate treatment periods. In each of these
periods, low or high doses of ENA-001 or placebo will be continuously perfused
throughout for a period of 270 minutes. Additionally, subjects will receive
different intravenous propofol dosages or placebo in set order: placebo *
propofol low dose * propofol high dose. Each treatment session of propofol or
placebo is 70-minutes. During each propofol treatment session, different
ventilatory conditions are applied.
Intervention
ENA-001:
A loading dose will be administered at 2.0 mg/kg/h for 10 (for low dose) or 20
minutes (for high dose) for both the low and high dose followed by continuous
infusion of the following for 250-260 minutes, so that the total infusion time
is 270 minutes:
* Low dose is fixed rate of 2 mg/kg/h for 10 minutes followed by 0.4 mg/kg/h
for 260 minutes or
* High dose is fixed rate of 2 mg/kg/h for 20 minutes followed by 1.1 mg/kg/h
for 250 minutes
Propofol will be administered over a 155-minute period per dosing session,
composed of two 70-minute low/high dosing regimens separated by a 15-minute
transition dose. Propofol will be infused from a 10 mg/ml preparation as
follows:
* Low dose: 3-min at 239 mcg/kg/min; 6-min at 0 mcg/kg/min; 61-min at 24
mcg/kg/min
* Transition dose: 15-min at 47 mcg/kg/min
* High dose: 3-min at 239 mcg/kg/min; 6-min at 0 mcg/kg/min; 61-min at 44
mcg/kg/min
Both products are for IV injection and are prepared as a sterile product ready
for use per subject by the investigational pharmacy, according to the
randomization schedule.
Matching placebo for ENA-001 will consist of the solution that is used as
diluent for ENA-001. ENA-001 solution is colorless and its identity (prior to
dilution and when mixed for injection) is similar to sterile normal saline
solution or Ringer*s lactate.
Study burden and risks
Both study drugs have been administered to humans before and no severe side
effects are expected at planned doses in this study, based on clinical
experience with propofol and previous studies with ENA-001. Study drugs will be
administered while remaining under appropriate surveillance in the LUMC
anesthesiology department. To adequately monitor important safety parameters,
an arterial line is placed which is itself associated with minimal risks and
unpleasantness. Because the study drugs may induce nausea, all subjects will
receive IV ondansetron prior to infusion of the study drugs. Aadditional
antiemetics may be administered as needed for management of nausea and
vomiting. During the study drug infusion, ventilatory measurements are
performed. For this, the subjects will breathe through a facemask, which may
cause slight discomfort. The ventilatory conditions applied (hypo- and
hyperoxia, and hypercapnia) may lead to slight discomfort, but are not
associated with relevant risks, especially given the fact that the measurements
are performed in a safe and controlled environment.
Hodge Road 161
Princeton New Jersey 08540
US
Hodge Road 161
Princeton New Jersey 08540
US
Listed location countries
Age
Inclusion criteria
The subject must meet ALL the criteria listed below for entry at baseline:
1. Subjects must be willing to give written informed consent for the trial and
able to adhere to dose and visit schedules.
2. Male and female, >18 to *55 years of age.
3. Subject must weigh *50 to *100 kg.
4. Subjects must have Body Mass Index [weight/height2 (kg/m2)] between 18 to 30
kg/m2 (inclusive).
5. Have no clinical or electrocardiographic signs of ischemic heart disease as
determined by the Investigator with normal cardiac intervals appropriate for
their gender. The Screening 12 lead ECG conduction intervals must be within
gender specific normal range (e.g., QTcf female * 470 msec QTcF males * 450
msec, PR interval * 220 msec). ECGs are to be judged by the investigator or
sub-investigator as per standardized procedures.
6. Subjects* clinical laboratory tests (blood hematology, blood chemistry,
coagulation and urinalysis) must not include any clinically significant
abnormalities.
7. Vital sign measurements must be within the following ranges during screening
and on Day -1: (Individuals with values outside (or indicate lower or higher)
of these ranges may be enrolled if clinically acceptable to the investigator
and sponsor.
a. body temperature, >35.5*C to *37.5*C
b. systolic blood pressure, >90 to *150 mm Hg
c. diastolic blood pressure, >40 to *95 mm Hg
d. pulse rate, >40 to *100 bpm
8. Non-vasectomized men must agree to use a condom with spermicide (when
marketed in the country), double-barrier contraception, abstain from
heterosexual intercourse, or have a sole-sexual partner of non-childbearing
potential during the trial and for 3 months after stopping the medication. Male
subjects must agree not to donate sperm from the time of dosing until 90 days
after dosing.
