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Trial record 43 of 72 for:    "The Swedish Research Council" [Exact]

Study Comparing Intravenous and Subcutaneous Infudopa With Intestinal Duodopa in Patients With Parkinson's Disease (IPO-001)

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ClinicalTrials.gov Identifier: NCT03419806
Recruitment Status : Recruiting
First Posted : February 2, 2018
Last Update Posted : March 7, 2018
Sponsor:
Collaborators:
The Swedish Research Council
Dizlin Medical Design AB
Göteborg University
Information provided by (Responsible Party):
Vastra Gotaland Region

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.


Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: Infudopa i.v. Drug: Infudopa s.c. Drug: LCIG (Duodopa) Phase 1

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Levodopa Pharmacokinetics in Patients With Parkinson's Disease and Symptom Fluctuation: A Phase I, Open-label, Randomized, Multicentre, Crossover Study Comparing Intravenous and Subcutaneous Infudopa With Intestinal Duodopa
Actual Study Start Date : February 16, 2018
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Infudopa i.v.
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.
Drug: Infudopa i.v.
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, administered as a morning rapid i.v. constant rate administration followed by continuous i.v. infusion up to 16 h. The subject's usual morning dose will be administered to rapidly achieve the therapeutic dose level. The maximum daily dose levodopa during i.v. administration should normally not exceed 2513 mg, and is not allowed to exceed 3000 mg (equal to 75% of the maximum allowed daily dosage for Duodopa that is 4000 mg).

Experimental: Infudopa s.c.
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.
Drug: Infudopa s.c.
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, also administered as a morning rapid s.c. constant rate administration followed by continuous s.c. infusion up to 16 h. The maximum daily dose levodopa during s.c. administration should normally not exceed 3350 mg, and is not allowed to exceed 4000 mg (equal to 100% of the maximum allowed daily dosage for Duodopa that is 4000 mg).

Active Comparator: LCIG (Duodopa)
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)
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.




Primary Outcome Measures :
  1. Steady state plasma concentration - levodopa [ Time Frame: 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. ]
    To demonstrate that Infudopa i.v. and s.c. yield steady state plasma concentration of levodopa that is equivalent with that of Duodopa.

  2. Steady state plasma concentration - carbidopa [ Time Frame: 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. ]
    To demonstrate that Infudopa i.v. and s.c. yield steady state plasma concentration of carbidopa that is equivalent with that of Duodopa.

  3. Peak-through fluctuation of plasma concentration - levodopa [ Time Frame: 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. ]
    Peak-through fluctuation of levodopa plasma concentrations during the dosage interval with Infudopa i.v. and s.c. will be compared to Duodopa.

  4. Peak-through fluctuation of plasma concentration - carbidopa [ Time Frame: 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. ]
    Peak-through fluctuation of carbidopa plasma concentrations during the dosage interval with Infudopa i.v. and s.c. will be compared to Duodopa.


Secondary Outcome Measures :
  1. Local skin tolerability to the investigated products, Draize score [ Time Frame: 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. ]
    The number of participants with treatment-related local skin reactions during or following s.c and i.v. infusion of the IMP will be assessed. Local skin reactions will be rated by a dermatologist using Draize scoring.

  2. Local skin tolerability to the investigated products, subjective symptom ratings [ Time Frame: 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. ]
    In participants with skin reactions the skin symptoms tenderness and itching will be rated by the participants using a horizontal 10 cm visual analogue scale graded 0-100 where 0 represents no symptom and 100 worst possible.

  3. Bioavailability - levodopa [ Time Frame: 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. ]
    To establish the bioavailability of levodopa given s.c. and as Duodopa compared to the i.v. administration

  4. Bioavailability - carbidopa [ Time Frame: 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. ]
    To establish the bioavailability of carbidopa given s.c. and as Duodopa compared to the i.v. administration

  5. Maximum plasma concentration (Cmax) - levodopa [ Time Frame: 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. ]
    Compare maximum plasma concentration (Cmax) of levodopa during treatment with s.c and i.v Infudopa versus Duodopa.

  6. Maximum plasma concentration (Cmax) - carbidopa [ Time Frame: 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. ]
    Compare maximum plasma concentration (Cmax) of carbidopa during treatment with s.c and i.v Infudopa versus Duodopa.

