Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Parkinson's Disease
Interventions Drug: Apomorphine hydrochloride
Drug: Placebo
Enrollment 107
Recruitment Details  
Pre-assignment Details Blinded treatment was administered over 12 weeks after which patients could choose to enrol in a 12-month open-label phase. Early switching to the open-label phase was permitted for lack of efficacy in the double-blind phase.
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description

Apo-go® Apomorphine hydrochloride 5 mg/ml solution in 10 mL pre-filled syringes for continuous infusion during the waking day using a Cane CRONO APO-Go® infusion pump. Hourly flow rate adjusted in increments of 0.5-1.0 mg/hour/day during titration to reach the patient's individualized required dose in a range of 3-8 mg/hour for 14-18 hours per day.

Concomitant medications were reduced/discontinued in the following order: dopamine agonists, MAO-B inhibitors, COMT inhibitors, levodopa dose then frequency.

Blinded Placebo: saline infusion; Open Label, placebo switched to apomorphine infusion.

Blinded phase: Sodium chloride 9 mg/ml continuous infusion during the waking day using a Cane CRONO APO-Go® infusion pump. Hourly flow rate adjusted in increments of 0.5-1.0 mg/hour/day during titration to reach the patient's individualized required dose in a range of 3-8 mg/hour for 14-18 hours per day.

Concomitant medications were reduced/discontinued in the following order: dopamine agonists, MAO-B inhibitors, COMT inhibitors, levodopa dose then frequency.

Open Label phase: as per apomorphine arm

Period Title: Double Blind Phase
Started 54 53
Completed 42 [1] 29 [2]
Not Completed 12 24
Reason Not Completed
Adverse Event             6             0
Lack of Efficacy             1             16
Withdrawal by Subject             3             4
Non-compliance with study drug             1             3
Minimum infusion rate poorly tolerated             1             0
Inconvenience of infusion system             0             1
[1]
Early switching to open label: 1 for lack of efficacy, 1 could not tolerate 3 mg/hour minimum rate
[2]
16 placebo-treated patients early switched to open label phase due to lack of efficacy
Period Title: Open Label Phase
Started 84 [1] 0 [2]
Completed 59 [3] 0
Not Completed 25 0
Reason Not Completed
Adverse Event             15             0
Lack of Efficacy             2             0
Protocol Violation             2             0
Withdrawal by Subject             3             0
Non-compliance with study drug             3             0
[1]
From Apo: 38 completers and 2 early switched; From Placebo: 28 completers and 16 early switched
[2]
No patients received placebo in the open label phase
[3]
30 who continued on apomorphine from blinded phase, 29 who switched to apomorphine from placebo
Arm/Group Title Apomorphine Hydrochloride Placebo Total
Hide Arm/Group Description Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe Placebo: saline infusion Sodium chloride 9 mg/ml Total of all reporting groups
Overall Number of Baseline Participants 53 52 105
Hide Baseline Analysis Population Description
Demographic Characteristics displayed for mITT population
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 52 participants 105 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
26
  49.1%
28
  53.8%
54
  51.4%
>=65 years
27
  50.9%
24
  46.2%
51
  48.6%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 53 participants 52 participants 105 participants
63.58  (9.32) 63.00  (8.32) 63.29  (8.80)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 52 participants 105 participants
Female
19
  35.8%
20
  38.5%
39
  37.1%
Male
34
  64.2%
32
  61.5%
66
  62.9%
1.Primary Outcome
Title 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
Hide Description 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.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised patients excluding those who had major protocol deviations who received at least one dose of trial medication during the course of the trial and for whom any post-baseline efficacy assessment is available.
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description:
Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe
Placebo: saline infusion Sodium chloride 9 mg/ml
Overall Number of Participants Analyzed 53 52
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Hours
-2.61
(-3.43 to -1.80)
-0.75
(-1.66 to 0.16)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apomorphine Hydrochloride, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0047
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
2.Secondary Outcome
Title 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
Hide Description 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.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised patients excluding those who had major protocol deviations who received at least one dose of trial medication during the course of the trial and for whom any post-baseline efficacy assessment is available.
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description:
Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe
Placebo: saline infusion Sodium chloride 9 mg/ml
Overall Number of Participants Analyzed 53 52
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Hours
2.90
(2.07 to 3.73)
0.85
(-0.09 to 1.78)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apomorphine Hydrochloride, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0022
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
3.Secondary Outcome
Title Patient Global Impression of Change (PGIC), Using the mITT Population
Hide Description 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.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised patients excluding those who had major protocol deviations who received at least one dose of trial medication during the course of the trial and for whom any post-baseline efficacy assessment is available and who completed the PGIC questionnaire
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description:
Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe
Placebo: saline infusion Sodium chloride 9 mg/ml
Overall Number of Participants Analyzed 43 34
Measure Type: Number
Unit of Measure: % of participants
79.1 23.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apomorphine Hydrochloride, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Mean Change in Oral Levodopa Dose From Baseline to Visit 10 Using MMRM for the mITT Population
Hide Description 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.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All patients who received at least one dose of randomized study medication and had at least one post-baseline observation for the primary endpoint
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description:

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

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

Placebo: saline infusion

Placebo: Sodium chloride 9 mg/ml

Overall Number of Participants Analyzed 41 32
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg
-242.09
(-346.58 to -137.61)
-76.46
(-185.17 to 32.25)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apomorphine Hydrochloride, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
5.Secondary Outcome
Title Mean Change in Levodopa Equivalent Dose From Baseline to Visit 10 (Week 12) Using MMRM in the mITT Population
Hide Description 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.
Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized patients treated at least once with study medication and who had at least one post-baseline observation for the primary endpoint
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description:

Apo-go® Apomorphine hydrochloride 5 mg/ml solution in 10 mL pre-filled syringes for continuous infusion during the waking day using a Cane CRONO APO-Go® infusion pump. Hourly flow rate adjusted in increments of 0.5-1.0 mg/hour/day during titration to reach the patient's individualized required dose in a range of 3-8 mg/hour for 14-18 hours per day.

Concomitant medications were reduced/discontinued in the following order: dopamine agonists, MAO-B inhibitors, COMT inhibitors, levodopa dose then frequency.

Blinded Placebo: saline infusion; Open Label, placebo switched to apomorphine infusion.

Blinded phase: Sodium chloride 9 mg/ml continuous infusion during the waking day using a Cane CRONO APO-Go® infusion pump. Hourly flow rate adjusted in increments of 0.5-1.0 mg/hour/day during titration to reach the patient's individualized required dose in a range of 3-8 mg/hour for 14-18 hours per day.

Concomitant medications were reduced/discontinued in the following order: dopamine agonists, MAO-B inhibitors, COMT inhibitors, levodopa dose then frequency.