9. Women of childbearing potential (defined as all women who are not surgically
sterile or postmenopausal for at least 1 year prior to informed consent) must
have a negative pregnancy test prior to enrolment and must agree to the
following contraception requirement from screening through at least 3 months
after the last dose of study drug:
a. Be sexually inactive (abstinent)
b. Intrauterine device in place for at least three months prior to dosing with
a barrier method (condom or diaphragm) and spermicide throughout the study.
c. Double barrier methods (e.g., condom and diaphragm) with spermicide for at
least 14 days prior to dosing and throughout the study.
d. Surgical sterilization of the partner (vasectomy at least six months prior
to dosing) with a barrier method (e.g., condom or diaphragm) and spermicide
throughout the study.
e. Female subjects who claim to be sexually inactive but become sexually active
during the course of the study must agree to use a double barrier method (e.g.,
condom and diaphragm) with spermicide from the time of the start of sexual
activity through completion of the study.
In addition, female subjects of childbearing potential must be advised to
remain sexually inactive or to keep the same birth control method for at least
14 days following study medication administration.
Females of non-childbearing potential must have undergone one of the following
sterilization procedures at least 6 months prior to dosing:
f. Hysteroscopic sterilization and be using a barrier method (e.g., condom or
diaphragm) and spermicide throughout the study.
g. Bilateral tubal ligation or bilateral salpingectomy and be using a barrier
method (e.g., condom or diaphragm) and spermicide throughout the study.
h. Hysterectomy.
i. Bilateral oophorectomy.
Women with amenorrhea for at least 1 year prior to dosing and who have
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal
status, are considered post-menopausal and therefore of non-childbearing
potential.
10. Subjects must be free of any clinically significant disease that would
interfere with the study evaluations.
Exclusion criteria
The subject will be excluded from entry if ANY of the criteria listed below are
met at baseline:
1. Current diagnosis of psychiatric disease requiring daily medication,
including controlled or uncontrolled schizophrenia, current or recently treated
depressive disorders, or Columbia-Suicide Severity Rating Scale (C-SSRS)
indicative of suicidal ideation or behavior at screening and day -1.
2. Past history of the anxiety disorder including panic attack, depression,
obsessive compulsive disorder, phobias restricting normal daily function,
social anxiety, and paranoia.
3. History of alcohol abuse (more than an average of 2-drinks per day) within
the past 2 years.
4. History of drug abuse within the past 2 years.
5. History of regular smoking within the past year (>5 per week means
exclusion).
6. Failure to take or test positive of the drug of abuse tests at screening or
check-in.
7. Positive for HIV, or Hepatitis B or C at screening.
8. Blood donation or blood loss within 60 days of screening or plasma donation
within 7 days of screening.
9. Subjects with a history of bleeding disorders or coagulopathies.
10. History of dyspnea, asthma, tuberculosis, chronic obstructive pulmonary
disease, sleep apnea or any other ventilatory / lung disease.
11. 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.
12. History of moderate to severe motion sickness.
13. Subjects who are unwilling to remove excessive facial hair preventing
sealing of the occlusive face mask.
14. Subjects who, in the opinion of the investigator, will not be able to
participate optimally in the study.
15. Any surgical or medical condition which might significantly alter the
distribution, metabolism or excretion of any drug. The investigator should be
guided by evidence of any of the following, and be discussed with the sponsor
prior to enrollment into the trial:
a. history of pancreatic injury or pancreatitis;
b. history or presence of liver disease or liver injury;
c. history or presence of impaired renal function as indicated by clinically
significant elevation in creatinine, BUN/urea, urinary albumin, or clinically
significant urinary cellular constituents ; or
d. history of urinary obstruction or difficulty in voiding.
16. Subject who has a history of any infectious disease within 4 weeks prior to
drug administration that in the opinion of the investigator, affects the
subject*s ability to participate in the trial.
17. Subjects who are part of the study staff personnel or family members of the
study staff personnel.
18. Subjects who have demonstrated allergic reactions (e.g., food, drug, atopic
reactions or asthmatic episodes) which, in the opinion of the investigator and
sponsor, interfere with their ability to participate in the trial.
19. Subjects who have a history of malignancy and are in remission >2 years.
20. Personal or family history of malignant hyperthermia.
21. Personal or family history of arrhythmias or ECG conductance abnormalities.
22. Subjects with a history of daily consumption of caffeine greater than 6
servings (40 mL each) from beverages (e.g., coffee, tea, soft drinks) and food
stuffs (e.g., chocolate, ice cream, cookies) (45 gm each) in the month prior to
screening.
23. Subjects with history of known difficult airway access, gastroesophageal
reflex disease, gastric motility disorders, or delayed gastric emptying, or any
condition that may lead to delayed gastric emptying such as diabetes.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-003013-19-NL |
| CCMO | NL78153.056.21 |
| OMON | NL-OMON24789 |