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

NCT03419806 | Completed Phase 1

• 1 other identifier: 2017-002488-17
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Parkinson Disease

Outcome Measures

Primary Outcomes (3)

• Steady state plasma concentration - levodopa

  To demonstrate that Infudopa i.v. and s.c. yield steady state plasma concentration of levodopa that is equivalent with that of Duodopa.

  For each treatment visit: Pre-dose, t=15 min, t=30 min, t=1h, t=1.5h, t=2h, t=2.5h, t=3h, t=3.5h, t=4h, t=5h, t=6h, t=7h, t=8h, t=10h, t=12h, t=14h, t=16h, t=16.5h, t=17h, t=17.5h, t=18h, t=23h, and t=24h from infusion start.

• Area under plasma concentration versus time curve (AUC) - levodopa

  AUC of levodopa plasma concentrations during the dosage interval with Infudopa i.v. and s.c. will be compared to Duodopa.

  For each treatment visit: Pre-dose, t=15 min, t=30 min, t=1h, t=1.5h, t=2h, t=2.5h, t=3h, t=3.5h, t=4h, t=5h, t=6h, t=7h, t=8h, t=10h, t=12h, t=14h, t=16h, t=16.5h, t=17h, t=17.5h, t=18h, t=23h, and t=24h from infusion start.

• Coefficient of variation (COV) for plasma levodopa concentrations

  COV for plasma levodopa concentrations during the dosage interval with Infudopa i.v. and s.c. will be compared to Duodopa.

  For each treatment visit: Pre-dose, t=15 min, t=30 min, t=1h, t=1.5h, t=2h, t=2.5h, t=3h, t=3.5h, t=4h, t=5h, t=6h, t=7h, t=8h, t=10h, t=12h, t=14h, t=16h, t=16.5h, t=17h, t=17.5h, t=18h, t=23h, and t=24h from infusion start.

Secondary Outcomes (17)

• Local skin tolerability to the investigated products, Draize score

  For each treatment visit - Baseline: Day -1; Post infusion: t=24h, day 30±5 (only s.c. infusion), 30+/-5 days after last treatment visit.

• Local skin tolerability to the investigated products, subjective symptom ratings

  For each treatment visit: Day 1 during infusion: t=2h, t=8h, t=16h after infusion start; Day 2 post infusion: t=24h after infusion start, day 30±5 (only s.c. infusion), 30+/-5 days after last treatment visit.

• Bioavailability - levodopa

  For each treatment visit: Pre-dose, t=15 min, t=30 min, t=1h, t=1.5h, t=2h, t=2.5h, t=3h, t=3.5h, t=4h, t=5h, t=6h, t=7h, t=8h, t=10h, t=12h, t=14h, t=16h, t=16.5h, t=17h, t=17.5h, t=18h, t=23h, and t=24h from infusion start.

• Bioavailability - carbidopa

  For each treatment visit: Pre-dose, t=15 min, t=30 min, t=1h, t=1.5h, t=2h, t=2.5h, t=3h, t=3.5h, t=4h, t=5h, t=6h, t=7h, t=8h, t=10h, t=12h, t=14h, t=16h, t=16.5h, t=17h, t=17.5h, t=18h, t=23h, and t=24h from infusion start.

• Maximum plasma concentration (Cmax) - levodopa

  For each treatment visit: Pre-dose, t=15 min, t=30 min, t=1h, t=1.5h, t=2h, t=2.5h, t=3h, t=3.5h, t=4h, t=5h, t=6h, t=7h, t=8h, t=10h, t=12h, t=14h, t=16h, t=16.5h, t=17h, t=17.5h, t=18h, t=23h, and t=24h from infusion start.

Study Arms (3)

Infudopa i.v.

EXPERIMENTAL

Infudopa i.v. in 75% of the subject's individual pre-study dosing of Duodopa will be delivered over a 16-h period, administered as a morning rapid i.v. constant rate administration followed by continuous i.v. infusion. From patient 6 and onwards: Infudopa i.v. in 81% of the subject's individual pre-study dosing of Duodopa will be delivered over a 16-h period, administered as a morning rapid i.v. constant rate administration followed by continuous i.v. infusion.

Drug: Infudopa i.v.

Infudopa s.c.

EXPERIMENTAL

Infudopa s.c. in the same dosage as the subject's individual pre-study dosing of Duodopa will be delivered over a 16-h period, administered as a morning rapid s.c. constant rate administration followed by continuous s.c. infusion. From patient 6 and onwards: Infudopa s.c. in 86% of the subject's individual pre-study dosing of Duodopa will be delivered over a 16-h period, administered as a morning rapid s.c. constant rate administration followed by continuous s.c. infusion.

Drug: Infudopa s.c.

