Parkinson's Disease
Conditions
Keywords
Parkinson's disease, motor fluctuations, not well controlled, medical treatment, apomorphine
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
Interventions
Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe
DRUGPlacebo
Sodium chloride 9 mg/ml
Sponsors
Britannia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 | 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 | 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. |
Countries
Austria, Denmark, France, Germany, Netherlands, Spain, United Kingdom
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Apomorphine Hydrochloride Apo-go® Apomorphine hydrochloride 5 mg/ml solution for infusion in pre-filled syringe | 53 |
| Placebo Placebo: saline infusion Sodium chloride 9 mg/ml | 52 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Phase | Adverse Event | 6 | 0 |
| Double Blind Phase | Inconvenience of infusion system | 0 | 1 |
| Double Blind Phase | Lack of Efficacy | 1 | 16 |
| Double Blind Phase | Minimum infusion rate poorly tolerated | 1 | 0 |
| Double Blind Phase | Non-compliance with study drug | 1 | 3 |
| Double Blind Phase | Withdrawal by Subject | 3 | 4 |
| Open Label Phase | Adverse Event | 15 | 0 |
| Open Label Phase | Lack of Efficacy | 2 | 0 |
| Open Label Phase | Non-compliance with study drug | 3 | 0 |
| Open Label Phase | Protocol Violation | 2 | 0 |
| Open Label Phase | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Apomorphine Hydrochloride | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 27 Participants | 24 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 28 Participants | 54 Participants |
| Age, Continuous | 63.58 years STANDARD_DEVIATION 9.32 | 63.00 years STANDARD_DEVIATION 8.32 | 63.29 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Male | 34 Participants | 32 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 53 |
| other Total, other adverse events | 94 / 98 | 30 / 53 |
| serious Total, serious adverse events | 23 / 98 | 2 / 53 |
Outcome results
Primary
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.
Time frame: Baseline and 12 weeks
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Apomorphine Hydrochloride | 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 | -2.61 Hours |
| Placebo | 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 | -0.75 Hours |
p-value: 0.0047Mixed Models Analysis
Secondary
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
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Apomorphine Hydrochloride | 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 | 2.90 Hours |
| Placebo | 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 | 0.85 Hours |
p-value: 0.0022Mixed Models Analysis
Secondary
Mean Change in Levodopa Equivalent Dose From Baseline to Visit 10 (Week 12) Using MMRM in the mITT Population
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
Population: All randomized patients treated at least once with study medication and who had at least one post-baseline observation for the primary endpoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Apomorphine Hydrochloride | Mean Change in Levodopa Equivalent Dose From Baseline to Visit 10 (Week 12) Using MMRM in the mITT Population | -502.02 mg |
| Placebo | Mean Change in Levodopa Equivalent Dose From Baseline to Visit 10 (Week 12) Using MMRM in the mITT Population | -150.87 mg |
p-value: <0.0001Mixed Models Analysis
Secondary
Mean Change in Oral Levodopa Dose From Baseline to Visit 10 Using MMRM for the mITT Population
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Apomorphine Hydrochloride | Mean Change in Oral Levodopa Dose From Baseline to Visit 10 Using MMRM for the mITT Population | -242.09 mg |
| Placebo | Mean Change in Oral Levodopa Dose From Baseline to Visit 10 Using MMRM for the mITT Population | -76.46 mg |
p-value: 0.005Mixed Models Analysis
Secondary
Patient Global Impression of Change (PGIC), Using the mITT Population
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Apomorphine Hydrochloride | Patient Global Impression of Change (PGIC), Using the mITT Population | 79.1 % of participants |
| Placebo | Patient Global Impression of Change (PGIC), Using the mITT Population | 23.5 % of participants |
p-value: <0.0001Wilcoxon (Mann-Whitney)