Parkinson Disease
Conditions
Brief summary
The objectives of this trial conducted in early Parkinson's disease (PD) patients are: * To assess if patients with early Parkinson's disease (PD) can be successfully switched (overnight switching) from Pramipexole (PPX) Immediate Release (IR) to Pramipexole Extended Release (ER). A successful switch at a specific visit is defined as no worsening of the Unified Parkinsons Disease Rating Scale (UPDRS) parts II+III score by more than 15% from baseline and no drug-related adverse events leading to withdrawal; * To establish if this successful switch can be obtained with or without dose-adaptation; * To provide information about the conversion ratio (mg:mg) from Pramipexole IR to Pramipexole ER.
Interventions
Sponsors
Boehringer Ingelheim
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
1. Male or female patient with idiopathic Parkinson's disease (PD) confirmed by at least two of the following signs: resting tremor, bradykinesia, rigidity. 2. Parkinson's disease diagnosed within 5 years. 3. Patients 30 years of age or older at the time of diagnosis. 4. Modified Hoehn and Yahr stage of 1 to 3. 5. Patients receiving pramipexole IR for at least three months prior to baseline visit (randomization visit, V2). 6. Pramipexole dose should be optimized (according investigator¿s judgement), greater or equal to 1.5 mg/day, stable and equally divided 3 times per day, for a least 4 weeks prior to baseline visit (V2). 7. Patients willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. 8. Signed informed consent obtained before any study procedures are carried out in accordance with International Conference on Harmonization - Good Clinical Practice (ICH-GCP) guidelines and local legislation).
Exclusion criteria
1. Motor complications under levodopa therapy at V1. 2. Atypical parkinsonian syndromes due to drugs, metabolic disorders, encephalitis or degenerative diseases. 3. Dementia, as defined by a Mini-Mental State Exam score \< 24 at V1 4. Any psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria 5. History of psychosis, except history of drug induced hallucinations 6. Clinically significant electrocardiogram (ECG) abnormalities at V1. 7. Clinically significant hypotension either at screening visit or at baseline visit. 8. Malignant melanoma or history of previously treated malignant melanoma. 9. Any other clinically significant disease 10. Pregnancy or breast-feeding. 11. Sexually active female of childbearing potential 12. Serum levels of Aspartate Aminotransferase (Serum Glutamic Oxaloacetic Transaminase) (AST (SGOT)), Alanine Aminotransferase (Serum Glutamate Pyruvate Transaminase) (ALT (SGPT)), alkaline phosphatases or bilirubin \> 2 Upper Limit of Normal (ULN) (on screening lab test). 13. Patients with a creatinine clearance \< 50 mL/min 14. Any dopamine agonist (except pramipexole IR) within three months prior to baseline visit. 15. History of discontinuation of treatment with pramipexole IR 16. Previous treatment with pramipexole ER. 17. Any medication (including intra-muscular formulations) with central dopaminergic antagonist activity within 4 weeks prior to the baseline visit (i.e. typical neuroleptics, atypical antipsychotics, reserpine, methyldopa, centrally-active antiemetics, etc). 18. Any of the following drugs within 4 weeks prior to the baseline visit: methylphenidate, cinnarizine, amphetamines. 19. Flunarizine within 3 months prior to baseline visit. 20. Known hypersensitivity to Pramipexole or its excipients. 21. Drug abuse (including alcohol), according to Investigator¿s judgement, within 2 years prior to screening. 