First-In-Human Study of Apramycin

• ClinicalTrials.gov Identifier: NCT04105205
• Recruitment Status: Completed
• First Posted: September 26, 2019
• Last Update Posted: February 23, 2021
• Sponsor: Juvabis AG
• Collaborator: Innovative Medicines Initiative
• Information provided by (Responsible Party): Juvabis AG

Tracking Information

• First Submitted Date: September 12, 2019
• First Posted Date: September 26, 2019
• Last Update Posted Date: February 23, 2021
• Actual Study Start Date: September 25, 2019
• Actual Primary Completion Date: July 16, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 24, 2019)

• Type and incidence of treatment-emergent adverse events (TEAEs) until 2 weeks after dosing. [ Time Frame: until 2 weeks after dosing ]
• Type and incidence of TEAEs related to auditory and vestibular function tests. [ Time Frame: until 3 months after dosing ]
• Number of subjects with clinically significant vital sign measurement blood pressure. [ Time Frame: until 2 weeks after dosing ]
  Frequency is defined as number of subjects with clinically significant observations.
• Number of subjects with clinically significant vital sign measurement pulse rate. [ Time Frame: until 2 weeks after dosing ]
  Frequency is defined as number of subjects with clinically significant observations.
• Number of subjects with clinically significant observation in physical examination. [ Time Frame: until 2 weeks after dosing ]
  Frequency is defined as number of subjects with clinically significant observations.
• Number of subjects with clinically significant changes in clinical laboratory parameters. [ Time Frame: until 2 weeks after dosing ]
  Frequency is defined as number of subjects with clinically significant observations.
• Number of subjects with clinically significant changes in ECG parameters. [ Time Frame: until 2 weeks after dosing ]
  ECG parameters include heart rate and PQ, QT, RS. Frequency is defined as number of subjects with clinically significant observations.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: First-In-Human Study of Apramycin
• Official Title: A Phase I, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Apramycin Administered Intravenously in Healthy Adults.
• Brief Summary: This is a first-in-human study to assess the safety, tolerability and pharmacokinetics of escalating single doses of apramycin. This trial will be conducted as a single ascending dose trial in up to 5 sequential dose cohorts (group-comparison). Each cohort will consist of 8 healthy subjects, 6 will receive apramycin and 2 placebo.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double blind

Primary Purpose: Basic Science

• Condition: Healthy Volunteers

Intervention

• Drug: Apramycin injection
  30-min infusion
• Drug: Placebo injection
  30-min infusion

Study Arms

• Experimental: Apramycin injection in escalating doses
  Apramycin, solution for infusion.
  Intervention: Drug: Apramycin injection
• Placebo Comparator: Placebo
  Physiological saline, solution for infusion.
  Intervention: Drug: Placebo injection

• Publications *: Roch M, Sierra R, Sands K, Martins WMBS, Schrenzel J, Walsh TR, Gales AC, Andrey DO. Vertical and horizontal dissemination of an IncC plasmid harbouring rmtB 16S rRNA methylase gene, conferring resistance to plazomicin, among invasive ST258 and ST16 KPC-producing Klebsiella pneumoniae. J Glob Antimicrob Resist. 2021 Mar;24:183-189. doi: 10.1016/j.jgar.2020.12.006. Epub 2020 Dec 26.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 2, 2020): 40
• Original Estimated Enrollment (submitted: September 24, 2019): 32
• Actual Study Completion Date: October 16, 2020
• Actual Primary Completion Date: July 16, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Healthy male and female subjects of non-childbearing potential, 18-45 years of age (both inclusive), body mass index 18.0 - 29.9 kg/m2 (inclusive) and body weight from 50 to 100 kg (inclusive).
• Glomerular filtration rate (GFR) ≥ 90 mL/min /1.73 m2.
• Subjects with systemic hearing, with air conduction thresholds no worse than 20 decibels (dB) hearing loss for the frequencies 0.5-1-2-4-6-8 kilohertz (kHz) bilaterally and, no threshold asymmetry ≥ 20 dB at any frequency, normal (reproducibility 70% or better) transient evoked otoacoustic emissions (TEOAE).
• From the signing of the informed consent until the last follow-up visit, subjects must be willing to avoid exposure to loud noise and Subjects must be willing to avoid excessive physical exercise within 48 h prior to dosing.
• Normal blood pressure and pulse rate, ECG recording without clinically significant abnormalities.
• Thyroid-stimulating hormone, free triiodothyronine and free thyroxine within the reference ranges.
• Having had no febrile or infectious illness for at least 7 days prior to the first administration of the Investigational medicinal product (IMP) of the study.
• Normal microscopic findings in the ears, normal tympanic membrane mobility and stapedial reflex present.

Exclusion Criteria:

• Vegetarian or vegan.
• Demonstrating excess in xanthine consumption.
• More than low-risk alcohol consumption (men: ≥24 g of pure alcohol regularly per day; women: ≥12 g of pure alcohol regularly per day).
• Any history of alcohol or drug abuse or a positive urine drug screen test. Positive alcohol breath test.
• Consumption of xanthine-containing food or beverages within 48 h before dosing.
• Smokers smoking more than 10 cigarettes or equivalent per day.
• Exposure to loud noise within 3 days prior to drug administration.
• Taking any medication on a regular basis, with the exception of solitary doses of up to 1000 mg paracetamol.
• Use of any investigational drug product within 30 days or 5 half-lives before screening.
• Use of aminoglycosides or other antibiotics within 3 months prior to screening.
• Use of neuromuscular blocking agents within 1 week or 5 half-lives prior to screening.
• Use of potentially nephrotoxic medication 2 weeks prior to the drug administration.
• Any history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis as well as hay fever with ongoing symptoms.
• Any history of hypersensitivity to aminoglycosides.
• Any history or signs of acute, chronic or recurrent metabolic, renal, hepatic, pulmonary, gastrointestinal, neurological, neuromuscular disorders, endocrinological, immunological, psychiatric or cardiovascular disease, myopathies, and bleeding tendency.
• Problems with hearing and/or balance.
• Previous injury or surgery to the middle or inner ears, family history of hearing loss before the age of 60.
• Genetic predisposition to aminoglycoside-driven ototoxicity.
• Laboratory values outside the reference range that are of clinical relevance.
• Positive test for HIV antibodies, hepatitis B-virus surface antigen, or anti-hepatitis C-virus antibodies.
• Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days before signing an informed consent to this trial.
• Judged by the investigator to have occupational noise exposure of high risk during the trial.
• Positive test for SARS-CoV-2.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04105205
• Other Study ID Numbers: JUV18-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Juvabis AG
• Original Responsible Party: Same as current
• Current Study Sponsor: Juvabis AG
• Original Study Sponsor: Same as current
• Collaborators: Innovative Medicines Initiative

Investigators

• Principal Investigator: Armin Schultz, Dr.med.; CRS Clinical Research Services Mannheim GmbH

• PRS Account: Juvabis AG
• Verification Date: November 2020