Clinical studies

Two clinical Phase I studies have been carried out where Flexilev® was compared with approved registered drugs.

Study 1

The first study was a so-called bioequivalence study, where the aim was to compare Sensidose’s own product, Flexilev® microtablets, with the same total dose of an existing drug product. This is a procedure that is common in the registration of generic drugs.

The aim of a bioequivalence study is to show that there is no significant difference in terms of absorption, distribution, metabolism or excretion of the active substance, what is also called pharmacokinetics. The drugs are given as single doses on one occasion, usually to healthy volunteers, under standardized conditions.

At predetermined points in time blood samples are drawn for analysis. In order for the substances to be considered bioequivalent, the rate of uptake as well as the degree of drug absorption and metabolism must be the same. If the tested product is bioequivalent with an already registered product, you can in principly apply for marketing approval of the new product.

The product that is closest to Flexilev® is Sinemet®, which contains the same active substances, levodopa and carbidopa. Sinemet® is, however, only available in standard doses that are considerably higher than the contents of a Flexilev® microtablet, which contains only 5 mg levodopa and 1.25 mg carbidopa.

A phase I investigation of bioavailability and pharmacokinetics (bioequivalence study) following single dosing of three formulations of levodopa with addition of a decarboxylase inhibitor in 18 healthy subjects was thus conducted during 2009. The clinical phase of the study was conducted at the Department of Clinical Pharmacology, C1:68, Huddinge, Karolinska University Hospital. The study was a single dose, open, randomized, three-way crossover, phase I study in healthy volunteers.

Subjects were randomized to one of three treatment sequences. All subjects received three treatments, one with each dosage form, with a minimum of a 4 day washout between. The objective of the study was to compare the bioavailability of Levodose® (20 micro-tablets corresponding to a total dose of 100mg/25mg levodopa/carbidopa) with two reference products -Madopark® Quick (levodopa/benserazide 100/25) and Sinemet®, (levodopa/carbidopa 100/25 mg) and to determine their bioequivalence.

The outcome of the study was to full satisfaction and in accordance with the expectations of the company. The data obtained for both levodopa and carbidopa compared to Sinemet®were within the acceptance levels, i.e. Flexilev® and Sinemet® are bioequivalent following single dosing. Both drugs gave measurable concentrations already after approximately 10 minutes and maximum concentration after approximately half an hour. After approximately 1.5 hours half of the levodopa had been eliminated from the bloodstream.

The results of study has been published in the journal Clinical Neuropharmacology, 30 April 2012 see this link: Pubmed.

Study 2

The rapid metabolism of levodopa is a problem for patients with Parkinson’s disease. In order to function normally they need to have a constant and individually adjusted plasma level of the drug. In this way a steady synthesis and availability of dopamine in the brain, with stable motor and psychomotor function is achieved. The drug Stalevo® contains levodopa and carbidopa, but also an inhibitor of the COMT enzyme and is considered to be the preparation in tablet form that best enables the desired steady supply of levodopa.

In a recently completed clinical study Flexilev was compared with Stalevo®. The study was a multiple dose, open, randomized, two-way crossover, phase I study in healthy volunteers. Subject’s treatment orders was randomized. All subjects received two treatments, one with each dosage form, with a minimum of a 4 day washout between.The aim was to demonstrate that repeated dosage with Flexilev® can achieve a plasma concentration that is at least as steady during the day as with Stalevo®. Both drugs were given to 10 healthy volunteers, who were all administered 300 mg levodopa through the respective drug during a day. Flexilev® was administered as follows: An initial 75 mg dose was given in the morning. Five 45 mg doses were then given at fixed time intervals. Stalevo® was given as three 100 mg tablets every six hours, starting in the morning. Blood was sampled throughout the day. It was of special interest to register the maximum and minimum plasma concentrations of each drug.

The results showed that Flexilev gave more steady concentrations than Stalevo®, i.e. Stalevo® gave both the lowest and the highest plasma concentrations during the day. Flexilev also gave a considerably faster absorption of levodopa, with shorter time to maximum plasma concentration, compared to Stalevo®. The study was performed by the Department of Clinical Pharmacology, C1:68, Huddinge, Karolinska University Hospital.

