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

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ClinicalTrials.gov Identifier: NCT03541356
Recruitment Status : Recruiting
First Posted : May 30, 2018
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Impel NeuroPharma Inc.

Tracking Information
First Submitted Date  ICMJE April 5, 2018
First Posted Date  ICMJE May 30, 2018
Last Update Posted Date March 26, 2019
Actual Study Start Date  ICMJE May 8, 2018
Estimated Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
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
Original Primary Outcome Measures  ICMJE
 (submitted: May 17, 2018)
Explore the safety and tolerability of single ascending doses of INP103 versus placebo [ Time Frame: 7 days ]
Assessment of safety and tolerability based on reported AE/SAE post-dosing with levodopa or placebo
Change History Complete list of historical versions of study NCT03541356 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
  • 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
  • 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)
  • 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)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2018)
  • Characterize the PK (AUC0-2h) of single ascending doses of INP103 [ Time Frame: 2 hours ]
    Area under the Plasma Concentration-time Curve for INP103
  • Characterize the PK (Cmax) of single ascending doses of INP103 [ Time Frame: 2 hours ]
    Maximum Observed Plasma Concentration for INP103
  • Characterize the PK (Tmax) of single ascending doses of INP103 [ Time Frame: 2 hours ]
    Time to Reach the Maximum Plasma Concentration (Cmax) of INP103
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Therapeutic Potential for Intranasal Levodopa in Parkinson's Disease -Off Reversal
Official Title  ICMJE 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
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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Parkinson's Disease
Intervention  ICMJE
  • Combination Product: Experimental: INP103
    Delivered via the I231 POD (Precision Olfactory Delivery) device with one puff to one nostril
    Other Name: L-dopa 35mg
  • Combination Product: Placebo
    Delivered via the I231 POD (Precision Olfactory Delivery) device with one puff to one nostril
    Other Name: Placebo 35mg
Study Arms  ICMJE
  • 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)
    Intervention: Combination Product: Experimental: INP103
  • Placebo Comparator: Placebo
    A single dose of placebo delivered via the I231 Precision Olfactory Device (POD)
    Intervention: Combination Product: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 15, 2019)
32
Original Estimated Enrollment  ICMJE
 (submitted: May 17, 2018)
24
Estimated Study Completion Date  ICMJE July 2019
Estimated Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jacki D Campbell 206-489-2471 jcampbell@impelnp.com
Contact: Meghan Swardstrom 206-489-2471 mswardstrom@impelnp.com
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03541356
Other Study ID Numbers  ICMJE INP103-201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Impel NeuroPharma Inc.
Study Sponsor  ICMJE Impel NeuroPharma Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Stephen B Shrewsbury, MD Impel NeuroPharma, Seattle, WA (USA)
Principal Investigator: Terry O'Brien, MD/Prof The Alfred Hospital, Melbourne, VIC (AUS)
PRS Account Impel NeuroPharma Inc.
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP