University of Groningen Inhalable levodopa: from laboratory to the patient Luinstra, Marianne

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University of Groningen

Inhalable levodopa: from laboratory to the patient

Luinstra, Marianne

DOI:

10.33612/diss.113190195

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Publication date: 2020

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Luinstra, M. (2020). Inhalable levodopa: from laboratory to the patient. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.113190195

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CHAPTER

6

EFFECTIVENESS OF INHALED LEVODOPA

IN PARKINSON’S DISEASE

A summary of the study design. (NTR7054)

Marianne Luinstra1,2_{, Anne Lexmond}2_{, Wijnand Rutgers}3_{, Paul Hagedoorn}2_,

Teus van Laar4_{, Henderik W. Frijlink}2

1_{Department of Clinical Pharmacy, Martini Hospital Groningen, the Netherlands}

2_{Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands.} 3_{Department of Neurology and Clinical Neurophysiology, Martini Hospital Groningen, the Netherlands.} 4_{Department of Neurology, University Medical Center Groningen, the Netherlands.}

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ABSTRACT

Rationale: Very limited treatment options are available to counter off periods in Parkinson’s

disease (PD) patients with a rapid onset of action. Therefore, the development of rapid onset levodopa formulations is warranted, for which an inhalable formulation of levodopa is being investigated.

Objective: The primary objective is to determine the time until maximum effect of inhaled

levodopa on motor function of PD patients during an off period is reached. The secondary objectives are to determine the pharmacokinetic profile of a dose of 90 mg inhaled levodopa in comparison to 100 mg levodopa orodispersible tablet and to determine the clinical improvement of the motor function of PD patients after inhalation of levodopa in comparison to oral levodopa.

Study design: Open-label randomised two-way one-period crossover trial.

Study population: Nine advanced PD patients on oral levodopa treatment (morning dose 100

mg levodopa) with predictable off periods that are recognisable for themselves and others totalling ≥ 2 h per waking day, who are ≥ 18 years of age and without active lung disease, symptomatic orthostatic hypotension, or cognitive dysfunction.

Intervention: 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.

Main study parameters/endpoints: 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 primary outcome is the time until maximum effect on motor function. A secondary study outcome is the levodopa blood profile after inhalation of 90 mg levodopa in comparison to 100/25 mg orally administered levodopa/benserazide. Pharmacokinetic parameters that will be derived from the concentration vs. time curve are T_max, C_max and AUC_0-180. Additional secondary study outcomes are the maximum improvements in timed tapping test, the TUG test, and the MDS-UPDRS III score compared to baseline.

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INTRODUCTION AND RATIONALE

Off periods in Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by a diminished dopamine production in the central nervous system (CNS) due to loss of dopamine-producing cells in the substantia nigra. The resulting shortage of dopamine causes disruptions of motor circuits in the CNS leading to motor function impairments like tremor, rigidity and bradykinesia. Treatment with oral levodopa initially alleviates these motor function impairments in PD patients. However, the effectiveness of this treatment subsides over the years and many patients develop fluctuations between so-called on periods, characterised by symptom control or possibly hyperkinesia, and off periods, in which the motor function is impaired. These off periods can be predictable, such as end-of-dose wearing off – when the effect of a given dose does not last until the next dose takes effect – and dose failure due to peripheral pharmacokinetics (“delayed on” or “no on”) (1). However, as the disease progresses also more unpredictable “on-off” effects that have no apparent relationship to levodopa dosing can occur (2). Early morning off periods due to a delayed onset of effect of the morning dose of oral levodopa is a common and debilitating problem and one of the first off-phenomena to arise (3-5). Contributing to this delayed onset of effect is gastrointestinal dysfunction, which is common in PD patients (6-8). In addition to decreased mobility, symptoms of sensory (e.g. restlessness, pain), autonomic (urinary incontinence) and psychiatric nature (e.g. anxiety, depression) can manifest during an off period. Experiencing off periods can therefore have a tremendous negative effect on the quality of life. About 50 per cent of PD patients are estimated to experience motor fluctuations after five years of levodopa treatment (9), which increases up to 80% after ten years (10). For patients with advanced disease, being off can occupy up to one-third of a typical waking day (11).

Development of an inhaled levodopa product

To investigate whether Parkinson’s disease patients in an off period benefit more from inhaling levodopa than from taking levodopa orally, we have initiated the development of an inhaled levodopa product that is suited to the specific needs and abilities of PD patients. Acorda therapeutics (previously Civitas) also developed an inhaled levodopa product (CVT-301 program; (12,13)) that is recently registered on the US and European market. However, as described in our previous study protocol (RTPO 949) this product has a number of drawbacks, related to both the inhaler (capsule-based) and the levodopa formulation (excipients and powder volume), which we believe will limit the usability of this inhaled levodopa product and leaves ample room for product optimisation.

As one of the main benefits of inhaled levodopa is claimed to be its faster onset of action compared to orally administered levodopa, we previously performed a pharmacokinetic evaluation of two doses of inhaled levodopa compared to an oral dose of levodopa. Additionally, safety of inhaled levodopa was studied, with special focus on the effects of inhaled levodopa on lung function.

EFFECTIVENESS OF INHALED LEVODOPA IN PARKINSON’S DISEASE

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Sufficient levodopa in the blood (and the CNS) is required for a therapeutic effect, but it is no effect measure. Therefore, our pharmacokinetic results now need to be complemented by investigation of the effects of inhaled levodopa powder in PD patients who are experiencing an off period. Based on the peak plasma levels we have measured, we will increase the investigational inhaled dose to 90 mg, since we expect 90 mg inhaled levodopa to correspond better with the mean (albeit much more variable) peak level of 100 mg oral levodopa when taken in a fasted state.

Objectives

The primary objective of this study is to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients during an off period. Motor function will be quantified with a timed tapping test and Timed Up & Go (TUG) test. The secondary objectives are:

1. to determine the pharmacokinetic plasma profile of 90 mg inhaled levodopa in comparison to oral administration of 100/25 mg levodopa/benserazide, expressed as maximum levodopa concentration in serum (C_max), time to maximum concentration (t_max) and the area under the concentration vs. time curve at 0 – 180 min (AUC_0-180).

2. to determine the maximum clinical improvement of motor function of PD patients after inhalation of levodopa in comparison to oral levodopa as measured with the timed tapping test, the TUG test, and the MDS-UPDRS III score for motor function.

Study design

The study is an open-label crossover trial in which the participants will receive one dose of inhaled levodopa (90 mg) and one dose (100/25 mg) of levodopa/benserazide orodispersible tablet on two consecutive days in randomised order. The study will last three days in total for each participant and will take place in the Punt voor Parkinson clinic in Maartenshof, Groningen. Admission is on the evening of Day 1, and the investigational drug administrations follow on the morning of Days 2 and 3. A timed tapping test and Timed Up & Go (TUG) test will be performed pre-dose and on set time points post-dose to assess motor function (T = 10, 20, 30, 40, 50, 60, 75 and 90 minutes post-dose). Additionally, the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III score will be assessed pre-dose and 20 and 60 minutes post-dose as pseudo-quantitative measure for motor function. Levodopa blood levels will be sampled pre-dose (T=0) and post-dose at T = 5, 10, 15, 20, 30, 45, 60, 90 and 180 minutes to evaluate the pharmacokinetic profile and allow for PK/PD correlation analysis. The study finishes on day 3 at 4 hours after administration of the investigational drug when spirometry shows that lung function is comparable to baseline. If lung function values (FEV₁, MEF₅₀, FVC) are >10% lower compared to baseline, the reduction will be considered clinically relevant and the participant’s stay will be extended by one hour and lung function will be measured again. If the participant’s lung function shows improvement but is not yet at least 90% of baseline, the stay will again be extended by one hour after which lung function will be measured. If no improvement is seen at all in this period a pulmonologist will be consulted.

