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Levodopa-Carbidopa Intestinal

Phase 3

Advanced Parkinson's Disease | Small molecule | Neurology |AbbVie Inc.|Last Updated: Dec 2, 2022

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
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Trial Design
RandomizedDouble-BlindACTIVE_CONTROLLEDDMCBiomarker
Total Trials6
Total Enrollment757
FDA Designations
No designations recorded
Clinical Trials (6)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT01960842A Study to Assess the Efficacy, Safety and Tolerability of ABT-SLV187 Monotherapy in Subjects With Advanced Parkinson's Disease (PD) and Persistent Motor Complications, Despite Optimized Treatment With Available Anti-Parkinsonian MedicationsPHASE3 COMPLETED 31Oct 1, 2013Mar 1, 2015May 30, 2018 -
NCT01736176A Study to Assess the Safety and Efficacy of Levodopa-carbidopa Intestinal Gel (LCIG) for the Treatment of Non-motor Symptoms in Patients With Advanced Parkinson's DiseasePHASE3 COMPLETED 39Mar 1, 2013Dec 1, 2015Jul 16, 2021 -
NCT00660387Study of Efficacy, Safety and Tolerability of Levodopa-Carbidopa Intestinal Gel in Levodopa-Responsive Parkinson's SubjectsPHASE3 COMPLETED 35Dec 1, 2009Oct 1, 2011Jan 16, 201514 United States, New Zealand
NCT00660673Open Label Continuation Treatment Study With Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's DiseasePHASE3 COMPLETED 262Nov 13, 2009Nov 30, 2021Dec 2, 202261 United States, Australia +9
NCT00357994Study of Efficacy, Safety and Tolerability of Levodopa-Carbidopa Intestinal Gel in Levodopa-Responsive Parkinson's SubjectsPHASE3 COMPLETED 36Jan 1, 2009Oct 1, 2011Jan 16, 201515 United States, Germany
NCT00335153Levodopa-Carbidopa Intestinal Gel Open-Label Study in Advanced Parkinson's DiseasePHASE3 COMPLETED 354Jan 1, 2008Jun 1, 2012Jan 16, 201583 United States, Australia +14
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Study Endpoints
Primary Endpoints
Average Daily Normalized "Off" Time: Change From Baseline To The Final PEG-J Visit
Baseline (end of screening period) and Final PEG-J Visit (up to week 12)

Based on the Parkinson's Disease Symptom Diary. "On" time is when PD symptoms are well controlled by the drug. "Off" time is when PD symptoms are not adequately controlled by the drug. The diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected clinic visits. It reflects both time awake and time asleep. Daily totals are normalized to a 16-hour scale (i.e. 16 hours of awake time). The normalized totals for the 3 days prior to the visit are averaged for the analysis. Negative change from baseline for "off" time indicates improvement.

Change From Baseline to Week 12 in the Non-Motor Symptom Scale (NMSS) Total Score
Baseline and Week 12

The NMSS measures the frequency and severity of a range of non-motor symptoms in Parkinson's Disease. It consists of 30 questions grouped into 9 domains: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastro-intestinal tract, urinary, sexual function, and miscellaneous (pain, taste/smell, weight change, excessive sweating). Severity is rated on a scale from 0 (none) to 3 (severe) and frequency is rated on a scale from 1 (rarely) to 4 (very frequent). Item scores are calculated as the product of severity and frequency; the total score is obtained by summing the item scores. The NMSS total score ranges from 0 to 360 with a lower score indicating fewer symptoms; a negative change from baseline indicates improvement in symptoms.

Change From Baseline to Week 12 in Average Daily Normalized "Off" Time
Baseline, Week 12

Based on the Parkinson's Disease Symptom Diary. "On" time is when PD symptoms are well controlled by the drug. "Off" time is when PD symptoms are not adequately controlled by the drug. The diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected clinic visits. It reflects both time awake and time asleep. Daily totals are normalized to a 16-hour scale (i.e. 16 hours of awake time). The normalized totals for the 3 days prior to the visit are averaged for the analysis. Negative change from baseline for "off" time indicates improvement.