LCIG (Duodopa)

ACTIVE COMPARATOR

Individually optimized dosing of LCIG (Duodopa) (delivered directly to the proximal small intestine via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube connected to a portable infusion pump) will be delivered over a 16-h period, administered as a morning rapid constant rate administration followed by continuous infusion.

Drug: LCIG (Duodopa)

Interventions

Infudopa i.v. DRUG

Infudopa i.v. infusion will be given through an indwelling catheter placed in the arm. Infudopa i.v. will be delivered in 75% of the subject's individual pre-study dosing of Duodopa. From patient 6 and onwards: Infudopa IntraV, at 81% of the subject's individual pre-study daily Duodopa dose, will be delivered over a 16-h period and administered as a continuous fixed infusion rate preceded by a morning bolus dose. The i.v. morning bolus is 110% of the hourly continuous dose delivered at the rate of 60 ml/h (mixed volume rate Infudopa Active + Infudopa Buffer IntraV). The morning dose will not exceed 24 mL, corresponding to 240 mg levodopa. The maximum daily dose levodopa during i.v. administration is not allowed to exceed 3240mg (equal to 81% of the maximum allowed daily dosage for Duodopa that is 4000 mg).

Also known as: Infudopa IntraV

Infudopa i.v.

Infudopa s.c. DRUG

A suitable infusion needle will be placed laterally on the abdomen for the s.c. infusion of Infudopa. Infudopa s.c. will be delivered in the same dosage as the subject's individual pre-study dosing of Duodopa, as a morning rapid s.c. constant rate administration followed by continuous s.c. infusion up to 16 h. From patient 6 and onwards: Two infusion needles will be placed on the abdomen for the s.c. infusion of Infudopa SubC in 86% of the the subject's individual pre-study daily Duodopa dose. The intervention is given as a continuous fixed infusion rate for 16h preceded by a morning bolus dose. The s.c. morning bolus is 155% of the hourly continuous dose delivered at the rate of 80 ml/h (mixed volume rate Infudopa Active + Infudopa Buffer SubC). The morning dose will not exceed 30 mL. The maximum daily dose levodopa during s.c. administration is not allowed to exceed 3440mg (equal to 86% of the maximum allowed daily dosage for Duodopa that is 4000 mg).

Also known as: Infudopa SubC

Infudopa s.c.

LCIG (Duodopa) DRUG

Duodopa will be administered directly to the proximal small intestine via a PEG-J tube connected to a portable infusion pump. Individually optimized dosing of Duodopa will be administered as a morning rapid constant rate administration followed by continuous infusion and, if needed, intermittent extra doses (subject-initiated based on symptom experience). The maximum daily dose levodopa during Duodopa administration should normally not exceed 3350 mg, and is not allowed to exceed 4000 mg. From patient 6 and onwards: The pre-study daily Duodopa dose will be delivered over a 16-h period and administered as a continuous fixed infusion rate preceded by a morning bolus dose. The morning bolus is 110% of the hourly continuous dose delivered at the rate of 40 ml/h. The morning dose will not exceed 15 mL, corresponding to 300 mg levodopa. The maximum daily dose levodopa is not allowed to exceed 4000mg.

LCIG (Duodopa)

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• Male or female patients at least 30 years old
• 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\*
• Patients with a Hoehn and Yahr (H\&Y) score of ≤ 3 on Duodopa treatment (including concomitant medication)
• Body mass index range from 18.0 to 35.0 kg/m2
• Patients in general good health, as judged by the Investigator, and as determined by vital signs, medical history, physical examination, ECG, and laboratory tests
• 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).
• 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)

You may not qualify if:

• \. 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)
• Simultaneous participation in any other clinical drug trial
• Clinically significant abnormal laboratory data at baseline or any abnormal laboratory value that could interfere with the study assessments.
• 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
• 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)
• 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
• 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)

Sponsors & Collaborators

• Vastra Gotaland Region: lead
• The Swedish Research Council: collaborator
• Dizlin Medical Design AB: collaborator
• Göteborg University: collaborator

Study Sites (1)

Sahlgrenska Universtiy Hospital, Dep of Neurology

Gothenburg, Sweden

Location

Related Publications (1)

• Bergquist F, Ehrnebo M, Nyholm D, Johansson A, Lundin F, Odin P, Svenningsson P, Hansson F, Bring L, Eriksson E, Dizdar N. Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease. Neurology. 2022 Sep 5;99(10):e965-e976. doi: 10.1212/WNL.0000000000200804.

  PMID: 35705502 DERIVED

MeSH Terms

Conditions

Parkinson Disease

Interventions

carbidopa, levodopa drug combination

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Filip Bergquist, Ass Prof

  Department of Pharmacolgy at Institute of Neuroscience and Physiology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2018
• First Posted: February 5, 2018
• Study Start: February 16, 2018
• Primary Completion: March 27, 2020
• Study Completion: April 20, 2020
• Last Updated: November 5, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)