Open Label phase: as per apomorphine arm

Overall Number of Participants Analyzed 49 48
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg
-502.02
(-626.45 to -377.60)
-150.87
(-280.14 to -21.59)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Apomorphine Hydrochloride, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Time Frame Adverse Events were collected during the double-blind and open label phases of the study. 98 patients were exposed to at least one dose of apomorphine with a cumulative person time of 4081 weeks of exposure. The range of exposure to apomorphine was 37-464 days (mean 397 days). In addition, 53 patients (44 of whom went onto apomorphine in the open label phase) were exposed to placebo treatment in the double blind phase with a maximum 12 weeks of exposure.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Apomorphine Hydrochloride Placebo
Hide Arm/Group Description Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe Placebo: saline infusion Sodium chloride 9 mg/ml
All-Cause Mortality
Apomorphine Hydrochloride Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/98 (0.00%)   0/53 (0.00%) 
Hide Serious Adverse Events
Apomorphine Hydrochloride Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   23/98 (23.47%)   2/53 (3.77%) 
Blood and lymphatic system disorders     
Lymphopenia  1  1/98 (1.02%)  0/53 (0.00%) 
Blood disorder  1  1/98 (1.02%)  0/53 (0.00%) 
Autoimmune haemolytic anaemia  1  1/98 (1.02%)  0/53 (0.00%) 
Cardiac disorders     
Myocardial infarction  1  1/98 (1.02%)  0/53 (0.00%) 
Angina pectoris  1  1/98 (1.02%)  0/53 (0.00%) 
Gastrointestinal disorders     
Colitis  1  1/98 (1.02%)  1/53 (1.89%) 
Constipation  1  1/98 (1.02%)  0/53 (0.00%) 
Diarrhoea  1  1/98 (1.02%)  0/53 (0.00%) 
Umbilical hernia  1  1/98 (1.02%)  0/53 (0.00%) 
Gastrointestinal haemorrhage  1  1/98 (1.02%)  0/53 (0.00%) 
General disorders     
Chest pain  1  1/98 (1.02%)  0/53 (0.00%) 
Infusion site extravasation  1  1/98 (1.02%)  0/53 (0.00%) 
Hepatobiliary disorders     
Cholelithiasis  1  1/98 (1.02%)  0/53 (0.00%) 
Infections and infestations     
Infusion site cellulitis  1  2/98 (2.04%)  0/53 (0.00%) 
Lower respiratory tract infection  1  1/98 (1.02%)  0/53 (0.00%) 
Pneumonia  1  1/98 (1.02%)  0/53 (0.00%) 
Urosepsis  1  1/98 (1.02%)  0/53 (0.00%) 
Injury, poisoning and procedural complications     
Fall  1  2/98 (2.04%)  0/53 (0.00%) 
Forearm fracture  1  1/98 (1.02%)  0/53 (0.00%) 
Lower limb fracture  1  1/98 (1.02%)  0/53 (0.00%) 
Radius fracture  1  1/98 (1.02%)  0/53 (0.00%) 
Investigations     
Eosinophil count decreased  1  1/98 (1.02%)  0/53 (0.00%) 
Haematocrit decreased  1  1/98 (1.02%)  0/53 (0.00%) 
Haemoglobin decreased  1  1/98 (1.02%)  0/53 (0.00%) 
Red blood cell count decreased  1  1/98 (1.02%)  0/53 (0.00%) 
Musculoskeletal and connective tissue disorders     
Pathological fracture  1  1/98 (1.02%)  0/53 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant  1  1/98 (1.02%)  0/53 (0.00%) 
Lymphoma  1  1/98 (1.02%)  0/53 (0.00%) 
Metastases to liver  1  1/98 (1.02%)  0/53 (0.00%) 
Nervous system disorders     
Neuroleptic malignant syndrome  1  1/98 (1.02%)  0/53 (0.00%) 
Parkinson's disease  1  1/98 (1.02%)  0/53 (0.00%) 
Carotid artery stenosis  1  1/98 (1.02%)  0/53 (0.00%) 
On Off phenomenon  1  1/98 (1.02%)  0/53 (0.00%) 
Radicular syndrome  1  1/98 (1.02%)  0/53 (0.00%) 
Product Issues     
Device difficult to use  1 [1]  1/98 (1.02%)  0/53 (0.00%) 
Psychiatric disorders     
Confusional state  1  1/98 (1.02%)  0/53 (0.00%) 
Depression  1  0/98 (0.00%)  1/53 (1.89%) 
Delirium  1  1/98 (1.02%)  0/53 (0.00%) 
Paranoia  1  1/98 (1.02%)  0/53 (0.00%) 
Renal and urinary disorders     
Urinary retention  1  1/98 (1.02%)  0/53 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary embolism  1  1/98 (1.02%)  0/53 (0.00%) 
Surgical and medical procedures     
Deep brain stimulation  1  1/98 (1.02%)  0/53 (0.00%) 
Vascular disorders     
Hypotension  1  1/98 (1.02%)  0/53 (0.00%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
[1]
Patient's carer admitted to hospital, he could not use pump and was admitted in OFF state. Retrained on pump and discharged on treatment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Apomorphine Hydrochloride Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   94/98 (95.92%)   30/53 (56.60%) 
Blood and lymphatic system disorders     
Eosinophilia  1  5/98 (5.10%)  0/53 (0.00%) 
Gastrointestinal disorders     
Nausea  1  20/98 (20.41%)  5/53 (9.43%) 
Vomiting  1  8/98 (8.16%)  2/53 (3.77%) 
Dyspepsia  1  5/98 (5.10%)  1/53 (1.89%) 
General disorders     
Infusion site nodule  1  46/98 (46.94%)  0/53 (0.00%) 
Infusion site erythema  1  15/98 (15.31%)  2/53 (3.77%) 
Infusion site haematoma  1  8/98 (8.16%)  5/53 (9.43%) 
Fatigue  1  6/98 (6.12%)  1/53 (1.89%) 
Oedema peripheral  1  7/98 (7.14%)  0/53 (0.00%) 
Infusion site pruritus  1  5/98 (5.10%)  0/53 (0.00%) 
Infections and infestations     
Nasopharyngitis  1  7/98 (7.14%)  3/53 (5.66%) 
Urinary tract infection  1  6/98 (6.12%)  1/53 (1.89%) 
Investigations     
Electrocardiogram QT prolonged  1  5/98 (5.10%)  0/53 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  6/98 (6.12%)  0/53 (0.00%) 
Back pain  1  7/98 (7.14%)  1/53 (1.89%) 
Nervous system disorders     
Somnolence  1  19/98 (19.39%)  2/53 (3.77%) 
Headache  1  10/98 (10.20%)  2/53 (3.77%) 
Dyskinesia  1  14/98 (14.29%)  0/53 (0.00%) 
Dizziness  1  11/98 (11.22%)  2/53 (3.77%) 
Psychiatric disorders     
Insomnia  1  13/98 (13.27%)  1/53 (1.89%) 
Hallucination, visual  1  6/98 (6.12%)  2/53 (3.77%) 
Sleep disorder  1  6/98 (6.12%)  1/53 (1.89%) 
Hallucination  1  5/98 (5.10%)  0/53 (0.00%) 
Vascular disorders     
Orthostatic hypotension  1  6/98 (6.12%)  1/53 (1.89%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Britannia Pharmaceuticals
Phone: +44 1189209500
EMail: reception@britannia-pharm.com
Layout table for additonal information
Responsible Party: Britannia Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT02006121    
Other Study ID Numbers: CT-37527-13-0124
2013-000980-10 ( EudraCT Number )
First Submitted: November 22, 2013
First Posted: December 9, 2013
Results First Submitted: October 16, 2018
Results First Posted: July 8, 2019
Last Update Posted: July 8, 2019