Number of Participants With Treatment-emergent Adverse Events
From first dose of LCIG in this study up to 30 days after the date of last PEG-J exposure; median duration of treatment was 1178 days, with a maximum of 4217 days (11.5 years).

Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) which started on or after the date of the first LCIG Infusion in this study and within 30 days of the date of the last PEG-J exposure. At least possibly drug-related is defined as TEAEs assessed as having a "Possible" or "Probable" or missing relationship to study drug. Serious AEs included any untoward medical occurrence that: * Resulted in death * Was life-threatening * Required inpatient hospitalization or prolongation of an existing hospitalization * Resulted in persistent or significant disability/incapacity * was a congenital anomaly/birth defect The severity of all AEs was characterized as mild, moderate or severe according to the following definitions: * Mild: usually transient and do not interfere with daily activities. * Moderate: low level of inconvenience or concern to the subject, may interfere with daily activities. * Severe: events interrupt the subject's usual daily activity.

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths and Discontinuations Due to AEs
Screening through Day 378 + 30 days

AE=any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that: results in death; is life-threatening (an event in which the subject was at risk of death at the time of the event); requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events. Treatment-emergent events (TEAE or TESAE)=those starting after the first dose of study drug. Severe=severity reported as 'severe' or missing. Possibly or Probably Treatment Related=drug-event relationship reported as 'possible', 'probable' or missing. Death=a fatal outcome of an SAE or AE.

Number of Participants With Device Complications During the Nasojejunal (NJ) Test Period
NJ Test Period (from 2 to 14 days)

Complications of the infusion device were collected during the NJ Test period. Pump, intestinal tube, NJ tube, and other complications included (but were not limited to) device breakage, device leakage, device malfunction, device misuse, device occlusion, intentional and unintentional device removal by participant, complication of device insertion, device dislocation, device breakage, device dislocation, and post-procedural hemorrhage.

Number of Participants With Device Complications During the Percutaneous Endoscopic Gastrostomy - With Jejunal Extension Tube (PEG-J) Surgery and Post-PEG Long Term Treatment Periods
PEG-J Surgery Period (from 2 to 14 days) through the Long Term Treatment Period (Day 28 to Day 378)

Complications of the infusion device were collected during the PEG-J Surgery and Post-PEG Long-Term Treatment periods. Pump, PEG-J, stoma, and other complications included (but were not limited to) device breakage, device leakage, device malfunction, device misuse, device occlusion, intentional and unintentional device removal by participant, complication of device insertion, device dislocation, device breakage, device dislocation, and post-procedural hemorrhage.

Number of Participants With Potentially Clinically Significant Values for Hematology Parameters
Screening through Day 378

Potentially clinically significant values for red blood cells (RBCs), hemoglobin, and hematocrit are specified for females (f) and males (m) separately in the category rows.

Number of Participants With Potentially Clinically Significant Values for Clinical Chemistry Parameters
Screening through Day 378

Terms abbreviated in the table include aspartate aminotransferase (AST), upper limit of normal (ULN), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), female (f), and male (m).

Number of Participants With Potentially Clinically Significant Vital Sign Parameters
up to 56 weeks

Terms abbreviated in the table include supine systolic blood pressure (SuSBP), standing systolic blood pressure (StSBP), orthostatic systolic blood pressure (OSBP), supine diastolic blood pressure (SuDBP), standing diastolic blood pressure (StDBP), orthostatic diastolic blood pressure (ODBP), supine pulse (SuP) in beats per minute (bpm), standing pulse (StP), and body temperature (Temp). Increase and decrease are signified by ↑ and ↓, respectively.

Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Parameters
Screening through Day 378

Terms abbreviated in the table include heart rate (HR) in beats per minute (bpm), PR interval (PRI), QT interval corrected for heart rate using Bazett's formula (QTcB), and QT interval corrected for heart rate using Fridericia's formula (QTcF). Increase and decrease are signified by ↑ and ↓, respectively.