  7. Time of the maximum plasma concentration (tmax) - levodopa [ Time Frame: 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. ]
    Compare time of the maximum plasma concentration (tmax) of levodopa during treatment with s.c and i.v Infudopa versus Duodopa.

  8. Time of the maximum plasma concentration (tmax) - carbidopa [ Time Frame: 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. ]
    Compare time of the maximum plasma concentration (tmax) of carbidopa during treatment with s.c and i.v Infudopa versus Duodopa.

  9. Area under the curve (AUC) - levodopa [ Time Frame: 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. ]
    Compare area under the curve (AUC) of levodopa during treatment with s.c and i.v Infudopa versus Duodopa.

  10. Area under the curve (AUC) - carbidopa [ Time Frame: 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. ]
    Compare area under the curve (AUC) of carbidopa during treatment with s.c and i.v Infudopa versus Duodopa.

  11. Elimination half-life (t½) - levodopa [ Time Frame: 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. ]
    Compare elimination half-life (t½) of levodopa during treatment with s.c and i.v Infudopa versus Duodopa.

  12. Elimination half-life (t½) - carbidopa [ Time Frame: 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. ]
    Compare elimination half-life (t½) of carbidopa during treatment with s.c and i.v Infudopa versus Duodopa.

  13. Parkinson's disease motor symptom ratings [ Time Frame: For each treatment visit: pre-dose, t=1,5h, t=5h, t=6h, t=7h, t=16h and t=24h from infusion start. ]
    Bradykinesia and dyskinesia will be assessed using the Treatment Response Scale, TRS (Nyholm et al, 2005). For this assessment the following items from the UPDRS will be performed: Finger tapping (item 23), Rapid alternating hand movements (item 25), eg agility (item 26), arising from chair (item 27), gait (item 29), and global bradykinesia (item 31). The occurrence of dyskinesia during these items will be assessed according to the definitions of the Modified Dyskinesia Scale (Goetz et al. 1994). The TRS outcome measure is a Likert scale that ranges from -3 to +3 (severely bradykinetic to severely dyskinetic).

  14. Parkinson Kinetigraph objective bradykinesia measurement (BK score) [ Time Frame: For each treatment visit: Between 9-18 as well as +1h to +16h after infusion start. ]
    The 25th, 50th and 75th percentiles of the BK scores from a 24h recording will be determined.

  15. Parkinson Kinetigraph objective dyskinesia measurement (DK score) [ Time Frame: For each treatment visit: Day 1: Between 9-18 as well as +1h to +16h after infusion start. ]
    The 25th, 50th and 75th percentiles of the DK scores from a 24h recording will be determined.

  16. Parkinson Kinetigraph objective tremor episodes [ Time Frame: For each treatment visit: Day 1: Between 9-18 as well as +1h to +16h after infusion start. ]
    The percent of time with ongoing tremor consisting of at least 10 seconds meeting the operational tremor criteria defined by Braybrook et al (2016) will be measured.

  17. Parkinson Kinetigraph objective Fluctuation dyskinesia score (FDS) [ Time Frame: For each treatment visit: Day 1: Between 9-18 as well as +1h to +16h after infusion start. ]
    The fluctuation dyskinesia score will be calculated from the interquartile range of BK and DK scores.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03419806


Contacts
Contact: Filip Bergquist, Ass Prof +46 702 223664 filip.bergquist@gu.se
Contact: Elias Eriksson, Prof +46 709 55 50 55 elias.eriksson@neuro.gu.se

Locations
Sweden
Sahlgrenska Universtiy Hospital, Dep of Neurology Recruiting
Gothenburg, Sweden
Contact: Filip Bergquist, MD, PhD    +46702223664    filip.bergquist@vgregion.se   
Sponsors and Collaborators
Vastra Gotaland Region
The Swedish Research Council
Dizlin Medical Design AB
Göteborg University
Investigators
Principal Investigator: Filip Bergquist, Ass Prof Department of Pharmacolgy at Institute of Neuroscience and Physiology

Responsible Party: Vastra Gotaland Region
ClinicalTrials.gov Identifier: NCT03419806     History of Changes
Other Study ID Numbers: 2017-002488-17
First Posted: February 2, 2018    Key Record Dates
Last Update Posted: March 7, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Levodopa
Carbidopa, levodopa drug combination
Carbidopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adjuvants, Immunologic
Immunologic Factors
Dopamine Agonists
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors