Safety of Intravenous Apramycin in Adults

Study Overview
=================
Brief Summary
-----------------
A Phase I, open label study of a single dose of 30 mg/kg of apramycin administered intravenously (IV) over 30 (+/- 5) minutes. Twenty subjects will be enrolled in the study to one of 5 cohorts, T1-T5, each corresponding to a timepoint after initiation of infusion at which a single fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is performed. There will be 4 subjects per cohort. Cohort T5 will be enrolled after plasma and lung apramycin concentrations and preliminary PK data analysis are completed in cohorts T1-T4. Enrollment and dosing will be determined by bronchoscopy schedule. For each cohort, if 2 subjects are scheduled to receive study drug on the same day, the dose will be administered sequentially at least 2 hours apart. The primary objective is to assess plasma pharmacokinetic (PK) profile of apramycin and lung penetration of apramycin in epithelial lining fluid (ELF) and alveolar macrophages (AM) after single intravenous (IV) apramycin dose of 30 mg/kg in healthy subjects.

Detailed Description
-----------------
A Phase I, open label study of a single dose of 30 mg/kg of apramycin administered intravenously (IV) over 30 (+/- 5) minutes. Twenty subjects will be enrolled in the study to one of 5 cohorts, T1-T5, each corresponding to a timepoint after initiation of infusion at which a single fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is performed. There will be 4 subjects per cohort. Cohort T5 will be enrolled after plasma and lung apramycin concentrations and preliminary PK data analysis are completed in cohorts T1-T4. Enrollment and dosing will be determined by bronchoscopy schedule. For each cohort, if 2 subjects are scheduled to receive study drug on the same day, the dose will be administered sequentially at least 2 hours apart. The primary objective is to assess plasma pharmacokinetic (PK) profile of apramycin and lung penetration of apramycin in epithelial lining fluid (ELF) and alveolar macrophages (AM) after single intravenous (IV) apramycin dose of 30 mg/kg in healthy subjects. The secondary objectives are to 1) assess the safety of single IV administration of 30 mg/kg apramycin in healthy subject and 2) to assess changes in otoacoustic testing.

Official Title
-----------------
A Phase I, Open-label Study to Assess Lung Pharmacokinetics and Safety of a Single Dose of Apramycin Administered Intravenously in Healthy Adult Subjects

