Parkinson's Disease (Disorder)
Conditions
Keywords
Idiopathic Parkinson's Disease, Lewy Body Parkinson's Disease, Paralysis Agitans, Primary Parkinsonism
Brief summary
To evaluate the safety and efficacy of IPX203 (carbidopa and levodopa) extended-release capsules (IPX203 ER CD-LD) in comparison to immediate release (IR) CD-LD in the treatment of CD-LD-experienced participants with Parkinson's disease (PD) who have motor fluctuations.
Detailed description
This was a multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study. The study consisted of a 3-week, open-label IR CD-LD dose adjustment period; a 4-week, open-label period for conversion to IPX203; followed by a 13-week double-blind treatment period with participants randomized in a 1:1 ratio, stratified by center, to receive either IPX203 (with matching IR CD-LD placebo) or IR CD-LD (with matching IPX203 placebo).
Interventions
DRUGIR CD-LD
Active comparator - IR CD-LD
DRUGIPX203 ER CD-LD
Investigational formulation - ER CD-LD
OTHERPlacebo Matching IPX203
Double dummy placebo capsules
OTHERPlacebo Matching IR CD-LD
Double dummy placebo tablets
Sponsors
Impax Laboratories, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double dummy, blinded drug
Intervention model description
Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants diagnosed at age ≥ 40 years with PD, consistent with the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria and who are being treated with stable regimens of CD-LD but experiencing motor fluctuations. * Able to provide written informed consent prior to the conduct of any study-specific procedures. * Female participants of childbearing potential must have a negative urine pregnancy test at Screening Visit. * Negative urine screen for drugs of abuse and negative alcohol breath test at Screening. * Hoehn and Yahr Stages 1, 2, 3, or 4 in the On state (part of Movement Disorders Society version of the Unified Parkinson's Disease Rating Scale \[MDS-UPDRS\] Part III) * Agrees to use a medically acceptable method of contraception throughout the study and for 6 weeks after completing the study. Medically acceptable methods of contraception that may be used by the participant and/or partner include but are not limited to: abstinence, oral contraception, NuvaRing or transdermal systems, diaphragm with vaginal spermicide, intrauterine device, condom and partner using vaginal spermicide, surgical sterilization (6 months), progestin implant or injection, or postmenopausal female (no menstrual period for ˃ 2 years) or vasectomy (˃ 6 months). * Montreal Cognitive Assessment (MoCA) score ≥ 24 at Screening Visit in On state. * Able to differentiate On state from Off state as determined by at least 75% concordance with a trained rater in On/Off ratings for 8 ratings over a 4-hour training period. The concordance must include at least 1 On and 1 Off rating and must be achieved within two 4-hour training sessions. * Able and willing to comply with the protocol, including completion of diaries and availability for all study visits. * Responsive to CD-LD therapy and currently being treated on a stable regimen with CD-LD for at least 4 weeks prior to Visit 1. * At Screening, the participant has predictable Off periods.