22. Participation in other investigational drug studies or use of other investigational drugs within 4 weeks or five times the half-life of the investigational drug (whichever is longer) prior to baseline visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Successfully Switched From Pramipexole Immediate Release (IR) to Pramipexole ER After a Possible Dose Adaptation, Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) | from baseline to week 9 | A successful switch was defined by no change of the Unified Parkinson's Disease Rating Scale (UPDRS) II+III by more than 15% from baseline to week 9, UPDRS II+III score ranging from 0 (no impairment) to 160 (worst impairment) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in UPDRS Part II+III Total Score at Week 9, FAS (LOCF) | Baseline and week 9 | Unified Parkinson's Disease Rating Scale part II+III total score on FAS, Week 9 - baseline, UPDRS II+III score ranging from 0 (no impairment) to 160 (worst impairment) |
| Change From Baseline in UPDRS Part II Total Score at Week 9, FAS (LOCF) | Baseline and week 9 | Unified Parkinson's Disease Rating Scale part II total score on FAS, Week 9 - baseline, UPDRS II score ranging from 0 (no impairment) to 52 (worst impairment) |
| Change From Baseline in UPDRS Part III Total Score at Week 9, FAS (LOCF) | Baseline and week 9 | Unified Parkinson's Disease Rating Scale part III total score on FAS, week 9 - baseline, UPDRS II+III score ranging from 0 (no impairment) to 108 (worst impairment) |
| Percentage of Patients Who Successfully Switched From Pramipexole IR to Pramipexole ER With no Dose Adaptation, FAS (LOCF) | from baseline to week 4 | A successful switch was defined by no change of the UPDRS II+III by more than 15% from baseline to week 4, UPDRS II+III score ranging from 0 (no impairment) to 160 (worst impairment). |
| Patient Global Impression - Improvement (PGI-I), FAS (LOCF) | Week 9 | Patient Global Impression - Improvement on FAS, PGI-I was rated from 1: very much better, to 7: very much worse, PGI-I responder are defined as being rated as 'unchanged', 'minimally better', 'much better', or 'very much better', PGI-I non-responder are defined as being rated as 'minimally worse', 'much worse', or 'very much worse' |
| Pramipexole Dose Adaptation, FAS (LOCF) | Week 9 | Patients with increase in daily Pramipexole dose on FAS |
| Final Pramipexole Dose (mg) After 9 Weeks, Treated Set | Week 9 | The mean final daily Pramipexole dose is displayed |
| Clinical Global Impression - Improvement (CGI-I), FAS (LOCF) | Week 9 | Clinical Global Impression - Improvement on FAS, CGI-I was rated from 1: very much improved, to 7: very much worse, CGI-I responder are defined as being rated as 'unchanged', 'minimally improved', 'much improved', or 'very much improved', CGI-I non-responder are defined as being rated 'minimally worse', 'much worse' or 'very much worse' |
Countries
France, Germany, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pramipexole Extended Release (ER) 0.375mg, 0.75 mg, 1.5 mg, 2.25 mg, 3.0 mg, 3.75 mg, 4.5mg, q.d (Quaque die, once per day), per os | 104 |
| Pramipexole Immediate Release (IR) 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, t.i.d (Tres in die, three times daily), per os | 52 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Pramipexole Extended Release (ER) | Pramipexole Immediate Release (IR) | Total |
|---|---|---|---|
| Age, Continuous | 63.8 Years STANDARD_DEVIATION 8.8 | 63.5 Years STANDARD_DEVIATION 9.7 | 63.7 Years STANDARD_DEVIATION 9.1 |
| Sex: Female, Male Female | 47 Participants | 21 Participants | 68 Participants |
| Sex: Female, Male Male | 57 Participants | 31 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 104 | 0 / 52 |
| serious Total, serious adverse events | 0 / 104 | 0 / 52 |
Outcome results
Primary
Percentage of Patients Who Successfully Switched From Pramipexole Immediate Release (IR) to Pramipexole ER After a Possible Dose Adaptation, Full Analysis Set (FAS), Last Observation Carried Forward (LOCF)
A successful switch was defined by no change of the Unified Parkinson's Disease Rating Scale (UPDRS) II+III by more than 15% from baseline to week 9, UPDRS II+III score ranging from 0 (no impairment) to 160 (worst impairment)
Time frame: from baseline to week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Percentage of Patients Who Successfully Switched From Pramipexole Immediate Release (IR) to Pramipexole ER After a Possible Dose Adaptation, Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) | Successfully switched | 84.5 Percentage of participants |
| Pramipexole Extended Release (ER) | Percentage of Patients Who Successfully Switched From Pramipexole Immediate Release (IR) to Pramipexole ER After a Possible Dose Adaptation, Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) | Not successfully switched | 15.5 Percentage of participants |
| Pramipexole Immediate Release (IR) | Percentage of Patients Who Successfully Switched From Pramipexole Immediate Release (IR) to Pramipexole ER After a Possible Dose Adaptation, Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) | Successfully switched | 94.2 Percentage of participants |
| Pramipexole Immediate Release (IR) | Percentage of Patients Who Successfully Switched From Pramipexole Immediate Release (IR) to Pramipexole ER After a Possible Dose Adaptation, Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) | Not successfully switched | 5.8 Percentage of participants |
Secondary
Change From Baseline in UPDRS Part II+III Total Score at Week 9, FAS (LOCF)
Unified Parkinson's Disease Rating Scale part II+III total score on FAS, Week 9 - baseline, UPDRS II+III score ranging from 0 (no impairment) to 160 (worst impairment)
Time frame: Baseline and week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Change From Baseline in UPDRS Part II+III Total Score at Week 9, FAS (LOCF) | -1.6 Score on scale | Standard Error 0.5 |
| Pramipexole Immediate Release (IR) | Change From Baseline in UPDRS Part II+III Total Score at Week 9, FAS (LOCF) | -0.5 Score on scale | Standard Error 0.7 |
p-value: 0.206195% CI: [-2.8, 0.6]ANCOVA
Secondary
Change From Baseline in UPDRS Part III Total Score at Week 9, FAS (LOCF)
Unified Parkinson's Disease Rating Scale part III total score on FAS, week 9 - baseline, UPDRS II+III score ranging from 0 (no impairment) to 108 (worst impairment)
Time frame: Baseline and week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Change From Baseline in UPDRS Part III Total Score at Week 9, FAS (LOCF) | -1.2 Score on Scale | Standard Error 0.4 |
| Pramipexole Immediate Release (IR) | Change From Baseline in UPDRS Part III Total Score at Week 9, FAS (LOCF) | -0.3 Score on Scale | Standard Error 0.6 |
p-value: 0.180495% CI: [-2.3, 0.4]ANCOVA
Secondary
Change From Baseline in UPDRS Part II Total Score at Week 9, FAS (LOCF)
Unified Parkinson's Disease Rating Scale part II total score on FAS, Week 9 - baseline, UPDRS II score ranging from 0 (no impairment) to 52 (worst impairment)
Time frame: Baseline and week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Change From Baseline in UPDRS Part II Total Score at Week 9, FAS (LOCF) | -0.3 Score on Scale | Standard Error 0.2 |
| Pramipexole Immediate Release (IR) | Change From Baseline in UPDRS Part II Total Score at Week 9, FAS (LOCF) | -0.1 Score on Scale | Standard Error 0.3 |
p-value: 0.469495% CI: [-0.8, 0.4]ANCOVA
Secondary
Clinical Global Impression - Improvement (CGI-I), FAS (LOCF)
Clinical Global Impression - Improvement on FAS, CGI-I was rated from 1: very much improved, to 7: very much worse, CGI-I responder are defined as being rated as 'unchanged', 'minimally improved', 'much improved', or 'very much improved', CGI-I non-responder are defined as being rated 'minimally worse', 'much worse' or 'very much worse'
Time frame: Week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Clinical Global Impression - Improvement (CGI-I), FAS (LOCF) | CGI-I responder | 90 participants |
| Pramipexole Extended Release (ER) | Clinical Global Impression - Improvement (CGI-I), FAS (LOCF) | CGI-I non-responder | 13 participants |
| Pramipexole Immediate Release (IR) | Clinical Global Impression - Improvement (CGI-I), FAS (LOCF) | CGI-I responder | 41 participants |
