Unpredictable motor fluctuation or “On-Off” or “Wearing-Off” Effects Fluctuating associated with Idiopathic Parkinson’s Disease MedDRA version: 11 Level: LLT Classification code 10067209 Term:
Conditions
Interventions
Product Name: Apomorphine hydrochloride 1.8mg inhalation powder, pre-dispensed
Product Code: VR040
Pharmaceutical Form: Inhalation powder, pre-dispensed
INN or Proposed INN: Apomorphine hydrochloride
Sponsors
Vectura Limited
Eligibility
Sex/Gender
All
Inclusion criteria
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 for at least the 30 days. Optimised oral therapy is defined as LD not greater than 1500 mg per day* (in combination with decarboxylase inhibitors), and the following outcomes from previous trials of drug regimens. •Patient has either a modest or marked improvement with LD (i.e. patients with minimal or no response to LD are not suitable subjects for apomorphine) •Patient has current or prior use of an oral dopamine agonist •Patient has current or prior use of a COMT-inhibitor *For patients receiving controlled-release (CR) formulations, the dose limit is based on a 70% bioavailability adjustment (ie 100 mg CR = 70 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 10.0 x109/L; Platelets 600 x109/L; Sodium 150 mmol/L; Potassium 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 the QT interval, unless the investigator considers the risk of avoiding such medications 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 apomo
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ;Secondary Objective: 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. ;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. | — |
Countries
Germany, Italy, United Kingdom
Outcome results
None listed