| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Levodopa Responsive Patients with Parkinson’s Disease Complicated by Motor Fluctuations ("OFF episodes") |
|
| E.1.1.1 | Medical condition in easily understood language |
| Central nervous system disease affecting the movement |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034006 |
| E.1.2 | Term | Parkinson's disease aggravated |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to demonstrate the efficacy of sublingual (sl) APL-130277 compared to subcutaneous (sc) apomorphine as a treatment of "OFF" episodes in subjects with Parkinson's Disease (PD) as measured by the change from pre-dose to 90 minutes post-dose in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to demonstrate the efficacy of sublingual (sl) APL-130277 compared to subcutaneous (sc) apomorphine as a treatment of "OFF" episodes in subjects with Parkinson's Disease (PD) as measured by:
• Durability of effect, defined as Investigator confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose;
• Subject preference for APL-130277 treatment (either somewhat or definately prefer APL) as recorded for question 9 of the TPQ. This assessment is scheduled to be performed after the subject has completed both APL-130277 and sc apomorphine treatment regimens;
• Subject confirmed durability of effect, defined as subject confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose;
• Patient Global Impression of Change of "OFF" episodes (PGI-C). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Optional Pharmacokinetic (PK) evaluation : Blood draws for APL-130277 and s.c. apomorphine PK analyses will occur during PART B at V2, V3, V5, and V6 at selected sites (dependent on feasibility). Blood draws will occur at t = 0 (just prior to dosing) and at t = 10, 20, 30, 60, 90, 120, 180 and 240 minutes post-dose. Sampling should occur as close as possible to the target time. Subjects must consent in order to participate in optional PK sub-study |
|
| E.3 | Principal inclusion criteria |
1 The subject (and caregiver, if applicable) must be fully informed of and understand the objectives, procedures, and possible benefits and risks of the study, and give written informed consent prior to performing any study-related activities.
2 Male or female ≥ 18 years of age.
3 Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank
Criteria (excluding the "more than one affected relative" criterion).
4 Clinically meaningful response to levodopa (L-Dopa), as determined by
the Investigator.
5 Subjects at Screening must demonstrate an adequate L-Dopa response on the MDS-UPDRS Part III in the "ON" state compared to the MDSUPDRS Part III in the "OFF" state and on the Hoehn and Yahr, as
determined during the review by Enrollment Adjudication Committee
(EAC), Sponsor, and Medical Monitor.
6 Receiving stable doses of L-Dopa/carbidopa and/or LDopa/
benserazide and/or L Dopa/carbidopa/entacapone (immediate or chronic release) administered at least 4 times per day OR Rytary™ administered at least 3 times per day for at least 4 weeks before the
initial Screening Visit (SV1). Adjunctive PD medication regimens are
permitted but must be maintained at a stable dose for at least 4 weeks
prior to SV1 with the exception of monoamine oxidase B (MAO-B)
inhibitors, which must be maintained at a stable level for at least 8
weeks prior to SV1. Use of Madopar PRN in the 4 weeks prior to
screening is permitted.
7 No planned medication change(s) or surgical intervention anticipated
during the course of study.
8 Subjects must experience at least one well defined "OFF" episode per
day and have a total daily "OFF" time duration of > 2 hours during the
waking day, based on judgment of physician and subject self assessment.
9 Subject must have predictable morning "OFF" periods, based on
judgment of physician and subject self-assessment.
10 Subject, and where appropriate caregiver, must be trained in
completing the home dosing diaries and able to recognize "ON" and
"OFF" states.
11 Stage III or less on the modified Hoehn and Yahr scale in the "ON"
state.
12 Mini–Mental State Examination (MMSE) score > 25.
13 Female subject of childbearing potential and male subject with
female partner of childbearing potential must agree to either remain
abstinent or use adequate and reliable contraception (see Section 10.4.1
for additional information on acceptable methods of birth control)
throughout the study and for at least 7 days after the last dose of study
drug has been taken. Note: Continued use of adequate and reliable
contraception is recommended through 30 days after study completion.
14 Willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study-related procedures to complete the
study.
15 Must be approved as a satisfactory candidate by the Enrollment
Adjudication Committee (EAC), Medical Monitor, and Sponsor. |
|
| E.4 | Principal exclusion criteria |
1 Atypical or secondary parkinsonism.
2 Major focal brain disorders including malignancy or stroke.
3 Prior treatment with any of the following: a neurosurgical procedure
for PD; continuous subcutaneous (sc) apomorphine infusion; sc
apomorphine injection; Duodopa/Duopa; or APL-130277.
4. Subjects who have permanently stopped use of s.c. apomorphine (injection).
5 Contraindications to domperidone, subcutaneous apomorphine, or
hypersensitivity to apomorphine hydrochloride or any of the ingredients
of subcutaneous apomorphine (notably sodium metabisulfite).
6 Female who is pregnant or lactating.
7 Participation in an interventional clinical study and/or receipt of any
investigational (ie, unapproved) medication within 30 days prior to SV1.
8 Currently taking selective 5HT3 antagonists (ie, ondansetron,
granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists
(excluding quetiapine or clozapine) or dopamine depleting agents.
Subjects receiving anti-depressants must be on a stable daily dose for at
least 8 weeks prior to SV1.
9 current diagnosis or history of substance abuse (excluding nicotine
and caffeine) or alcohol abuse (in the opinion of the investigator) < 6
months prior to SV1.
10 positive urine drug screen result. NOTE: Benzodiazepines, opiates, and
oxycodone will be allowed provided the subject has been on a stable
dose for 4 weeks prior to SV1, provided the subject has a valid
prescription. Cotinine is not exclusionary.
11 The recreational use of cannabinoids and hallucinogenic(including
formulations of CBD) and hallucinogenics are excluded, as well any use
of a sublingual formulation of any drug.
12 history of malignancy within 5 years prior to SV1, except for
adequately treated basal cell or squamous cell skin cancer or in situ
cervical cancer.
13 clinically significant abnormality on screening evaluation including
physical examination, vital signs, electrocardiogram (ECG), or laboratory
tests that the Investigator considers to be inappropriate to allow
participation in the study.
14 screening laboratory test results of: BUN value ≥ 1.5 times the upper
limit of normal (ULN) for the reference range; serum creatinine > 1.5
times the ULN for the reference range; or ALT or AST value ≥ 2 times the
ULN for the reference laboratory.
15 random (non-fasting) screening glucose of ≥ 200 mg/dL (11.1
mmol/L) or HbA1c > 7.0%.
16 Subjects with type 1 diabetes, or insulin-dependent diabetics are
excluded. Subjects with type 2 diabetes are eligible for study inclusion if
the following conditions are met:
• Subject's screening glucose is < 200 mg/dL (11.1 mmol/L). Note:
Subjects with random (non-fasting) blood glucose at screening ≥ 200
mg/dL (11.1 mmol/L) must be retested in a fasted state; and
• Subject's HbA1c ≤ 7.0%; and
• If the subject is currently being treated with oral anti-diabetic
medication(s), the dose must have been stable for at least 4 weeks prior
to SV1. Such medication may be adjusted or discontinued during the
study, as clinically indicated.
17 The subject's screening ECG results of corrected QT interval using
Fridericia's formula (QTcF) ≥ 450 msec for male subjects or ≥ 470 msec
for female subjects. Eligibility will be based on the core laboratory ECG
interpretation report.
18 positive screening laboratory test result for HIV.
19 positive screening laboratory test result for hepatitis B surface
antigen or hepatitis C antibodies and has liver function test results at
screening above the ULN for the reference laboratory.
20 any other medical disorder that, in the opinion of the Investigator,
could interfere with the subject's participation in the study.
