Clinical trial NCT03781167
Conditions: Parkinson's Disease (PD)
Keywords: Parkinson's Disease (PD) ABBV-951 Levodopa/Carbidopa
Sponsor: AbbVie
Start date: 2019-04-29; Completion date: 2022-08-17
Enrollment: 244 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the safety and tolerability of ABBV-951 (Foslevodopa/Foscarbidopa) in participants with Parkinson's disease (PD).

This was a single-arm study with preplanned analyses conducted by dose subgroup (Low Dose or High Dose) based on the modal total daily dose (most frequent dose) over the treatment period.

Detailed description:

Arms: arm 1: After a 4-week Optimization Period, participants continued receiving ABBV-951 by continuous subcutaneous infusion (CSCI) during the 48-week Maintenance Period. Participants whose modal total daily dose (most frequent dose) over the entire study was \< 2530 mg of Foslevodopa/day were analyzed as the Low Dose Subgroup. arm 2: After a 4-week Optimization Period, participants continued receiving ABBV-951 by continuous subcutaneous infusion (CSCI) during the 48-week Maintenance Period. Participants whose modal total daily dose (most frequent dose) over the entire study was ≥ 2530 mg of Foslevodopa/day were analyzed as the High Dose Subgroup.
Interventions: intervention 1: ABBV-951
Intervention descriptions: intervention 1: Solution for continuous subcutaneous infusion (CSCI)