The results of study has been published in the journal Acta Neurol

Study 3

A recurring question is whether the results we obtained in healthy volunteers (see study 1) are applicable to patients with Parkinson’s disease in a more advanced phase. This study was conducted to answer this question. The study had two main objectives: 1) to investigate the pharmacokinetics (absorption, distribution, metabolism or excretion) of Flexilev in patients and 2) to monitor the effect of the dose by repeated examinations of motion with different measurement methods.

The study was a single dose, open, phase I study and was conducted at Uppsala University Hospital. 19 patients who had a average of 9.5 years duration of Parkinson’s disease participated in the study. After a night’s fast, a Flexilev dose, corresponding to 150% of patients’ normal morning dose, was given. Blood samples and test were then performed up to 15 times at specified times. The tests were video-filmed and these films were reviewed by three independent experts who had no information about times of test in relation to dose intake or amount of dose. The experts graded patient mobility according to a response scale from -3 to +3, where 0 is normal mobility, -3 = severe bradykinesia and +3 = severe dyskinesia.

The result showed that the absorption of Flexilev is slightly higher in patients compared to healthy volunteers. The time to reach the highest plasma concentration of levodopa was basically the same for patients compared to that of healthy volunteers. Likewise, elimination of levodopa from plasma between patients and healthy volunteers did not differ. This shows that the disease does not affect the ability to absorb Flexilev from the intestine. One can express it so that there is nothing wrong with the ability of the intestine to absorb drugs or the body’s ability to handle the drug Flexilev in Parkinson’s patients.
The median time until a clear clinical effect was measured was 21 minutes and duration of the effect was 201 minutes (i.e. 3 hours and 20 minutes). It was also noted that there is a very large variation between individuals, which underlines the importance of individualizing treatment with levodopa.
The results have been published in the journal Eur J Clin Pharmacol. 2017; 73 (5): 563-571. See this link: Pubmed.

The study has given important information on how to treat this patient group with Parkinsons disease for a relatively long time and who has an unstable effect of present treatment. Flexilev treatment is very suitable for the individualized dose adjustments needed to provide a correct dose at the correct time.

Study 4

Flexilev contains the same active ingredients as similar approved medicines. The difference is that treatment with Flexilev is individualized, ie the dose is adjusted according to each individual’s needs in steps of 5 mg. This accuracy in dosage can only be obtained with Flexilev. But is it effective? In this study, personalized treatment with Flexilev minitablets was compared to standard treatment.

The study was a four week open observational study conducted at the Sahlgrenska Hospital in Gothenburg. 24 patients participated and, on average, they had their Parkinson’s diagnosis for 9.5 years. To be able to participate in the study, the requirement was to take levodopa at least four times a day and have remaining symptoms. The study period was divided into two two-week periods. During the first, the participants received the same medication as before but given with Flexilev minitablets and the MyFID dosing device. However, the treatment itself was identical to that the patient had before the study. In the second two-week period, the dose was adjusted according to patient needs and in line with a motion measurement. Participants underwent the same type of tests before the study and after each of the two two-week intervals with different treatment.

The result showed that the dose of levodopa was increased by 15% and the number of daily doses went from an average of 5.8 to 6.7, ie an increase of about one dose per day. The participants showed significant improvements in mobility (Scale: UPDRS II and III), with 17 of the 24 participants improving. The number of non-motor symptoms was reduced, as well as wearing off. Depressive symptoms decreased and quality of life increased. All these changes from study start to study end were statistically significant. The adherence to the treatment was very good, more than 90% of the doses were taken according to the dosage schedule. The treatment was well tolerated. Three patients completed the study prematurely, one each after nausea, diarrhea and with increased wearing-off disorders.

The results of the study have been published in the journal CNS Neurosci Ther. 2018; 1-9 Pubmed.

The study shows that the individualized treatment given with Flexilev and the MyFID dosing device improved treatment outcome and increased patient quality of life. The study is a short-term study and provides a basis to study how the outcome looks after longer treatment times. However, we can note that Flexilev treatment is highly suitable for an individualized dose adjustment that is needed to provide a correct dose at the right time, with high compliance and that this brings clinically significant improvements.