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Trial registered on ANZCTR


Registration number
ACTRN12618000427279
Ethics application status
Approved
Date submitted
12/03/2018
Date registered
26/03/2018
Date last updated
20/06/2019
Date data sharing statement initially provided
5/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Therapeutic potential for intranasal levodopa in Parkinson’s Disease – Off Reversal (THOR 201)
Scientific title
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
Secondary ID [1] 293252 0
None
Universal Trial Number (UTN)
Trial acronym
THOR201
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Parkinson's Disease 305302 0
Condition category
Condition code
Neurological 304607 304607 0 0
Parkinson's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase IIa randomized, double-blind, placebo controlled, single dose study to compare the safety, tolerability and PK/pharmacodynamic of intranasal L-dopa following administration of INP103 (L-dopa via I231 POD device ) to that of placebo participants (placebo via I231 POD device) in L-dopa Responsive PD patients in the presence of Decarboxylase Inhibitor during an OFF episode.

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 intranasally. Dosing will take place once OFF episode is confirmed and will not include predosing with oral benserazide.

Two hours post study dosing, participants will take their usual anti-OFF medication (e.g. Madopar rapid) if they have not returned to ON, and their usual morning dose of PD medications (e.g. their regular Madopar morning dose). Participants will remain under observation for another 2 hours before they can be allowed to leave (health status permitting). At various times during this 2 hour period, the subjects will have the following assessments to monitor safety: vital signs, ECG, physical exam, adverse event and dyskinesia checks.

Participants will visit the clinic on day 7 for a follow-up assessment which will include the following assessments: vital signs, ECG, physical exam, blood tests, adverse event and dyskinesia checks
Intervention code [1] 299515 0
Treatment: Drugs
Comparator / control treatment
The placebo consists of microcrystalline cellulose that will be delivered using the I231 POD device.
Control group
Placebo

Outcomes
Primary outcome [1] 303860 0
The primary outcome of this study is the safety and tolerability of POD L-dopa, including the assessment of physical examinations (including nasal inspection), electrocardiograms (ECGs), vital signs (including supine and standing blood pressure), clinical laboratory results, and adverse events (AEs; specifically, overall dyskinesia assessments).

As this is the first time that L-dopa will be delivered with the POD device, the potential risks and side effects are not known at this time.

The following side effects were reported by patients following use of L-dopa and benserazide in their usual medication, usually over a long period, or high dose, or both:
• Blood disorders (low levels of iron, low levels of while cells and low levels of platelets)
• Low appetite
• Disorders of mood (depression, agitation, anxiety)
• Trouble sleeping (insomnia)
• Hallucinations, delusions and disorientation
• Abnormal movements of the face and extremities
• Involuntary muscle movements or jerks
• Cardiac palpitations or other rhythm changes
• Sleepiness
• Muscle cramps
• Low muscle tone
• Low blood pressure when moving from sitting to standing
• Nausea, vomiting, diarrhoea and constipation have been reported.

Risks associated with exposure to L-dopa and carbidopa when administered orally:
• Involuntary muscle movements or jerks
• Abnormal movements of the face and extremities
• Blurred vision
• Hallucinations, confusion, delusions, disorientation and anxiety
• Depression with or without development of suicidal tendencies
• Trouble sleeping (insomnia), sleepiness and dream abnormalities
• Lack of energy
• Dizziness
• Dementia
• Nausea, vomiting, constipation, flatulence and weight disorders such as anorexia and swelling/weight gain
• Dry mouth, bitter taste, excessive drooling, difficulty swallowing and hiccups
• Abdominal pain, gastrointestinal bleeding and development of small intestine ulcers
• Dark urine, trouble urinating and urinary incontinence
• Increased sweating, itchy skin and skin rashes
• Cardiac palpitations or other rhythm changes
• Low blood pressure when moving from sitting to standing
• High blood pressure
• Inflammation of the blood vessels and blood disorders (breakdown of red blood cells, low levels of white cells and low levels of platelets)
• Trouble breathing and chest pain
• Pins and needles
• Rarely convulsions have occurred however it is not known if this was due to the L-dopa and carbidopa
Timepoint [1] 303860 0
For 4 hours following INP103/placebo dosing and over 7 days of Follow-up
Secondary outcome [1] 340302 0
PK profile of L-dopa for 120 minutes following dosing (AUC0-2h, Cmax and Tmax) assessed by serum analysis
Timepoint [1] 340302 0
Cohort 1-3: 30, 60, 90 and 120 mins following dosing with INP103/Placebo
Cohort 4: 5, 10, 15, 30, 45, 60, 90 and 120 mins following dosing with INP103/Placebo
Secondary outcome [2] 340303 0
Motor function, evaluated by MDS-UPDRS part III score
Timepoint [2] 340303 0
Cohort 1-3: 15, 30, 45, 60, 90 and 120mins post INP103/Placebo dose

Cohort 4: and 30, 60, 90 and 120 minutes for cohort 4.

Eligibility
Key inclusion criteria
1. Adult males and females, 40 to 80 years of age (inclusive) at the time of Screening (Visit 1)
2. Diagnosed with Idiopathic PD (per 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 (more than or equal to 30% improvement in MDS-UPDRS Part III Motor Examination score) as assessed during Screening
5. On a stable dose of L-dopa containing medication for at least 2 weeks prior to Visit 1 (up to 1200 mg per 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, but WILL take oral benserazide 25 mg on arrival at the research site (at 60 to 65 minutes before dosing with INP103 or placebo)
Subjects in Cohorts 1, 2 and 3 ONLY will take oral benserazide 25 mg 60 ± 5 minutes before Visit 3 dosing with INP103 or placebo)..
Cohorts 4 will OMIT oral benserazide and may dose subjects once OFF episode confirmed and all baseline assessments have been completed.
7. If female and of childbearing potential must agree to use adequate contraception 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
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Severe dyskinesia (defined as per MDS-UPDRS) during a ‘normal day’ that would significantly interfere with the participant’s ability to perform study assessments
2. In receipt of L-dopa containing medication at more than 1200 mg per 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 more than 50 mg per day, risperidone more than 1 mg per day or olanzipine more than 2.5 mg per day)
4. Mini Mental State Examination (MMSE) less than or equal to 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 participant will comply with or be able to complete the study requirements
10. Use of any medication likely to interact with INP103
11. Clinically significant laboratory test abnormalities at screening. Participants must have clinical laboratory values less than 2 SD below upper limit of normal (ULN) or more than 2 SD above the lower limit of normal AND considered of no clinical significance by the PI
12. History or presence of alcoholism or drug abuse within the 2 years prior to the first INP103 or placebo administration
13. Administration of an investigational product in another trial within 30 days or 5 half-lives (whichever is longer) prior to the first INP103 or placebo administration
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be provided by the holder of the allocation schedule once eligibility has been confirmed. The holder of the allocation schedule will be located centrally and independent of the study sites
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Thirty-two (32) subjects (8 per dose group) are considered sufficient for assessment of safety and tolerability of SADs of INP103. However, we are proposing that Cohort 4 may enrol an additional 4 patients (for a maximum of 12) under the same randomization scheme (3:1). With at least eight subjects per group, the study has 80% power to detect an improvement of 13 points from baseline in MDS-UPDRS Part III scores within each dose level, assuming a standard deviation of 11 points, using a two-sided significance level of 0.05. This study is not powered for between-group comparisons of the pharmacodynamic endpoints.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/04/2018
Actual
29/05/2018
Date of last participant enrolment
Anticipated
18/06/2019
Actual
4/06/2019
Date of last data collection
Anticipated
27/06/2019
Actual
11/06/2019
Sample size
Target
32
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
QLD,WA,VIC
Recruitment hospital [1] 9474 0
The Alfred - Prahran
Recruitment hospital [2] 9475 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment hospital [3] 13561 0
Scientia Clinical Research - Randwick
Recruitment hospital [4] 13562 0
The Western Australian Neuroscience Research Institute - Nedlands
Recruitment hospital [5] 13573 0
Mater Adult Hospital - South Brisbane
Recruitment postcode(s) [1] 18207 0
3004 - Prahran
Recruitment postcode(s) [2] 18208 0
4007 - Herston
Recruitment postcode(s) [3] 26206 0
2031 - Randwick
Recruitment postcode(s) [4] 26207 0
6009 - Nedlands
Recruitment postcode(s) [5] 26219 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 297883 0
Commercial sector/Industry
Name [1] 297883 0
Impel NeuroPharma Inc.
Country [1] 297883 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services (CNS) Pty Ltd
Address
Level 2, 381 MacArthur Ave,
HAMILTON QLD 4007
Country
Australia
Secondary sponsor category [1] 296932 0
Commercial sector/Industry
Name [1] 296932 0
Impel NeuroPharma Inc.
Address [1] 296932 0
201 Elliott Ave West, Suite 260
Seattle, Washington 98119
Country [1] 296932 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298931 0
Alfred Hospital Ethics Commitee
Ethics committee address [1] 298931 0
89 Commercial Road
Melbourne
VIC 3004
Ethics committee country [1] 298931 0
Australia
Date submitted for ethics approval [1] 298931 0
11/12/2017
Approval date [1] 298931 0
28/02/2018
Ethics approval number [1] 298931 0
5/18
Ethics committee name [2] 299144 0
Bellberry Limited
Ethics committee address [2] 299144 0
129 Glen Osmond Road
Eastwood South
Australia 5063
Ethics committee country [2] 299144 0
Australia
Date submitted for ethics approval [2] 299144 0
06/12/2017
Approval date [2] 299144 0
29/01/2018
Ethics approval number [2] 299144 0
2017-11-894

Summary
Brief summary
This research project is designed to test the safety, tolerability, the effect on movement and pharmacokinetics (how the body processes the study drug) of INP103. INP103 is a drug-device combination product; the drug is L-dopa (levo-dopamine); the device is the I231 Precision Olfactory Delivery (POD) device, which is a novel nasal (nose) spray.

This study will measure the results of administration of L-dopa given by the intra-nasal POD device, against the effect of placebo, also given by the intra-nasal POD device. Participants will be given either L-dopa or placebo to determine how effective the new POD device is at delivering the drug to the body.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78694 0
Prof Terry O'Brien
Address 78694 0
The Alfred Hospital,
55 Commercial Road
Melbourne 3004 VIC
Country 78694 0
Australia
Phone 78694 0
+ 61 3 8344 5490
Fax 78694 0
Email 78694 0
[email protected]
Contact person for public queries
Name 78695 0
Stephen Shrewsbury
Address 78695 0
Impel NeuroPharma
201 Elliott Avenue W, Suite 260
Seattle WA 98119
Country 78695 0
United States of America
Phone 78695 0
+1 2065681466
Fax 78695 0
Email 78695 0
[email protected]
Contact person for scientific queries
Name 78696 0
Stephen Shrewsbury
Address 78696 0
Impel NeuroPharma
201 Elliott Avenue W, Suite 260
Seattle WA 98119
Country 78696 0
United States of America
Phone 78696 0
+1 2065681466
Fax 78696 0
Email 78696 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All publications and data analysis from the INP103-201 study would be generated by and delivered to Impel. However we would expect the PI to review and sign off both.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.