Therapeutic Potential for Intranasal Levodopa in Parkinson's Disease -Off Reversal
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: Placebo; L-dopa 35 mg; L-dopa 70mg; L-dopa 140 mg; L-dopa 70mg/carbidopa 7mg
Intervention description: Delivered via the I231 POD (Precision Olfactory Delivery) device; Delivered via the I231 POD (Precision Olfactory Delivery) device via one puff to one nostril; Delivered via the I231 POD (Precision Olfactory Delivery) device with two puffs, one to each nostril; Delivered via the I231 POD (Precision Olfactory Delivery) device with four puffs, two to each nostril; Delivered via the I231 POD (Precision Olfactory Delivery) device with two puffs, one to each nostril
Intervention MeSH terms: Carbidopa; Levodopa; Dihydroxyphenylalanine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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
Enrollment: 32.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Parkinsons; L-dopa; levodopa; ON; OFF; PD; POD device; I231; benserazide; Precision olfactory delivery; MDS-UPDRS; Carbidopa; DCI; Decarboxylase Inhibitor

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
    

Eligibility 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