| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unpredictable motor fluctuation or “On-Off” or “Wearing-Off” Effects Fluctuating associated with Idiopathic Parkinson’s Disease |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 11 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067209 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To identify optimal doses of Apomorphine inhalation powder for future evaluation in controlling the “on-off” and “wearing-off” effects associated with fluctuating idiopathic PD.
In-clinic objectives: To determine efficacy as determined by Unified Parkinson’s Disease Rating, Part 3 (UPDRS III) assessments and safety/tolerability profile as assessed by the incidence and severity of spontaneously reported AEs, vital signs (orthostatic challenge), ECGs, lung function, laboratory measurements, and physical examinations.
At-home objectives: To determine efficacy as determined by patient Diary Card data and the safety/tolerability profile as assessed by the incidence and severity of spontaneously reported AEs.
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| E.2.2 | Secondary objectives of the trial |
| Device objectives: To determine the extent of patient acceptance of the Aspirair® inhaler as measured by the Patient Acceptability Questionnaire and to verify the ability of patients with PD to use the Aspirair® inhaler as measured by the need for retraining. To verify the suitability of the Aspirair® inhaler for use at home by the patient or the carer. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Male and female patients between 30 and 90 years of age with a clinical diagnosis of PD for at least 5 years duration.
2 Provides voluntary written informed consent.
3 Is willing and able to comply with study procedures.
4 Fulfils Steps 1 and 2 of the UK Brain Bank Criteria.
5 Classifies as Hoehn and Yahr Stage II-IV in an “on” state.
6 Experiences motor fluctuations with recognisable “off” periods in control of motor symptoms, as assessed by the Motor Fluctuation Questionnaire. Patients should reliably recognise their "off" symptoms and should report at least 1 “Yes” response to the questions.
7 Suffers motor fluctuations associated with fluctuating idiopathic PD, and a minimum of a 2-hour average daily “off” time
8 Has received optimised oral therapy (as documented by the modified FLASQ-PD), including Levodopa not greater than 1500 mg/day (in combination with decarboxylase inhibitors) for at least the 30 days before Screening. For patients receiving controlled-release (CR) formulations, the dose limit is based on a 70% bioavailability adjustment (ie, 2143 mg CR = 1500 mg non-CR).
9 Has received for at least the 30 days prior to Screening, or has received in the past but discontinued due to AEs, at least 1 of the following types of medications: DA (eg, cabergoline), COMT inhibitor (eg, entacapone), or monoamine oxidase B inhibitor (eg, selegiline).
10 Shows dopaminergic responsiveness as defined by ≥30% change (reduction) in UPDRS III score compared to the pre-dose value.
11 Uses adequate contraceptive measures. If sexually active and the female is of childbearing potential, the patient (and his/her partner) should use adequate contraceptive measures, consisting of 2 forms of contraception, at least 1 of which must be a barrier method (eg, male partner uses condoms, plus female partner uses diaphragm and spermicidal gel, or cervical cap and spermicidal gel, or intrauterine device, or oral contraceptive pill) used successfully and reliably for at least 3 months prior to Screening.
12 Understands (with carer assistance) his/her daily PD medications.
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| E.4 | Principal exclusion criteria |
1 Participation in a trial with an investigational medicinal product within 3 months prior to Screening.
2 Serious uncontrolled disease, including serious psychological disorders likely to interfere with the study and/or likely to cause death within 6 months of the study completion.
3 Previous intolerance to apomorphine.
4 Previous significant complication from oral dopamine agonist therapy including hospitalisation following DA introduction and/or the development of hallucinations or other adverse neuropsychiatric features. Specific severe mental side effects include compulsive behaviour, psychosis, or hallucination that led to withdrawal of oral DA therapy.