Exclusion criteria
* Received any investigational medications within 30 days or 5 times the half-life, whichever is longer, prior to Visit 1. * Female participants who are currently breastfeeding or lactating. * Had prior neurosurgical treatment for PD or if such procedure is planned or anticipated during the study period. * Allergic to any excipient in the study drugs. * History of medical conditions or of a prior surgical procedure that would interfere with LD absorption, such as gastrectomy, proximal small-bowel resection, or bariatric surgery. * History of upper gastrointestinal hemorrhage in participants with peptic ulcer disease within the past 5 years. * History of glaucoma with intraocular pressures that are elevated despite appropriate medical management. * History of seizure or epilepsy and experienced at least 1 seizure during the past 12 months or has not been compliant with medically recommended therapy or visits. * History of myocardial infarction with residual atrial, nodal, or ventricular arrhythmias that are not controlled with medical and/or surgical interventions. A recent (≤ 12 months) history of myocardial infarction with secondary arrhythmias is exclusionary regardless of the therapeutic control. * History of neuroleptic malignant syndrome or of nontraumatic rhabdomyolysis. * Liver enzyme values ≥ 2.5 times the upper limit of normal; or history of severe hepatic impairment. * Serum creatinine level ≥ 1.75 times the upper limit of normal; or requires dialysis at the time of Screening. * Participant with a history of malignant melanoma or with a suspicious undiagnosed skin lesion which in the opinion of the investigator could be melanoma. * History of drug or alcohol abuse within the 12 months prior to Screening. * Received within 4 weeks of Screening or planning to take during participation in the clinical study: * Any doses of a CR CD-LD apart from a single daily bedtime dose, any doses of Rytary, additional CD (eg, Lodosyn) or benserazide (eg, Serazide), or catechol-O-methyl transferase inhibitors (entacapone or tolcapone) or medications containing these inhibitors (Stalevo), * Nonselective monoamine oxidase inhibitors (MAOI), apomorphine, or antidopaminergic agents, including antiemetics. * Employees or family members of the investigator, study site, or sponsor. * Participants who have previously participated in an IPX203 study. * Participants who, in the opinion of the clinical investigator, should not participate in the study. * Based on clinical assessment, participant does not adequately comprehend the terminology needed to complete the PD diary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET) | Baseline (Week 7) and Week 20/ET | Good on time was derived from the 3-day PD Diaries. For each day, Good on time was calculated by adding the number of half-hour intervals in which either an On without dyskinesia or On with nontroublesome dyskinesia was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. Least square mean (LSM), standard error (SE), confidence interval (CI), Mixed model repeated measures (MMRM), Change from baseline (CFB). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Off Time Per Day at Week 20/ET | Baseline (Week 7) and Week 20/ET | Off time was derived from the 3-day PD Diaries. For each day, Off time was calculated by adding the number of half-hour intervals in which the Status Off was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. |
| Percentage of Participants With Either Much Improved or Very Much Improved in Patient Global Impression of Change (PGI-C) Scores at Week 20/ET | Week 20/ET | The Patient Global Impression of Change (PGIC) is self assessment questionnaire which was used by participants to compare his/her condition on a 7-point scale ranging from 1-Very Much Worse, 2-Much Worse, 3-Minimally Worse, 4-No Change, 5-Minimally Improved, 6-Much Improved, 7-Very Much Improved. Percentage of participants with either Much Improved or Very Much Improved was reported. |
| Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET | Baseline (Week 7) and Week 20/ET | MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). Part III score ranges from 0 to 136. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. |
| Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET | Baseline (Week 7) and Week 20/ET | MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). The scale range for Part II+III score is 0-188. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. |
Countries
Czechia, France, Germany, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 630 enrolled participants entered the immediate release carbidopa-levodopa (IR CD-LD) dose adjustment period of which 589 participants entered IPX203 conversion period of which 506 participants entered double-blind maintenance period. Participants were randomized in a 1:1 ratio in double blind period.
