Pharmacokinetic Evaluation and Local Tolerability of Dry Powder Amikacin Via the Cyclops™

NCT04249531 | Unknown Phase 1

• 1 other identifier: Amika-01
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Multidrug-resistant tuberculosis (MDR-TB) is defined as tuberculosis resistant to isoniazid and rifampicin. The incidence of MDR-TB worldwide is 3.9% for new cases and 21% for previously treated cases. However, the incidence of previously treated cases can rise to above 50% in eastern European countries. With increasing frequency of MDR-TB (and even extensively drug-resistant types), morbidity and mortality due to TB fail to decline worldwide. Amikacin, one of the drugs against MDR-TB, has the most potent effect when reaching a high peak serum concentration and this means that high doses have to be administered. Treatment with amikacin by inhalation would be a tremendous advantage due to the high local dose in the lungs, obtaining high local levels without the possible toxicity due to high serum levels. With the currently available inhalation techniques these local levels cannot be reached easily. In this protocol, the investigators will perform a pharmacokinetic and local tolerability study of dry powder amikacin using the Cyclops™ in patients with drug susceptible tuberculosis. Objective:

• primary objective is to investigate the pharmacokinetic properties of dry powder amikacin at different dosages and compare the peak serum values to a single i.v. dose.
• secondary objective is to assess the local tolerability of dry powder amikacin via the Cyclops™ at different dosages. Study design: single center, active control, ascending dose response study Study population: 8 patients with DSTB. Main study parameters/endpoints: the following pharmacokinetic parameters: actual dose (dose minus remainder in inhaler after inhalation), AUC0-24 (area under the curve from 0-24 h), Cmax (maximum serum concentration), Tmax (time to maximum serum concentration). For the local tolerability the following procedures will be done, drop of FEV1 of \>15 % (lung function measurement) and any other reported adverse event are all considered critical to decide on proceeding into a phase 2B (and/or a phase 3) trial. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All participants included in this study are patients with DSTB, who are admitted at the Tuberculosis Center Beatrixoord. They will receive 3 different doses of amikacin using the DPI with (at least) one week in between doses, they will also receive one dose of intravenous amikacin. Before using the dry powder inhaler (DPI) they will receive instructions and their inspiratory flow will be tested. Before each test dose an indwelling cannula will be inserted and before and after each test dose in total 9 blood samples will be collected. To investigate local tolerability, lung function tests will be performed and the occurrence of adverse events will be scored.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (6)

• The actual dose will be calculated

  actual dose

  1 day

• The AUC0-24 will be calculated

  AUC0-24

  1 day

• The Cmax will be calculated

  Cmax

  1 day

• The Tmax will be calculated

  Tmax

  1 day

• Local tolerability of the inhalation of dry powder amikacin will be established.

  drop of forced expiratory volume in 1 second (FEV1)FEV1 of \>15 % (lung function measurement)

  1 day

• The tolerability of the inhalation of dry powder amikacin will be established

  questioning and registration of adverse events.

  1 day

Secondary Outcomes (6)

• The dPmax (maximum pressure drop) will be measured

  15 - 30 minutes

• The Vi (inhaled volume) will be measured

  15 - 30 minutes

• The Ti (total inhalation time) will be measured

  15 - 30 minutes

• The PIF (peak inspiratory flow rate) will be measured

  15 - 30 minutes

• The MIF (mean inspiratory flow rate) will be measured

  15 - 30 minutes

Study Arms (1)

Amikacin

EXPERIMENTAL

Patients will receive once amikacin i.v. 7,5 mg/kg in the first week

Drug: Amikacin Inhalation Dry Powder; Drug: Amikacin Injectable Product

Interventions

Amikacin Inhalation Dry Powder DRUG

Patient will inhale the weeks after iv amikacin, dry powder amikacin per inhalation once 400 mg, next week once 700 mg and the last week 1000 mg

Amikacin

Amikacin Injectable Product DRUG

patient wil receive one dose of 400 mg amikacine intravenously in week 1

Amikacin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years and older
• Diagnosed with DSTB, either by culture or molecular testing
• Obtained written informed consent

You may not qualify if:

• Pregnancy or breast feeding
• Subjects with known or suspected (by spontaneous reporting or by active questioning) renal, auditory, vestibular or neuromuscular dysfunction.
• History of adverse events on previous amikacin or other aminoglycoside use (by spontaneous reporting nor by active questioning)
• Concurrent use of cyclosporin, cisplatin, amfotericin B, cephalosporins, polymyxins and vancomycin.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

University Medical Center Groningen

Groningen, Netherlands

RECRUITING

MeSH Terms

Conditions

Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Central Study Contacts

Onno Akkerman, MD, PhD

CONTACT

0031503610857; o.w.akkerman@umcg.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: August 19, 2019
• First Posted: January 31, 2020
• Study Start: June 1, 2020
• Primary Completion: April 1, 2022
• Study Completion: June 1, 2022
• Last Updated: May 3, 2021

Record last verified: 2021-04

Locations

NL (1)