The purpose of this study was to assess efficacy, safety, tolerability, and pharmacokinetics of ABBV-8E12 in participants with progressive supranuclear palsy (PSP).
This was a Phase 2, randomized, double-blind, placebo-controlled, multiple dose, multicenter study consisting of a screening period of up to 8 weeks (56 days), a 52-week double-blind treatment period, and a post-treatment follow-up period of approximately 20 weeks following last study drug administration (for those participants who prematurely discontinued from treatment, declined to participate in or did not qualify for participation in a long term extension \[LTE\] study). At the end of the treatment period, extended treatment was available for eligible participants who completed the 52-week treatment period and entered the separate long-term extension study (NCT03391765; Study M15-563). There were 3 cohorts in the study (Cohort 1, Cohort J1, and Cohort 2). Cohort 1 had augmented safety and pharmacokinetic (PK) assessments in the first 30 participants enrolled into the global study from countries other than Japan. Cohort J1 had augmented safety and PK assessments in the first 9 participants enrolled into the study from Japan. Cohort 2 consisted of all other participants enrolled in the global study not participating in Cohort 1 or Cohort J1. This study was prematurely discontinued because the program for progressive supranuclear palsy was discontinued due to lack of efficacy of study drug.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
378
Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW \>59 kg, 4.7 mL/min or 282 mL/hr.
Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW \>59 kg, 4.7 mL/min or 282 mL/hr. For participants in Cohort 2, ABBV-8E12 doses may have been decreased after the evaluation by the Data Monitoring Committee of available safety, tolerability and pharmacokinetic data.
Change From Baseline to Week 52 in Progressive Supranuclear Palsy Rating Scale (PSPRS) Total Score
The PSPRS consists of 28 items grouped in six domains: daily activities (by history); behavior; bulbar; ocular motor; limb motor; and gait/midline. Items are scored on a 0 to 4 scale, except for six items that are scored on a 0 to 2 scale, with the total score ranging from 0 to 100. Higher scores indicate more severe disability or movement abnormality. Positive changes in score indicate worsening from baseline.
Time frame: Baseline, Week 52
Number of Participants With Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs) are defined as any event that began or worsened in severity from first dose of study drug until 20 weeks after the last dose. For more details on AEs please see the Adverse Event section.
Time frame: From the first dose of study drug until 20 weeks following discontinuation of study drug administration have elapsed (approximately 5 half-lives), up to 80 weeks
Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living)
The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part II score is the sum of the answers to the 13 questions related to Activities of Daily Living, and ranges from 0-52. Higher scores are associated with more disability. Positive changes in score indicate worsening from baseline.
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University of Alabama at Birmingham - Main /ID# 144892
Birmingham, Alabama, United States
Mayo Clinic - Scottsdale /ID# 144893
Scottsdale, Arizona, United States
Cedars-Sinai Medical Center /ID# 149775
Beverly Hills, California, United States
Ucsd /Id# 144905
La Jolla, California, United States
Usc /Id# 149773
Los Angeles, California, United States
University of California, Los Angeles /ID# 144896
Los Angeles, California, United States
Univ California, San Francisco /ID# 144897
San Francisco, California, United States
Rocky Mountain Movement Disorders Center /ID# 153397
Englewood, Colorado, United States
University of Florida - Archer /ID# 144906
Gainesville, Florida, United States
Mayo Clinic /ID# 144911
Jacksonville, Florida, United States
...and 56 more locations
Time frame: Baseline, Week 52
Clinical Global Impression of Change (CGI-C) Score at Week 52
The Clinical Global Impression of Change (CGI-C) score is a clinician's rating scale for assessing Global Improvement of Change. The CGI-C rates improvement by 7 categories: very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7). The CGI-C score ranges from 1 to 7, with lower scores indicating improvement.
