Clinical trial of apomorphine subcutaneous infusion in patients with advanced Parkinson’s disease

• Register: EUCTR
• Last refreshed on: 2 October 2017
• Main ID: EUCTR2013-000980-10-AT
• Date of registration: 31/07/2013
• Prospective Registration: Yes
• Primary sponsor: Britannia Pharmaceuticals Limited
• Public title: Clinical trial of apomorphine subcutaneous infusion in patients with advanced Parkinson’s disease
• Scientific title: TOLEDO Multicenter, parallel-group, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of apomorphine subcutaneous infusion in Parkinson’s disease patients with motor complications not well controlled on medical treatment - TOLEDO
• Date of first enrolment: 18/10/2013
• Target sample size: 102
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-000980-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Denmark, France, Germany, Netherlands, Spain

Contacts

• Name: Clinical Operations
• Affiliation: AMS Advanced Medical Services GmbH

• Name: Clinical Operations
• Affiliation: AMS Advanced Medical Services GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
- Male or female patients aged =30
- Diagnosis of idiopathic Parkinson’s disease of >3 years’ duration, defined by the UK Brain Bank criteria (with the exception of >1 affected relative being allowed), without any other known or suspected cause of Parkinsonism
- Hoehn & Yahr stage up to 3 in the ON and 2 to 5 in the OFF state
- Motor fluctuations not adequately controlled on medical treatment including L-dopa which was judged to be optimal by the treating physician
- Average of OFF time>= 3 h/day based on screening and baseline diary entries with no day with < 2 hours of OFF time recorded
- Stable medication regimen, with a stable dose of L-dopa administered in at least 4 intakes, for at least 28 days prior to baseline. All oral or transdermal antiparkinsonian drugs are permitted, with the exception of budipine. This regimen may include the use of L-dopa /DDCI rescue medication if this occurs up to 2 times a day, at doses of up to 200 mg L-dopa/day
- Patients must be able to differentiate between the ON and OFF state and between troublesome and non-troublesome dyskinesias
- Male and female patients must be compliant with a highly effective contraceptive method (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method) during the study and for 12 months open-label phase, if sexually active
- Females of childbearing potential must have a negative serum hCG or urine pregnancy test at screening
- Ability to accurately complete a paper diary on designated days (with assistance from caregivers, if required), recording periods when they are “ON without troublesome dyskinesia”, “ON with troublesome dyskinesia”, OFF, and sleeping
- Written informed consent prior to enrolment, after being provided with detailed information about the nature, risks, and scope of the clinical trial as well as the expected desirable and adverse effects of the study treatments
- Patients considered reliable and capable of adhering to the protocol, visit schedule, and medication intake according to the judgment of the investigator
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 27
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 75

Exclusion criteria:
-History of respiratory depression
- Hypersensitivity to apomorphine or any excipients of the
medicinal product
- High suspicion of other parkinsonian syndromes
- Presence of severe freezing or clinically relevant postural instability leading to falls during the ON state
- Concomitant therapy or within 28 days prior to baseline with: apomorphine pen injections, alpha-methyl dopa, metoclopramide, reserpine, neuroleptics, methylphenidate, or amphetamine; intrajejunal L-dopa
- Previous use of apomorphine pump treatment
- History of deep brain stimulation or lesional surgery for PD
- Any medical condition that is likely to interfere with an adequate participation in the study, including e.g. current diagnosis of unstable epilepsy; clinically relevant cardiac dysfunction and/or myocardial infarction or stroke within the last 12 months
- Symptomatic, clinically relevant and medically uncontrolled orthostatic hypotension
- Patients with a borderline QT interval corrected for heart rate according to Bazett’s formula (QTc) of >450 ms for male and >470 ms for female at Screening or history of long QT syndrome; or >450 ms absolute duration
- Clinically relevant hepatic dysfunction (total bilirubin >2.0 mg/dL, ALT and AST >2 times the upper limit of normal)
- Clinically relevant renal dysfunction (serum creatinine >2.0 mg/dL);
- Pregnant and breastfeeding women
- Clinically relevant cognitive decline, defined as MMSE =24 or according to DSM IV criteria for dementia
- Active psychosis or history of at least moderate psychosis in the past year, or with medically uncontrolled severe depression; very mild illusions or hallucinations in the sense of “feelings of passage or presence” with fully retained insight are not an exclusion criterion
- Known history of melanoma
- Any investigational therapy in the 4 weeks prior to randomization
- History or current drug or alcohol abuse or dependencies


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Parkinson Disease (PD) in patients with motor fluctuations not well controlled on medical treatment
MedDRA version: 18.0 Level: LLT Classification code 10034006 Term: Parkinson's disease aggravated System Organ Class: 100000004852

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Apo-go®
Product Name: Apomorphine hydrochloride
Product Code: Apo-go®
Pharmaceutical Form: Solution for infusion in pre-filled syringe
INN or Proposed INN: Apomorphine hydrochloride
CAS Number: 314-19-2
Other descriptive name: Apomorphine hydrochloride
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Solution for infusion in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: After 12 weeks of treatment

Main Objective: The primary objective is to investigate the efficacy of apomorphine subcutaneous infusion compared to placebo in PD patients with motor fluctuations not well controlled on medical treatment.

Secondary Objective: To investigate the safety and tolerability of apomorphine subcutaneous infusion therapy.

Primary end point(s): Primary efficacy variable is the absolute change in time spent “OFF” from baseline to the end of 12 weeks double-blind treatment period based on patient diaries.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: After 12 weeks of treatment

Secondary end point(s): - Percentage of patients with response to therapy, defined as an OFF-time reduction of at least 2 hours, from baseline to end of 12 weeks double-blind treatment period
- Patient Global Impression of Change
- Absolute change in time spent “ON” without troublesome dyskinesia”
- Change in oral L-dopa and L-dopa equivalent dose
- Change in Unified Parkinson’s Disease Rating Scale (UPDRS Part III motor examination) during ON periods
- Change in Quality of Life (using PDQ-8)

Secondary ID(s)

CT-37527-13-0124

Source(s) of Monetary Support

Britannia Pharmaceuticals Limited