| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10034005 |
| E.1.2 | Term | Parkinson's disease and parkinsonism |
| 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 assess the efficacy, safety and tolerability of Accordion Pill carbidopa/levodopa (AP-CD/LD) compared to Immediate Release carbidopa/levodopa (IR-CD/LD) in fluctuating Parkinson's Disease patients. |
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| E.2.2 | Secondary objectives of the trial |
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| 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 |
Gastroscopy Sub-Study:
The gastroscopy sub-study is designed to evaluate the effect of the Accordion Pill on the gastric mucosa and to establish the long-term Accordion Pill safety and tolerability. |
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| E.3 | Principal inclusion criteria |
General Study Inclusion Criteria:
1. Subjects must be approved for suitability by an Enrollment Approval Committee that is assembled of PD clinical experts
2. Able and willing to give written (signed and dated) informed consent, which includes compliance with study requirements and restrictions prior to admission to the study and adhere to visit schedule and available to complete the study
3. Men or women 30 years of age and higher at initial screening assessment. For the 100 subjects who enter the Gastroscopy sub-study, the age limits are 30-80 years of age, inclusive, at initial screening assessment.
4. Diagnosed with Parkinson's disease, consistent with UK brain bank criteria
5. Has a good response to levodopa and is taking at least 4 doses of a levodopa containing medication (or 3 doses of Rytary) per day during waking hours (not including nighttime long acting levodopa) at a stable dose for at least 28 days prior to initial screening assessment
6. Other Anti-PD treatment (such as dopamine agonists, selective MAOB inhibitors, anticholinergic agents or amantadine) are permitted if stable for at least 28 days prior to study entry and provided they are not anticipated to be changed during the course of the study
7. Total LD immediate release daily dose of 400mg to 1300 mg or equivalent prior to initial screening assessment. Specifically, for Rytary, doses up to 1755 mg daily are acceptable
8. Able to complete a Hauser Home Diary and can tell the difference between "On" and "Off" time
a. Achieved at least 75% diary concordance with an approved site rater in a 4-hour training session including at least one "Off time" assessment
b. Returned a valid 2-day practice diary after training has been completed. A valid diary record will not have more than 4 invalid entries (i.e. double or missed entries)
9. At least 2.5 hours "Off time" per day during waking hours on Screening 2-Day practice Hauser Home Diary, (morning akinesia should be incorporated into the total "Off time" assessment)
10. Other than PD, the subject is in satisfactory health, as assessed by physical examination and screening tests. No clinically significant medical, psychiatric or laboratory abnormality that could compromise safety or interfere with study procedures in the opinion of either the investigator or the Enrollment Approval Committee/Sponsor.
11. Living in an area that is within 3 hours driving distance from the study site or is willing to stay in such a place the night before each study visit.
Gastroscopy sub-study inclusion criteria:
Subjects entering the study in the period when gastroscopy examinations are required will have to comply with the following additional requirements:
1. Men or women between 30 and 80 years of age, inclusive, at initial screening assessment
2. Willingness to undergo two gastroscopies during the study period and to sign a separate informed consent form
3. No contraindications for sedation / anesthesia |
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| E.4 | Principal exclusion criteria |
General Study Exclusion criteria:
1. Participation in another drug clinical trial within 28 days prior to initial screening assessment (calculated from the previous study's last dosing date)
2. Atypical Parkinsonism (subjects with Parkinsonian features caused by disorder such as multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies or multiple brain infarcts)
3. Clinically significant cardiac, pulmonary, hepatic or renal disease or other condition which contraindicates his/her participation in the opinion of either the investigator or the Enrollment Approval Committee/Sponsor.
4. Severe dyskinesia in the opinion of either the investigator or the Enrollment Approval Committee
5. Treatment with non-selective monoamine oxidase (MAO) inhibitors during the last 28 days prior to initial screening assessment or planning to take during study participation
6. Previous or planned neurosurgical treatment for Parkinson's Disease (e.g., procedures including ablation or deep brain stimulation) during the course of the study
7. Significant cognitive impairment as defined by the Mini-Mental State Examination (MMSE) score <26
8. Clinically significant psychiatric illness, including major depression (Hamilton Depression Rating Scale-17 ≥14). Subjects with a lifetime history of suicidal attempt (including an active attempt, interrupted attempt or aborted attempt)
9. Current or previous treatment for more than 28 days within the past 2 years with any neuroleptic drug (antipsychotic) or any other drug with anti-dopaminergic properties (e.g. metoclopramide, domperidone).