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
STUDY OBJECTIVES AND ENDPOINTS
9
3.1
OBJECTIVES
9
3.2
PRIMARY ENDPOINTS
9
3.3
SECONDARY ENDPOINTS
9
3.4
EXPLORATORY ENDPOINT
10
3.5
EXPLORATORY RESEARCH:  BIOMARKER RESEARCH ENDPOINTS
10
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
15
4.3
LOADING DOSE, CONTINUOUS INFUSION RATES, TITRATION, AND EXTRA DOSES
17
5
STUDY ACTIVITIES
24
5.1
ELIGIBILITY CRITERIA
24
5.2
CONTRACEPTION RECOMMENDATIONS
27
5.3
PROHIBITED MEDICATIONS AND THERAPY
29
5.4
PRIOR AND CONCOMITANT THERAPY
30
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
31
5.6
TEMPORARY SUSPENSION OF STUDY DRUG TREATMENT
31
5.7
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
32
5.8
STUDY DRUG AND STUDY DEVICES
32
5.9
PROTOCOL DEVIATIONS
38
6
SAFETY CONSIDERATIONS
38
6.1
COMPLAINTS AND ADVERSE EVENTS
38
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
45
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7.1
STATISTICAL AND ANALYTICAL PLANS
45
7.2
DEFINITION FOR ANALYSIS POPULATIONS
45
7.3
STATISTICAL ANALYSES FOR EFFICACY
45
7.4
STATISTICAL ANALYSES FOR SAFETY
45
7.5
INTERIM ANALYSIS
46
8
ETHICS
46
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
46
8.2
ETHICAL CONDUCT OF THE STUDY
46
8.3
SUBJECT CONFIDENTIALITY
47
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
47
10 DATA QUALITY ASSURANCE
47
11 COMPLETION OF THE STUDY
47
12 REFERENCES
47
LIST OF TABLES
TABLE 1.
LD DOSE DISTRIBUTION FROM LCIG STUDY S187.3.004
16
TABLE 2.
LEVODOPA EQUIVALENT DOSE RANGE
18
TABLE 3.
SUGGESTED ABBV-951 STARTING INFUSION RATE
19
TABLE 4.
GUIDANCE FOR ALTERNATIVE INFUSION RATE LIMITS AND NUMBER OF EXTRA DOSES BASED ON
BASE CONTINUOUS INFUSION RATE
22
TABLE 5.
PROHIBITED MEDICATIONS
29
TABLE 6.
ALLOWED CONCOMITANT MEDICATIONS/THERAPY
30
TABLE 7.
ALLOWED RESCUE MEDICATIONS/THERAPY
30
TABLE 8.
IDENTITY OF STUDY DRUG
32
TABLE 9.
IDENTITY OF STUDY DEVICES
33
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LIST OF FIGURES
FIGURE 1.
STUDY DESIGN SCHEMATIC
11
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
49
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
52
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
53
APPENDIX D.
ACTIVITY SCHEDULE
54
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
59
APPENDIX F.
OPERATIONS MANUAL
61
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2 INTRODUCTION
2.1 Background and Rationale
Why This Study is Being Conducted
ABBV-951 (carbidopa phosphate/levodopa phosphate [CDP/LDP]) is a soluble formulation of 
carbidopa/levodopa (CD/LD) prodrugs that is deliverable by continuous subcutaneous infusion (CSCI).  
ABBV-951 undergoes enzymatic conversion to CD/LD and has the potential to achieve efficacy similar to 
levodopa-carbidopa intestinal gel (LCIG, denominated carbidopa-levodopa enteral suspension [CLES] in 
the United States [US]) by subcutaneous delivery.
Patients with Parkinson's disease (PD) require a therapeutic approach that is tailored to their unique 
needs and responses to levodopa.  ABBV-951 enables continuous, subcutaneous, and individualized 
delivery of CD/LD, covering the wide range of levodopa doses required to adequately control motor 
symptoms in patients with advanced PD (aPD).  Therefore, this novel treatment may provide an 
alternative therapy to many patients whose motor complications are inadequately controlled by their 
current treatment.
While the systemic toxicology and tolerability profiles of CD/LD are well established preclinically and in 
humans, the local (skin) and systemic tolerability following subcutaneous delivery of ABBV-951 are less 
known and are being assessed within the scope of this study.
Systemic and local tolerability have been measured in animal models, as well as in the clinical setting.  In 
Good Laboratory Practice (GLP)-compliant preclinical studies in rats and monkeys, doses of ABBV-951, 
considered therapeutically relevant in PD patients, were demonstrated to be well tolerated at the 
infusion site and did not significantly increase serum phosphate levels.  Local irritation was assessed in 
dogs at a 50/200 mg/mL concentration, following CSCI for 28 days with a fixed indwelling catheter at a 
rate of 0.1 or 0.25 mL/hour (120/480 mg/day and 300/1200 mg/day, respectively).  120/480 mg/day 
was well tolerated, and the infusion site findings were similar to those of the vehicle control without 
signs of irritation or inflammation stemming from ABBV-951.  Findings at the infusion site of animals 
treated with the higher infusion rate (0.25 mL/hour) were confounded by a concurrent bacterial 
infection, and it was not possible to clearly determine whether ABBV-951 was well tolerated; however, 
the infusion of ABBV-951 at the same concentration (50/200 mg/mL), but at a higher infusion rate 
(0.5 mL/hour) for fewer days (5 days) was well tolerated, with only minimal signs of irritation at the 
infusion site.  In cohorts from the Phase 1 study in healthy volunteers (Study M15-733), in which 
ABBV-951 was administered as a loading dose followed by a continuous infusion for up to 72 hours, 
levodopa exposure showed a low degree of fluctuation, similar to what was observed with the LCIG 
registration studies.  ABBV-951 was generally well tolerated, with only mild reports of pain at the 
infusion site related to high flow rates used to deliver loading doses.  These reports of infusion site pain 
were significantly reduced when the flow rate was adjusted to deliver the loading dose over a longer 
period of time.  No other local tolerability issues were observed, and no subject discontinued the study 
due to these events.  No pain or other safety or tolerability interim issues have been reported from 
ongoing Phase 1 studies in PD patients, where ABBV-951 is administered at therapeutic doses for 24 or 
72 hours (Study M15-738) or for up to 28 days (Study M15-739).
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The dose ranges of ABBV-951 to be utilized in this study are similar to those administered in the Phase 1 
studies in PD subjects (Studies M15-738 and M15-739); however, the duration of the continuous 
infusion administration will be long-term.  Therefore, subject safety and tolerability over long-term 
exposure will need to be assessed.
This open-label, single-arm, Phase 3 study will be conducted in an outpatient setting to evaluate local 
and systemic safety and tolerability, and explore the efficacy of therapeutic doses of ABBV-951 infused 
continuously for 52 weeks in subjects with PD.
Clinical Hypothesis
CSCI of ABBV-951 is safe and well-tolerated for up to 52 weeks in PD patients with motor fluctuations no 
longer controlled by current PD medications.
2.2 Benefits and Risks to Subjects
The combination of oral levodopa and DOPA decarboxylase inhibitors (DDCI), such as carbidopa or 
benserazide, has been used for many years in patients with PD to control motor symptoms, and the 
systemic safety profile is well established.  Furthermore, achieving stable plasma levodopa 
concentrations through continuous infusion has been demonstrated previously with LCIG and resulted in 
greater efficacy than oral CD/LD as assessed by a reduction in overall daily "Off" time accompanied by 
increased "On" time without troublesome dyskinesia.  Therefore, it is anticipated that ABBV-951 can 
provide a similar benefit if plasma levodopa concentrations can be maintained stable and within the 
therapeutic window.
Potential risks of receiving an ABBV-951 dose lower than required for PD symptom control include 
experiencing an exacerbation of PD symptoms ("Off" state) characterized by increased difficulty with 
movement, tremor, and stiffness.  Potential risks of receiving an ABBV-951 dose higher than what is 
required for motor symptom control include experiencing dyskinesias (abnormal or uncontrolled 
movements) and hallucinations.  Other anticipated risks are well characterized levodopa-related side 
effects, including nausea, vomiting, and dizziness; however, not all of the potential side effects of the 
drug are known.  Subjects may also experience general discomfort or inconvenience related to study 
procedures.
Since ABBV-951 is administered as a CSCI, there is a potential for safety issues related to infusion site 
tolerability.  These issues may include infusion site irritation and inflammation (swelling, redness, pain, 
itching), bruising, skin infection, and discomfort related to the feeling of liquid flowing through the 
needle/cannula.  Data from preclinical studies and from a study in healthy volunteers show that infusion 
is generally well tolerated; however, the ABBV-951 infusion rates (i.e., flow rates) that will be used in the 
current study are anticipated to be higher than those used in the healthy volunteer study and therefore 
local tolerability at the infusion site will be a specific focus in this study.
For details, please see the safety data in the ABBV-951 investigator's brochure.1
Based on the limited information available to date, exposure to ABBV-951 does not appear to pose 
additional risks to study participants because of the coronavirus disease-2019 (COVID-19).  ABBV-951 
metabolizes into LD and CD, sharing the same characteristics of these compounds, which are commonly 
used as symptomatic treatment of PD globally.
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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary
To assess the local and systemic safety and tolerability of ABBV-951 delivered as a CSCI for 24 hours 
daily for up to 52 weeks.
Secondary
To assess the efficacy of ABBV-951 as measured by patient-reported and rater-measured efficacy 
endpoints.
3.2 Primary Endpoints
1.
Percentage of subjects with adverse events (AEs) and serious adverse events (SAEs) during the 
study
2.
Percentage of subjects with AEs of special interest (AESIs) during the study
3.
Percentage of subjects with numeric grade equal to or higher than 5 and percentage of subjects 
with letter grade equal to or higher than D on the Infusion Site Evaluation Scale at any time 
during the study
4.
Change in clinical laboratory test data from Baseline to end of study
5.
Change in vital sign measurements from Baseline to end of study
6.
Change in electrocardiograms (ECGs) from Baseline to end of study
3.3 Secondary Endpoints
The efficacy endpoints are change from Baseline to end of study for the following:
1.
Average normalized daily "Off" time and "On" times as assessed by the PD Diary
2.
PD symptoms as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) Parts I-IV (or the UPDRS Parts I-V in countries where a validated translation 
of the MDS-UPDRS is not available)
3.
Sleep symptoms as assessed by the PD Sleep Scale-2 (PDSS-2)
4.
Quality of life as assessed by the PD Questionnaire-39 items (PDQ-39)
5.
Health-related quality of life as assessed by the EuroQol 5-dimensions questionnaire (EQ-5D-5L)
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3.4 Exploratory Endpoint
PD symptoms (including tremor, bradykinesia, dyskinesia, daytime somnolence, and indication of 
propensity for impulsive behaviors) as assessed by the Parkinson's KinetiGraph™/Personal KinetiGraph™ 
(PKG) wearable device (as allowed by local regulations) from Baseline to the Week 26 Visit.
3.5 Exploratory Research:  Biomarker Research Endpoints
Optional samples will be collected during the study to evaluate known and/or novel biomarkers related 
to PD, related conditions, ABBV-951, or drugs of a similar class.  Deoxyribonucleic acid (DNA) samples 
may be analyzed for genetic markers that may help to understand PD and the subject's response to 
ABBV-951.  Genes of interest may include (but are not limited to) those associated with 
pharmacokinetics (drug metabolizing enzymes, drug transport proteins), genes within the target 
pathway (dopaminergic pathways), or other genes believed to be related to PD (alpha-synuclein 
[SNCA]).  Research may also include epigenetic changes in DNA that may correlate with the subject's 
response to treatment or disease.  Research on samples collected will follow country-specific 
regulations.  This research is exploratory in nature, and the results may not be included within the 
clinical study report.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
Design and Schematic
This is a 52-week, Phase 3, open-label, single-arm, multicenter study to assess the local and systemic 
safety and tolerability, as well as efficacy, of ABBV-951 administered as a CSCI for 24 hours daily for up 
to 52 weeks.  At study completion, subjects may transition to a 24-hour CSCI of ABBV-951 open-label 
extension study.  Approximately 240 adult subjects with PD whose motor symptoms are inadequately 
controlled despite their current optimized PD therapy will be enrolled.
Two interim analyses will be performed during the course of this study.  The first interim analysis will be 
performed after at least 100 subjects have completed 26 Weeks of therapy; the second interim analysis 
will be performed after at least 100 subjects have completed 52 Weeks of therapy.
See Section 5.1 for eligibility criteria.  Safety parameters, such as clinical laboratory test results, ECGs, 
and vital signs will be monitored throughout the study (see Sections 3.11, 3.14, and 3.15, respectively, of 
the Operations Manual [Appendix F]).
A schematic of the study is shown in Figure 1.  Details regarding study procedures are located in 
Section 3 of the Operations Manual (Appendix F).
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Figure 1.
Study Design Schematic
D = Day; V = Visit; W = Week
a.
The Screening Period may be extended up to a total of 90 days for extenuating circumstances, e.g., supply constraints.
b.
The Monitoring Period can occur any time before V3, as long as it lasts for 6 consecutive days.  PD Diaries will also be 
collected for at least 2 consecutive days during the Monitoring Period.  In countries where the PKG watch is not approved, 
the Monitoring Period may be reduced to at least 2 days to account for the collection of PD Diaries and pump training.
Note:  As allowed by local regulations, subjects will receive the PKG-watch following Screening Visit 1 (V1) and will be required 
to wear it (refer to the currently approved manufacturer's directions) during the Monitoring Period and at least until the 
completion of Week 26 (V11); thereafter, wearing of the PKG-watch will be optional.  The Monitoring Period consists of at least 
6 consecutive days during the Screening Period (prior to V3) where subjects will be required to collect PD diaries and wear the 
PKG watch at the same time.  "As allowed by local regulations" is applicable to all wearable device references throughout this 
protocol and its appendices.  The AbbVie Therapeutic Area Medical Director (TA MD) should be consulted if, in the opinion of
the Investigator, there are circumstances that might interfere with the use of the PKG device (e.g., religious reasons, atopic 
dermatitis).  A subject's inability to wear the PKG watch, due to logistics hindering the watch from being made available, will 
not preclude him/her from study participation.
Study Periods
Screening Period
The intended 10- to 42-day Screening Period (may be extended up to a total of 90 days for extenuating 
circumstances) will consist of 2 screening visits (V1 and V2) and a 6-day Monitoring Period, to be
completed any time before V3.  Subjects will become familiar with the wearable device and the PD Diary 
during the Screening Period.  During the Screening Period, subjects must be on a stable oral PD 
medication regimen for at least 30 days prior to commencing ABBV-951.  Historical data (medical 
records, etc.) are acceptable documentation for the use of stable medication.
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Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 30 days prior to 
initial study drug administration, whichever is longer, with the exception of medications containing 
levodopa and catechol-O-methyltransferase (COMT) inhibitors, which must be discontinued for at least 
12 hours before initiation of study drug and for the duration of the Treatment Period.  The Screening 
Period may be extended up to a total of 90 days for extenuating circumstances, e.g., supply constraints.
Subjects must be consented for the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility.  See Section 5.3.  The investigator or his/her designee must confirm 
continued subject eligibility at V3, prior to enrollment.  Considering historical data and the minimum 
time required for the Monitoring Period, the Screening Period may be completed in as short as 10 days; 
it should be targeted to be completed in approximately 40 days and should not exceed a total of 90 days 
overall.
Subjects will be required to wear the wearable device for 6 consecutive days prior to Visit 3 (i.e., the 
6-Day Monitoring Period), in countries where such devices are approved.  The PD Diaries should be 
completed for at least 2 consecutive days of the 6-day Monitoring Period, prior to Visit 3 (Day 1).
Treatment Period
The Treatment Period starts with the initiation of ABBV-951 and consists of 2 parts:  a 4-week 
Optimization Period and a 48-week Maintenance Period.
Optimization Period:  during the 4 weeks of the Optimization Period, investigators will make all 
necessary adjustments to the subject's ABBV-951 dose until the optimal clinical response for the 
individual subject is obtained.  Additional adjustments may be required for the subject's concomitant PD 
medications (e.g., dopamine-agonists, selective monoamine oxidase B [MAO-B] inhibitors, amantadine, 
safinamide), including tapering down or even suspending such medications, in accordance with the 
prescribing information, to achieve the therapeutic approach that, in the investigator's opinion, controls 
the subject's symptoms in the most satisfactory way.
Maintenance Period:  the Maintenance Period will consist of 48 weeks of a 24-hour daily CSCI of 
ABBV-951 at the optimal therapeutic dose.  During this 48-week period, subjects should maintain a 
stable regimen of all concomitant medications unless changes are considered medically necessary, in 
the opinion of the investigator.  ABBV-951 can be adjusted throughout the study.  In the event of dose 
adjustments for ABBV-951 or other concomitant medications (including adding or suspending other PD 
medications) these adjustments should be documented in the electronic case report form (eCRF).
On the morning of Day 1 (V3) subjects will need to be in a clinically defined "Off" state (i.e., no PD 
medications for at least 12 hours before initiation of study drug).  After confirmation of eligibility and a 
brief clinical examination, subjects will receive an oral loading dose of LD+DDCI followed by the 
beginning of the subcutaneous infusion of ABBV-951 at their calculated starting dose.
For each subject, the starting dose level for the continuous infusion rate of ABBV-951 will be calculated 
according to their baseline dose of oral levodopa (or levodopa equivalent dose [LED]), based on the 
proposed conversion rates from Tomlinson et al,2 guidance from Espay et al,3 and a conversion 
algorithm based on data from Phase 1 studies (see Section 4.2).
Subjects might also resume PD medications that do not contain levodopa or COMT inhibitors (such as 
dopamine agonists, MAO-B inhibitors, amantadine, safinamide, etc.) as these concomitant medications 
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are not required to be suspended before starting ABBV-951.  However, per the investigator's judgment 
and according to the prescribing information, subjects may start to taper off concomitant PD 
medications during the 4 weeks of the Optimization Period.
Subjects will be evaluated on the day of, and the day after, initiating ABBV-951, and then weekly during 
the Optimization Period.  During each visit, the investigator will assess the subject's PD symptoms by 
interview and neurologic examination and may adjust the subject's therapeutic regimen by continuing 
tapering off and/or suspending previous concomitant PD medications, and at the same time increasing, 
decreasing, or maintaining the ABBV-951 infusion rate based on the subject's clinical response.  If all 
concomitant PD medications have been tapered off, the dose of ABBV-951 may be further adjusted until 
the optimal clinical response for the individual subject is obtained, as determined by the investigator.  
Optimal clinical response is defined by maximizing the functional "On" time and minimizing the number 
of "Off" episodes during the day.  This optimization also minimizes "On" time with troublesome 
dyskinesia.
During the Optimization Period, study visits will occur as follows:
Day 1 (V3)
Day 2 (V4)
Week 1 (V5)
Week 2 (V6)
Week 3 (V7)
Week 4 (V8)
The investigator may perform unscheduled visits to make any needed adjustments within the 4-week 
Optimization Period.
After Week 4 (V8), all subjects will begin the Maintenance Period and should maintain a stable 
treatment regimen of ABBV-951 and other concomitant medications, including any PD medications that 
are still being administered after the Optimization Period.  Dose adjustments of medications, including 
ABBV-951, can be made if considered medically necessary, in the opinion of the investigator.  Any 
changes to medications or the dose of ABBV-951 should be recorded in the eCRF.
During the Maintenance Period, study visits will occur as follows: 
Week 6 (V9)
Week 13 (V10)
Week 26 (V11)
Week 39 (V12)
Week 52 (V13) or in case of premature discontinuation.
All visits, apart from the Screening visits (V1 and V2) and V3 (Day 1), will be allowed a window of 
± 3 days.
As part of the study procedures, study drug is intended to be dispensed to subjects every 2 weeks during 
the Treatment Period with or without a clinic visit being completed.
Unscheduled clinic visits may occur per investigator discretion as deemed necessary.  The appropriate 
protocol assessments to be conducted at an unscheduled clinic visit are to be determined by the 
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investigator.  Additionally, a subject (or authorized representatives, if allowed per local regulations) may 
return to the clinic site for additional study drug or drug delivery system components or accessories.
In rare situations where a visit cannot be completed onsite due to an extenuating event (e.g., COVID-19-
related conditions), some assessments may be performed remotely.  Refer to the Operations Manual 
(Appendix F) for further guidance.
Treatment Arm
Subjects will receive an oral loading dose on Day 1 (V3) followed by a 24-hour daily subcutaneous 
infusion of ABBV-951.  The loading dose will be established by the investigator per the subject's oral 
regimen prior to commencing ABBV-951 (see Section 4.2).  The starting continuous infusion rate (F1) will 
