Therapeutic Potential for Intranasal Levodopa in Parkinson's Disease -Off Reversal (THOR 201)

• ClinicalTrials.gov Identifier: NCT03541356
• Recruitment Status: Completed
• First Posted: May 30, 2018
• Last Update Posted: June 18, 2019
• Sponsor: Impel NeuroPharma Inc.
• Information provided by (Responsible Party): Impel NeuroPharma Inc.

Study Description

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

Condition or disease	Intervention/treatment	Phase
Parkinson's Disease	Combination Product: Experimental: INP103; Combination Product: Placebo	Phase 2

Detailed Description:

This is a Phase IIa randomized, double-blind, placebo-controlled, single dose study to compare the safety, tolerability and PK/PDyn of intranasal L-dopa following administration of INP103 in the presence of L-dopa decarboxylase inhibitor (DCI) during an OFF episode.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

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.

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blind
• Primary Purpose: Treatment
• Official Title: A Phase IIa, Randomized, Double Blind, Placebo Controlled, Single Ascending Dose, Safety and Pharmacokinetic/Pharmacodynamic Study of INP103 (POD L-dopa) Administered in the Presence of DCI to L-dopa Responsive Parkinson's Disease Patients
• Actual Study Start Date: May 8, 2018
• Actual Primary Completion Date: June 11, 2019
• Actual Study Completion Date: June 11, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Experimental: INP103-201 (L-dopa or L-dopa:carbidopa); A single dose of active drug INP103 (L-dopa or L-dopa:carbidopa) delivered via the I231 Precision Olfactory Device (POD)	Combination Product: Experimental: INP103; Delivered via the I231 POD (Precision Olfactory Delivery) device with one puff to one nostril; Other Name: L-dopa 35mg
Placebo Comparator: Placebo; A single dose of placebo delivered via the I231 Precision Olfactory Device (POD)	Combination Product: Placebo; Delivered via the I231 POD (Precision Olfactory Delivery) device with one puff to one nostril; Other Name: Placebo 35mg

Outcome Measures

Primary Outcome Measures :

1. Explore the safety and tolerability of single doses of INP103 (L-dopa or L-dopa:carbidopa) versus placebo [ Time Frame: 7 days ]
   Assessment of safety and tolerability based on reported AE/SAE post-dosing with levodopa, L-dopa:carbidopa, or placebo

Secondary Outcome Measures :

1. Characterize the PK (AUC0-2h) of single doses of INP103 (L-dopa or L-dopa:carbidopa) [ Time Frame: 2 hours ]
   Area under the Plasma Concentration-time Curve for INP103
2. Characterize the PK (Cmax) of single doses of INP103 (L-dopa or L-dopa:carbidopa) [ Time Frame: 2 hours ]
   Maximum Observed Plasma Concentration for INP103 (L-dopa or L-dopa:carbidopa)
3. Characterize the PK (Tmax) of single ascending doses of INP103 (L-dopa or L-dopa:carbidopa) [ Time Frame: 2 hours ]
   Time to Reach the Maximum Plasma Concentration (Cmax) of INP103 (L-dopa or L-dopa:carbidopa)
4. Evaluate change from baseline to 30 minutes post-dose in MDS-UPDRS Part III score (primary motor function endpoint) [ Time Frame: 30 minutes ]
   MDS-UPDRS is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society with high internal consistency. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III, motor examination (18 items). The subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.
5. Evaluate time to response (defined as improvement of 30% in MDS-UPDRS Part III score from baseline) post dose of INP103 or placebo [ Time Frame: 2 hours ]
   MDS-UPDRS is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society with high internal consistency. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III, motor examination (18 items). The subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.
6. Evaluate duration of response (defined as improvement of 30% in MDS-UPDRS Part III score from baseline) post dose of INP103 or placebo [ Time Frame: 7 days ]
   MDS-UPDRS is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society with high internal consistency. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III, motor examination (18 items). The subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.
7. Evaluate Under the Curve (AUC) changes in MDS-UPDRS Part III scores from pre-dose at 15, 30, 45, 60, 90, and 120 minutes post-dose of INP103 or placebo [ Time Frame: 2 hours ]
   MDS-UPDRS is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society with high internal consistency. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III, motor examination (18 items). The subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.
8. Evaluate Maximum response in MDS-UPDRS Part III scores from pre-dose at 15, 30, 45, 60, 90, and 120 minutes post-dose of INP103 or placebo [ Time Frame: 2 hours ]
   MDS-UPDRS is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society with high internal consistency. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III, motor examination (18 items). The subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.
9. Explore subjective assessments of "Time to ON" as evaluated by the Investigator [ Time Frame: 4 hours ]
   Investigators will evaluate subjects' fluctuations in motor functions at 15, 30, 45, 60, 90, 120, and 240 minutes post-dose to determine if they are "ON" (ON meaning when medication - namely levodopa - is working optimally.
10. Explore subjective assessments of "Time to ON" as evaluated by subject self-assessment [ Time Frame: 4 hours ]
    Subjects will be asked to provide self-assessments at 15, 30, 45, 60, 90, 120, and 240 minutes post-dose if they consider they are "ON" (ON meaning when medication - namely levodopa - is working optimally.
11. Explore PK/pharmacodynamic relationship of single ascending doses of INP103 and motor function [ Time Frame: 7 days ]
    Changes in motor function will be measured (MDS-UPDRS Part III assessment) and compared against the overall PK profile findings following ascending doses of INP103 (or placebo)

