VR040/2/003: Phase IIa Multicentre Study Investigating of VR040 in Parkinson's Disease

Sponsor

South Glasgow University Hospitals NHS Trust (Other)

Overall Status

Completed

CT.gov ID

NCT01693081

Collaborator

Vectura Limited (Industry)

Enrollment

Locations

Arms

Duration (Months)

5.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

'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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: VR040/Aspirair® inhaler Drug: placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

47 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2007

Actual Primary Completion Date :

Jul 1, 2007

Actual Study Completion Date :

Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: VR040/Aspirair® inhaler Dry Powder inhaled apomorphine Other Names: Inhaled apomorphine
Placebo Comparator: 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.	Drug: placebo

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: VR040/Aspirair® inhaler

Dry Powder inhaled apomorphine

Other Names:

Inhaled apomorphine

Placebo Comparator: 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.

Drug: placebo

Outcome Measures

Primary Outcome Measures

The maximum UPDRS 3 improvement from pre-dose to post-dose [90 minutes]
The primary efficacy endpoint was the maximum UPDRS 3 improvement from pre-dose to post-dose at the highest dose used.

Secondary Outcome Measures

Time to improvement from 'off' to 'on' [90 minutes]
Time to improvement from 'off' to 'on'.
The duration of 'on' [90 minutes]
The duration of 'on', the duration of time when the patient can function well.
The proportion of patients converting to 'on' any time after treatment administration. [90 minutes]
The proportion of patients converting to 'on' any time after treatment administration.

Other Outcome Measures

Safety variables [90minutes]
Safety variables were: the pre- to post-dose change in vital signs, 12-lead ECG and continuous 12-lead Holter ECG, and lung function.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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).

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Neurology Clinical Military Medical Academy, Crnotravska 17	Belgrade	Serbia	11 000
2	Institute of Neurology Clinical Center Serbia Dr Subotica 6	Belgrade	Serbia	11000
3	University Hospital, Wales	Cardiff	United Kingdom	CF14 4XW
4	Department of Neurology, Southern General Hospital	Glasgow	United Kingdom	G51 4TF
5	The Walton Centre	Liverpool	United Kingdom	L9 7LJ
6	Llandudno Hospital	Llandudno	United Kingdom	LL30 1LB
7	Newark Hospital	Newark	United Kingdom	NG24 4DE
8	Neurology Dept, Radcliffe Infirmary	Oxford	United Kingdom	OX2 6HE
9	Essex Neurosciences, UnitOld Church Hospital, Essex	Romford Essex	United Kingdom	RM7 0BE