be calculated taking into consideration the LED and the pharmacokinetic characteristics of ABBV-951 
(see Section 4.2).  The investigator may adjust the prescribed infusion rate during visits to reach 
optimization of motor symptoms control.  Subjects may choose their daily continuous infusion rate from 
3 preprogrammed infusion rates.  The investigator will determine and program the base daily infusion 
rate (F1) within the allowable range (0.17 to 1.04 mL/hr) and may program 2 additional infusion rates 
(F2 and F3) within a ± 20% limit from the prescribed base infusion rate.  F2 should be an alternative 
higher continuous dose, and F3 should be an alternative lower continuous dose.  F3 may be reduced 
beyond the 20% limit from the prescribed base infusion rate (F1) if medically necessary and only with 
approval from the AbbVie therapeutic area medical director (TA MD).  If programmed, the alternative 
infusion rates (F2 and F3) must be within the allowable range (0.17 to 1.04 mL/hr).  If the alternative 
infusion rates (F2 and F3) are not required, they must be programmed to "OFF."  Subjects will receive a 
System User Manual that contains instructions for the daily management of their infusion.
Dermatologic Assessment
Subcutaneous delivery of study drug calls for attention during the procedures related to administration 
(general hygiene, skin disinfection, maintenance of a dirt-free environment while manipulating the 
system components, etc.), and subject training and adherence to proper techniques are critical.  
Manipulation at the level of the cannula pad due to disconnection and reconnection of the tubing might 
also lead to skin irritation, abrasion, and other lesions, which could evolve to infection and cellulitis 
because of bacterial contamination.  Infusion site reactions including erythema, pain, or any other 
inflammation signs have been observed.4  Most are mild or moderate in severity and resolve with 
treatment with antibiotics and interventions such as incision and drainage.  Some cases might require 
further management and clinical correlation is recommended.  Investigators should obtain dermatologic 
consult if needed.
Absorption of study drug by the subcutaneous tissue may vary depending on the volume of drug 
solution infused/day, skin characteristics, hydration, etc.  Accumulation of study drug under the skin, 
manifesting as an elevated area of the skin, with or without induration and/or seepage of study drug 
from the infusion site after removal of the cannula or during infusion, might be a sign of reduced 
absorption, which could lead to irritation of the area and increased risk of bacterial contamination.  In 
these cases, more frequent rotation of the infusion site (using a new cannula/infusion set) is 
recommended to minimize the risk of infection.
If any moderate to severe infusion site-related AE, such as cellulitis/abscess formation, ecchymoses, 
subcutaneous nodules, or scarring occurs, or if any infusion site-related reaction is assessed with an 
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irritation numeric grade equal to 7 on the Infusion Site Evaluation scale (see Section 3.6 of the 
Operations Manual [Appendix F]), the investigator or designee is instructed to do the following:
1.
Photograph the skin reaction and follow the appropriate procedure for submission of 
photographs.  In rare situations where an assessment or visit cannot be completed onsite due to 
an extenuating event (e.g., COVID-19-related conditions), the subject may be asked to obtain 
and submit a self-captured photograph of the skin reaction.
2.
Refer the subject to a dermatologist for comprehensive evaluation (including skin biopsy if 
applicable), treatment, and follow-up per standard practice.  The subject should be referred to a 
dermatologist within 2 business days after the photographs are taken.  The dermatologic visit 
should be completed within 2 weeks from identification of the AE or skin reaction that meets 
the above criteria.  While an in-person dermatology evaluation is preferred, this assessment 
may be performed as a telemedicine visit per the dermatologist's standard practice.
Post-Treatment Activities
Subjects who prematurely discontinue or are not enrolled in the extension study (M15-737) will receive 
a 30-day follow-up call after the end of infusion of study drug, if the subject is willing.  See Section 5.7
for additional information.
4.2 Discussion of Study Design
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be used in this study.  All efficacy 
measurements are qualified for assessing disease activity in subjects with PD.
Suitability of Subject Population
The subject population will consist of subjects with PD who report motor complications that are 
inadequately controlled by oral medications and who experience a minimum of 2.5 hours of "Off" time 
per day as assessed by PD diaries completed prior to enrollment/Day 1 (V3).  Subjects must be on a 
stable oral PD medication regimen for at least 30 days prior to commencing ABBV-951.
Rationale for Selection of Therapeutic Dose Range
CD/LD remains the standard of care for PD.  It is, however, recognized that the treatment of PD is highly 
individualized; both the treatments administered and their doses must be customized, based on the 
patients' signs and symptoms and their response to medication.  In practice, this provides a wide 
distribution of patient doses, even within clinical trials.
In the LCIG double-blind, double dummy pivotal trial (Studies S187.3.001/S187.3.002), the median dose 
of levodopa was 1013 mg/day and the mean dose was 1117 mg/day for 16-hour daily infusion.  These 
data represent a small subset of subjects where dosing was constrained to maintain the blinding of the 
study.  Therefore, > 90% of subjects used less than 2000 mg over a 16-hour treatment period.
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In the LCIG open-label safety study (Study S187.3.004), in which > 300 subjects were enrolled, the dosing 
was more reflective of clinical practice, where a significant proportion of subjects were able to simplify 
their therapy by discontinuing concomitant oral medications and maintaining only LCIG during the 
waking time.  The LD doses from this study ranged from less than 500 mg/day to more than 
3500 mg/day over a 16-hour treatment period (Table 1).
ABBV-951 is intended to be a 24-hour/day therapy (i.e., subjects will be exposed 8 more hours – or 50% 
longer – compared to LCIG exposure).  The results of a pharmacokinetic study (Study M18-764) 
comparing LD plasma concentrations between LCIG plus LD/CD tablets and ABBV-951 in healthy 
volunteers demonstrated that LD from ABBV-951 is 8% more bioavailable than enterally-absorbed LD.  
Based on molecular weight (MW), 100 mg of LD are equivalent to 141 mg of levodopa phosphate (LDP).
Using these data, it is estimated that LD doses could range from less than 700 mg/day to about 
4260 mg/day, over a 24-hour treatment period (approximately 1000-6000 mg LDP).
Table 1.
LD Dose Distribution from LCIG Study S187.3.004
Distribution of LD Doses
over 16 hours (mg)
Frequency
Cumulative 
Percent (%)
Estimated Doses over 
24 hours
(N)
(%)
LD (mg)
LDP (mg)
<
500
1
0.3
0.3
695
1000
500 -
750
12
3.8
4.1
750 -
1000
29
9.1
13.2
1000 -
1250
48
15.1
28.4
1250 -
1500
61
19.2
47.6
1500 -
1750
53
16.7
64.4
1750 -
2000
47
14.8
79.2
2000 -
2250
22
6.9
86.1
2250 -
2500
17
5.4
91.5
2500 -
2750
13
4.1
95.6
2750 -
3000
5
1.6
97.2
3000 -
3250
4
1.3
98.4
3250 -
3500
3
0.9
99.4
> 3500
2
0.6
100.00
4260
6000
Total:  317
LCIG = levodopa-carbidopa intestinal gel; LD = levodopa; LDP = levodopa phosphate
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4.3 Loading Dose, Continuous Infusion Rates, Titration, and Extra 
Doses
Oral Loading Dose
The purpose of the oral loading dose is to allow subjects to achieve symptom control quickly upon 
initiation of treatment.  The loading dose for this study will be an oral dose of LD+DDCI corresponding as 
closely as possible to the subject's habitual first morning dose of LD+DDCI.  Immediate-release 
formulations of LD+DDCI medications should be utilized for the oral loading doses.
Loading doses will be administered only once, at the initiation of ABBV-951 treatment, unless dosing is 
discontinued for ≥ 3 hours.  Temporary disconnection (< 1 hour) for daily hygiene or to change empty 
syringes does not count as discontinuation and does not require a loading dose upon resuming the 
infusion (see Section 5.8).
Continuous Infusion Rate
Following the oral loading dose, ABBV-951 will be delivered continuously (24 hours daily) via an infusion 
set connected to a pump.  Each subject's initial base continuous infusion rate (F1) will be calculated 
based on the subject's oral LD therapy over the 16-hour treatment period and an algorithm developed 
following a combination of pharmacokinetic and clinical considerations from ABBV-951 Phase 1 studies.  
A subject's baseline dose of immediate release (IR) LD+DDCI is the starting point for establishing the 
levodopa equivalent dose (LED) for dose selection (note: the levodopa contained in Stalevo® 
[CD/LD/entacapone] counts as IR).  If a subject is not taking an IR formulation of LD+DDCI, the LED is 
calculated from the primary levodopa-containing medication.  The conversion factors to use in 
calculating the total LED for dose selection are provided in Table 2 and are based on data from the 
literature.2,3  The applicable calculation from Table 2 and a subject's baseline CD/LD IR dose should be 
added together to provide the total starting LED for ABBV-951 conversion.
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Table 2.
Levodopa Equivalent Dose Range
Medication
Conversion Factors to Calculate LED
Controlled-release levodopa 
(e.g., Sinemet CR, Madopar CR)
For subjects taking controlled-release levodopa, multiply their daily dose of 
controlled-release levodopa by 0.75 to obtain their LED.
Extended-release levodopa 
(Rytary)
For subjects taking extended-release levodopa, multiply their total daily dose 
of Rytary by the appropriate conversion ratio in the following table to obtain 
their LED.
Rytary Dose Range (mg)
Conversion Ratio (Rytary to LED)
0 – 855
0.42
856 – 1755
0.48
1756 – 2340
0.56
2341 or above
0.67
Adjustment for subjects taking 
COMT inhibitors such as 
entacapone (e.g., Comtan or 
Stalevo) or tolcapone 
(e.g., Tasmar)
If subjects are taking tolcapone or entacapone, all LED calculated from the 
levodopa-containing products must be multiplied by 1.33.
Note:  The levodopa dose contained in Stalevo counts as IR.
COMT = catechol-O-methyltransferase; CR = controlled release; IR = immediate release; LED = levodopa equivalent dose
Once a subject's daily LED has been determined, the starting infusion rate for ABBV-951 should be 
selected from Table 3.  The continuous infusion rates below are estimated for the mid-point of the LED 
intervals provided and are designed to deliver therapeutic levodopa exposure.  The ABBV-951 infusion 
will be delivered continuously via an infusion set connected to an ambulatory pump.
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Table 3.
Suggested ABBV-951 Starting Infusion Rate
LED From all Oral LD-Containing 
Medications Taken Over a Waking 
Time of 16 Hours (mg)a
Suggested ABBV-951
Starting Hourly Infusion Rate (mL/hr)b
Approximate 
Corresponding Hourly LD 
Amount (mg/hr)c
< 500
0.17
29
500 – 599
0.17 – 0.20
30 – 34
600 – 699
0.20 – 0.24
34 – 41
700 – 799
0.24 – 0.27
41 – 46
800 – 899
0.27 – 0.30
46 – 51
900 – 999
0.30 – 0.34
51 – 58
1000 – 1099
0.34 – 0.37
58 – 63
1100 – 1199
0.37 – 0.40
63 – 68
1200 – 1299
0.40 – 0.44
68 – 75
1300 – 1399
0.44 – 0.47
75 – 80
1400 – 1499
0.47 – 0.51
80 – 87
1500 – 1599
0-51 – 0.54
87 – 92
1600 – 1699
0.54 – 0.57
92 – 97
1700 – 1799
0.57 – 0.61
97 – 104
1800 – 1899
0.61 – 0.64
104 – 109
1900 – 1999
0.64 – 0.68
109 – 116
>2000
0.70
119
LD = levodopa; LED = levodopa equivalent dose; MW = molecular weight
a.
Based on Table 2.
b.
The suggested infusion rates are calculated for the mid-point of the interval to which they refer.
c.
Based on the ABBV-951 concentration of LDP 240 mg/mL and MW conversion factor 100 mg LD = 141 mg LDP.
Titration
The ABBV-951 base infusion rate (F1) may be adjusted at the investigator's discretion at any time 
throughout the study to achieve and maintain an optimal therapeutic response for the individual 
subject, which means maximizing the functional "On" time during the day by minimizing the number 
and duration of "Off" episodes (bradykinesia) and minimizing "On" time with troublesome dyskinesia.  
Due to the capabilities of the infusion pump utilized in Study M15-741, the infusion rate must be 
increased or decreased by multiples of 0.01 mL/hr, corresponding to approximately 1.7 mg LD/hr, or 
approximately 40 mg LD over the 24-hour period.  Therefore, an increase in the base infusion rate of 
0.02 mL/hr will result in total increase of approximately 80 mg of LD over the 24-hour period.  An 
increase of 0.04 mL/hr will result in a total increase of approximately 160 mg of LD over the 24-hour 
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period.  A decrease of 0.06 mL/hr will result in a total decrease of approximately 240 mg of LD over the 
24-hour period, etc.
Should the calculated daily LED from oral medications at Baseline (based on the 16-hour treatment 
period) for a subject be ≥2000 mg, the starting base infusion rate (F1) should be set at 0.70 mL/hr.
The investigator may decide to increase the infusion rate only after assessing the subject for clinical 
efficacy (achieving optimal therapeutic response, as defined above) and safety.  The safety profile of 
ABBV-951 at doses higher than 200/4000 carbidopa phosphate/levodopa phosphate (CDP/LDP) resulting 
from infusion rates > 0.70 mL/hr will be assessed throughout the study via neurological examinations 
and physical assessment, as described in Appendix D.  All AEs will be assessed, with particular attention 
to AESIs of polyneuropathy, weight loss, somnolence, and hallucinations/psychosis.
Alternative Continuous Infusion Rates (F2, F3)
Like other therapeutic approaches for PD, which require an individualized optimization, this study 
provides subjects the ability to select from alternative infusion rates within a specified range, if allowed 
by the investigator.
Two additional infusion rates (F2 and F3) may be preprogrammed into the pump by the investigator.  
F2 should be an alternative higher continuous dose, and F3 should be an alternative lower continuous 
dose.  The additional infusion rates must be selected within a ± 20% limit from the prescribed base 
continuous infusion rate (F1).  F3 may be reduced beyond the 20% limit from the prescribed base 
infusion rate (F1) if medically necessary and only with approval from the AbbVie TA MD.
Infusion rates lower than 0.17 mL/hr or higher than 1.04 mL/hr are not allowed.
If, during the study, the base daily infusion rate (F1) is programmed at 0.17 mL/hr, the alternative lower 
infusion rate (F3) must be disabled.  If, at any point during the study the base daily infusion rate (F1) is 
programmed at 1.04 mL/hr, the alternative higher infusion rate (F2) and the extra dose option (see 
below) must be disabled.
The starting infusion rate must not be higher than 0.70 mL/hr; adjustments may be done only after 
clinical assessment (neurological and physical examination).
If the alternative infusion rates (F2 and F3) are not required, the investigator or his/her designee must 
disable them by programming them to "OFF" and the subject will not be able to choose alternative 
infusion rates.  If the investigator enables these options, the subject may select the infusion rate from 
these 3 preprogrammed choices (F1, F2, or F3) and will be required to record on the dosing diary the 
time of the day when they change the infusion rate.  The numerical values of the infusion rates cannot 
be modified by the subjects.
Extra Doses
If the investigator allows it, subjects may self-administer extra doses of ABBV-951 during the course of 
the 24 hours to address immediate medical needs, such as the rapid deterioration of motor function.  
The ability to self-administer extra doses, the extra dose volume and lockout time (the interval between 
extra doses) are determined and programmed by the investigator or his/her designee and cannot be 
modified by the subjects.  The investigator can choose the volume of the extra doses from the following 
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options:  0.11, 0.15, 0.19, 0.24, or 0.3 mL (which are equivalent to ~20, ~25, ~33, ~40, and ~50 mg of 
levodopa, respectively).  The lockout time is programmable from 1 hour to 24 hours in 15-minute 
increments; the minimum lockout duration is 60 minutes.  If the investigator elects not to allow the use 
of extra doses, this function can be disabled by setting the volume to "0.00."
If the extra dose function is enabled, subjects are required to record on the dosing diary the time of the 
day when they self-administered an extra dose.  Dosing diaries will be reviewed by the study personnel 
at every study visit.
If the need for extra doses is greater than 5 times per day, the investigator should consider increasing 
the base infusion rate and increasing the lockout time to limit the number of extra doses per day.  If at 
any time in the study F1 or F2 are set at 1.04 mL/hr, the extra dose option should be disabled.  Doses 
of LDP higher than 6000 mg/24 hr (equivalent to 4260 mg LD/24 hr) are not allowed under any 
circumstances during the study.
The investigator should consider this upper limit when programming alternative infusion rates and/or 
volumes and lockout time of extra doses.  Guidance is provided in Table 4.
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The investigator should consider whether to enable alternative infusion rates and extra doses and 
provide those options to subjects, based on his/her clinical judgment of the subject's cognitive 
performance, compliance, and personality traits.
Allowing an alternative higher infusion rate (F2) could facilitate refining the base continuous infusion 
rate during the optimization period.  Subjects who report troublesome dyskinesia, freezing of gate, or 
nocturnal akinesia at baseline are often treated with sub-optimal oral daily doses of LD.5,6  In these 
cases, programming F1 as suggested in Table 3 could result in a sub-optimal dose of ABBV-951.  The 
investigator may program F2, starting with small increments (e.g., 5% – 10%), and enable subjects who 
feel underdosed to switch to the alternative higher infusion rate.  Similarly, if subjects are expected to 
sustain extended physical activity (e.g., sport) or require higher doses of levodopa at a specific time of 
day, F2 could be temporarily selected to account for the higher dopaminergic demand.  Also, if subjects 
require more than 5 extra doses during the day, they may be instructed to switch to F2 and reduce the 
use of extra doses, while waiting for of the investigator to adjust the base infusion rate at the next study 
visit after reviewing the dosing diary.  It is important that subjects be reminded to log on the dosing 
diary any time they self-administer an extra dose or switch the infusion rate to one of the enabled 
options.
If the investigator prefers not to provide this option or considers the subject not suitable to choose 
among the provided options, he/she should disable the alternative higher infusion rate by programming 
it to "OFF."
Investigators may consider whether to allow subjects to switch to an alternative lower infusion rate (F3) 
before going to bed, if subjects report no complaints of nocturnal akinesia or nighttime symptoms at 
baseline or if subjects have known history of impulse control disorders or nocturnal hallucinations.6-8
Additionally, data suggest that the low variability and fluctuations in plasma LD exposure from 
continuous delivery may translate in an average reduction of efficacious daily levodopa doses;9 hence, if 
between visits during the optimization period, subjects experience sustained dyskinesia, they may be 
instructed to select the alternative lower infusion rate and record it in their dosing diary, until the 
investigator adjusts the base parameters at the following study visit.  The alternative lower infusion rate, 
F3, may be programmed to be up to 20% lower than F1.  F3 may be reduced beyond the 20% limit from 
the prescribed base infusion rate (F1) if medically necessary and only with approval from the AbbVie TA 
MD.
If nocturnal akinesia is present or if bothersome nighttime symptoms exist, investigators should consider 
maintaining the base infusion rate (F1) consistent for the 24 hours and disable the option for the 
alternative lower infusion rate (programming it to "OFF").  Similarly, if the investigator prefers not to 
provide this option or considers the subject not suitable to choose among the provided options, he/she 
should disable the alternative lower infusion rate by programming it to "OFF."
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
All subjects will be evaluated to ensure that they meet the eligibility criteria at Screening Visits 1 and 2 
(V1 and V2) and prior to enrollment on Day 1 (V3).
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Consent
1.
Subject must be able to understand the nature of the study and have had the opportunity to 
have any questions answered by the investigator.
2.
Subject, if judged by the investigator to have decision making capacity, must voluntarily sign and 
date an informed consent form approved by an independent ethics committee 
(IEC)/institutional review board (IRB), prior to initiation of any study-specific procedures.
Demographic and Laboratory Assessments
3.
Subject must be an adult male or female, 30 years of age, or older.
4.
Subject is willing and able to comply with procedures required in this protocol.
5.
Subject does not have a low vitamin B12 level (< 200 pg/mL); or does not have low-normal 
vitamin B12 level (< 300 pg/mL) with elevated methylmalonic acid (MMA > 0.41 µmol/L) at 
Screening Visit 1 (V1).a
6.
Subject has normal cognitive function (Mini-Mental State Examination [MMSE] score of 24 or 
greater).  Subjects with mild cognitive impairment (MMSE score of 19 – 23 inclusive) may be 
enrolled if in the investigator's opinion, are able to adhere to all study requirements.  Subjects 
with moderate or severe impairment (MMSE scores of 18 or below) may not be enrolled.
7.
Subject is not considered by the investigator to be an unsuitable candidate to receive ABBV-951 
for any reason.
Disease Activity
8.
Subject must have a diagnosis of levodopa-responsive idiopathic PD.
9.
Subject must meet the following disease activity criteria:

Must be taking a regimen of oral medications for PD that has remained unchanged for at 
least 30 days before commencing ABBV-951 (rescue medications taken "as needed" may be 
disregarded when assessing whether the regimen of oral medications has remained 
unchanged); this regimen must include levodopa-containing formulations such as CD/LD IR 
(e.g., Sinemet, Madopar), CD/LD-CR (e.g., Sinemet controlled release [CR]), CD/LD extended 
release (e.g., Rytary), CD/LD/entacapone (e.g., Stalevo).

Must have a recognizable/identifiable "Off" and "On" state (motor fluctuations) as 
established through investigator observation and confirmed by PD diary entries recorded 
during the concordance test performed during the Screening Period.b
10. Must be judged to be inadequately controlled by current therapy in the opinion of the 
investigator and experience a minimum of 2.5 hours of "Off" time per day as assessed by PD 
Diary prior to Day 1 (V3).  Subjects who have received DBS therapy are eligible for the study, 
provided they are considered stable, are still levodopa responsive, and meet all other eligibility 
criteria.
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Subject History
11. Subject does not have a history of significant skin conditions or disorders (e.g., psoriasis, atopic 
dermatitis) or evidence of recent sunburn, acne, scar tissue, tattoo, open wound, branding, or 
colorations that in the investigator's opinion would interfere with the infusion of study drug or 
could interfere with study assessments.c
12. Subject does not have a recent (within 6 months prior to study drug administration) history of 
drug or alcohol abuse that could preclude adherence to the protocol in the opinion of the 
investigator.
13. Subject does not have significant current suicidal ideation within 1 year prior to study drug 
administration as evidenced by answering "yes" to questions 4 or 5 on the suicidal ideation 
portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at either screening 
visit, or any history of suicide attempts within the last 2 years.
14. Subject does not have a history or presence of psychotic episodes that in the investigator's 
judgment are not adequately controlled by second generation (atypical) antipsychotics and that 
could preclude adherence to the protocol.
15. Subject does not have other clinically significant unstable medical conditions or any other
reason that the investigator determines would interfere with the subject's participation in this 
study or would make the subject an unsuitable candidate to receive study drug.
16. Subject does not have a history of allergic reaction or significant sensitivity to levodopa or 
constituents of the study drug (and its excipients) and/or other products in the same class.
17. Subject does not have any known medical condition for which levodopa is contraindicated 
(e.g., suspicious undiagnosed melanoma, narrow-angle glaucoma, severe heart failure, severe 
cardiac arrhythmia, pheochromocytoma, untreated hyperthyroidism, or Cushing's syndrome 
and other circumstances where adrenergics are contraindicated).
18. Subject has not donated or lost 550 mL or more blood volume (including plasmapheresis) or 
received a transfusion of any blood product within 8 weeks prior to initial study drug 
administration.
19. Subject has no known active COVID-19 infection.  Subject must not have signs/symptoms 
associated with COVID-19 infection or known exposure to a confirmed case of COVID-19 
infection during 14 days prior to Screening.

Subjects who do not meet COVID-19 eligibility criteria must be screen failed and may only 
rescreen after they meet the following COVID-19 viral clearance criteria:

Symptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart after at 
least 10 days have passed since recovery, defined as resolution of fever without use of 
antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of 
breath)

Asymptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart after at 
least 10 days have passed since prior positive result (Note: subjects who develop 
symptoms will follow guidance above for symptomatic subjects).
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
Frequency or timing of COVID-19 testing and interval between testing for the above viral 
clearance criteria may be adjusted to account for epidemiological trends, updated 
information regarding infectivity and local/institutional guidelines.
Contraception
20. If female of childbearing potential, subject must have a negative serum pregnancy test at 
Screening Visit 1 (V1) and a negative urine pregnancy test on Day 1 (V3) prior to the start of the 
infusion of study drug.  Female subjects of non-childbearing potential (either postmenopausal or 
permanently surgically sterile as defined in Section 5.2) at Screening Visit 1 (V1) do not require 
pregnancy testing.
21. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for 
women of childbearing potential (WOCBP) practicing at least 1 protocol-specified method of 
birth control, that is effective from Day 1 (V3) through at least 30 days after the end of the
infusion (end of Treatment Period).
22. If male and sexually active with female partner(s) of childbearing potential, subject must 
agree, from Day 1 (V3) through 30 days after the end of the infusion of study drug, to practice 
protocol-specified contraception.
23. If female, subject is not pregnant, breastfeeding, or considering becoming pregnant or donating 
eggs during the study or within 30 days after the end of the infusion of study drug.
24. If male, subject is not considering fathering a child or donating sperm during the study or within 
30 days after the end of the infusion of study drug (end of Treatment Period).
Concomitant Medications
25. Subject has not received an investigational product other than ABBV-951 within a time period 
equal to 5 half-lives, if known, or within 6 weeks, whichever is longer, prior to study drug 
administration.
a.
Subjects with a low vitamin B12 or low-normal vitamin B12 and high MMA plasma level may undergo supplemental vitamin 
therapy.  A re-test for vitamin B12 is allowed within the Screening Period without repeating other screening procedures. 
Subjects with normal vitamin B12 or low-normal vitamin B12 without elevated MMA plasma level at re-test are eligible for 
enrollment.  If a subject is rescreened due to vitamin B12 deficiency, all screening procedures, with the exception of the PD 
diary concordance test, will need to be repeated to be eligible for enrollment.
b.
The PD diary concordance test may be omitted for subjects previously enrolled in Study M15-739, for whom 
recognizable/identifiable "Off" and "On" state (motor fluctuations) have been already established and confirmed.  The PD 
diary concordance test may also be omitted for subjects for whom recognizable/identifiable "Off" and "On" state (motor 
fluctuations) have been already established and confirmed, and for unforeseen circumstances, require rescreening.
c.
Subjects with evidence of transient skin conditions such as recent sunburn or open wound that resolved within the 
Screening Period are eligible for enrollment.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
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
Females, Non-childbearing Potential
Females of non-childbearing potential do not need to use birth control during or following study 
drug treatment if considered to be of non-childbearing potential due to any of the following 
criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy during study drug infusion and for 
at least 30 days after the end of the infusion.  Females of childbearing potential must 
commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal*, transdermal*, injectable*) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Day 1.

Progestogen-only hormonal contraception (oral, injectable*, implantable*) associated 
with inhibition of ovulation, initiated at least 1 month prior to Day 1.

Bilateral tubal occlusion/ligation (can be hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized sexual partner(s): The vasectomized partner(s) has received medical 
assessment of the surgical success and is the sole sexual partner of the study subject.

True abstinence, defined as refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable).
*
Not approved in Japan.
Contraception Requirements for Males
Male subjects who are sexually active with a woman of childbearing potential, even if the male subject 
has undergone a successful vasectomy, must agree from Day 1 (V3) through at least 30 days after the 
end of the infusion to:

Use condoms
AND
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
His female partner(s) must use at least one of the following methods of birth control:
1.
Combined (estrogen and progestogen-containing) hormonal birth control (oral, 
intravaginal*, transdermal*, injectable*) associated with inhibition of ovulation initiated at 
least 1 month prior to Day 1
2.
Progestogen-only hormonal birth control (oral, injectable*, implantable*) associated with 
inhibition of ovulation initiated at least 1 month prior to Day 1
3.
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure)
4.
IUD
5.
IUS
*
Not approved in Japan.
5.3 Prohibited Medications and Therapy
The medications listed in Table 5 are prohibited during the Treatment Period.
Table 5.
Prohibited Medications
Apomorphinea,b
Dopamine-depleting agents (such as, but not limited to, reserpine, tetrabenazine, amphetamines)
MAO-A inhibitors and other non-selective MAO inhibitorsc
Ergot dopamine agonists (lisuride, bromocriptine, cabergoline, etc.)
Dopamine antagonist or partial agonist, first generation antipsychotics, antiemetic medications, and 
second-generation antipsychotic with higher dopamine receptors interaction (such as, but not limited to, 
fluphenazine, loxapine, perphenazine, thiothixene, haloperidol, metoclopramide, aripiprazole, asenapine, 
risperidone, paliperidone, perospiron)
Oral and/or inhaled medications containing levodopaa,d
COMT inhibitors (such as entacapone, tolcapone, opicapone)a
COMT = catechol-O-methyltransferase; DDCI = DOPA decarboxylase inhibitor; IR = immediate release; LD = levodopa; 
MAO = monoamine oxidase
a.
Allowed during the Screening Period; must be discontinued for at least 12 hours before commencing ABBV-951 and is 
prohibited for the duration of the Treatment Period.
b.
Apomorphine for continuous subcutaneous delivery (approved in Europe) must be discontinued 30 days before 
commencing ABBV-951.
c.
Non-selective MAO inhibitors are contraindicated for use with levodopa and should not be taken by study subjects.  MAO 
inhibitors with selectivity for MAO type B (e.g., rasagiline, selegiline, safinamide) are allowed.
d.
LD+DDCI IR or levodopa inhalation powder is allowed in case of serious medical need such as in the case of pump 
malfunction.
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5.4 Prior and Concomitant Therapy
Any medication or vaccine (including COVID-19 vaccine, over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from 30 days prior to the time of 
screening (V1) or receives during the study must be recorded through the end of the study.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with ABBV-951 is located in the ABBV-951 
Investigator's Brochure.1
With the exception of the Optimization Period, subjects should remain on stable anti-PD medication for 
the duration of the study, unless medically needed.
All subjects should fill a prescription provided by the investigator or their general practitioner for oral 
LD+DDCI IR tablets or levodopa inhalation powder in case rescue therapy is needed.  Once ABBV-951 
treatment has been initiated, rescue tablets or the inhalation powder capsules should only be used in 
the case of a serious medical need, such as rapid deterioration of motor symptoms that do not respond 
to an extra dose of ABBV-951 or to an increase in the preset infusion rate.  The subject should be 
instructed to record all oral levodopa tablets or inhalations on the Subject Dosing Diary on the assigned 
days.
The following concomitant (Table 6) and rescue (Table 7) medications are allowed:
Table 6.
Allowed Concomitant Medications/Therapy
Non-ergolinic dopamine agonistsa (pramipexole, ropinirole, rotigotine)
Selective MAO-B inhibitors (e.g., rasagiline, selegiline)
Amantadine (IR and ER formulations)
Safinamide
Zonisamideb
Istradefyllineb,c
ER = extended release; IR = immediate release: MAO = monoamine oxidase
a.
Apomorphine and ergot dopamine agonists (lisuride, bromocriptine, cabergoline, etc.) are NOT allowed.
b.
Approved in Japan.
c.
Approved in the United States.
Table 7.
Allowed Rescue Medications/Therapy
100 mg of oral LD+DDCI (e.g., Sinemet 25/100).  The DDCI may vary, 
based on the country of interest (e.g., benserazide vs. carbidopa; 
10 mg vs. 25 mg, etc.)
84 mg of levodopa inhalation powder (e.g., 2 capsules of Inbrija)a

Allowed as rescue therapy 
(e.g., in the case of pump 
malfunction)
DDCI = DOPA decarboxylase inhibitor; LD = levodopa 
a.
Approved in the United States.
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5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD.

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.

Subject answers "yes" to question 4 and/or question 5 on the suicidal ideation portion of the 
C-SSRS and/or positive responses to any category of the suicidal behavior portion of the C-SSR; 
these subjects should be referred for appropriate follow-up care and the AbbVie TA MD should 
be notified.
For subjects considered to be lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures.
5.6 Temporary Suspension of Study Drug Treatment
A subject's study drug treatment may need to be temporarily suspended for medical reasons 
(i.e., illness, hospitalization).  If such a situation occurs, subjects who experience a suspension up or 
equal to 30 days in duration may be reinitiated on study drug at the discretion of the investigator.  A 
suspension of study drug, greater than 30 days in duration, will require approval from the AbbVie TA MD 
prior to drug being restarted.
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5.7 Follow-Up After Subject Discontinuation of Study Drug or From
Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they prematurely 
discontinue treatment with study drug.
If a subject prematurely discontinues study participation and is willing, the procedures outlined for the 
Premature Discontinuation Visit (Appendix D) should be completed as soon as possible, preferably 
within 2 weeks.  In addition, if a subject discontinues study participation or completes the study but will 
not participate in the extension study and is willing, a 30-day follow-up phone call after the end of the 
infusion of study drug will be completed to ensure all treatment-emergent AEs/SAEs have been 
resolved.
5.8 Study Drug and Study Devices
The investigational product consists of study drug (solution for infusion) and study devices.  Some of the 
devices specified below are approved in some countries in which this study will be conducted; however, 
will be labeled for investigational use.  Information about the ABBV-951 formulation and devices to be 
used in this study are presented in Table 8 and Table 9, respectively.
Table 8.
Identity of Study Drug
Study Drug
Dosage Form
Deliverable Content per Vial
Manufacturer
ABBV-951 12/240 mg/mL 
(CDP4´/LDP4´) S.INF.  
15 mL
Solution for infusion
180 mg/3600 mg 
(CDP4´/LDP4´)
AbbVie
CDP4 = carbidopa phosphate 4; LDP4 = levodopa phosphate 4; S.INF = solution for infusion
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 9.
Identity of Study Devices
Description
Usage
Manufacturer
Model Number
Crono PAR Series 3 Pumpa
Delivery of ABBV-951
Canè S.p.A.
Medical Technology
CRONO PAR V3
20 mL syringe without 
needle
Delivery of ABBV-951
Canè S.p.A.
Medical Technology
CRN/20/WN
Neria Guard infusion set, 
6 mm cannula, 60 cm tubingb
Delivery of ABBV-951
Unomedical
A ConvaTec Company
Unomedical reference #:
704060-5226 USA (US)
704060-5226 (OUS)
Neria Guard infusion set, 
9 mm cannula, 60 cm tubingb
Delivery of ABBV-951
Unomedical
A ConvaTec Company
Unomedical reference#:
704060-5229 USA (US)
704060-5229 (OUS)
Cleo 90 infusion set, 6-mm 
cannula with inserter, 
24-inch tubing with buckle 
Delivery of ABBV-951
Smiths Medical
21-7220-24
Cleo 90 infusion set, 9-mm 
cannula with inserter, 
24-inch tubing with buckle
Delivery of ABBV-951
Smiths Medical
21-7230-24
Vial adapter
Facilitates transfer of 
ABBV-951 to 
syringe/reservoir
West Pharmaceutical 
Services
West Item ID:
36098056
Medimop Cat #:  8073005
OUS = Outside United States; US = United States; V = Visit
a.
Software version "DL.v01.05" is installed on the pumps.
b.
Subjects enrolled under protocol v6.0 (or after) will use the Neria Guard infusion set at the start of enrollment (Day1/V3). 
Subjects may transition between Neria Guard and Cleo 90 if the investigator determines this to be clinically necessary. 
Subjects enrolled prior to protocol v6.0 may continue to use the Cleo 90 infusion set or transition to Neria Guard at the 
investigator's discretion.
The pump comes in a kit form that includes Canè mini suitcase, Canè elastic belt, Canè collar strap, Canè 
fabric case, Canè Battery Compartment opener tool.
Clinical study personnel will receive the System User Manual and System Programming Guide.  Subjects 
will receive the ABBV-951 System User Manual and Placemat guide for daily use.
Subject dosing will be recorded in a subject dosing diary for 2 consecutive days prior to any study visits 
as specified in the study activity schedule in Appendix D.  The subject will be instructed on how to return 
all drug containers (even if empty), devices and ancillaries.  Clinical study personnel will document 
compliance.
Treatments Administered
Subjects will receive an oral loading dose of CD/LD on Day 1 (V3), followed by a 24-hour daily CSCI of 
ABBV-951.
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The oral loading dose will be determined by the investigator per therapeutic management prior to 
infusion.  The infusion rate of ABBV-951 (and therefore the total amount of ABBV-951 administered) will 
be calculated based on the subject's levodopa equivalent dose (LED) and an ABBV-951 conversion 
algorithm.  The initial dose of study drug and corresponding infusion rate can be adjusted during the 
Optimization Period to reach the individualized therapeutic dose that most adequately controls the 
subject's motor symptoms as assessed by the investigator through subject interviews and/or other 
evaluations of symptom severity.  The ABBV-951 basal infusion rate can also be adjusted throughout the 
study at the discretion of the investigator.  The investigator may preprogram 3 infusion rates into the 
pump, 1 that corresponds to the base prescribed daily infusion rate (F1) and 2 additional infusion rates 
(F2 and F3) that are programmable within a ± 20% limit from the prescribed base infusion rate and 
always within the allowable range (0.17 to 1.04 mL/hr); F2 should be an alternative higher continuous 
dose and F3 should be an alternative lower continuous dose.  F3 may be reduced beyond the 20% limit 
from the prescribed base infusion rate (F1) if medically necessary and only with approval from the 
AbbVie TA MD.  If the alternative infusion rates (F2 and F3) are not required, the investigator or his/her 
designee must program them to "OFF."  Thus, subjects might have the freedom to choose among the 
preprogrammed infusion rates or to self-administer extra doses of ABBV-951 during the day, per the 
investigator's judgment.  The pump will be programmed by the site per instructions in the System 
Programming Guide.
During the Treatment Period, the ABBV-951 infusion will be self-administered by the subject using study 
devices (i.e., infusion set connected to an infusion pump) indicated for subcutaneous delivery.  The drug 
delivery system will need to be loaded with the investigational drug at the same time every day for 
subjects who require 1 vial per day (every 24 hours), or at the same times of the day (every 12 hours) for 
subjects who require 2 vials per day.  To prepare the drug delivery system, reference the System User 
Manual instructions: study drug will be loaded into a syringe that will then be connected to the pump.  
The infusion site will be prepared.  The insertion device will be used to insert the cannula and apply the 
cannula pad to the skin.  The infusion set tubing will be attached to the syringe, primed, and then 
attached to the cannula pad on the subject.  The daily dose will be initiated by starting the 
pre-programmed pump.  When vial changes are performed, depending on how long the infusion set has 
already been in use, subjects may need to either:  a) obtain all new components or b) obtain all new 
components except for a new infusion set (i.e., infusion set tubing and insertion device/cannula pad, 
which can be used up for 3 consecutive days).  For the latter situation, the subject will use a new syringe 
and a new vial adapter to draw their therapy from a new vial, connect the new syringe to the pump, 
connect their existing infusion set to the syringe, and start their therapy.
The infusion set and the infusion site (area of the skin where the subcutaneous cannula is inserted) can 
be left unchanged for up to 3 days when the drug is infused continuously.  This includes maintaining the 
same infusion set when changing empty syringes or using a new vial (for those who require two vials per 
day).  However, a new vial adapter and a new syringe are required any time a new vial is used.  The 
infusion set should be changed, and the infusion site rotated every 3 days unless a more frequent 
rotation schedule is medically indicated (investigators should consider instructing the subject to rotate 
the infusion site more frequently than every 3 days (e.g., every 2 days or every day) if skin irritation 
and/or drug pooling is observed).  Temporary interruptions of study drug are allowed (e.g., for hygiene, 
or changing empty syringes).  A change in vial, vial adapter, syringe and infusion set, and rotation of the 
infusion site are required before resuming infusion for interruptions longer than approximately 1 hour.  
If study drug is interrupted for approximately 3 hours or more, a loading dose is recommended to 
quickly achieve symptomatic control (see table below):
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Duration of drug 
suspension
Use new entire 
infusion set
Use new vial/new vial 
adapter/new syringe
Rotate
infusion site
Self-administer
oral dose
1 to < 3 hours