21 major psychiatric disorder(s), including but not limited to: bipolar
disorder, psychosis (eg, Parkinson's Disease Psychosis), major
depressive episode, or any disorder that, in the opinion of the
Investigator, would require treatment that could make study
participation unsafe or make treatment compliance difficult.
22 History of clinically significant impulse control disorder(s).
23 History of symptomatic orthostatic hypotension requiring medication.
24 History of severe dyskinesia based on a score of 4 on the MDS-UPDRS
Part IV. for either "time spent with dyskinesia" OR "the functional
impact of dyskinesia"
25 Current/recent suicidal ideation as evidenced by answering "yes" to
"Suicidal Ideation" item 4 (active suicidal ideation with some intent to
act, without specific plan) or item 5 (active suicidal ideation with specific
plan and intent) on the C-SSRS assessment at Screening (using the
"Screening/Baseline Version" scale, in the past 12 months) or attempted
suicide within the last 5 years.
26 Presence of canker or mouth sores in the 30 days prior to SV1, or
other clinically significant oral pathology in the opinion of the
Investigator. The Investigator should follow-up with an appropriate
specialist on any finding, if indicated, before enrolling a subject into the
study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the change from pre-dose to 90 minutes post-dose in MDS-UPDRS Part III score after 4 weeks of dosing in each crossover period (assessed by the blinded-rater in-clinic at V3 and V6 of PART B). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The change from pre-dose to 90 minutes post-dose in MDS-UPDRS Part III score after 4 weeks of dosing in each crossover period (assessed by the blinded-rater in-clinic at V3 and V6 of PART B). |
|
| E.5.2 | Secondary end point(s) |
1 Durability of effect, defined as an Investigator confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed by the blinded-rater inclinic at V3 and V6 of PART B).
2 Subject preference for APL- 130277 treatment (either somewhat or definitely prefer APL-130277) after the subject has completed both APL-130277 and sc apomorphine treatment regimens (assessed inclinic at V6 of PART B).
3 Subject confirmed durability of effect, defined as subject confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed in-clinic at V3 and V6 of PART B).
4 Patient Global Impression of Change (PGI-C): Subject improvement of "OFF" episodes, defined as very much better, much better or a little better after 4 weeks of dosing in each crossover period (assessed inclinic at V3 and V6 of PART B).
Other Efficacy Endpoints (PART B):
Other efficacy variables will include analysis of: Clinical Global Impression of Improvement (CGI-I), MDS-UPDRS – Parts I, II, III and IV Score, Time to Full and Partial "ON", Expanded Home Dosing Diaries including percent of "ON" episodes without troublesome dyskinesia based on the 3 consecutive days prior to V2, V3, V5, and V6, dyskinesia questionnaire, Parkinson's Disease Questionnaire-39 (PDQ-39) Total Index Score and subscale scores, and European Quality of Life – 5 Dimensions (EQ-5D-5L)., and Ease of Use of questionnaire. Methodology concerning the analysis of these variables will be provided in the Statistical Analysis Plan (SAP).
Safety Endpoints:
Evaluation of safety and tolerability of APL-130277 compared to sc apomorphine as measured by AEs, physical examination including assessment of oropharyngeal AEs and injection-site related AEs, 12-lead ECGs, vital signs including OH, clinical laboratory tests, and C-SSRS and QUIP-RS assessments.
Pharmacokinetic Endpoints:
Pharmacokinetic concentration-time data for apomorphine and metabolites (apomorphine sulfate, norapomorphine, and others as deemed necessary) will be evaluated and PK parameters (including but not limited to Cmax, tmax, AUCt, parent-to-metabolite ratios of Cmax and AUCt) will be estimated by noncompartmental methods from plasma samples using actual elapsed time from dosing. Details and methodology concerning the analysis of these variables will be provided in a separate PK analysis plan. A separate and stand‑alone PK report will be provided. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Ease of use and Tolerability |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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