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

NCT02006121 | Completed Phase 3 Results

• 2 other identifiers: CT-37527-13-01242013-000980-10
• Study Type: interventional
• Target: 107
• Locations: 7 countries
• Sites: 20

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.

Conditions

Parkinson's Disease

Keywords

Parkinson's disease; motor fluctuations; not well controlled; medical treatment; apomorphine

Outcome Measures

Primary Outcomes (1)

• Mean Change in Daily OFF Time From Baseline (Start of Blinded Treatment) to the End of Double-blind Phase (Visit 10) Based on Patient Diaries Using MMRM mITT Population

  The least squares mean reduction (improvement) in OFF time as reported by the patient using the Hauser Parkinson's disease home diary. Patients categorised their motor symptoms into OFF, ON with dyskinesia, ON without troublesome dyskinesia or sleeping using half hour blocks over 24 hours. Daily OFF time was computed from the average of valid motor diaries from the two days preceding each visit. Correct diary completion was evaluated during screening and observed by the investigator to ensure patients could categorise their motor symptoms correctly. A diary was considered valid if no more than 4 half-hour periods were either absent or duplicated. There were no invalid diaries at Baseline or Week 12.

  Baseline and 12 weeks

Secondary Outcomes (4)

• Mean Change in Daily Time Spent "ON Without Troublesome Dyskinesia" From Baseline to the End of the Double-blind Phase (Visit 10), Based on Patient Diaries Using MMRM mITT Population

  Baseline and 12 weeks

• Patient Global Impression of Change (PGIC), Using the mITT Population

  Baseline and 12 weeks

• Mean Change in Oral Levodopa Dose From Baseline to Visit 10 Using MMRM for the mITT Population

  Baseline and 12 weeks

• Mean Change in Levodopa Equivalent Dose From Baseline to Visit 10 (Week 12) Using MMRM in the mITT Population

  Baseline and 12 weeks

Study Arms (2)

Apomorphine hydrochloride

ACTIVE COMPARATOR

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

Drug: Apomorphine hydrochloride

Placebo

PLACEBO COMPARATOR

Placebo: saline infusion

Drug: Placebo

Interventions

Apomorphine hydrochloride DRUG

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

Also known as: Apo-go

Apomorphine hydrochloride

Placebo DRUG

Sodium chloride 9 mg/ml

Placebo

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Known history of melanoma

Sponsors & Collaborators

• Britannia Pharmaceuticals Ltd.: lead

Study Sites (20)

Medizinische Universität Graz / Univ. Klinik für Neurologie

Graz, Austria

Location

Medizinische Universität Innsbruck

Innsbruck, Austria

Location

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

Vienna, 1220, Austria

Location

Bispebjerg University Hospital, Movement Disorder Centre

Copenhagen, Denmark

Location

CHRU Clermont- Ferrand Gabriel-Montpied

Clermont-Ferrand, France

Location

CHU de Rennes, Hôpital Pontchaillou

Rennes, France

Location

CHU Toulouse, Hôpital Purpan, Centre d'Investigation Clinique

Toulouse, France

Location

Neurologisches Fachkrankenhausfür Bewegungsstörungen / Parkinson

Beelitz-Heilstätten, Germany

Location

Klinikum Bremerhaven-Reinkenheide gGmbH, Neurologische Klinik

Bremerhaven, Germany

Location

Paracelsus Elena-Klinik Kassel

Kassel, Germany

Location

Schön Klinik München Schwabing / Neurologie und Klinische Neurophysiologie

München, Germany

Location

Universitair Medisch Centrum

Groningen, Netherlands

Location

Atrium MC parkstad

Heerlen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, Spain

Location

The Walton Centre Nhs Foundation Trust

Liverpool, United Kingdom

Location

Kings College Hospital NHS Foundation Trust

London, United Kingdom

Location

St George's Heathcare NHS Trust

London, United Kingdom

Location

Newcastle University, Clinical Ageing Research Unit (CARU)

Newcastle, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 33486139 DERIVED

• 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.

  PMID: 30055903 DERIVED

MeSH Terms

Conditions

Parkinson Disease

Interventions

Apomorphine

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Aporphines; Benzylisoquinolines; Alkaloids; Heterocyclic Compounds; Isoquinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 4 or More Rings

Results Point of Contact

• Title: Medical Director
• Organization: Britannia Pharmaceuticals

reception@britannia-pharm.com

+44 1189209500

Study Officials

• Regina Katzenschlager, Doz. Dr.

  Donauspital KH SMZ Ost, Neurologie

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2013
• First Posted: December 9, 2013
• Study Start: March 3, 2014
• Primary Completion: June 6, 2016
• Study Completion: June 8, 2017
• Last Updated: July 8, 2019
• Results First Posted: July 8, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3); ES (2); DE (4); GB (4); DK (1); AU (3); FR (3)