Time frame: Week 52
Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify midbrain atrophy. Negative changes in values indicate a reduction in volume.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL)
The Schwab and England Activities of Daily Living (SEADL) consists of ten items intended to evaluate the daily life activities of a participant. The SEADL is composed of two sections: the first is a self-reported questionnaire in which participants grade their own daily life activities, such as dressing, using the toilet, resting, eating, and social activities (subjective assessment), and the second is an assessment of motor functions, such as postural balance, speaking, rigidity, and tremors, conducted by a clinician (objective assessment). It is a percentage scale divided into deciles, and the results are reported between 0% (bedridden) and 100% (healthy). Negative changes in values indicate a decline in health.
Time frame: Baseline, Week 52
Maximum Observed Serum Concentration (Cmax) for ABBV-8E12
The maximum observed serum concentration after the first and the fifth doses in Cohort 1 and Cohort J1 was determined.
Time frame: First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113
Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12
The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax, the maximum plasma concentration. Tmax was measured after the first and the fifth doses in Cohort 1 and Cohort J1.
Time frame: First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113
Area Under the Concentration Time Curve (AUC) for ABBV-8E12
The area under the plasma concentration-time curve (AUC; measured in µg•day/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ABBV-8E12 was estimated using non-compartmental methods after the first and the fifth doses in Cohort 1 and Cohort J1.
Time frame: First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113
Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough)
The concentration of ABBV-8E12 immediately prior to infusion of the fifth dose (Ctrough; measured in µg/mL) was estimated using non-compartmental methods in Cohort 1 and Cohort J1.
Time frame: First day of the Fifth Dosing Interval, Day 85
Mean Change From Baseline to Week 52 in Clinical Global Impression of Severity (CGI-S) Score
The CGI-S is a clinician's rating of disease severity. The CGI-S rates severity of illness on a 7-point scale, using a range of responses from 1 (normal) through 7 (the most severely ill). This rating is based upon observed and reported symptoms, behavior, and function in the past 7 days. Positive changes in score indicate worsening from baseline.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSP-QoL) Total Score
The PSP-QoL is a validated patient-reported outcome measure, specifically designed to assess the quality of life of participants with PSP. There are 45 items and two subscales: physical and mental impact. Items are scored from 0 (no problem) to 4 (extreme problems). The total subscale sum scores are linearly converted into a 0 to 100 scale, and higher scores indicate a lower quality of life. Positive changes in score indicate a decline in quality of life.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score
The Progressive Supranuclear Palsy Rating Scale (PSPRS) consists of 28 items grouped in six domains: daily activities (by history); behavior; bulbar; ocular motor; limb motor; and gait/midline. Items are scored on a 0 to 4 scale, except for four items that are scored on a 0 to 2 scale, with the total score ranging from 0 to 100. Higher scores indicate more severe disability or movement abnormality. The PSP-SS score is a composite of the dysphagia and gait items from the PSPRS. Positive changes in score indicate worsening from baseline.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify third ventricle atrophy. Positive changes in values indicate an increase in volume.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify Superior cerebellar peduncle atrophy. Negative changes in values indicate a reduction in volume.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify brainstem atrophy. Negative changes in values indicate a reduction in volume.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify whole brain atrophy. Negative changes in values indicate a reduction in volume.
Time frame: Baseline, Week 52
Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify frontal lobe atrophy. Positive changes in values indicate an increase in volume.
Time frame: Baseline, Week 52
Time to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26
The PSPRS consists of 28 items grouped in six domains: daily activities (by history); behavior; bulbar; ocular motor; limb motor; and gait/midline. Items are scored on a 0 to 4 scale, except for six items that are scored on a 0 to 2 scale, with the total score ranging from 0 to 100. Higher scores indicate more severe disability or movement abnormality. Item 26 pertains to gait, scored as either 0 (normal); 1 (slightly wide-based or irregular or slight pulsion on turns); 2 (must walk slowly or occasionally use walls or helper to avoid falling, especially on turns); 3 (must use assistance all or almost all the time); or 4 (unable to walk, even with walker; may be able to transfer).
Time frame: From Baseline to Week 52