Therapeutic Potential for Intranasal Levodopa in Parkinson's Disease -Off Reversal

NCT03541356 | Completed Phase 2 Results DMC FDA Drug FDA Device

• 1 other identifier: INP103-201
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 5

Brief Summary

A Phase IIa, Randomized, Double Blind, Placebo Controlled, Single Dose, Safety and Pharmacokinetic/Pharmacodynamic Study of INP103 (POD L-dopa) Administered in the Presence of Decarboxylase Inhibitor to L-dopa Responsive Parkinson's Disease Patients

Conditions

Parkinson's Disease

Keywords

Parkinsons; L-dopa; levodopa; ON; OFF; PD; POD device; I231; benserazide; Precision olfactory delivery; MDS-UPDRS; Carbidopa; DCI; Decarboxylase Inhibitor

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Treatment Emergent Adverse Events

  Assessment of treatment emergent adverse events after single dosing with INP103 (L-dopa or L-dopa/carbidopa)

  7 days

Secondary Outcomes (14)

• AUC0-2hr for L-dopa

  For L-dopa 35 mg, 70 mg, 140 mg plasma samples were taken at pre-dose, 30, 60, 90 and 120 minutes post-dose. For L-dopa 70 mg/carbidopa 7 mg, plasma samples were taken at pre-dose, 5, 10, 15, 30, 45, 60, 90 and 120 min

• Cmax of L-dopa

  For L-dopa 35 mg, 70 mg, 140 mg plasma samples were taken at pre-dose, 30, 60, 90 and 120 minutes post-dose. For L-dopa 70 mg/carbidopa 7 mg, plasma samples were taken at pre-dose, 5, 10, 15, 30, 45, 60, 90 and 120 minutes post-dose.

• Tmax of L-dopa

  For L-dopa 35 mg, 70 mg, 140 mg plasma samples were taken at pre-dose, 30, 60, 90 and 120 minutes post-dose. For L-dopa 70 mg/carbidopa 7 mg, plasma samples were taken at pre-dose, 5, 10, 15, 30, 45, 60, 90 and 120 minutes post-dose.

• Mean Change From Baseline in MDS-UPDRS Score Over 2 Hours for C1, C2, C3 and Change From Baseline at 30, 60, 90, 120 Minutes for C4, in MDS-UPDRS Part III Score

  For L-dopa 35 mg, 70 mg, 140 mg, assessment occurred at pre-dose, 15, 30, 45, 60, 90 and 120 minutes post-dose. For L-dopa 70 mg/carbidopa 7 mg, assessment occurred at pre-dose, 30, 60, 90 and 120 minutes post-dose.

• Time to Response (Defined as Improvement of 30% in MDS-UPDRS Part III Score From Baseline)

  2 hours

Study Arms (5)

Placebo

PLACEBO COMPARATOR

Combination Product: Placebo

L-dopa 35 mg

ACTIVE COMPARATOR

Combination Product: L-dopa 35 mg

L-dopa 70 mg

ACTIVE COMPARATOR

Combination Product: L-dopa 70mg

L-dopa 140 mg

ACTIVE COMPARATOR

Combination Product: L-dopa 140 mg

L-dopa 70 mg/carbidopa 7 mg

ACTIVE COMPARATOR

Combination Product: L-dopa 70mg/carbidopa 7mg

Interventions

Placebo COMBINATION_PRODUCT

Delivered via the I231 POD (Precision Olfactory Delivery) device

Placebo

L-dopa 35 mg COMBINATION_PRODUCT

Delivered via the I231 POD (Precision Olfactory Delivery) device via one puff to one nostril

L-dopa 35 mg

L-dopa 70mg COMBINATION_PRODUCT

Delivered via the I231 POD (Precision Olfactory Delivery) device with two puffs, one to each nostril

L-dopa 70 mg

L-dopa 140 mg COMBINATION_PRODUCT

Delivered via the I231 POD (Precision Olfactory Delivery) device with four puffs, two to each nostril

L-dopa 140 mg

L-dopa 70mg/carbidopa 7mg COMBINATION_PRODUCT

Delivered via the I231 POD (Precision Olfactory Delivery) device with two puffs, one to each nostril