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Study population

The study participants will be recruited within the Punt voor Parkinson centre, where all Parkinson’s disease patients from the UMCG and Martini Hospital are treated for their disease.

Inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria: Diagnosed with Parkinson’s disease; at least 18 years of age; predictable off periods totalling ≥2 h per waking day despite PD medications, including oral levodopa taken at least four times daily; recognisable off periods for themselves and others; sufficiently large (measurable) difference between on and off state (at least 10 points on the UPDRS III scale); at least 2 years of levodopa use; at least 4 weeks on a stable medication scheme prior to inclusion; first morning levodopa dose equivalent to 100 mg levodopa; able to perform spirometry; signed informed consent.

Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study: cognitive dysfunction, which precludes good understanding of instructions and/ or informed consent; current treatment with apomorphine or duodopa by pump; severe off periods during the night; current or past experience with depression/depressed mood; known symptomatic orthostatic hypotension; active pulmonary disease; prolonged QT-interval; pregnancy or breast-feeding.

Sample size calculation

The sample size calculation is based on the difference in mean time until maximum effect is reached (T_max) for inhaled levodopa and oral levodopa (Wilcoxon signed-rank test for matched pairs). Based on an estimated mean of 25 min for levodopa inhalation powder and 40 min for levodopa orodispersible tablet, both with a standard deviation of 10 min and a correlation between groups of 0.5, an effect size of 1.5 is obtained. To show this difference with a power of 90% and an α of 0.05 (two-sided) a sample size of eight patients is required. PD patients in a more advanced stage of their disease sometimes experience a failure of a levodopa dose to induce an on state, a so-called “no on” episode. In a previous study that investigated “delayed on” and “wearing off” in advanced PD patients a “no on” episode was experienced in 13 out of a 100 cases (3). Anticipating and correcting for this chance of a “no on” episode, a sample size of nine patients is required.

Investigational product

The investigational product in this study is the same inhaled levodopa product that was used in study RTPO 949. Briefly, the inhaled levodopa consists of a dry powder formulation of levodopa co-micronized with 2% l-leucine. A dose of 90 mg levodopa with 2% l-leucine inhalation powder will be administered. The levodopa formulation will be inhaled with the Cyclops inhaler; a disposable dry powder inhaler developed by the department of Pharmaceutical Technology

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and Biopharmacy of the University of Groningen (14). The Cyclops has a relatively high internal resistance to airflow, which reduces the influence of the patient’s breathing behaviour on device performance.

The comparator medication consists of oral levodopa/benserazide orodispersible (Madopar) tablets in a dose of 100 mg levodopa and 25 mg benserazide.

Use of co-intervention

Use of all chronic non-Parkinson medication is allowed during the study. The time between administration of the investigational treatment with inhaled levodopa (or comparator) and the last regular oral levodopa dose should be at least five times the half-life of levodopa, which is 5 x 90 min = 450 min (7.5 h). Therefore, the participants will be admitted on the night before they receive the first investigational treatment in the morning. They will receive their last regular dose at 23:59 at the latest. 90 min after administration of the investigational treatment, the individual subject’s regular oral levodopa treatment will be resumed until ultimately 23:59, if necessary tailored by the neurologist to the individual needs of the subject on that day. This scheme of pausing and resuming of regular oral levodopa treatment will be followed for the duration of the study.

Dosages, dosage modifications and method of administration

In our previous pharmacokinetics study we estimated that an inhaled levodopa dose of 60 mg would compare to an oral dose of 108 mg or less. The study was designed to study safety, to which end patients first inhaled 30 mg on visit 1, followed by 60 mg on visit 2. As can be seen in Figure 1, the total levodopa exposure (area under the concentration vs. time curve: AUC) was lower after inhalation than after oral administration, and C_max after inhalation of 60 mg levodopa was approximately 1.5 times lower than after oral administration of 100 mg. Since the present study is intended to study effectiveness, we will use a higher dose of inhaled levodopa of 90 mg, which is estimated to give a similar C_max as 100 mg oral levodopa, but at an earlier time point after administration. This dose extrapolation is based on the assumption that levodopa exhibits linear pharmacokinetics after inhalation. We expect linear absorption kinetics in the lungs, since levodopa is a small molecule, which is easily absorbed through the lung membrane by passive diffusion.. The driving force for absorption is thus the concentration gradient. The absorptive surface area in the lungs is extremely large and we do not expect to reach a saturation concentration upon administration of doses of levodopa in the mg-range. We therefore expect that a 1.5-fold dose increase will result in a 1.5-fold higher C_max. The 60-mg dose showed C_max values that were twice as high as the C_max values after inhalation of 30 mg, which further substantiates our expectation of linear absorption kinetics in the lungs.

Since 100 mg oral levodopa is a typical dose, we do not expect any issues due to systemic exposure from a 90 mg inhaled dose. Many patients receive much higher doses of levodopa and levodopa blood levels far exceeding 2000 ng/mL are not uncommon (15,16) which is more than double the value we expect after inhalation of 90 mg levodopa. However, even if the patient would experience an episode of hyperkinesia, these episodes are generally considered less burdensome

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The levodopa blood levels we found so far after inhalation of 30 and 60 mg levodopa correspond well with the 25 and 50 mg doses of CVT-301, which have been shown to significantly improve motor symptoms during off periods. However, we want to use a higher dose of 90 mg inhaled levodopa. The reason for this is the difference in study design between our study and the CVT-301 efficacy study. CVT-301 was tested as add-on therapy; to which end the study participants received CVT-301 once they reached an off state after their morning dose levodopa (at least four hours later) (12). Based on the pharmacokinetic profile of oral levodopa in healthy volunteers (12), levodopa blood levels can still be around 250 ng/mL at four hours after an oral dose of levodopa. We aim to eliminate the effects of inter-individual differences in levodopa pharmacokinetics as much as possible. Therefore, we want to study the effects of inhaled levodopa in comparison to oral levodopa in the morning, when there is no residual levodopa left in the blood. However, to overcome this difference in baseline levodopa blood level, we anticipate the need of a higher inhaled dose.

Study parameters/endpoints

Main study parameter/endpoint

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 to estimate motor function. The primary outcome is the time until the maximum effect on motor function (largest change from baseline) is found.

Secondary study parameters/endpoints Pharmacokinetic endpoints

Levodopa blood profile after inhalation of 90 mg levodopa will be assessed in comparison to 100/25 mg orally administered levodopa/benserazide by drawing blood samples pre-dose and on set time points up to 180 minutes post-dose administration. Pharmacokinetic parameters that will be derived from the concentration vs. time curve are t_max, C_max and AUC_0-180.

Pharmacodynamic endpoints

In addition to the timed tapping test and the TUG test, the MDS-UPDRS III score will be assessed pre-dose and on set time points up to 90 min post-dose as pseudo-quantitative measure for the clinical improvement of motor function. Secondary endpoints are the maximum changes in timed tapping test, TUG test, and the MDS-UPDRS III score compared to baseline.

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Other study parameters

The following patient characteristics will be retrieved: demographics such as age, gender, height, and weight; and health characteristics such as co-morbidities and medication.

Randomisation, blinding and treatment allocation

A randomisation list for a maximum of thirteen participants will be produced for the order in which the two intervention treatments 1) 90 mg inhaled levodopa, and 2) 100/25 mg orodispersible levodopa/benserazide tablet are taken. Participants with an uneven enrolment number will start with treatment 1 (inhaled levodopa) on day 1 and continue with treatment 2 (orodispersible tablet) on day 2. Participants with an even enrolment number will take treatment 2 on day 1 and treatment 1 on day 2.

Study procedures

Lung function measurement

Lung function will be measured using a calibrated pneumotachograph as safety check upon admission and again upon discharge from the clinic (end of study). A forced vital capacity (FVC) manoeuvre will be recorded from which the forced expiratory volume in 1 s (FEV₁) and maximum expiratory flow after 50% of expired FVC (MEF₅₀) will be obtained additionally.

