Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT04249531 |
Other study ID # |
Amika-01 |
Secondary ID |
|
Status |
Recruiting |
Phase |
Phase 1
|
First received |
|
Last updated |
|
Start date |
June 1, 2020 |
Est. completion date |
June 1, 2022 |
Study information
Verified date |
April 2021 |
Source |
University Medical Center Groningen |
Contact |
Onno Akkerman, MD, PhD |
Phone |
0031503610857 |
Email |
o.w.akkerman[@]umcg.nl |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
Description:
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. Cornerstones of MDR-TB treatment are aminoglycosides, like amikacin, and
fluoroquinolones. Amikacin is given intravenously for 6-8 months in the usual MDR-TB
treatment. Since 2016 it can also be given for 4-6 months in the short-course treatment for
MDR-TB. In many countries, this implicates long hospital admissions for the patients, as well
as problems in venous access, often necessitating surgical insertion of venous access ports.
Amikacin 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 (DSTB, as opposed to MDRTB).
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 will be calculated: 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 of the inhalation of dry powder amikacin 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.
The inspiratory parameters during the inhalation maneuver are critical to explore predictors
for drug exposure. The following parameters will be calculated: dPmax (maximum pressure
drop), Vi (inhaled volume), Ti (total inhalation time), PIF (peak inspiratory flow rate), MIF
(mean inspiratory flow rate) and the FIR (average flow increase rate between 20% and 80% of
PIF) 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.