Study Comparing Intravenous and Subcutaneous Infudopa With Intestinal Duodopa in Patients With Parkinson's Disease

In patients with Parkinson's disease, the characteristic motor symptoms, i.e., slowness of movement (bradykinesia), tremor and rigidity, are consequences of the progressive degeneration of neurons containing and releasing dopamine. The first-line treatment of Parkinson´s is oral administration of levodopa - a precursor to dopamine that (unlike dopamine) passes the blood brain barrier. After the first few years of treatment with levodopa, many patients do however develop a highly variable response to the drug characterised by rapid shifts between impaired locomotion and drug induced dyskinesias (referred to as the on-off syndrome). This is cased by the marked variation in serum levodopa levels following per oral administration, and it is known that intravenous administration of levodopa give a more stable level of levodopa with improved on-off symptoms.

Levodopa-carbidopa intestinal gel (LCIG) - under the name of Duodopa® - is delivered directly to the proximal jejunum via a tube connected to a portable infusion pump. Infusion of Duodopa in the jejunum bypasses gastric emptying, helping to avoid the fluctuation in plasma levodopa levels. However, while clearly confirming that an even administration of levodopa is of considerable benefit to Parkinson patients with on-off symptomatology, the LCIG approach is marred by the need for surgery (for the insertion of the intestinal tube) and various possible complications following this, as well as by side effects such as abdominal pain.

Researchers have now succeeded in producing a physiologically acceptable levodopa solution (called Infudopa) in a concentration allowing for a continuous intravenous (i.v.) or subcutaneous (s.c.) administration of therapeutic doses to humans. Early experience of this strategy confirms that both s.c. and i.v. administration of this solution results in even serum levodopa levels and markedly improved motor functioning. The aim of this study is to compare the pharmacokinetic profile of Infudopa administered i.v. and s.c. with that of Duodopa administered enterally in parkinsonian patients with on-off complications.

IPO-001 is a prospective, randomized, 3-period cross-over, open-label multicentre trial comparing intravenous and subcutaneous Infudopa with intestinal Duodopa. The patients will be identified and recruited at neurology clinics at university hospital clinical sites in Sweden, and travel from their living location to a clinical phase I site with full Good Clinical Practice (GCP) standard at the Sahlgrenska University Hospital in Gothenburg for the three treatment visits.

At the phase I study clinic, patients will receive Duodopa at optimal dosage for 16 hours at one of the treatment visits, i.v. Infudopa at a concentration estimated to yield corresponding serum levels of levodopa for the same duration at another treatment visit, and they will again receive the corresponding amount of levodopa but in the form of s.c. Infudopa at a third visit. The study will hence have a cross-over design with a minimum of three days on Duodopa between the different treatment visits, where the order of treatments will be non-blinded but randomized.

Blood samples will be drawn according to a set schedule during the treatment visits, and subjects will be monitored for safety throughout the study, with focus on the local tolerability at the injection sites of i.v. and s.c. administration.

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent
2. Male or female patients at least 30 years old
3. Patients with advanced Parkinson's disease who are already on LCIG (Duodopa®) for at least 30 days, on a stable treatment regimen of 685 mg to 4000 mg levodopa per day, and with approximately 16- or 24-h Duodopa infusion regimens\*
4. Patients with a Hoehn and Yahr (H\&Y) score of ≤ 3 on Duodopa treatment (including concomitant medication)
5. Body mass index range from 18.0 to 35.0 kg/m2
6. Patients in general good health, as judged by the Investigator, and as determined by vital signs, medical history, physical examination, ECG, and laboratory tests
7. Females of childbearing potential must have a negative pregnancy test prior to randomization and must be willing to use a highly effective contraceptive measure during relevant systemic exposure to the investigational drug and the first menstrual cycle after treatment cessation (see section 7.3).
8. Males must be willing to refrain from fathering a child, including sperm donation, during the study and 3 months following the last dose.

   * Criterion 3 updated to "...a stable treatment regimen of 600 mg to 4000 mg levodopa per day" after first interim analysis (patient 6 and onwards)

Exclusion Criteria\*\*:

1. Simultaneous participation in any other clinical study 2. Known drug abuse of any kind, or other condition that may render the patient more likely to be non-compliant to the protocol, as judged by the investigator 3. Patients who are considered to be violent or patients considered at suicidal risk by the investigator 4. Clinically significant abnormal laboratory data at baseline or any abnormal laboratory value that could interfere with the study assessments 5. Patients with serious symptomatic cerebral disease, cerebrovascular disease, focal neurological lesions (previous brain surgery), any acute brain trauma requiring treatment with anticonvulsant therapy, or acute stroke 6. Current diagnosis or history of drug or alcohol abuse within 12 months of baseline 7. Other psychiatric, neurological, or behavioral disorders that may interfere with the conduct or interpretation of the study, as judged by the Investigator 8. History of, or current, seizure disorders and patients requiring treatment with anticonvulsants 9. History or presence of any condition that might interfere with absorption, distribution, metabolism, or excretion of study drug, however, the PEG/J (percutaneous endoscopic gastrojejunostomy) tube that Duodopa patients have is not considered as such condition 10. Patients on medication with warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, monoamine oxidase-A inhibitors and alpha-methyldopa (within last 60 days); selegiline, catechol-O-methyltransferase (COMT) inhibitors, dopamine, parenteral ergots, methylphenidate, amphetamine, beta blockers for treating tremor, isoprenaline, adrenaline, dobutamide, reserpine, flunarizine or cinnarizine, isoniazid, metoclopramide, and anticholinergics (within last 30 days); and iron salts (within last 7 days), or any other treatment that could affect the metabolism of levodopa 11. Patients who use antineoplastic and immunosuppressants (within the last 5 years), and drugs known to increase risks for cardiac toxicity, Torsade de Pointes, sudden death or prolonged QT interval (within five elimination half-lives before baseline and for the duration of the study)

\*\*) Replaced by the following exclusion criteria after interim analysis (patient 6 and onwards):

1. Simultaneous participation in any other clinical drug trial
2. Clinically significant abnormal laboratory data at baseline or any abnormal laboratory value that could interfere with the study assessments.
3. Patients with current serious symptomatic CNS-lesions, neurological, psychiatric, or behavioral disorders other than Parkinson's disease (e.g. major stroke, epilepsy, substance use disorder, previous neurosurgery including DBS) and that may interfere with the conduct or interpretation of the study
4. History or presence of any condition that can interfere with absorption, distribution, metabolism, or excretion of study drug (not including the percutaneous endoscopic gastrojejunostomy tube needed for Duodopa administration)
5. Patients on medication with warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, monoamine oxidase-A inhibitors and alpha-methyldopa (within the last 60 days); selegiline, catechol-O-methyltransferase (COMT) inhibitors other than a single daily dose of entacaponeparenteral ergots, anticholinergics, methylphenidate, amphetamine, isoprenaline, adrenaline, dobutamide, reserpine, or other drugs with known dopamine receptor antagonistic effect (within the last 30 days); and iron salts (within the last 7 days), or any other treatment that could affect the metabolism of levodopa
6. Patients who use antineoplastic chemotherapy or biological immunosuppressants (within the last 5 years), and drugs known to increase risks for cardiac toxicity, Torsade de Pointes, sudden death or prolonged QT interval (within five elimination half-lives before baseline and for the duration of the study)