Pre-assignment details
Participants with parkinsons disease (PD) who were treated with stable regimens of carbidopa - levodopa (CD - LD) were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| IPX203 - Double-Blind Maintenance Participants received IPX203 capsules orally, every 6 - 12 hours for 13 weeks at a stable dose established at the end of dose conversion period along with placebo matched to IR CD-LD. | 256 |
| IR CD-LD - Double -Blind Maintenance Participants received IR CD - LD tablets daily orally, for 13 weeks at a stable dose established at the end of dose adjustment period along with placebo matched to IPX203. | 250 |
| Not Randomized Participants who discontinued from dose adjustment and dose conversion. | 124 |
| Total | 630 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Dose Adjustment (Weeks 1- 3) | Adverse Event | 4 | 0 | 0 | 0 |
| Dose Adjustment (Weeks 1- 3) | Lack of Efficacy | 1 | 0 | 0 | 0 |
| Dose Adjustment (Weeks 1- 3) | Miscellaneous | 21 | 0 | 0 | 0 |
| Dose Adjustment (Weeks 1- 3) | Protocol Violation | 6 | 0 | 0 | 0 |
| Dose Adjustment (Weeks 1- 3) | Withdrawal by Subject | 9 | 0 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Adverse Event | 0 | 35 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Lack of Efficacy | 0 | 10 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Miscellaneous | 0 | 2 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Non compliance | 0 | 2 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Protocol Violation | 0 | 1 | 0 | 0 |
| Dose Conversion (Weeks 4 - 7) | Withdrawal by Subject | 0 | 32 | 0 | 0 |
| Double Blind Maintenance (Weeks 8 - 20) | Adverse Event | 0 | 0 | 14 | 3 |
| Double Blind Maintenance (Weeks 8 - 20) | Lack of Efficacy | 0 | 0 | 5 | 8 |
| Double Blind Maintenance (Weeks 8 - 20) | Miscellaneous | 0 | 0 | 1 | 0 |
| Double Blind Maintenance (Weeks 8 - 20) | Non compliance | 0 | 0 | 1 | 0 |
| Double Blind Maintenance (Weeks 8 - 20) | Protocol Violation | 0 | 0 | 3 | 1 |
| Double Blind Maintenance (Weeks 8 - 20) | Withdrawal by Subject | 0 | 0 | 10 | 11 |
Baseline characteristics
| Characteristic | IPX203 - Double-Blind Maintenance | IR CD-LD - Double -Blind Maintenance | Not Randomized | Total |
|---|---|---|---|---|
| Age, Continuous | 66.1 years STANDARD_DEVIATION 9.02 | 66.5 years STANDARD_DEVIATION 8.85 | 67.3 years STANDARD_DEVIATION 9 | 66.5 years STANDARD_DEVIATION 8.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 31 Participants | 14 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 223 Participants | 215 Participants | 106 Participants | 544 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 244 Participants | 242 Participants | 120 Participants | 606 Participants |
| Sex: Female, Male Female | 97 Participants | 73 Participants | 64 Participants | 234 Participants |
| Sex: Female, Male Male | 159 Participants | 177 Participants | 60 Participants | 396 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 630 | 0 / 589 | 0 / 256 | 0 / 250 |
| other Total, other adverse events | 40 / 630 | 130 / 589 | 35 / 256 | 32 / 250 |
| serious Total, serious adverse events | 7 / 630 | 12 / 589 | 8 / 256 | 4 / 250 |
Outcome results
Primary
Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET)
Good on time was derived from the 3-day PD Diaries. For each day, Good on time was calculated by adding the number of half-hour intervals in which either an On without dyskinesia or On with nontroublesome dyskinesia was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. Least square mean (LSM), standard error (SE), confidence interval (CI), Mixed model repeated measures (MMRM), Change from baseline (CFB).
Time frame: Baseline (Week 7) and Week 20/ET
Population: The Modified Intent-to-Treat (mITT) Analysis Set included all participants who were randomized and treated and had a valid baseline PD Diary and at least one valid post-randomization PD Diary. Participants with available data at specified time point were included in analysis. Data was planned to be reported only for double-blind Maintenance period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IPX203 - Double-Blind Maintenance | Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET) | Baseline (Week 7) | 11.67 hours/day | Standard Deviation 2.943 |
| IPX203 - Double-Blind Maintenance | Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET) | Change at Week 20/ET | -0.39 hours/day | Standard Deviation 2.706 |
| IR CD-LD - Double -Blind Maintenance | Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET) | Baseline (Week 7) | 11.72 hours/day | Standard Deviation 2.759 |
| IR CD-LD - Double -Blind Maintenance | Mean Change From Baseline in Good on Time Per Day at Week 20/Early Termination (ET) | Change at Week 20/ET | -0.97 hours/day | Standard Deviation 3.081 |
p-value: 0.019495% CI: [0.09, 0.97]MMRM
Secondary
Change From Baseline in Off Time Per Day at Week 20/ET
Off time was derived from the 3-day PD Diaries. For each day, Off time was calculated by adding the number of half-hour intervals in which the Status Off was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization.