Inhalation of levodopa powder

The patient will receive instruction with a dummy inhaler (similar to the levodopa inhaler) on the first night of their study period. The patient will have the opportunity to practice until they master the inhalation manoeuvre. The Cyclops inhaler will be provided to the patient with a prefilled dose compartment containing 30 mg of levodopa inhalation powder with 2% l-leucine. The 90 mg dose will be inhaled in three subsequent inhalations using three 30 mg levodopa inhalers. The investigator will check whether the blister has been emptied completely. If not, the patient will be instructed to inhale again. During the inhalation, the pressure drop that the patient creates over the inhaler will be measured, from which the flow rate is calculated and displayed on a computer screen as a function of inhalation time. This allows for control whether the patient reached the required flow rate. In case of an insufficient inhalation, the patient can be instructed to inhale again. Recording of the flow curves also provides the opportunity to calculate inspiratory parameters, such as inhaled volume, afterwards.

No problems are expected concerning the multiple inhalations that are required for administration of the full study dose. Previous studies at the Department of Pharmaceutical Technology and Biopharmacy showed that up to eight inhalations per administration caused no problem in patients with impaired lung function (14).

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Blood sampling

Venous cannulation in the forearm will be performed to secure venous access, from which blood samples can be taken during the study day without requiring a further needle-stick procedure. A blood sample will be drawn immediately before the patient receives the study medication. Subsequent blood samples will be drawn at time points 5, 10, 15, 20, 30, 45, 60, 90, and 180 minutes after administration of the study medication. The blood samples will be analysed for levodopa concentration as described earlier (17) and kinetic analysis of the obtained data will be performed as in the previous study too.

Motor function examination Timed tapping test

In the timed tapping test (18) the participant is instructed to tap the screen of a smartphone / tablet device with tap recording software successively with the index finger of their most affected hand as rapidly as possible for the duration of 30 s. The software will record the number of taps.

Timed Up & Go (TUG) test

The TUG test (19) measures in seconds the time it takes an individual to stand up from a chair, walk a distance of 3 m, turn around, walk back to the chair, and sit down again. During this exercise no physical assistance is given. The individual is instructed to walk at a comfortable and safe pace.

MDS-UPDRS III motor examination

The Unified Parkinson’s Disease Rating Scale (UPDRS) is a tool to assess severity of PD symptoms (20). The UPDRS is the primary outcome measure in most clinical trials of PD therapeutics (21). The UPDRS consists of six sections, in which all items (unless otherwise indicated) are rated from zero (normal) to four (severely affected). The Movement Disorder Society (MDS)-sponsored new version of the UPDRS (MDS-UPDRS) has been published in 2008 and has incorporated important recommendations for improvement. The MDS-UPDRS consists of four sections, of which section III (motor examination) will be used in this study.

Since motor symptoms (rigidity, bradykinesia) are major symptoms during an off period, the MDS-UPDRS III motor examination section will be useful to assess the clinical state of motor function immediately before the inhalation tests will start. The MDS-UPDRS motor examination section is a 14-item rating of motor signs. It rates tremor, facial and generalized bradykinesia, and performance on several straightforward tasks. Each item is rated from zero (normal) to four (severely affected). In this study, an accredited MDS-UPDRS scorer will rate Parkinson’s disease symptoms as defined by the MDS-UPDRS III motor section for each patient, immediately before the administration of the investigational product or comparator. Subsequently, the MDS-UPDRS III score will be taken on the time points 20 and 60 minutes after administration of the investigational product or comparator.

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The MDS-UPDRS motor examinations will be recorded on film to allow for later assessment by a second scorer who will be blinded to treatment and the time point at which the score was taken. If a certain score deviates by one point (per item), the score of the second scorer will be used. In case of larger deviations, the scorers will meet to discuss which score should be assigned. The motor function examination results and the levodopa blood levels of the patients will be assessed too be able to discover relationships between levodopa concentration and clinical effect.

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