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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02006121
Recruitment Status : Completed
First Posted : December 9, 2013
Results First Posted : July 8, 2019
Last Update Posted : July 8, 2019
Sponsor:
Information provided by (Responsible Party):
Britannia Pharmaceuticals Ltd.

Tracking Information
First Submitted Date  ICMJE November 22, 2013
First Posted Date  ICMJE December 9, 2013
Results First Submitted Date  ICMJE October 16, 2018
Results First Posted Date  ICMJE July 8, 2019
Last Update Posted Date July 8, 2019
Actual Study Start Date  ICMJE March 3, 2014
Actual Primary Completion Date June 6, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
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 [ Time Frame: Baseline and 12 weeks ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 4, 2013)
Absolute change in time spent "OFF" from baseline to the end of 12 weeks treatment period based on patient diaries [ Time Frame: after 12 weeks of treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • 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 [ Time Frame: Baseline and 12 weeks ]
    The least squares mean change in "ON time without troublesome dyskinesia" as reported by the patient using the Hauser Parkinson's disease home diary. Each half hour of the day categorised as OFF, ON with dyskinesia, ON without troublesome dyskinesia or asleep. "ON time without troublesome dyskinesia" measures good ON time for a Parkinson's disease patient.
  • Patient Global Impression of Change (PGIC), Using the mITT Population [ Time Frame: Baseline and 12 weeks ]
    PGIC is a self-administered questionnaire measuring personal general state of health on a 7-point rating scale. The 7 ordinal categories from which patients must choose are 'very much improved', 'much improved', 'minimally improved', 'no change', 'minimally worse', 'much worse', and 'very much worse. Results are presented as the % of patients who reported at least minimal improvement in general health status at week 12 compared to Baseline. A Wilcoxon range sum test was performed to test for treatment differences from baseline to end of 12 weeks' treatment period.
  • Mean Change in Oral Levodopa Dose From Baseline to Visit 10 Using MMRM for the mITT Population [ Time Frame: Baseline and 12 weeks ]
    The least squares mean change in oral levodopa dose from Baseline to Visit 10 (week 12) was calculated excluding 3 centres who declined to participate in collecting the necessary details of PRN use of levodopa.
  • Mean Change in Levodopa Equivalent Dose From Baseline to Visit 10 (Week 12) Using MMRM in the mITT Population [ Time Frame: Baseline and 12 weeks ]
    Levodopa equivalent dose is an indication of the burden of medication taken to control symptoms of Parkinson's disease with all medications other than levodopa itself being converted to a calculated levodopa dose using the methodology published by Tomlinson et al, 2010. The computation of LED excludes the study drug.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2013)
  • Evaluation of adverse events and local tolerability [ Time Frame: 1 year ]
    The safety parameters will be summarized by treatment group
  • Skin changes [ Time Frame: 1 year ]
    The safety parameters will be summarized by treatment group
  • Full blood count [ Time Frame: 1 year ]
  • Epworth Sleepiness Scale [ Time Frame: 1 year ]
  • Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease [ Time Frame: 1 year ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Trial of Apomorphine Subcutaneous Infusion in Patients With Advanced Parkinson's Disease
Official Title  ICMJE Multicentre,Parallel-group,Double-blind,Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Apomorphine sc Infusion in Parkinson's Disease Patients With Motor Complications Not Well Controlled on Medical Treatment
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Parkinson's Disease
Intervention  ICMJE
  • Drug: Apomorphine hydrochloride
    Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe
    Other Name: Apo-go
  • Drug: Placebo
    Sodium chloride 9 mg/ml
Study Arms  ICMJE
  • Active Comparator: Apomorphine hydrochloride
    Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe
    Intervention: Drug: Apomorphine hydrochloride
  • Placebo Comparator: Placebo
    Placebo: saline infusion
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 10, 2016)
107
Original Estimated Enrollment  ICMJE
 (submitted: December 4, 2013)
102
Actual Study Completion Date  ICMJE June 8, 2017
Actual Primary Completion Date June 6, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Denmark,   France,   Germany,   Netherlands,   Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02006121
Other Study ID Numbers  ICMJE CT-37527-13-0124
2013-000980-10 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Britannia Pharmaceuticals Ltd.
Study Sponsor  ICMJE Britannia Pharmaceuticals Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Regina Katzenschlager, Doz. Dr. Donauspital KH SMZ Ost, Neurologie
PRS Account Britannia Pharmaceuticals Ltd.
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP