Progressive Supranuclear Palsy
Conditions
Keywords
PSP, Steele-Richardson-Olszewski syndrome, Tauopathy
Brief summary
The purpose of this study was to assess efficacy, safety, tolerability, and pharmacokinetics of ABBV-8E12 in participants with progressive supranuclear palsy (PSP).
Detailed description
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.
Interventions
DRUGPlacebo
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.
DRUGABBV-8E12
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.
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female participant with age 40 years or greater at the time of signed consent * Meets the criteria for possible or probable progressive supranuclear palsy (PSP; Steele-Richardson-Olszewski Syndrome) * Presence of PSP symptoms for less than 5 years * Participant is able to walk 5 steps with minimal assistance (stabilization of one arm or use of cane/walker) * Participant has an identified, reliable, study partner (e.g., caregiver, family member, social worker, or friend) Key
Exclusion criteria
* Participants who weigh less than 44 kg (97 lbs) at screening * Mini-Mental State Examination (MMSE) score less than 15 at screening * Any contraindication or inability to tolerate brain magnetic resonance imaging (MRI) * Participant resides at a skilled nursing or dementia care facility, or admission to such a facility is planned during the study period * Evidence of any clinically significant neurological disorder other than PSP * The participant has a history of or currently has schizophrenia, schizoaffective disorder or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) or International Classification of Diseases (ICD-10) criteria * Participant has had a significant illness or infection requiring medical intervention in the past 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 52 in Progressive Supranuclear Palsy Rating Scale (PSPRS) Total Score | Baseline, Week 52 | 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. |
| Number of Participants With Adverse Events | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL) | Baseline, Week 52 | 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. |
| Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113 | The maximum observed serum concentration after the first and the fifth doses in Cohort 1 and Cohort J1 was determined. |
| Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113 | 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. |
| Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113 | 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. |
| Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough) | First day of the Fifth Dosing Interval, Day 85 | 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. |
| Mean Change From Baseline to Week 52 in Clinical Global Impression of Severity (CGI-S) Score | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living) | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | 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. |
| Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | 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 to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26 | From Baseline to Week 52 | 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). |
| Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSP-QoL) Total Score | Baseline, Week 52 | 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. |
| Clinical Global Impression of Change (CGI-C) Score at Week 52 | 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. |
Countries
Australia, Canada, France, Germany, Italy, Japan, Spain, United States
Participant flow
Pre-assignment details
All randomized participants; one participant in the ABBV-8E12 2000 mg dose group never received study drug
Participants by arm
| Arm | Count |
|---|---|
| Placebo 0.9% Sodium Chloride Injection/Solution for Infusion; intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks | 126 |
| ABBV-8E12 2000mg Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain) | 126 |
| ABBV-8E12 4000mg Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain) | 125 |
| Total | 377 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 9 | 7 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 |
| Overall Study | Other, not specified | 62 | 58 | 58 |
| Overall Study | Withdrew consent | 6 | 8 | 10 |
Baseline characteristics
| Characteristic | Total | ABBV-8E12 2000mg | ABBV-8E12 4000mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 6.82 | 68.3 years STANDARD_DEVIATION 7.25 | 70.0 years STANDARD_DEVIATION 6.85 | 68.1 years STANDARD_DEVIATION 6.22 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 49 Participants | 17 Participants | 15 Participants | 17 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 324 Participants | 106 Participants | 109 Participants | 109 Participants |
| Sex: Female, Male Female | 158 Participants | 49 Participants | 56 Participants | 53 Participants |
| Sex: Female, Male Male | 219 Participants | 77 Participants | 69 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 126 | 9 / 126 | 9 / 125 |
| other Total, other adverse events | 83 / 126 | 75 / 126 | 80 / 125 |
| serious Total, serious adverse events | 33 / 126 | 29 / 126 | 34 / 125 |
Outcome results
Primary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 52 in Progressive Supranuclear Palsy Rating Scale (PSPRS) Total Score | 10.5 units on a scale | Standard Error 0.94 |
| ABBV-8E12 2000mg | Change From Baseline to Week 52 in Progressive Supranuclear Palsy Rating Scale (PSPRS) Total Score | 10.5 units on a scale | Standard Error 0.96 |
