| 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)
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| E.1.1.1 | Medical condition in easily understood language |
Central nervous system disease affecting the movement
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| 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 | 19.0 |
| 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 |
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| 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 |
| To evaluate the efficacy and safety of APL-130277 versus placebo in patients with Parkinson's disease over a 12 week period. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age.
2. Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria.
3. Clinically meaningful response to Levodopa (L-Dopa) with well defined early morning “OFF” episodes, as determined by the Investigator.
4. Receiving stable doses of L-Dopa/carbidopa (immediate or chronic
release [CR]) administered at least 4 times per day OR Rytary™ administered 3 times per day, for at least 4 weeks before the initial screening visit (SV1). Adjunctive PD medication regimens must be maintained at a stable dose for at least 4 weeks prior to the initial Screening Visit (SV1) with the exception that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks prior to the initial screening visit (SV1).
5. No planned medication change(s) or surgical intervention anticipated during the course of study.
6. Patients must experience at least one well defined “OFF” episode per day with a total daily “OFF” time duration of ≥ 2 hours during the waking day, based on patient self-assessment.
7. Patient and/or caregiver must be trained in performing home dosing diary assessments of the motor state and must be able to recognize “ON” and “OFF” state.
8. Stage III or less on the modified Hoehn and Yahr scale in the “ON” state.
9. Mini–Mental State Examination (MMSE) score > 25.
10. If female and of childbearing potential, must agree to use one of the
following methods of birth control:
• Oral contraceptive;
• Contraceptive patch;
• Barrier (diaphragm, sponge or condom) plus spermicidal preparations;
• Intrauterine contraceptive system;
• Levonorgestrel implant;
• Medroxyprogesterone acetate contraceptive injection;
• Complete abstinence from sexual intercourse;
• Hormonal vaginal contraceptive ring; or
• Surgical sterilization or partner sterile (must have documented proof).
11. Male subjects must be either surgically sterile, agree to be sexually
abstinent or use a barrier method of birth control (e.g., condom) from
first study drug administration until 30 days after final drug administration.
12. Willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study-related procedures to complete the
study.
13. Able to understand the consent form, and to provide written informed consent.
14. Must be approved as a satisfactory candidate by an enrollment
adjudication committee (EAC)."
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| E.4 | Principal exclusion criteria |
1. Atypical or secondary parkinsonism.
2. Previous treatment with any of the following: a neurosurgical procedure for PD; continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa.
3. Treatment with any form of s.c. apomorphine within 7 days prior to the initial Screening Visit (SV1). Patients that stopped s.c. apomorphine for any reason other than systemic safety concerns or lack of efficacy may be considered.
4. Contraindications to APOKYN®, or hypersensitivity to apomorphine
hydrochloride or any of the ingredients of APOKYN® (notably sodium metabisulfite); Tigan® (trimethobenzamide hydrochloride; patients from US sites only); or domperidone (patients from non-US sites only).
5. Female who is pregnant or lactating.
6. Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1).
7. Receipt of any investigational (i.e., unapproved) medication within 30 days prior to the initial Screening Visit (SV1).
8. Currently taking selective 5HT3 antagonists (i.e., ondansetron,
granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (excluding quetiapine and clozapine) or dopamine depleting agents.
9. Drug or alcohol dependency in the past 12 months.
10. History of malignant melanoma.
11. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.
12. Major psychiatric disorder including, but not limited to, dementia,
bipolar disorder, psychosis, or any disorder that, in the opinion of the
Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.
13. History of clinically significant hallucinations during the past 6 months.
14. History of clinically significant impulse control disorder(s).
15. Dementia that precludes providing informed consent or would interfere with participation in the study.
16. Current suicidal ideation within one year prior to the second Screening Visit (SV2) as evidenced by answering “yes” to Questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 5 years.
17. Donation of blood or plasma in the 30 days prior to first dosing.
18. Cankers or mouth sores within 30 days prior to the initial Screening Visit (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 patient into the study."
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS-UPDRS MOTOR) score at 30 minutes after dosing at the 12 week visit (MV4) of the Maintenance Treatment Phase.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
MDS-UPDRS: Screening visit 2, Titration Visit 1(TV1, Day 1) ), TV2 (Day 4), TV3 (Day 7), TV4 (Day 10), TV5 (Day 13), TV6 (Day 16), Maintenance visit (MV 1, Day 23), MV 2 (Day 51) MV 3 (Day 79), MV 4 (Day 100)
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| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint
1. Percentage of patients with a patient-rated full “ON” response within 30 minutes at the 12 week visit (MV4) of the Maintenance Treatment Phase.
Other Secondary Endpoints
1. The percentage of instances where a full “ON” response was achieved at 30 minutes after self-administration of study medication based on the home dosing diary entries.
2. Change from pre-dose in MDS-UPDRS MOTOR score at 15 minutes at the 12 week visit (MV4) of the Maintenance Treatment Phase.
3. Time (in minutes) to when study medication is starting to have an effect.
4. Percent of patients with a patient-rated full “ON” response within 30 minutes, whose duration from time when study medication begins to have an effect until their “OFF” (if applicable) lasts for at least 30 minutes at the 12 week visit (MV4) of the Maintenance Treatment Phase.
5. CGI-I post dosing.
6. PGI-I post dosing.
7. PDQ-39.
8. MDS-UPDRS – Part II: Motor Aspects of Experiences of Daily Living.
9. Evaluation of safety and tolerability data collected, including 12-lead ECGs, OH, oropharyngeal and dopaminergic AEs.
Other Patient-Reported Secondary Endpoints
1. Change in sleep measures on the ESS.
2. EQ-5D."
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CGI, PGI: Day 23, Day 51, Day 79, Day 100, Day 107.
PDQ-39: Screening visit 2 (SV2), Day 23, Day 51, Day 79, Day 100, Daya107.
MDS-UPDRS: SC2 and Day 100
ECG: SV2, Day 1, Day 44, Day 7, Day 10, Day 13, Day 16, Day 23, Day 51, Day 79, Day 100, Day 107
Vital signs: SV2, Day 1, Day 44, Day 7, Day 10, Day 13, Day 16, Day 23, Day 51, Day 79, Day 100, Day 107, and also in dose adjustment visit
Adverse events: Continuous monitoring starting from Screening visit 2 to Day -4, Day1, Day 4, Day 7, Day 10, Day 13, Day 16, Day 23, Day 37, Day 51, Day 55, Day 79, Day 93, Day 100, Day 107 and dose adjustment visit.
EQ-5D: SV2, Day 23, Day 51, Day 79, day 100 and day 107"
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| 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 | No |
| 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 |
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| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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