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult males and females, 40 to 80 years of age (inclusive) at the time of Screening (Visit1)
2. 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
3. Subjects who are prone to (and recognize) OFF episodes (when their usual PD medication has worn off)
4. 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)
5. 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.

6. 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.

7. If female and of childbearing potential must agree to use adequate contraception (see Section 4.4) during the study
8. Able and willing to attend the necessary visits at the study centre
9. Willing to provide voluntary written informed consent signed prior to entry into the study

Exclusion Criteria:

1. Severe dyskinesia (defined as per MDS-UPDRS) during a 'normal day' that would significantly interfere with the subject's ability to perform study assessments
2. In receipt of L-dopa containing medication at > 1200 mg/day
3. 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)
4. Mini Mental State Examination (MMSE) ≤ 25 as documented within the previous 36 months or as assessed by Investigator during Screening
5. History of suicidal ideation or attempted suicide within previous 12 months
6. Narrow-angle glaucoma
7. Presence of skin lesions that, in the opinion of the Investigator, may be cancerous
8. Females who are pregnant, planning a pregnancy or lactating
9. 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
10. Use of any medication likely to interact with benserazide, carbidopa or INP103 (see Appendix 5)
11. Laboratory test abnormalities at Screening (Visit 1) deemed clinically significant by the Investigator.
12. History or presence of alcoholism or drug abuse within the 2 years prior to INP103 or placebo dosing
13. Administration of an investigational product in another trial within 30 days or 5 half-lives (whichever is longer) prior to INP103 or placebo dosing
14. Significant nasal congestion, physical blockage in either nostril, or significantly deviated nasal septum as evaluated by the PI or other suitably trained healthcare professional
15. 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

Contacts and Locations

Locations

Australia, New South Wales

The Brain and Mind Centre / Scientia Clinical Research

Sydney, New South Wales, Australia, 2031

Australia, Queensland

Q-Pharm

Brisbane, Queensland, Australia

The Mater Hospital

Brisbane, Queensland, Australia

Australia, Victoria

The Alfred Hospital

Melbourne, Victoria, Australia

Australia, Western Australia

Perron Institute

Perth, Western Australia, Australia, 6009

Sponsors and Collaborators

Impel NeuroPharma Inc.

Investigators

• Study Chair: Stephen B Shrewsbury, MD; Impel NeuroPharma, Seattle, WA (USA)
• Principal Investigator: Terry O'Brien, MD/Prof; The Alfred Hospital, Melbourne, VIC (AUS)

More Information

• Responsible Party: Impel NeuroPharma Inc.
• ClinicalTrials.gov Identifier: NCT03541356
• Other Study ID Numbers: INP103-201
• First Posted: May 30, 2018
• Last Update Posted: June 18, 2019
• Last Verified: June 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Impel NeuroPharma Inc.:

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

Additional relevant MeSH terms:

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