Time frame: Baseline (Week 7) and Week 20/ET
Population: mITT population with available data at specified time point. Data was planned to be reported only for double-blind Maintenance period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IPX203 - Double-Blind Maintenance | Change From Baseline in Off Time Per Day at Week 20/ET | Baseline (Week 7) | 3.95 hours/day | Standard Deviation 2.524 |
| IPX203 - Double-Blind Maintenance | Change From Baseline in Off Time Per Day at Week 20/ET | Change at Week 20/ET | 0.29 hours/day | Standard Deviation 2.235 |
| IR CD-LD - Double -Blind Maintenance | Change From Baseline in Off Time Per Day at Week 20/ET | Baseline (Week 7) | 4.02 hours/day | Standard Deviation 2.466 |
| IR CD-LD - Double -Blind Maintenance | Change From Baseline in Off Time Per Day at Week 20/ET | Change at Week 20/ET | 0.76 hours/day | Standard Deviation 2.901 |
p-value: 0.025295% CI: [-0.9, -0.06]MMRM
Secondary
Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET
MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). Part III score ranges from 0 to 136. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization.
Time frame: Baseline (Week 7) and Week 20/ET
Population: ITT population with available data at specified time point. Data was planned to be reported only for double-blind Maintenance period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IPX203 - Double-Blind Maintenance | Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET | Baseline (Week 7) | 26.9 score on a scale | Standard Deviation 16.62 |
| IPX203 - Double-Blind Maintenance | Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET | Change at Week 20/ET | 1.1 score on a scale | Standard Deviation 11.07 |
| IR CD-LD - Double -Blind Maintenance | Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET | Baseline (Week 7) | 27.0 score on a scale | Standard Deviation 16.83 |
| IR CD-LD - Double -Blind Maintenance | Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET | Change at Week 20/ET | 0.9 score on a scale | Standard Deviation 10.1 |
p-value: 0.958795% CI: [-1.8, 1.7]MMRM
Secondary
Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET
MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). The scale range for Part II+III score is 0-188. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization.
Time frame: Baseline (Week 7) and Week 20/ET
Population: ITT population with available data at specified time point. Data was planned to be reported only for double-blind Maintenance period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IPX203 - Double-Blind Maintenance | Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET | Baseline (Week 7) | 38.9 score on a scale | Standard Deviation 22.2 |
| IPX203 - Double-Blind Maintenance | Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET | Change at Week 20/ET | 2.0 score on a scale | Standard Deviation 13.54 |
| IR CD-LD - Double -Blind Maintenance | Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET | Baseline (Week 7) | 39.3 score on a scale | Standard Deviation 21.65 |
| IR CD-LD - Double -Blind Maintenance | Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET | Change at Week 20/ET | 1.8 score on a scale | Standard Deviation 12.39 |
p-value: 0.966895% CI: [-2.2, 2.1]MMRM
Secondary
Percentage of Participants With Either Much Improved or Very Much Improved in Patient Global Impression of Change (PGI-C) Scores at Week 20/ET
The Patient Global Impression of Change (PGIC) is self assessment questionnaire which was used by participants to compare his/her condition on a 7-point scale ranging from 1-Very Much Worse, 2-Much Worse, 3-Minimally Worse, 4-No Change, 5-Minimally Improved, 6-Much Improved, 7-Very Much Improved. Percentage of participants with either Much Improved or Very Much Improved was reported.
Time frame: Week 20/ET
Population: The Intent-to-treat (ITT) Analysis Set included all participants who were randomized and treated with any study drug and had a baseline and at least one post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IPX203 - Double-Blind Maintenance | Percentage of Participants With Either Much Improved or Very Much Improved in Patient Global Impression of Change (PGI-C) Scores at Week 20/ET | 29.7 percentage of participants |
| IR CD-LD - Double -Blind Maintenance | Percentage of Participants With Either Much Improved or Very Much Improved in Patient Global Impression of Change (PGI-C) Scores at Week 20/ET | 18.8 percentage of participants |
p-value: 0.001595% CI: [3.5, 18.3]Cochran-Mantel-Haenszel