Number of Participants With Sleep Attacks at Baseline
Baseline

To prospectively monitor for the possible development of sleep attacks, participants were asked if they had experienced any events in which they fell asleep suddenly or unexpectedly, including while engaged in some activity (e.g., eating/drinking, speaking, or driving) or at rest, with or without any previous warning of sleepiness. Those participants who reported 1 or more sleep attacks were asked to report the number of sleep attacks they experienced, whether they experienced sleepiness or drowsiness prior to the sleep attack, whether they experienced a 'bad' outcome or problem due to a sleep attack, and if so, how many 'bad' outcomes or problems they experienced.

Number of Participants With Sleep Attacks During the Post-PEG Long-Term Treatment Period
During the Post-PEG Long-Term Treatment Period (Day 28 through Day 378)

To prospectively monitor for the possible development of sleep attacks, participants were asked if they had experienced any events in which they fell asleep suddenly or unexpectedly, including while engaged in some activity (e.g., eating/drinking, speaking, or driving) or at rest, with or without any previous warning of sleepiness. Those participants who reported 1 or more sleep attacks were asked to report the number of sleep attacks they experienced, whether they experienced sleepiness or drowsiness prior to the sleep attack, whether they experienced a 'bad' outcome or problem due to a sleep attack, and if so, how many 'bad' outcomes or problems they experienced.

Summary of Minnesota Impulsive Disorder Interview (MIDI) Assessment of Intense Impulsive Behavior at Baseline (BL) and During the Post-PEG Long-term Treatment (PPLT) Period
Baseline, during the Post-PEG Long-term Treatment Period (Day 28 through Day 378)

The MIDI is a validated assessment of impulsive behavior consisting of a semistructured clinical interview assessing pathological gambling, trichotillomania (compulsive hair-pulling), kleptomania (compulsive stealing), pyromania (compulsive fire setting), intermittent explosive disorder, compulsive buying, and compulsive sexual behavior.

Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score at Endpoint
Baseline, Endpoint (last Post-PEG Long-Term Period visit up to Day 378)

The AIMS is an investigator-completed rating scale that has a total of 12 items rating involuntary movements of various areas of the participant's body. Items 1 through 10 are rated on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe), and items 11 and 12 are yes/no questions regarding issues with teeth or dentures. The total AIMS score was calculated by summing items 1-10, with a possible range of 0-40; a negative change indicates improvement. The AIMS was to be performed at consistent times, when the subject was experiencing his/her worst "On" time (dyskinesia \[involuntary muscle movement\]).

Number of Participants With Confirmed Cases of Melanoma
Screening up to Day 378

A comprehensive assessment for the presence of melanoma was performed during the screening period and at early termination or end of study by a dermatologist experienced with the diagnosis of the condition. If a suspicious lesion was present, a biopsy was obtained for proper diagnosis.

Number of Participants Taking at Least 1 Concomitant Medication During the Study
Screening up to Day 378

Concomitant medications include those started on or after the first open-label LCIG infusion as well as medications started prior to the first open-label infusion but continued during the study.

