Crossover Study of the PD of ENA-001 and hypoxia.

Conditions: Respiratory impairment

Registration Number: NL-OMON24789

Lead Sponsor: Enalare Therapeutics

Brief Summary: .A.

Detailed Description: Not available

Recruitment & Eligibility

Status: Pending

Sex: Not specified

Target Recruitment: 12

Inclusion Criteria

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 =60 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 be within normal limits or clinically acceptable to the investigator. However, subject’s liver function test results (i.e., AST, ALT) must not be elevated >2x above the normal limits at Screening and on Day -1.
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.
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 use a medically acceptable means of contraception (double barrier) from screening through at least 3 months after the last dose of study drug, abstain from heterosexual intercourse or have a sole-sexual partner that is vasectomized.
10.Subjects must be free of any clinically significant disease that would interfere with the study evaluations.
11.Subjects presenting out of range values of lab/ECG/vital signs compatible with normal variation of the normal healthy subject can be included in the study at the investigator’s discretion and sponsor written approval.

Exclusion Criteria

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 <5 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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Tolerability / safety endpoints<br>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.<br>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.<br><br>Pharmacodynamic endpoints<br>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 Measures

Name	Time	Method
Pharmacodynamic endpoints<br>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.<br>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.<br><br>Pharmacokinetic endpoints<br>PK parameters will include, but will not be limited to, Cmax, AUC; AUCinf, and Tmax, and if possible, t½ for ENA-001, and potentially propofol.<br><br>PK/PD endpoints<br>EC50 and Emax for ENA-001 effects on ventilatory measurements as determined by PK/PD models may be determined.<br>