L-dopa 70 mg/carbidopa 7 mg

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult males and females, 40 to 80 years of age (inclusive) at the time of Screening (Visit1)
• Diagnosed with Idiopathic PD (by UK Brain Bank Criteria) with Modified Hoehn \& Yahr (H\&Y) Stage I-III during an ON period at Visit 1
• Subjects who are prone to (and recognize) OFF episodes (when their usual PD medication has worn off)
• Shown to be responsive to L-dopa medication (≥ 30% improvement in MDS-UPDRS Part III Motor Examination score) as assessed during the Screening period (Visit 2)
• On a stable dose of L-dopa containing medication for at least 2 weeks prior to Visit 1 (up to 1200 mg/day) with no single dose exceeding 250 mg. All other anti-PD medication (e.g. dopamine agonists \[DAs\], monoamine oxidase-B inhibitor (MAOB-I) or catechol-O-methyl transferase (COMT) inhibitors ARE allowed if the subject has been on a stable dose for at least 30 days prior to Visit 1.
• Willing to omit their (usual) PD drugs (e.g. usual regular anti-PD medication including any L-dopa containing medication, DAs and/or COMT inhibitors and any required anti-OFF treatment) from 22:00 pm the evening prior to study dosing until 120 minutes post study treatment dosing.
• Cohorts 1, 2 and 3 ONLY WILL take oral benserazide 25 mg on arrival at the research site (at 60 ± 5 minutes before dosing with INP103 or placebo).
• Cohort 4 will omit oral benserazide and subjects may be dosed once OFF episode has been confirmed and all baseline assessments have been completed.
• If female and of childbearing potential must agree to use adequate contraception (see Section 4.4) during the study
• Able and willing to attend the necessary visits at the study centre
• Willing to provide voluntary written informed consent signed prior to entry into the study

You may not qualify if:

• Severe dyskinesia (defined as per MDS-UPDRS) during a 'normal day' that would significantly interfere with the subject's ability to perform study assessments
• In receipt of L-dopa containing medication at \> 1200 mg/day
• History of significant psychotic episode(s) within the previous 12 months in the opinion of the Investigator, or currently receiving anti-psychotic medication at a moderate dose (quetiapine \>50 mg/day, risperidone \>1 mg/day or olanzapine \>2.5 mg/day)
• Mini Mental State Examination (MMSE) ≤ 25 as documented within the previous 36 months or as assessed by Investigator during Screening
• History of suicidal ideation or attempted suicide within previous 12 months
• Narrow-angle glaucoma
• Presence of skin lesions that, in the opinion of the Investigator, may be cancerous
• Females who are pregnant, planning a pregnancy or lactating
• Subjects with any underlying physical condition that, in the opinion of the Investigator, would make it unlikely that the subject will comply with or be able to complete the study requirements
• Use of any medication likely to interact with benserazide, carbidopa or INP103 (see Appendix 5)
• Laboratory test abnormalities at Screening (Visit 1) deemed clinically significant by the Investigator.
• History or presence of alcoholism or drug abuse within the 2 years prior to INP103 or placebo dosing
• Administration of an investigational product in another trial within 30 days or 5 half-lives (whichever is longer) prior to INP103 or placebo dosing
• Significant nasal congestion, physical blockage in either nostril, or significantly deviated nasal septum as evaluated by the PI or other suitably trained healthcare professional
• Subjects who have previously shown hypersensitivity to L-dopa or benserazide (for Cohorts 1, 2 and 3), or L-dopa or carbidopa (for Cohort 4) or any of their excipients

Sponsors & Collaborators

• Impel Pharmaceuticals: lead

Study Sites (5)

The Brain and Mind Centre / Scientia Clinical Research

Sydney, New South Wales, 2031, Australia

Location

Q-Pharm

Brisbane, Queensland, Australia

Location

The Mater Hospital

Brisbane, Queensland, Australia

Location

The Alfred Hospital

Melbourne, Victoria, Australia

Location

Perron Institute

Perth, Western Australia, 6009, Australia

Location

MeSH Terms

Conditions

Parkinson Disease

Interventions

Levodopa; Carbidopa

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Dihydroxyphenylalanine; Catecholamines; Amines; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Tyrosine; Methyldopa; Hydrazines

Results Point of Contact

• Title: Karen Craig, PhD (Medical Writer)
• Organization: Impel NeuroPharma

kcraig@impelnp.com

206-568-1466

Study Officials

• Stephen B Shrewsbury, MD

  Impel NeuroPharma, Seattle, WA (USA)

  STUDY CHAIR

• Terry O'Brien, MD/Prof

  The Alfred Hospital, Melbourne, VIC (AUS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Thirty-Two (32) to Thirty-Six (36) subjects will be randomized to treatment or placebo. INP103 is a drug-device combination product containing a drug component, L-dopa, and device component, the I231 Precision Olfactory Delivery (POD) device. In Cohorts 1, 2, and 3, L-dopa will be administered intranasally in single doses of one (35 mg), two (70 mg) or four (140 mg) puffs of INP103, 60 minutes after oral benserazide hydrochloride 25 mg. In Cohort 4 the INP103 formulation will contain L-dopa:carbidopa administered nasally. Dosing will take place once OFF episode is confirmed and will not include predosing with oral benserazide.

Study Record Dates

• First Submitted: April 5, 2018
• First Posted: May 30, 2018
• Study Start: May 8, 2018
• Primary Completion: June 11, 2019
• Study Completion: June 11, 2019
• Last Updated: August 12, 2020
• Results First Posted: August 12, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

AU (5)