Secondary Endpoints
Average Daily Normalized "On" Time Without Troublesome Dyskinesia: Change From Baseline To The Final PEG-J Visit
Baseline (end of screening period) and Final PEG-J Visit (up to week 12)
Parkinson's Disease Questionnaire (PDQ-39) Summary Index: Change From Baseline To The Final PEG-J Visit
Baseline (end of screening period) and Final PEG-J Visit (up to week 12)
Clinical Global Impression - Change (CGI-I) Score at the Final PEG-J Visit
Final PEG-J Visit (up to week 12)
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Study Design & Arms
AllocationNA
MaskingNONE
ModelSINGLE_GROUP
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
Levodopa-Carbidopa Intestinal Gel (LCIG)EXPERIMENTALAll participants received LCIG via the N-J tube during the nasojejunal (N-J) Test Period and delivered to the proximal small intestine via percutaneous endoscopic gastrostomy - with jejunal extension tube (PEG-J) during the Post-PEG-J Long-Term Treatment Period. The starting dose was individually determined based on the daily dose of oral levodopa prior to study enrollment. The infusion dose was individually optimized for each participant on the basis of response and potential adverse events. During the PEG-J Period, LCIG was expected to be infused continuously over approximately 16 hours daily with a rate of infusion ranging from 1 to 10 mL/hour (20 to 200 mg of levodopa/hour).
Levodopa-Carbidopa Intestinal GelEXPERIMENTALParticipants had the PEG-J tube placement procedure performed on Study Day 1 and, at the discretion of the investigator, began initiation and titration of LCIG infusion. Dosing was determined individually. The starting total daily dose of LCIG was based solely on the daily dose of the oral levodopa taken immediately prior to Study Day 1 and was adjusted to obtain the optimal clinical response for the individual participant. Participants received treatment for up to 60 weeks; participants who completed their Week 60 visit before LCIG was commercially available had the option to extend their LCIG therapy, if in the opinion of the investigator, the participant would benefit from continued LCIG treatment.
Levodopa-Carbidopa Intestinal Gel (LCIG) + Placebo CapsulesEXPERIMENTALParticipants were randomized to LCIG (levodopa, 20 mg/mL and carbidopa monohydrate, 5 mg/mL) and placebo capsules. Participants received the percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) procedure for gel administration of LCIG.
Placebo Gel + Levodopa-Carbidopa CapsulesACTIVE_COMPARATORParticipants were randomized to placebo intestinal gel and oral levodopa-carbidopa (levodopa, 100 mg and carbidopa, 25 mg) Immediate Release (IR) capsules. Participants received the percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) procedure for gel administration of placebo.
Interventions
NameTypeDescription
Levodopa-carbidopa intestinal gelDRUGDose levels will be individually optimized. Infusion should be kept within a range of 0.5-10 mL/hour (10-200 mg levodopa/hour) and is usually 2-6 mL/hour (40-120 mg levodopa/hour)
CADD-Legacy® 1400 ambulatory infusion pumpDEVICE -
PEG tubeDEVICEpercutaneous endoscopic gastrostomy tube
J-tubeDEVICEjejunal tube
Percutaneous Endoscopic Gastrostomy with Jejunal Extension (PEG-J)PROCEDURE -
Levodopa-carbidopa Immediate Release (LC-IR) TabletsDRUGAfter LCIG initiation, participants could take prescribed oral levodopa-carbidopa immediate or continuous release (i.e., oral LC prescribed by the investigator) for nighttime use.
Levodopa carbidopa intestinal gel (LCIG)DRUGinfusion should be kept within a range of 0.5-10 mL/hour (10-200 mg levodopa/hour) and is usually 2-6 mL/hour (40-120 mg levodopa/hour)
Placebo GelDRUG -
Levodopa-carbidopa (LC) oral encapsulated immediate release (IR) tabletsDRUG -
Placebo (PBO) oral capsulesDRUG -
Levodopa-Carbidopa Intestinal Gel (LCIG)DRUGLCIG for upper-intestinal infusion is a suspension of levodopa (20 mg/mL) and carbidopa (5 mg/mL) in an aqueous gel that is dispensed in a medication cassette reservoir containing 100 mL of LCIG.
Percutaneous Endoscopic Gastrostomy with jejunal extension tube (PEG-J)DEVICEAll participants previously had a PEG-J placed in one of the prior LCIG studies.
Levodopa carbidopa (LC) oral encapsulated immediate release (IR) tabletsDRUG -
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Eligibility Criteria
Age Range30 Years — N/A
SexALL
Healthy VolunteersNo

Inclusion Criteria: 1. Diagnosis of idiopathic Parkinson's disease according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria. 2. Subjects have 4 or 5 in modified Hohn and Yahr (H \& Y) classification of disease severity at "Off" state determined by the UPDRS Part V at ...

Countries:United StatesNew ZealandAustraliaCanadaCzechiaIsraelPolandPortugalRussiaThailandUnited KingdomGermanyFinlandItalyNetherlandsSpain
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