A Clinic-Based, Phase IIa, Double-Blind, Placebo- Controlled, Ascending-Dose, Multicentre Study of Safety, Tolerability, Efficacy and Pharmacokinetics of VR040 in Parkinson's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 47
- 试验地点
- 9
- 主要终点
- The maximum UPDRS 3 improvement from pre-dose to post-dose
研究概览
简要总结
'Off periods' where people with Parkinson's disease are slow, stiff and unable to function are disabling, and a treatment which can converts people to a "on", good, able to function state would be extremely useful. We assessed safety, tolerability and efficacy of inhaled dry powder apomorphine (VR040) in a clinic-based study in this setting.
详细描述
Background: 'Off' periods increase as Parkinson's disease progresses and the benefits of standard therapy wane. Subcutaneous apomorphine rescues 'off' periods, but patient self-injection and adverse cutaneous effects are sometimes problematic.
Methods: We assessed safety, tolerability and efficacy of inhaled dry powder apomorphine (VR040) in a clinic-based Phase II study. Of 48 patients recruited at 9 sites, 47 were randomized 2:1 inhaled apomorphine:placebo. Respirable doses (drug predicted to reach the lung) ascending through 1.5mg, 2.3mg, 3.0mg, and 4.0mg until efficacy was achieved, were administered to patients in a practically defined 'off' state. The primary endpoint was the response in unified Parkinson's disease rating scale Part 3 (UPDRS 3), at the highest dose received by the patient. Secondary endpoints included time to 'on', the proportion of patients converting from 'off' to 'on', and pharmacokinetics.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 30 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female between 30 and 90 years old with idiopathic PD for at least 5 years.
- •Voluntary written informed consent provided.
- •Willing and able to comply with study procedures.
- •Fulfilled steps 1 and 2 of the UK Brain Bank Criteria.
- •Classified as Hoehn and Yahr Stage II to IV in "on" state.
- •Motor fluctuations with recognisable "off" periods in control of motor symptoms, as assessed by the Motor Fluctuation Questionnaire.
- •Optimised oral therapy.
- •Dopaminergic responsiveness as defined by ≥ 30% improvement(reduction) in UPDRS III score compared with pre-dose value.
排除标准
- •Participated in a trial with an investigational product within prior 3 months.
- •Serious uncontrolled disease including serious psychological disorders.
- •Previous intolerance to apomorphine.
- •Previous significant complication from oral dopamine agonist therapy
- •Women lactating, pregnant or of child-bearing potential not using a reliable contraceptive method (eg, barrier, intrauterine device, abstinence).
- •Known HIV or active chronic hepatitis B or C infection.
- •Any clinically significant abnormality following review of screening observations
- •Patients who, in the Investigator's opinion, were unsuitable for the study for any reason.
- •Major ECG abnormalities.
- •Patients with a FEV1 ≤ 65% predicted.
- •Patients showing a postural decrease in systolic blood pressure (BP) of ≥20 mm Hg or showing significant clinical symptoms associated with orthostatic hypotension.
- •Patients with persistent arterial hypotension, with average systolic readings of ≤110 mm Hg.
- •Patients with persistent elevation of BP, with average systolic readings of ≥160 mm Hg.
- •or average diastolic readings of ≥100 mm Hg.
- •Patients taking apomorphine at any time during these study visits, anabolic steroids,traditional antipsychotics (unless low dose) and vasodilators other than for the treatment of hypertension. The following atypical antipsychotics were permitted: Quetiapine (up to and including 50 mg per day), risperidone (up to and including 1 mg per day) and olanzapine (up to and including 2.5 mg per day).
- •Patients taking agents of the 5HT3 antagonist class including ondansetron, granisetron,dolasetron, palonosetron and alosetron.
- •Patients with existing cancer and those in remission for less than 5 years.
- •Patients with evidence (as ascertained from examination, tests or history) to indicate cardiovascular, gastrointestinal tract, liver, kidney, central nervous system, pulmonary system or bone marrow disorders that in the Investigator's opinion compromised patient safety.
- •Patients who were known non-responders to apomorphine treatment for "off" episodes(eg, in previous challenge tests or trials).
- •Patients with a history of drug or alcohol abuse in the 12 months prior to entry.
- •Patients with a history of clinically significant allergies to VR040 formulation constituents (including lactose and opioids) and domperidone.
- •Patients with signs or symptoms suggestive of psychosis, dementia, "Parkinson-plus" syndromes or unstable systemic disease.
- •Patients with history of stroke, seizure or other neurological conditions.
- •Patients with dyskinesia rated 4 in Item 32 of UPDRS IV assessment at Screening(dyskinesia present ≥76% of a waking day).
研究组 & 干预措施
VR040/Aspirair® inhaler
VR040 was administered as an inhaled dry powder, in a dosage of 1.5, 2.3, 3.0 and 4.0mg, single dose given at each dose level.
干预措施: VR040/Aspirair® inhaler (Drug)
Placebo
Placebo was administered as an inhaled dry powder, matching to active comparator at dosages of 1.5, 2.3, 3.0 and 4.0mg, single dose given at each dose level.
干预措施: placebo (Drug)
结局指标
主要结局
The maximum UPDRS 3 improvement from pre-dose to post-dose
时间窗: 90 minutes
The primary efficacy endpoint was the maximum UPDRS 3 improvement from pre-dose to post-dose at the highest dose used.
次要结局
- Time to improvement from 'off' to 'on'(90 minutes)
- The proportion of patients converting to 'on' any time after treatment administration.(90 minutes)
- The duration of 'on'(90 minutes)
研究者
Dr Donald Grosset
Consultant Neurologist
South Glasgow University Hospitals NHS Trust