Clinical Trial of Apomorphine Subcutaneous Infusion in Patients With Advanced Parkinson's Disease

NCT ID: NCT02006121

Last Updated: 2019-07-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-03
• Study Completion Date: 2017-06-08

Brief Summary

The primary objective of the trial was to investigate the efficacy of apomorphine continuous subcutaneous infusion compared to placebo in Parkinson's Disease patients with motor fluctuations not well controlled on medical treatment.

The secondary objective of the study was to investigate the safety and tolerability of apomorphine continuous subcutaneous therapy.

Detailed Description

The primary efficacy variable is the mean change in time spent "OFF" from baseline (start of blinded treatment) to the end of a 12 weeks' double-blind treatment period based on patient diaries. Patients recorded their motor symptoms in half-hour blocks as OFF, ON without dyskinesia, ON without troublesome dyskinesia, or sleeping using the Hauser Parkinson's Disease home diary.

Key secondary Endpoints (tested hierarchically):

• Change in time spent "ON without troublesome dyskinesia"
• Patient Global Impression of Change

Other Endpoints:

• Percentage of patients with response to therapy, defined as a mean OFF time reduction of at least 2 hours
• Change in oral levodopa and levodopa equivalent dose

Conditions

Parkinson's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Apomorphine hydrochloride

Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe

Group Type: ACTIVE_COMPARATOR

Apomorphine hydrochloride

Intervention Type: DRUG

Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe

Placebo

Placebo: saline infusion

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Sodium chloride 9 mg/ml

Interventions

Apomorphine hydrochloride

Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe

Intervention Type: DRUG

Placebo

Sodium chloride 9 mg/ml

Intervention Type: DRUG

Other Intervention Names

Apo-go

Eligibility Criteria

Inclusion Criteria

• Male or female patients aged ≥30 years
• Diagnosis of idiopathic PD 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 levodopa which was judged by the treating physician to be optimal
• Average of OFF time > 3 hours/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 levodopa administered in at least 4 intakes, for at least 28 days prior to baseline. All oral or transdermal antiparkinsonian drugs were permitted, with the exception of budipine. This regimen might include the use of levodopa/DDCI rescue medication, if this occurred up to 2 times a day, at doses of up to 200 mg levodopa/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 the 12-month OLP, if sexually active
• Females of childbearing potential must have a negative serum human chorionic gonadotropin (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

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 levodopa
• 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 (QTcB) of >450 msec for male and >470 msec for female at screening or history of long QT syndrome; or >450 msec absolute duration
• Clinically relevant hepatic dysfunction (total bilirubin >2.0 mg/dL, alanine transaminase [ALT] and aspartate transaminase [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 Diagnostic and Statistical Manual of Mental Disorders (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

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Britannia Pharmaceuticals Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Regina Katzenschlager, Doz. Dr.

Role: PRINCIPAL_INVESTIGATOR

Donauspital KH SMZ Ost, Neurologie

Locations

Medizinische Universität Graz / Univ. Klinik für Neurologie

Graz, , Austria

Medizinische Universität Innsbruck

Innsbruck, , Austria

Donauspital / SMZ-Ost, Abteilung für Neurologie, Sekretariat (Stock 1, Ebene 4)

Vienna, , Austria

Bispebjerg University Hospital, Movement Disorder Centre

Copenhagen, , Denmark

CHRU Clermont- Ferrand Gabriel-Montpied

Clermont-Ferrand, , France

CHU de Rennes, Hôpital Pontchaillou

Rennes, , France

CHU Toulouse, Hôpital Purpan, Centre d'Investigation Clinique

Toulouse, , France

Neurologisches Fachkrankenhausfür Bewegungsstörungen / Parkinson

Beelitz-Heilstätten, , Germany

Klinikum Bremerhaven-Reinkenheide gGmbH, Neurologische Klinik

Bremerhaven, , Germany

Paracelsus Elena-Klinik Kassel

Kassel, , Germany

Schön Klinik München Schwabing / Neurologie und Klinische Neurophysiologie

München, , Germany

Universitair Medisch Centrum

Groningen, , Netherlands

Atrium MC parkstad

Heerlen, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Hospital Clínic de Barcelona

Barcelona, , Spain

Hospital Universitario Fundación Jiménez Díaz

Madrid, , Spain

The Walton Centre Nhs Foundation Trust

Liverpool, , United Kingdom

Kings College Hospital NHS Foundation Trust

London, , United Kingdom

St George's Heathcare NHS Trust

London, , United Kingdom

Newcastle University, Clinical Ageing Research Unit (CARU)

Newcastle, , United Kingdom

Countries

Austria; Denmark; France; Germany; Netherlands; Spain; United Kingdom

References

Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, Henriksen T, van Laar T, Lockhart D, Staines H, Lees A. Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study. Parkinsonism Relat Disord. 2021 Feb;83:79-85. doi: 10.1016/j.parkreldis.2020.12.024. Epub 2021 Jan 12.

Reference Type: DERIVED

PMID: 33486139 (View on PubMed)

Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, Henriksen T, van Laar T, Spivey K, Vel S, Staines H, Lees A. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018 Sep;17(9):749-759. doi: 10.1016/S1474-4422(18)30239-4. Epub 2018 Jul 25.

Reference Type: DERIVED

PMID: 30055903 (View on PubMed)

Other Identifiers

2013-000980-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CT-37527-13-0124

Identifier Type: -

Identifier Source: org_study_id