Conditions
-----------------
Bacterial Infection

Intervention / Treatment
-----------------
* Drug: Apramycin (EBL-1003)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject reads and signs the Informed Consent Form (ICF) and agree to have bronchoscopy with bronchoalveolar lavage under sedation or light anesthesia and comply with study procedures. Healthy male or non-pregnant, non-lactating female subjects 18 to 45 years of age (both inclusive) at the time of dosing. *Note 1: Determined by medical history (MH), medication use, physical examination (PE), and vital signs, clinical laboratory tests and 12-lead ECG within reference ranges at Screening and Day-2. (See Sections 8.1 and 8.2; and Appendix B, Table 2, Table 3 and Table 4 and the study-specific MOP.) Exceptions to BP, HR and laboratory test values being with normal ranges are: Abnormal HR and BP on first measurement may be repeated twice more with the subject resting between measurements for at least 5 min according to Section 8.1.6. Subjects with baseline HR >/= 45 to 50 bpm may be accepted if otherwise healthy adults with known history of asymptomatic bradycardia. Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be accepted if otherwise healthy. A laboratory value that is Grade 1 will be allowed if not considered to be clinically significant by the investigator, with the exception of ALT, AST, AP, BUN, urine protein, serum creatinine or estimated glomerular filtration rate (eGFR) <70 mL/min /1.73 m^2 by the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation. Female subjects of childbearing potential should use highly effective methods of contraception from the time of screening to 30 days after dosing. Note 1: A female is considered of childbearing potential unless post-menopausal (defined as history of >/=1 year of spontaneous amenorrhea and a FSH level >40 IU/L), or permanently surgically sterilized. Note 2: Highly effective contraceptive methods include: (a) surgical sterilization methods, such as tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful tubal obliteration (e.g., Essure(R)) with documented radiological confirmation test at least 90 days after the procedure, or (b) long-acting reversible contraception, such as progestin-releasing subdermal implants, copper intrauterine devices (IUDs), levonorgestrel-releasing IUDs. Note 3: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented. Males, including vasectomized men, having sexual intercourse with women of childbearing potential must agree to consistent use of condoms from IMP administration through at least 30 days after dosing, and must also agree to not donate sperm during this same time period. *Note: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented. BMI 18.0 to 32.0 kg/m^2 (inclusive) and body weight not less than 50 kg. Subjects with normal hearing, i.e., symmetric hearing with air conduction thresholds no worse than 20 dB hearing loss for the frequencies 0.5-1-2-4-6-8 kHz bilaterally. Normal (reproducibility 70% or better) of distortion product otoacoustic emissions (DPOAEs). *Note: Absence of DPOAEs at no more than two consecutive or non-consecutive DPOAEs in each ear is acceptable. Normal otoscopic findings in the ears, normal tympanic membrane mobility and stapedial reflex present. From the signing of the informed consent until the last follow-up visit, subjects must be willing to avoid exposure to loud music or noise. *Note: Noise avoidance to include continuous usage of earpieces at high volume, attending loud concerts or dance events, or using firearms or attending fireworks. Normal lung function with Forced Expiratory Volume in the first second (FEV1) predicted >/= 80% and FEV1/Forced Vital Capacity (FVC) > 70%. Subjects must be willing to avoid excessive physical exercise within 48 h prior to dosing until discharge from the CTU on Day 3, and 24 h before each follow-up visit (Day 14 +/- 3 days and Day 30 +/- 4 days). No history of acute febrile or infectious illness for at least 7 days prior to the administration of the IMP. No history of lower respiratory tract infection within 4 weeks prior to screening. Have adequate venous access for infusion and blood draws. Exclusion Criteria: All must be answered NO for the subject to be eligible for study participation: Lactating females. Medical and surgical history: Any history of hypersensitivity to aminoglycosides. Any history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis. Any history of seasonal allergies with ongoing symptoms for more than a week prior to dosing requiring glucocorticoids and/or frequent use of antihistamines for treatment. Any history of a chronic condition that may increase risk to subject or interfere with endpoint assessment, or any unstable chronic disease. Note 1: Unstable chronic disease is defined by need for frequent medical interventions that lead to a change in medications and/or required hospitalization, surgery or an invasive procedure or emergency department/urgent care visit. Note 2: Any chronic disease, that has been diagnosed within 90 days of screening is excluded. History of any psychiatric medical condition that has required hospitalization in the last 5 years or subject is considered psychologically unstable by the investigator. History of acute or chronic problems with hearing and/or balance in the last 24 months. -Note: These include but not limited to use of hearing aid, head injury leading to otologic damage, tumor of the head or neck, autoimmune disease of the inner ear, tinnitus, vestibular disease, auditory neurinoma, endolymphatic hydrops and/or Meniere's disease, perilymphatic fistula, otitis media, labyrinthitis, sudden hearing loss, known retrocochlear hearing impairment, conductive hearing loss exceeding 10 dB at any frequency, ear canal and/or middle ear disease including inflammation or effusion, pathological tympanometry. Past injury or surgery to the middle or inner ears. -Note: Myringotomy or tympanic tube insertion in childhood with complete healing and normal hearing test are excluded. Family history of hearing loss before the age of 60. Subjects who have had previous intolerance or contraindications to medications applied for sedation or anesthesia during bronchoscopy. -Note: These include benzodiazepines or topical anesthetic agents (lidocaine or xylocaine) including reversal agents such as flumazenil. Laboratory examinations: Positive serum pregnancy test for women at screening or urine pregnancy test at check-in. Positive test for HIV antibodies, hepatitis B-virus surface antigen (HBsAg), or anti-hepatitis C-virus antibodies (anti-HCV). Prior medication: Use of any prescription or non-prescription medication prior to the dose of IMP -Note: Exceptions are hormonal contraceptives, which are permitted throughout the study, and solitary doses of up to 1,000 mg paracetamol. Use of any investigational drug product within 30 days or 5 half-lives (whichever is longer) before dosing. Planned participation in a clinical research study that requires treatment with a study drug or blood draws or other invasive assessments during the study period (screening until final visit). Lifestyle restrictions: More than low-risk alcohol consumption (men: >/= 24 g of pure alcohol regularly per day; women: >/=12g of pure alcohol regularly per day) for the previous 3 months. Any history of alcohol or drug abuse or positive alcohol breathalyzer test. Suspicion of illicit drug use / abuse or positive urine drug screen test. History of >/=10 pack-years smoking, or history of any nicotine use in the 6 months before check-in (Day -2) or positive urine cotinine screen at check-in. Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, nicotine patch. Note 2: A positive urine cotinine at screening is allowed if negative at check-in (Day -2). Caffeinated beverages/foods are prohibited within 48 hours before dosing to Day 3 of the trial. During the follow up period, consumption is restricted to not more than 3 cups or equivalent per day. Judged by the investigator to have occupational noise exposure of high risk during the trial (e.g., construction site workers, military workers, etc.). Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days before signing informed consent or planned donation prior to completion of this trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T1<br>Subjects 18 to 45 years of age to receive 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 0.5 h (+/- 5 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4 | Drug: Apramycin (EBL-1003)<br>* A mono-substituted 2-deoxystreptamine comprising a unique bicyclic octadiose moiety. It is a crystalline free base of the amoniglycoside apramycin.<br>|
| Experimental: T2<br>Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 2 h (+/- 5 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4 | Drug: Apramycin (EBL-1003)<br>* A mono-substituted 2-deoxystreptamine comprising a unique bicyclic octadiose moiety. It is a crystalline free base of the amoniglycoside apramycin.<br>|
| Experimental: T3<br>Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 4 h (+/-10 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4 | Drug: Apramycin (EBL-1003)<br>* A mono-substituted 2-deoxystreptamine comprising a unique bicyclic octadiose moiety. It is a crystalline free base of the amoniglycoside apramycin.<br>|
| Experimental: T4<br>Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 8 h (+/- 15 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4 | Drug: Apramycin (EBL-1003)<br>* A mono-substituted 2-deoxystreptamine comprising a unique bicyclic octadiose moiety. It is a crystalline free base of the amoniglycoside apramycin.<br>|
| Experimental: T5<br>Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. Cohort T5 will be enrolled after plasma and lung apramycin concentrations and preliminary PK data analysis are completed in cohorts T1-T4 24 h (+/- 1 h) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4 | Drug: Apramycin (EBL-1003)<br>* A mono-substituted 2-deoxystreptamine comprising a unique bicyclic octadiose moiety. It is a crystalline free base of the amoniglycoside apramycin.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration time-curve from time zero to 24 h of total apramycin in lung. |  | Through Day 2 | 
| Area under the concentration time-curve from time zero to 24 h of total apramycin in plasma. |  | Through Day 3 | 
| Area under the concentration time-curve from time zero to infinity of total apramycin in plasma. |  | Through Day 3 | 
| Area under the concentration time-curve from time zero to time infinity of total apramycin in lung. |  | Through Day 2 | 
| Area under the concentration time-curve from time zero to time T of total apramycin in lung. |  | Through Day 2 | 
| Area under the concentration time-curve from time zero to time T of total apramycin in plasma. |  | Through Day 3 | 
| Central volume of distribution (Vd) of total apramycin in plasma. |  | Through Day 3 | 
| Maximum concentration (Cmax) of total apramycin in lung. |  | Through Day 2 | 
| Maximum concentration (Cmax) of total apramycin in plasma. |  | Through Day 3 | 
| Ratio of Lung to Plasma apramycin exposure parameters |  | Through Day 3 | 
| Terminal elimination half-life (t1/2) of total apramycin in lung. |  | Through Day 2 | 
| Terminal elimination half-life (t1/2) of total apramycin in plasma. |  | Through Day 3 | 
| Time to reach maximum concentration (Tmax) of total apramycin in lung. |  | Through Day 2 | 
| Time to reach maximum concentration (Tmax) of total apramycin in plasma. |  | Through Day 3 | 
| Total Clearance (CLT) of total apramycin in plasma. |  | Through Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of changes in electrocardiographic (ECG) intervals | Electrocardiographic (ECG) intervals measured: QTcF interval, PR interval, QRS interval, Heart Rate (HR) | Through 24 hours after dosing | 
| Frequency of clinically significant Treatment-emergent adverse events (TEAEs) in Physical examination (PE) findings | Physical examination (PE) findings or changes from baseline in vital signs (VS) and clinical laboratory parameters | Through Day 14 | 
| Incidence of serious adverse events (SAEs) |  | Through Day 30 | 
| Incidence of treatment-emergent adverse events (TEAEs) |  | Through Day 30 | 
| Incidence of treatment-emergent adverse events (TEAEs) related to auditory (cochlear) function tests | Type and Incidence of pure-tone audiometry and distortion product otoacoustic emissions [DPOAEs]) | Through Day 30 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Apramycin, Lung Pharmacokinetics, Open-label, Phase I, Respiratory