5 Women during the lactation period or pregnancy.
6 Known human immunodeficiency virus or active chronic hepatitis B or C infection.
7 Patients with the following abnormal Screening laboratory values: Haemoglobin < 100 g/L; Absolute neutrophil count < 1.2 x109/L or > 10.0 x109/L; Platelets < 100 x109/L or > 600 x109/L; Sodium < 130 mmol/L or > 150 mmol/L; Potassium < 3.1 mmol/L or > 5.6 mmol/L; ALT and/or AST > 3 x upper limit of normal
8 Any other clinically significant abnormality following review of Screening laboratory data, previous medical history/intercurrent illness, and full physical examination, which may compromise the safety of the patient in the study.
9 In the investigator’s opinion, the patient is unsuitable for the study for any reason.
10 ECG abnormalities that, in the opinion of the investigator, would preclude study entry, including significant QTc prolongation at Screening and/or baseline, i.e. QTc > 450 ms for males or QTc > 470 ms for females, or any clinically significant atrial or ventricular arrhythmias that may impact the safety of the subject or the conduct of the study as judged by the investigator.
11 FEV1 ≤65% predicted.
12 A postural decrease in systolic BP of ≥20 mmHg and/or showing significant clinical symptoms associated with orthostatic hypotension.
13 Persistent arterial hypotension, with average systolic readings of ≤110 mmHg.
14 Persistent elevation of BP, with average systolic readings of ≥160 mmHg or average diastolic readings of ≥100 mmHg.
15 Taking prohibited concomitant medications
16 Consumption of anabolic steroids or antipsychotics. Administration of the following low-dose atypical antipsychotics is permitted:
- Quetiapine (up to and including 50 mg per day)
- Risperidone (up to and including 1 mg per day)
- Olanzipine (up to and including 2.5 mg per day)
17 Consumption of the 5HT3 antagonist class including ondansetron, granisetron, dolasetron, palonosetron, and alosetron.
18 Consumption of clozapine.
19 Consumption of any medication known to prolong QTc interval, unless the investigator considers the risk of avoiding such medication to significantly outweigh the risk of taking them.
20 Existing cancer and those in remission for less than 5 years.
21 Evidence, as ascertained from examination, tests, or history, to indicate cardiovascular, gastrointestinal tract, liver, kidneys, central nervous system, pulmonary system, or bone marrow disorders that, in the investigator’s opinion, compromises patient safety - specifically including renal and hepatic impairment/drug clearance issues.
22 Known non-responders to apomorphine treatment for “off” episodes, eg, in previous challenge tests or trials.
23 History of drug or alcohol abuse in the 12 months prior to study entry.
24 A history of clinically significant allergies to apomorphine inhalation powder formulation constituents (including lactose, magnesium stearate, and opioids) or domperidone (or equivalent anti-emetic).
25 Patients with, or a history of, hypersensitivity to domperidone, pituitary tumour(prolactinoma), or gastrointestinal blockage or haemorrhage.
26 Signs or symptoms suggestive of psychosis and/or cognitive disturbance (unless temporary, eg, in relation to an intercurrent illness, and resolving at least 3 months before study entry), dementia, “Parkinson-plus” syndromes, or unstable systemic disease.
27 History of stroke, seizure, or other neurological conditions.
28 Patients with dyskinesias rated ≥2 in Item 32 of the UPDRS IV assessment (dyskinesias present for ≥26% of a waking day) and ≥2 in Item 33 of the UPDRS IV assessment (dyskinesias are moderately, severely, or completely disabling) at Screening. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary Efficacy Endpoints: Change in “off” time per day compared with baseline, derived from patient diary information prior to Visit 1 and prior to Visits 5 and 6 during the At-Home Dosing Period and maximum change in total Unified Parkinson’s Disease Rating Scale, Part 3 score from pre-dose to post-dose during the clinic visits.
Primary Safety Endpoints: AEs, Clinical laboratory evaluations, Vital signs, FVC and FEV1, ECGs. |
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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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | Information not present in EudraCT |
| 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
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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