| ABBV-8E12 4000mg | Change From Baseline to Week 52 in Progressive Supranuclear Palsy Rating Scale (PSPRS) Total Score | 11.4 units on a scale | Standard Error 0.94 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.99895% CI: [-2.63, 2.63]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.46495% CI: [-1.63, 3.58]Mixed-effects model, repeated measures
Primary
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
Population: Safety Dataset: all randomized participants who received at least one dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events | 108 Participants |
| ABBV-8E12 2000mg | Number of Participants With Adverse Events | 111 Participants |
| ABBV-8E12 4000mg | Number of Participants With Adverse Events | 111 Participants |
Secondary
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
Population: Participants in Cohort 1 and Cohort J1 with available data
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 5070 µg•day/mL | Geometric Coefficient of Variation 25 |
| Placebo | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 13900 µg•day/mL | Geometric Coefficient of Variation 28 |
| ABBV-8E12 2000mg | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 31600 µg•day/mL | Geometric Coefficient of Variation 36 |
| ABBV-8E12 2000mg | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 10400 µg•day/mL | Geometric Coefficient of Variation 21 |
| ABBV-8E12 4000mg | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 5950 µg•day/mL | Geometric Coefficient of Variation 12 |
| ABBV-8E12 4000mg | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 15200 µg•day/mL | Geometric Coefficient of Variation 21 |
| Cohort J1, ABBV-8E12 4000 mg | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 10400 µg•day/mL | Geometric Coefficient of Variation 11 |
| Cohort J1, ABBV-8E12 4000 mg | Area Under the Concentration Time Curve (AUC) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 23900 µg•day/mL | Geometric Coefficient of Variation 15 |
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression of Change (CGI-C) Score at Week 52 | 5.1 units on a scale | Standard Error 0.11 |
| ABBV-8E12 2000mg | Clinical Global Impression of Change (CGI-C) Score at Week 52 | 5.1 units on a scale | Standard Error 0.11 |
| ABBV-8E12 4000mg | Clinical Global Impression of Change (CGI-C) Score at Week 52 | 5.0 units on a scale | Standard Error 0.11 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.75695% CI: [-0.36, 0.26]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.40995% CI: [-0.44, 0.18]Mixed-effects model, repeated measures
Secondary
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
Population: Participants in Cohort 1 and Cohort J1 with available data
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 714 µg/mL | Geometric Coefficient of Variation 32 |
| Placebo | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 1070 µg/mL | Geometric Coefficient of Variation 56 |
| ABBV-8E12 2000mg | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 2350 µg/mL | Geometric Coefficient of Variation 23 |
| ABBV-8E12 2000mg | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 1450 µg/mL | Geometric Coefficient of Variation 20 |
| ABBV-8E12 4000mg | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 853 µg/mL | Geometric Coefficient of Variation 6 |
| ABBV-8E12 4000mg | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 1010 µg/mL | Geometric Coefficient of Variation 21 |
| Cohort J1, ABBV-8E12 4000 mg | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 1580 µg/mL | Geometric Coefficient of Variation 13 |
| Cohort J1, ABBV-8E12 4000 mg | Maximum Observed Serum Concentration (Cmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 1960 µg/mL | Geometric Coefficient of Variation 15 |
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -374.5 mm^3 | Standard Error 38.42 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -400.9 mm^3 | Standard Error 38.6 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -341.3 mm^3 | Standard Error 40.61 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: 0.62595% CI: [-132.76, 79.94]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.5595% CI: [-76.34, 142.71]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Clinical Global Impression of Severity (CGI-S) Score | 0.6 units on a scale | Standard Error 0.1 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Clinical Global Impression of Severity (CGI-S) Score | 0.6 units on a scale | Standard Error 0.1 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Clinical Global Impression of Severity (CGI-S) Score | 0.6 units on a scale | Standard Error 0.1 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.76195% CI: [-0.31, 0.23]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.67895% CI: [-0.32, 0.21]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | 1052.6 mm^3 | Standard Error 425.55 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | 1260.5 mm^3 | Standard Error 423.96 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | 1186.1 mm^3 | Standard Error 445.18 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.72695% CI: [-962.98, 1378.88]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.82895% CI: [-1075.26, 1342.4]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -122.0 mm^3 | Standard Error 9.64 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -129.1 mm^3 | Standard Error 9.69 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -128.3 mm^3 | Standard Error 9.69 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.59795% CI: [-33.86, 19.53]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.64295% CI: [-33.04, 20.42]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSP-QoL) Total Score | 9.2 units on a scale | Standard Error 1.63 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSP-QoL) Total Score | 10.3 units on a scale | Standard Error 1.65 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSP-QoL) Total Score | 10.0 units on a scale | Standard Error 1.64 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.65395% CI: [-3.5, 5.57]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.74895% CI: [-3.5, 5.57]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score | 0.8 units on a scale | Standard Error 0.24 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score | 0.9 units on a scale | Standard Error 0.24 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score | 1.0 units on a scale | Standard Error 0.24 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.82895% CI: [-0.6, 0.74]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.54395% CI: [-0.46, 0.87]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL) | -20.6 percentage of independence | Standard Error 1.79 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL) | -18.0 percentage of independence | Standard Error 1.82 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL) | -20.5 percentage of independence | Standard Error 1.77 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.32395% CI: [-2.48, 7.51]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.97495% CI: [-4.86, 5.02]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -8.3 mm^3 | Standard Error 2.78 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -4.3 mm^3 | Standard Error 2.74 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -3.7 mm^3 | Standard Error 2.74 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.30495% CI: [-3.65, 11.65]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.24395% CI: [-3.11, 12.19]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | 157.9 mm^3 | Standard Error 18.27 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | 152.4 mm^3 | Standard Error 18.04 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | 125.0 mm^3 | Standard Error 18.57 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.82995% CI: [-55.66, 44.63]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.20695% CI: [-83.94, 18.23]Mixed-effects model, repeated measures
Secondary
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.
Time frame: Baseline, Week 52
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living) | 5.6 units on a scale | Standard Error 0.62 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living) | 5.8 units on a scale | Standard Error 0.63 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living) | 7.0 units on a scale | Standard Error 0.63 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.81295% CI: [-1.52, 1.93]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.10495% CI: [-0.3, 3.16]Mixed-effects model, repeated measures
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug and those with available data at baseline and at Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -22496.2 mm^3 | Standard Error 1793.36 |
| ABBV-8E12 2000mg | Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -20757.1 mm^3 | Standard Error 1783 |
| ABBV-8E12 4000mg | Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI) | -18811.3 mm^3 | Standard Error 1740.72 |
Comparison: ABBV-8E12 2000 mg vs Placebop-value: =0.48895% CI: [-3201.75, 6680.02]Mixed-effects model, repeated measures
Comparison: ABBV-8E12 4000 mg vs Placebop-value: =0.1495% CI: [-1225.46, 8595.29]Mixed-effects model, repeated measures
Secondary
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
Population: Participants in Cohort 1 and Cohort J1 with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough) | 353 µg/mL | Geometric Coefficient of Variation 27 |
| ABBV-8E12 2000mg | Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough) | 657 µg/mL | Geometric Coefficient of Variation 45 |
| ABBV-8E12 4000mg | Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough) | 345 µg/mL | Geometric Coefficient of Variation 32 |
| Cohort J1, ABBV-8E12 4000 mg | Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough) | 595 µg/mL | Geometric Coefficient of Variation 16 |
Secondary
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
Population: ITT dataset: all randomized participants who received at least one dose of study drug with available data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26 | 169.0 days |
| ABBV-8E12 2000mg | Time to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26 | 170.0 days |
| ABBV-8E12 4000mg | Time to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26 | 203.0 days |
Secondary
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
Population: Participants in Cohort 1 and Cohort J1 with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 4.0 hours |
| Placebo | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 3.6 hours |
| ABBV-8E12 2000mg | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 4.0 hours |
| ABBV-8E12 2000mg | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 4.1 hours |
| ABBV-8E12 4000mg | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 5.0 hours |
| ABBV-8E12 4000mg | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 5.0 hours |
| Cohort J1, ABBV-8E12 4000 mg | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | First Dosing Interval, 2 weeks, Day 1-14 | 4.8 hours |
| Cohort J1, ABBV-8E12 4000 mg | Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12 | Fifth Dosing Interval, 4 weeks, Day 85-113 | 3.4 hours |