None
≥ 3 hours



Loading dosea
a.
An oral dose of immediate-release formulations LD+DDCI corresponding as closely as possible to the subject's habitual first 
morning dose taken prior to commencing ABBV-951.
The investigator will select the length of the infusion set cannula among those provided, considering 
individual subject characteristics such as thickness of the abdominal subcutaneous fat tissue. The 
appropriate cannula will be long enough to deliver study drug solution to the subcutaneous tissue 
without infiltrating the muscle wall, which can cause pain and/or occlusion of the cannula.
The infusion should be administered to a site with ample subcutaneous tissue and at least 5 centimeters 
(or 2 inches) away from the site of application of ECG electrodes, and at least 5 centimeters (or 2 inches) 
away from the umbilicus (if the selected area for infusion is the abdomen).  Infusions should not be 
administered to areas of scarred or hardened tissue or stretch marks, to skin folds or creases where the 
body naturally bends a great deal, or to areas where clothing might cause irritation (e.g., near the 
beltline).
In the event of an infusion pump malfunction or other event that temporarily prevents delivery of study 
drug, the time period during which study drug was not delivered will be recorded by the site, in the 
electronic data capture system.  The subject should call the clinical study personnel, so that they may 
attempt to resume the study drug infusion.  The time that the infusion stopped and/or malfunction will 
be recorded to the minute if known (otherwise, an estimated time will be recorded).  If the infusion is 
resumed, the restart time will be recorded to the minute.  If the study drug infusion is not able to be 
resumed or if the investigator is concerned that the subject may not be able to successfully complete 
the study drug infusion requirements, the subject may be discontinued from the study.
Alternative Infusion Site Locations
Although the abdomen is the preferred infusion site location, situations may occur where an alternative 
infusion site may need to be considered for a subject.  If the investigator believes that an alternative 
infusion site is needed for a particular subject, for example, due to abdominal skin reactions that do not 
heal fast enough to allow for rotation, surgical interventions, scar tissue, or anatomical restrictions, the 
following alternative sites may be considered after obtaining approval from AbbVie TA MD:

Thighs:  anterior (both lateral and medial)

Arms:  posterior (both lateral and medial)

Flanks
Investigators should factor in the following when considering one of these sites:

Body composition and distribution of subcutaneous tissue:  look for places on the skin where 
you can "pinch an inch" to ensure there is adequate subcutaneous tissue (e.g., for males, more 
around the abdomen; for females, more around hips and upper thighs).
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
Ability to use alternative infusion site.  It might be difficult for subjects to apply the cannula to 
the flank or to the dominant arm by themselves.

Hirsutism:  to minimize issues with adhesiveness of cannula pad, avoid areas with excess hair or 
consider removing hair without causing blade-related skin trauma.  If shaving with razor, 
consider doing 1 day or 2 days prior to cannula insertion.  Alternatives to razor shaving are 
trimming or use of hair removal creams.

Sweating:  to minimize issues with adhesiveness of cannula pad and risk of folliculitis (especially 
if blade-shaven), avoid areas where the subject sweats significantly and avoid tight-fitting 
clothes on the chosen area.  Also consider using commercially available ancillary adhesive 
materials.

Sleep position:  discuss expectation with subject to either adjust sleeping position or consider an 
alternative location that does not impact sleep habits.

Physical activity and exercise:  consider choosing sites with the least risk of being impacted by 
the physical activity and consider using ancillary adhesive materials to prevent activity-related 
dislodgement of the cannula and subsequent inadequate infusion delivery (intradermal rather 
than subcutaneous).  Avoid sunscreen or lotion on the area and if used, ensure the area is 
cleaned with alcohol pad/wipes and allowed to dry completely before inserting the cannula.

Subject preference:  subject's desire for cannula concealment (thigh and flank) versus no 
concealment (arm).
The alternative infusion site(s) may be used sporadically or integrated into the routine with the 
abdomen rotation at the investigator's discretion.  If an alternative site is used exclusively long term, it is 
preferable to alternate (right/left) and maintain the 2.5-cm (1-inch) distance from the previous infusion 
site when returning to the same side. Sites will record information in subject's source documentation 
on the alternative infusion site(s) used.
Packaging and Labeling
ABBV-951 will be supplied as solution for infusion in vials in an open-labeled fashion and packaged in a 
carton containing 6 vials per carton.  ABBV-951 will be labeled as ABBV-951 12/240 mg/mL 
(CDP4´/LDP4´) S. INF. 15 mL Vial.  Each vial and carton will be labeled as required per country 
requirements.  Each label must remain affixed to the vial and carton.
AbbVie will supply ABBV-951 and the study pump, its accessories, syringe/drug reservoir, infusion sets, 
and vial adapters.  Non-investigational medicinal products (e.g., rescue therapy with LD+DDCI IR tablets 
or levodopa inhalation powder) must be obtained commercially, unless local regulations require the 
sponsor to provide them.
Storage and Disposition of Study Drug
ABBV-951 must be stored under refrigeration between 2°C to 8°C (36°F to 46°F) and must be protected 
from light.  ABBV-951 must be allowed to warm in the sealed vial to room temperature for 30 minutes 
prior to transfer to the drug reservoir/syringe.  The investigational products are for investigational use 
only and are to be used only within the context of this study.  The study drug supplied for this study 
must be maintained under adequate security and stored under the conditions specified on the label 
(refrigerated) until the time of use or until returned to AbbVie.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Tote bags, cold packs, cooler bags, disposal containers, and alcohol swabs, may be provided to study 
subjects.  Batteries might be provided by AbbVie, based on country-specific regulations and will be 
locally sourced.
The drug delivery system, including the infusion pump, infusion set, and syringes, must be used as 
indicated and training will be provided to the clinical study personnel and/or a home care nurse 
provided by the sponsor.  Detailed instructions for the use of the drug delivery system pump are listed in 
the pump ABBV-951 System User Manual and the ABBV-951 System Programming Guide.
Subject Identifier Assignment
An interactive response technology (IRT) system will assign a unique identification number to each 
subject at Screening Visit 1 (V1).  For subjects who do not meet the study selection criteria, clinical study 
personnel must register the subject as a screen failure in the IRT system.
For subjects who rescreen (e.g., due to Vitamin B12 deficiency), the screening number assigned by the 
IRT at the initial screening visit should be used.  Treatment will be administered in an open-label 
manner.
Subjects who are enrolled will retain the subject number assigned to them at Screening Visit 1 (V1) 
throughout the study.
Contact information and user guidelines for the IRT use will be provided to each site.
Selection and Timing of Dose for Each Subject
A CSCI of study drug will be delivered over 24 hours daily for up to 52 weeks via an infusion set 
connected to a pump.  Each subject's base continuous infusion rate (F1) will be initially calculated based 
on the subject's daily LED and an algorithm developed following the analysis of pharmacokinetic data 
from Phase 1 studies.  The dose should be adjusted based on the clinical response for the individual 
subject, which means maximizing the functional "On" time during the day by minimizing the number 
and duration of "Off" episodes (bradykinesia) and minimizing "On" time with disabling dyskinesia.
Study Drug/Study Devices Accountability
The investigator or his representative will verify that study drug and study devices are received intact 
and in the correct amounts.  This will be documented by signing and dating a proof of receipt or similar 
document.  A current (running) and accurate inventory of study drug and study devices will be 
maintained in the IRT system.  For those subjects who are allowed to benefit from a direct to patient 
shipment of the study drug and study devices, the third-party vendor contracted by the sponsor may be 
responsible of those steps described above.
Subjects will be instructed to return used drug vials with vial adapters attached within the original vial 
carton; subjects will also be instructed to return unused vials in the original vial carton.  Used syringes, 
infusion sets (inserter and infusion set tubing) will be collected into a disposal container and returned to 
the study site for proper disposal or an alternative sponsor-approved method of disposal shall be used.  
Unused syringes, infusion sets (inserter and infusion set tubing) and vial adapters will be returned by the 
subject to the site at the end of the study.  At the end of the study, subjects will be instructed to return 
the pumps, and the sites would reconcile the pump in the IRT system.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Site personnel will review returned study drug kits, empty study drug packaging, devices, and ancillaries 
to verify compliance at each visit.  Returned study drug kits will be reconciled in IRT at each visit.  Each 
site will be responsible for maintaining drug accountability records including product description, 
manufacturer, and lot numbers for all non-investigational products (e.g., rescue therapy with LD+DDCI 
IR tablets or levodopa inhalation powder) dispensed by the site.  Returned study drug should not be 
re-dispensed to the subject.
Upon completion or termination of the study, all original containers (containing unused investigational 
product) will be returned to AbbVie or destroyed on site, according to instructions from AbbVie and 
according to local regulations.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic),
the investigator is responsible for notifying the IEC/IRB, regulatory authorities (as applicable) and 
AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the drug component of the product or to the medical 
device components.
This may include, but is not limited to, damaged/broken product or packaging, product appearance 
whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
For medical devices, a product complaint also includes:
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●
All deaths of a subject using the device
●
Any illness, injury, or AE in the proximity of the device
●
An AE that could be a result of using the device
●
Any event needing medical or surgical intervention including hospitalization while using the 
device
●
Malfunctions, use errors, or inadequacy in the information supplied by the manufacturer
Medical Complaints/Adverse Events and Serious Adverse Events:  Study Drug
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during the study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure was 
planned prior to study entry; however, if the pre-existing condition deteriorates unexpectedly during 
the study (e.g., surgery performed earlier than planned), then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or contract research organization (as appropriate) as an 
SAE within 24 hours of the site being made aware of the SAE (refer to Section 4.2 of the Operations 
Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
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Disability/Incapacity
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the start of study drug infusion until 30 days after discontinuation of study drug 
administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, study procedure-related serious and nonserious AEs will be collected from the time the subject 
signs the study-specific informed consent.
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.
Adverse Reactions and Serious Adverse Reactions
An adverse reaction (AR) implies at least a reasonable possibility of a causal relationship between a 
suspected medicinal product and an AE.  An AR, in contrast to an AE, is characterized by the fact that a 
causal relationship between a medicinal product and an occurrence is suspected.
Serious adverse reactions (SARs) are defined as all noxious and unintended responses to an 
investigational medicinal product (IMP) related to any dose administered that result in death, are 
life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in 
persistent or significant disability or incapacity, or are a congenital anomaly or birth defect.
A suspected unexpected serious adverse reaction (SUSAR) refers to individual SAE case reports from 
clinical trials where a causal relationship between the SAE and the IMP is suspected by either the 
sponsor or the investigator, is not listed in the applicable Reference Safety Information, and meets 
one of the following serious criteria:  results in death, is life-threatening, requires hospitalization or 
prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, or is 
a congenital anomaly or birth defect.  All individually reported SARs are considered suspected.
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines.
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Adverse Events of Special Interest
The following AESIs will be monitored during the study:
●
Polyneuropathy
●
Weight loss
●
Hallucinations/psychosis
●
Somnolence
Hallucinations, especially visual hallucinations, are a common symptom in patients with PD and could be 
associated with disease progression, comorbid pathologies, and/or concomitant medications.  Older 
subjects, especially with history of hallucination and psychosis, are more at risk of exacerbating 
psychotic symptoms even if these are well controlled with antipsychotic medications at Baseline.  
Hallucinations might be prevented by managing psychogenic medications that might have been 
introduced during the parent study or while in the current study.  Should hallucinations appear during 
this study, standard of care may be applied.  This should include a conservative approach of assessing 
alternative etiologies and addressing them as appropriate and if none are found, waiting a few days to 
see if the phenomenon resolves spontaneously; the ultimate decision on how an individual subject is 
managed during the study, however, is the responsibility of the investigator or designee.
Local tolerability will be assessed.  Infusion site evaluations will be performed at each scheduled clinic 
visit and may be performed at an unscheduled clinic visit.  Any observation of infusion site 
irritation/reaction (> 2 or > C on the infusion site evaluation scale) must be recorded as an AE.  Other 
infusion site-related reactions such as cellulitis/abscess formation, ecchymoses, subcutaneous nodules, 
or scarring should be evaluated and recorded as AEs.  An independent review of moderate and severe 
infusion site-related reactions will be performed.
Adverse Event Severity and Relationship to Study Drug
Investigators will rate the severity of each AE as mild, moderate, or severe.
Investigators will use the following definitions to rate the severity of each AE:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The adverse event causes considerable interference with the subject's usual 
activities and may be incapacitating or life threatening.
The investigator will use the following definitions to assess the relationship of the AE to the use of the 
study drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
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No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Medical Complaints/Adverse Events and Serious Adverse Events:  Study Medical Device
Adverse Event
An AE is defined as any untoward medical occurrence, unintended disease or injury or any untoward 
clinical signs (including an abnormal laboratory finding) in subjects, users or other persons whether or 
not related to the investigational medical device.
If an AE meets any of the following criteria, it is to be reported to AbbVie as an SAE within 24 hours after 
the site is made aware of the SAE:

Led to death, injury, or permanent impairment to a body structure of body function

Led to a serious deterioration in the health of a subject that either resulted in:

a life-threatening illness or injury, or

a permanent impairment of a body structure or a body function, or

inpatient hospitalization or prolongation of existing hospitalization, or

medical or surgical intervention to prevent life threatening illness

Led to fetal distress, fetal death, or a congenital abnormality or birth defect.
A planned hospitalization for a preexisting condition, or a procedure required by the protocol, without a 
serious deterioration in health, is not considered an SAE.
Adverse Device Effects
Adverse device effects are AEs related to the use of an investigational medical device.  This includes any 
AE resulting from insufficiencies or inadequacies in the instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the investigational medical device.  
This includes any event that is a result of a use error or intentional abnormal use of the investigational 
medical device.
Serious Adverse Device Effects
Serious adverse device effects are adverse device effects that have resulted in any of the consequences 
characteristic of an SAE.
Device Deficiency
A device deficiency is an inadequacy of an investigational medical device related to its identity, quality, 
durability, reliability, safety, or performance.  This may include malfunctions, use error, or inadequacy in 
the information supplied by the manufacturer.
If a device deficiency meets any of the following criteria, it is to be reported to AbbVie within 24 hours 
after the site is made aware:
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
Any SAE

Any device deficiency that may have led to a SAE if:

suitable action had not been taken or

intervention had not been made or

circumstances had been less fortunate

New findings/updates in relation to already reported events
Device Causality Assessment
The investigator will use the following definitions to assess the relationship of the reportable device 
event.
Not Related – Relationship to the device can be excluded when:

the event is not a known side effect of the product category the device belongs to or of a similar 
devices and procedures;

the event has not temporal relationship with the use of the investigational device or the 
procedures;

the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible;

the discontinuation of medical device application or the reduction of the level of 
activation/exposure – when clinically feasible – and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious event;

the event involves a body site or an organ not expected to be affected by the device or 
procedure;

the serious event can be attributed to another cause (e.g., and underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment, or other risk factors);

the event does not depend on a false result given by the investigational device use for diagnosis 
when applicable;

harm to the subject are not clearly due to use error.
In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious event.
Unlikely – the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained.
Possible – the relationship with the use of the investigational device is weak but cannot be ruled out 
completely.  Alternative causes are also possible (e.g., an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug, or treatment).  Cases were relatedness cannot be 
assessed or no information has been obtained should also be classified as possible.
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Probable – the relationship with the use of the investigational device seems relevant and/or the even 
cannot reasonably explained by another cause, but additional information may be obtained.
Causal relationship – the serious event is associated with the investigational device or with procedures 
beyond reasonable doubt when:

the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures;

the event has a temporal relationship with investigational device use/application or procedures;

the event involves a body site or organ that

the investigational device or procedures are applied to;

the investigational device or procedures have an effect on;

the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known);

the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of level of activation/exposure), 
impact on the serious event (when clinically feasible);

other possible causes (e.g., an underlying or concurrent illness/clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out;

harm to the subject is due to error in use;

