Therapeutic effects of an inhaled levodopa dry powder formulation on the recovery from off periods in patients with Parkinson's disease

Very limited treatment options are available with a rapid onset to counter off
periods in Parkinson*s disease patients. Therefore, the development of rapid
onset levodopa formulations is warranted, for which an inhalable formulation of
levodopa is being investigated. In a former study, we assessed the ability of
Parkinson's disease patients to perform a correct inhalation manoeuvre during
an off period. Based on their inspiratory capacities, a levodopa inhaler with
levodopa powder for inhalation combination has been developed. This levodopa
inhaler has subsequently been tested in mild Parkinson's disease patients to
assess the pharmacokinetics of levodopa after inhalation in comparison to oral
administration.

The primary objective is to determine the time until maximum effect is reached
of inhaled levodopa on motor function of Parkinson's disease patients during an
off period. The secondary objectives are to determine the clinical improvement
of motor function of Parkinson's disease patients after inhalation of levodopa
in comparison to oral levodopa and to determine the pharmacokinetic profile of
a dose of 90 mg inhaled levodopa in comparison to 100 mg levodopa
orodispersible tablet .

. The study is an open-label randomized two-way one-period crossover trial.
Participants will stay in the clinic for three days and receive one dose of
inhaled levodopa (90 mg) and one dose (100 mg) of levodopa orodispersible
tablet on two consecutive days in randomised order. A timed tapping test and
Timed Up & Go test will be performed pre-dose and on set time points up to 90
min post-dose as measure for motor function. The MDS-UPDRS III score will be
assessed pre-dose and on set time points up to 60 min post-dose as
pseudo-quantitative measure for the clinical improvement of motor function.
Levodopa blood profile after inhalation of 90 mg levodopa in comparison to
100/25 mg orally administered levodopa/benserazide will be determined by blood
sampling pre-dose and on set time points up to 180 min post-dose.

Participants will receive one dose of inhaled levodopa (90 mg) and one dose
(100 mg) of levodopa orodispersible tablet on two consecutive days in
randomised order.

To minimise the burden of the study on the patient, they will be admitted to
the Punt voor Parkinson clinic for the entire duration of the study (three
days). Standard, oral levodopa treatment will be withheld during each night for
two nights and each following morning. Once the patient has become off,
interventional medication will be administered. 180 minutes post-administration
the patient*s standard, oral levodopa treatment will be resumed and they can
spend the rest of the day as they wish, although they have to stay in the
clinic for supervision. The burden of the intervention and measurements on the
patient is considered to be mild. Pharmacokinetics and safety of inhaled
levodopa have been investigated previously at lower doses and so far inhaled
levodopa is found to be well-tolerated and safe to use. Although no effects of
levodopa inhalation on lung function have been found, lung function will be
checked upon admission and discharge as a safety control. Since this study aims
to determine the effectiveness of inhaled levodopa, it has to be performed in
advanced PD patients who experience regular, predictable off periods. Their
participation is essential for further clinical development of this new
administration method of a well-known drug.