| Pramipexole Immediate Release (IR) | Clinical Global Impression - Improvement (CGI-I), FAS (LOCF) | CGI-I non-responder | 11 participants |
p-value: 0.1623Cochran-Mantel-Haenszel
Secondary
Final Pramipexole Dose (mg) After 9 Weeks, Treated Set
The mean final daily Pramipexole dose is displayed
Time frame: Week 9
Population: Treated Set (TS) includes all patients randomized and who received treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Final Pramipexole Dose (mg) After 9 Weeks, Treated Set | 2.75 mg | Standard Deviation 0.95 |
| Pramipexole Immediate Release (IR) | Final Pramipexole Dose (mg) After 9 Weeks, Treated Set | 2.83 mg | Standard Deviation 0.86 |
Secondary
Patient Global Impression - Improvement (PGI-I), FAS (LOCF)
Patient Global Impression - Improvement on FAS, PGI-I was rated from 1: very much better, to 7: very much worse, PGI-I responder are defined as being rated as 'unchanged', 'minimally better', 'much better', or 'very much better', PGI-I non-responder are defined as being rated as 'minimally worse', 'much worse', or 'very much worse'
Time frame: Week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Patient Global Impression - Improvement (PGI-I), FAS (LOCF) | PGI-I responder (unchanged to very much better) | 84 participants |
| Pramipexole Extended Release (ER) | Patient Global Impression - Improvement (PGI-I), FAS (LOCF) | PGI-I non-responder | 19 participants |
| Pramipexole Immediate Release (IR) | Patient Global Impression - Improvement (PGI-I), FAS (LOCF) | PGI-I responder (unchanged to very much better) | 37 participants |
| Pramipexole Immediate Release (IR) | Patient Global Impression - Improvement (PGI-I), FAS (LOCF) | PGI-I non-responder | 15 participants |
p-value: 0.1299Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Who Successfully Switched From Pramipexole IR to Pramipexole ER With no Dose Adaptation, FAS (LOCF)
A successful switch was defined by no change of the UPDRS II+III by more than 15% from baseline to week 4, UPDRS II+III score ranging from 0 (no impairment) to 160 (worst impairment).
Time frame: from baseline to week 4
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Percentage of Patients Who Successfully Switched From Pramipexole IR to Pramipexole ER With no Dose Adaptation, FAS (LOCF) | Successfully switched | 81.6 Percentage of participants |
| Pramipexole Extended Release (ER) | Percentage of Patients Who Successfully Switched From Pramipexole IR to Pramipexole ER With no Dose Adaptation, FAS (LOCF) | Not successfully switched | 18.4 Percentage of participants |
| Pramipexole Immediate Release (IR) | Percentage of Patients Who Successfully Switched From Pramipexole IR to Pramipexole ER With no Dose Adaptation, FAS (LOCF) | Successfully switched | 92.3 Percentage of participants |
| Pramipexole Immediate Release (IR) | Percentage of Patients Who Successfully Switched From Pramipexole IR to Pramipexole ER With no Dose Adaptation, FAS (LOCF) | Not successfully switched | 7.7 Percentage of participants |
Comparison: Successfully switched patients95% CI: [-20.51, 1.48]Wilson score interval
p-value: 0.0803Cochran-Mantel-Haenszel
Secondary
Pramipexole Dose Adaptation, FAS (LOCF)
Patients with increase in daily Pramipexole dose on FAS
Time frame: Week 9
Population: Full Analysis Set (FAS), all randomized patients that received treatment and had baseline and post baseline measurements for the primary endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pramipexole Extended Release (ER) | Pramipexole Dose Adaptation, FAS (LOCF) | Daily dose increased | 17 participants |
| Pramipexole Extended Release (ER) | Pramipexole Dose Adaptation, FAS (LOCF) | Daily dose not increased | 86 participants |
| Pramipexole Immediate Release (IR) | Pramipexole Dose Adaptation, FAS (LOCF) | Daily dose increased | 7 participants |
| Pramipexole Immediate Release (IR) | Pramipexole Dose Adaptation, FAS (LOCF) | Daily dose not increased | 45 participants |
p-value: 0.619Cochran-Mantel-Haenszel