10. Currently experiencing or any known history of psychosis or delusions within 2 years prior to Screening.
11. Known history of substance abuse within the past 2 years
12. Moderate or greater level of alcohol consumption
13. Unable to swallow large pills (e.g., large vitamin pills)
14. History of Melanoma or suspicious skin lesion which could be a Melanoma
15. Narrow-angle Glaucoma
16. History of small bowel or gastric surgery (Including PEG-J placement for Duopa/Duodopa) or bowel obstruction, diagnosis of small bowel narrowing, diagnosis of Crohn's disease, or frequent nausea or emesis, regardless of etiology. (Previous appendectomy or hernioplasty will not be exclusionary.
17. Active peptic ulcer disease or a history of peptic ulcer or upper GI bleeding
18. Regular use of opioids (Intermittent opioid use is not exclusionary)
19. Symptomatic gastroparesis with frequent vomiting (at least once a week)
20. Concomitant use of NSAIDs and oral steroids within the past 28 days
21. Allergy to the study drug or any of its excipients, or to Yellow Dye #5 (tartrazine)
22. Women who are pregnant or nursing. Women of childbearing potential who are not willing to use a medically acceptable method of contraception. Medically acceptable methods of contraception that may
be used by the subject and /or partner include: True abstinence when this is in line with the preferred and usual lifestyle of the subject, oral contraceptive agents, intrauterine devices (IUDs), implantable contraceptives (e.g., Norplant), transdermal hormonal contraceptives (e.g., Ortho-Evra), and injectable contraceptives (e.g., Depo-Provera),
condom and /or diaphragm, diaphragm with vaginal spermicide, surgical sterilization (6 months), or postmenopausal females ( no menstrual period for > 2years) or vasectomy ( > 6 months). The current contraceptive therapy must be maintained through the end of the study (End of study visit or final follow-up phone visit, whichever is later).
Hormonal contraceptive therapy must be a stable dose for at least 90 days prior to first study drug administration.
Gastroscopy sub-study exclusion criteria:
Subjects who meet the exclusion criterion listed below will not be eligible for the study during the period of the safety sub-study:
1. Current treatment with drugs known to induce gastric ulcers such as regular use of NSAIDs, use of aspirin (ASA) at a dose higher than 100 mg per day, iron supplements >30mg/day, or treatment with any of these drugs above the specified doses/ regular use of NSAIDs within the 28 days prior to initial Screening assessment. (Intermittent use of NSAIDs is not exclusionary).
2. Any clinically significant, abnormal gastric mucosal initial gastroscopic finding of an erosion, ulcer (of any size) or tumor, as per independent gastroenterologist's review |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this study is the change from Baseline to EOS in the percentage of daily "Off time" during waking hours based on Hauser Home Diary assessments. Total number of "Off" hours normalized to 16-hour waking day will also be calculated but only a single p-value applicable to both the percentage and hours will be reported. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Change from Baseline to EOS in "On time" without troublesome dyskinesia during waking hours
2. Change from Baseline to EOS in the number of daily Levodopa doses
3. CGI-I at EOS as recorded by physician
4. CGI-I at EOS as recorded by patient
5. Change from Baseline in total UPDRS Score (Sum of Parts I-III)
6. Change from Baseline to EOS in UPDRS Part II (Activities of Daily Living)
7. Change from Baseline to EOS in UPDRS Motor Examination (part III - evaluated 2-3 hours after last LD dose)
8. Change from Baseline to EOS in PDQ-39 summary index
9. Change from Baseline to EOS in troublesome dyskinesia
10. Change from Baseline to EOS in "On time" without dyskinesia during waking hours. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Immediate Release Carbidopa/Levodopa comparator |
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| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 68 |
| 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 |
| Bulgaria |
| Germany |
| Hungary |
| Israel |
| Italy |
| Poland |
| Slovakia |
| Spain |
| Ukraine |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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