the event depends on a false result given by the investigational device used for diagnosis, when 
applicable;
In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious event.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partner(s) will be collected from the 
date of initiation of the infusion through 30 days after the end of the infusion.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
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7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the interim database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
Sample Size Estimation
Approximately 240 subjects will be enrolled to obtain exposure data from at least 100 subjects treated 
with 24-hour daily CSCI of ABBV-951 for at least 12 months and to meet country requirements.  With 
240 subjects receiving ABBV-951, the probability to observe an AE with an annual incidence rate of 
0.005, 0.01, and 0.02 is 70%, 91%, and 99%, respectively.
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) consists of all subjects who receive at least 1 ABBV-951 infusion and have a 
baseline and treatment observation for at least 1 efficacy outcome measure.  The Treatment-Naive 
Analysis Set (TNAS) consists of all subjects in the FAS who have the initial exposure to ABBV-951 in 
Study M15-741, i.e., subjects who had received ABBV-951 in another study prior to participating in 
Study M15-741 are excluded from the TNAS.
The Safety Analysis Set consists of all subjects who receive any ABBV-951 infusion.
All analyses will be conducted by dose subgroup (low dose or high dose) with a cutoff of 2800 mg LDP 
but could be revised based on an assessment conducted when 50 subjects reach Week 4 or the end of 
the Optimization Period.  Each subject will be categorized to a dose subgroup based on the average total 
daily dose over the treatment period.
7.3 Statistical Analyses for Efficacy
This is a single-arm, open-label study.  Unless stated otherwise, all analyses on efficacy variables will be 
performed with the FAS using data collected no more than 1 day after the end of the infusion of 
ABBV-951.  An exploratory efficacy analysis of normalized daily "Off" time will be conducted on the 
TNAS.  A paired-sample t-test will be performed for testing the change from Baseline.
For all efficacy endpoints, the change from Baseline to each planned visit and to the final visit will be 
summarized in a descriptive manner for each dose subgroup and overall subjects.  The statistics include 
the number of observations, mean, standard deviation, minimum, median, and maximum.
7.4 Statistical Analyses for Safety
Safety analyses will be carried out using the Safety Analysis Set.  Safety will be assessed by AEs, the 
Infusion Site Evaluation Scale, laboratory values, vital sign measures, ECGs, and safety scales including 
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the C-SSRS and Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS).  All AEs 
will be coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
The number and percentage of subjects with treatment emergent AEs by MedDRA system organ class 
and preferred term, by severity, and by relationship to study treatment as assessed by the investigator 
will be provided for each dose subgroup and overall subjects.  For continuous safety outcomes, the 
change from Baseline will be analyzed in a descriptive manner by visit for each dose subgroup and 
overall subjects.  For categorical safety outcomes, the number and percentage of each category will be 
summarized by visit for each dose subgroup and overall subjects.  Hypothesis testing will not be 
performed.
7.5 Interim Analysis
Two interim analyses will be performed during the course of this study.  The first interim analysis will be 
performed after at least 100 subjects have completed 26 Weeks of therapy; the second interim analysis 
will be performed after at least 100 subjects have completed 52 Weeks of therapy.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
A subject may withdraw consent for optional biomarker samples at any time and remain in the clinical 
study.  Data generated from optional biomarker samples before subject withdrawal of consent will be 
retained.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, applicable regulations and 
guidelines governing clinical study conduct, and the ethical principles that have their origin in the 
Declaration of Helsinki.  Responsibilities of the investigator are specified in 0.
In the event a significant disaster/crisis (including the COVID-19 pandemic) occurs leading to difficulties 
in performing protocol-specified procedures, AbbVie may engage with study site personnel in efforts to 
ensure the safety of subjects, maintain protocol compliance, and minimize risks to the integrity of the 
study while trying to best manage subject continuity of care.  This may include alternative methods for 
assessments (e.g., phone contacts or virtual site visits), alternative locations for data collection (e.g., use 
of a local laboratory instead of a central laboratory), and shipping investigational product and/or 
supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, these 
alternative measures must be allowed by local regulations and permitted by IRB/IEC.
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8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed by the local 
regulatory authority, IRB/IEC, and the study site.
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11 COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or date of the last follow-up 
contact, whichever is later.
12 REFERENCES
1.
AbbVie. ABBV-951 Investigator's Brochure.
2.
Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa dose equivalency reporting in 
Parkinson's disease. Mov Disord. 2010;25(15):2649-53.
3.
Espay AJ, Pagan FL, Walter BL, et al. Optimizing extended-release carbidopa/levodopa in Parkinson 
disease: Consensus on conversion from standard therapy. Neurol Clin Pract. 2017;7(1):86-93.
4.
Houghton D, Hurtig H, Metz S, et al. Parkinson's Disease Medications 2017 [Available from: 
https://www.parkinson.org/Understanding-Parkinsons/Treatment/Prescription-Medications.
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5.
Cruse B, Morales-Briceno H, Chang FCF, et al. 24-hour levodopa-carbidopa intestinal gel may reduce 
troublesome dyskinesia in advanced Parkinson's disease. NPJ Parkinsons Dis. 2018;4:34.
6.
Chang FC, Tsui DS, Mahant N, et al. 24 h Levodopa-carbidopa intestinal gel may reduce falls and 
"unresponsive" freezing of gait in Parkinson's disease. Parkinsonism Relat Disord. 
2015;21(3):317-20.
7.
Ricciardi L, Bove F, Espay KJ, et al. 24-Hour infusion of levodopa/carbidopa intestinal gel for 
nocturnal akinesia in advanced Parkinson's disease. Mov Disord. 2016;31(4):597-8.
8.
Busk K, Nyholm D. Long-term 24-h levodopa/carbidopa gel infusion in Parkinson's disease. 
Parkinsonism Relat Disord. 2012;18(8):1000-1.
9.
Othman AA, Rosebraugh M, Chatamra K, et al. Levodopa-Carbidopa Intestinal Gel Pharmacokinetics: 
Lower Variability than Oral Levodopa-Carbidopa. J Parkinsons Dis. 2017;7(2):275-8.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
aPD
advanced Parkinson's disease
AR
adverse reaction
CD
carbidopa
CD/LD
carbidopa/levodopa
CDP
carbidopa phosphate
CDP/LDP
carbidopa phosphate/levodopa phosphate
CLES
carbidopa-levodopa enteral suspension
COMT
catechol-O-methyltransferase
CR
controlled release
CSCI
continuous subcutaneous infusion
C-SSRS
Columbia-Suicide Severity Rating Scale
DDCI
DOPA decarboxylase inhibitor
DNA
deoxyribonucleic acid
DO
Doctor of Osteopathy
ECG
Electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
EuroQol 5-dimensions questionnaire
EQ VAS
EQ visual analogue scale
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GLP
Good Laboratory Practice
ICD
impulse control disorder
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
independent ethics committee
IMP
investigational medicinal product
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IR
immediate release
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
IU
International Unit
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
LCIG
levodopa-carbidopa intestinal gel
LD
levodopa
LDP
levodopa phosphate
LED
levodopa equivalent dose
MAO
monoamine oxidase
MDS-UPDRS
Movement Disorder Society-Unified Parkinson's Disease Rating Scale
MedDRA
Medical Dictionary for Regulatory Activities
M-EDL
Motor Aspects of Experiences of Daily Living
MMA
methylmalonic acid
MMSE
Mini-Mental State Examination
MW
molecular weight
nM-EDL
Non-Motor Aspects of Experiences of Daily Living
NP
Nurse Practitioner
PA
Physician's Assistant
PCS
potentially clinically significant
PD
Parkinson's disease
PDQ-39
PD Questionnaire-39 item
PDSS-2
PD Sleep Scale-2
PhD
Doctor of Philosophy
PKG
Parkinson's KinetiGraph™ or Personal KinetiGraph™ (United States)
PLMS
periodic leg movements of sleep
PRO
patient-reported outcome
QTc
QT interval corrected for heart rate
QTcF
QTc using Fridericia's correction formula
QUIP-RS
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease – Rating Scale
RBD
rapid eye movement behavior disorder
RLS
restless leg syndrome
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RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
S.INF
solution for infusion
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
therapeutic area medical director
TN
treatment-naïve
TNAS
Treatment-Naïve Analysis Set
UPDRS
Unified Parkinson's Disease Rating Scale
US
United States
VAS
visual analog scale
WOCBP
women of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M15-741:  A 52-Week, open-label, single-arm study to evaluate the safety and tolerability of 
24-hour daily exposure of CSCI of ABBV-951 in subjects with Parkinson's disease
Protocol Date:  11 February 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol, and making changes to a protocol only after notifying AbbVie and the 
appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except when 
necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Group Medical Director
Neuroscience Development
Medical Director
Neuroscience Development
Assistant Scientific Director
Neuroscience Development
Senior Director and Statistics TA Head
Data and Statistical Sciences
Program Lead I
Clinical Program Development
Study Project Manager II
Clinical Program Development
Principal Medical Writer
Medical Writing
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collected for at least 2 consecutive days during the same 6-day Monitoring Period.  In countries where the PKG watch is not approved, the Monitoring Period may be reduced to 
at least 2 days to account for the collection of PD Diaries and pump training.
b.
Urine pregnancy tests will be performed monthly for women of childbearing potential.  If there is a scheduled visit, the test will be performed on site; if there is not a scheduled 
visit, the test may be performed at an unscheduled visit or at home.
c.
Dispensing visits may occur with or without a clinic visit being completed.
d.
If the subject is willing, the post-study completion/premature discontinuation follow-up call will occur 30 days after premature discontinuation from the study or 30 days after 
completion of Week 52 for subjects not enrolling in the extension study.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
17 July 2018
Version 2.0
15 November 2018
Version 3.0
11 February 2019
Version 3.1 (United States and Japan)
18 April 2019
Version 3.1.1 (United States and Japan)
26 April 2019
Version 4.0
28 August 2019
Version 4.1 (Germany only)
02 January 2020
Version 5.0
02 March 2020
Version 6.0
09 April 2020
Version 6.1 (Sweden only)
11 June 2020
Version 6.2 (Germany only)
11 June 2020
Version 6.1.1 (Sweden only)
08 September 2020
Version 6.1.1.1 (Sweden only)
20 November 2020
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol 
and incorporate necessary protocol modifications due to the COVID-19 pandemic, as well as other 
changes as follows:
1.
Sample size estimation was updated to approximately 240 subjects to accommodate 
participation of additional countries, to account for the higher-than-expected dropout rate and 
to gain additional safety data.
2.
Clarified that F3 infusion rate may be reduced beyond the 20% limit from the prescribed base 
infusion rate (F1) if medically necessary and only with approval from the AbbVie TA MD.
3.
Included information on the re-evaluation of the benefit and risk to subjects participating in the 
study to reflect that there is no additional risk to subjects due to COVID-19 (Protocol 
Section 2.2).
4.
Modified/added eligibility criteria to minimize additional risk to study subjects or exclude 
subjects positive for COVID-19 (Protocol Section 5.1).
5.
Clarified that protocol deviations may include modifications due to COVID-19 (Protocol 
Section 5.9)
6.
Added instructions for COVID-19 pandemic-related acceptable protocol modifications and to 
refer to the Operations Manual for details on how to handle necessary changes to activities or 
procedures (Protocol Section 4.1 and Section 5.5).
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7.
Noted that AbbVie will modify the study protocol as necessary due to the COVID-19 pandemic.  
Investigators must also notify AbbVie if any urgent safety measures are taken (Protocol 
Section 8.2).
8.
Noted that remote monitoring during the COVID-19 pandemic may be employed as needed 
(Protocol Section 9).
9.
Operations Manual (Appendix F) updated to include details on how to perform specific 
activities/procedures that may be impacted by changes in global/local regulations due to the 
COVID-19 pandemic.
10. Added additional details regarding ABBV-951 and infusion site reactions (Protocol Section 4.1).
Rationale:  To provide further guidance to Investigators in the event of an infusion site reaction.
11. Added hallucinations/psychosis as a common symptom in patients with PD and included general 
guidance (Protocol Section 6.1).
Rationale:  To provide general guidance to investigators on possible causes of 
hallucinations/psychosis in the study population and management approaches that can be 
considered.
12. Added text to clarify that the appropriate cannula length will be selected by the investigator 
based on individual subject characteristics (thickness of the abdominal subcutaneous fat tissue) 
and noted that the investigator should consider instructing the subject to rotate the infusion site 
more frequently (Protocol Section 5.8).
Rationale:  To mitigate the risk of muscle wall infiltration leading to pain and/or occlusion of the 
cannula and to prevent overuse of an infusion site area.
13. Added alternative infusion site locations and considerations guidance (Protocol Section 5.8).
14. Removed references to "caregivers" throughout protocol and Operations Manual.
15. Changed the reporting timeframe for product complaints to 24 hours (Protocol Section 6.1).
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APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical Contact
Sponsor Contact:
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064
Emergency Medical Contact:
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Office:
Mobile:
Fax:
Email:
Office:
Mobile:
Fax:
Email:
EMERGENCY 24-hour Number:
+1 973-784-6402
Safety Concerns
Neuroscience Safety Team
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 847-938-4191
Email:
SafetyManagement_Neuroscience@abbvie.com
SAE Reporting 
outside of RAVE
Clinical Pharmacovigilance
Fax:
+1 847-938-0660
Email:
PPDINDPharmacovigilance@abbvie.com
Protocol 
Deviations
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Email:
Certified Clinical 
Laboratory
Covance Central Laboratory Services SA
8211 Scicor Drive
Indianapolis, IN 46214
Phone:
+1 866-762-6209 (toll free)
+1 317-271-1200 (local calls)
Fax:
+1 317-616-2361
Biomarker 
Sample 
Laboratory
Pharmacogenetics and 
Pharmacogenomics
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 847-938-8525
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
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TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
SCREENING PERIOD ACTIVITIES
6
2.2
TREATMENT PERIOD ACTIVITIES
7
2.3
POST-TREATMENT ACTIVITIES
19
3
STUDY PROCEDURES
19
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
19
3.2
ELIGIBILITY CRITERIA
20
3.3
MEDICAL HISTORY
20
3.4
CLINICAL ASSESSMENTS
20
3.5
STUDY DRUG PRESCRIPTION RECORD
20
3.6
INFUSION SITE EVALUATION
21
3.7
DRUG AND ALCOHOL SCREEN
22
3.8
ADVERSE EVENT ASSESSMENT
22
3.9
PRIOR AND CONCOMITANT MEDICATIONS
23
3.10 PATIENT-REPORTED OUTCOMES
23
3.11 CLINICAL LABORATORY TESTS
30
3.12 SUBJECT WITHDRAWAL FROM STUDY
33
3.13 BIOMARKER SAMPLING
33
3.14 12-LEAD ELECTROCARDIOGRAM
33
3.15 VITAL SIGNS
34
3.16 HEIGHT AND WEIGHT
35
3.17 PHYSICAL EXAMINATION
35
3.18 NEUROLOGICAL EXAMINATION
35
3.19 DRUG DELIVERY SYSTEM TRAINING
36
3.20 DRUG DELIVERY SYSTEM DISPENSING AND RETURN
36
4
SAFETY MANUAL
36
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
36
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
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4.2
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
37
4.3
PRODUCT COMPLAINT REPORTING
39
5
COUNTRY-SPECIFIC REQUIREMENTS
39
5.1
SAMPLE RETENTION REQUIREMENTS
39
5.2
SUSAR REPORTING
39
5.3
TREATMENT AFTER END OF STUDY
40
6
REFERENCES
40
LIST OF APPENDICES
APPENDIX A.
NEUROLOGY LABORATORY GRADING
41
APPENDIX B.
CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT VITAL SIGN VALUES AND WEIGHT 
VALUES
46
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes such as remote 
visits, visits at alternative locations, or changes in the visit frequency and timing of study procedures, 
among others.  Additional details are provided in the subsequent section.  Every effort should be made 
to ensure the safety of subjects and site staff, while maintaining the integrity of the study.  If visits 
cannot be conducted onsite due to travel restrictions or other pandemic-related reasons, follow the 
guidance below on how to proceed.
If a subject has screened and is unable to complete screening activities on site after Screening Visit 1, 
the Screening Period should be extended as described in Protocol Section 4.1 rather than performing 
remote Visit 2, since Day 1 and Day 2 visits are required to be completed onsite.  The guidance that is 
provided for Week 1 visit and beyond should be followed if the COVID-19 restrictions at your site have 
changed once your subject is enrolled.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, if it is not possible for all study procedures to be performed as specified 
due to travel restrictions or other reasons, the following modifications are allowed:

If permitted by local regulations, the IRB/IEC and the subject, study visits for Weeks 1, 2, 3, 4, 6, 
13, and 39 may be conducted remotely.  The Enrollment Visit (Day 1), Day 2 visit, Week 26 visit, 
and the Final Week 52/Premature Discontinuation visit are required to be completed onsite.  It 
is highly recommended that all visits during the Optimization Period (Weeks 1, 2, 3 and 4 visits) 
be conducted onsite whenever possible.

Some study visits and/or activities may be performed by phone/remotely.  These are indicated 
by a hashtag (#) in the appropriate visit tables below.

During a phone/remote visit, activities that do not need to be performed are indicated by a 
minus sign (–).

Scheduled and unscheduled labs may be drawn by a local clinic/hospital/laboratory if COVID-19 
restrictions prevent a subject to visit the site.  All procedures performed at local facilities must 
be performed by appropriately qualified personnel.

Study visits and/or activities should be performed as scheduled whenever possible.  If it is not 
possible to do so due to the pandemic, the following modifications are allowed:

For Week 26 and Week 52, if the visit cannot be rescheduled within the visit window, 
contact the sponsor.  Subjects should remain on study drug as much as possible through 
Week 52/Premature Discontinuation.
If an activity is missed during a remote visit, perform the activity at the earliest feasible opportunity.  
Laboratory draws must be obtained as soon as feasible.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
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substantial changes in study conduct in accordance with local regulations.  The subject's source 
documentation should indicate that verbal consent was obtained.
Informed consent will be obtained at Screening Visit 1 (V1) as shown in Section 2.
3.2 Eligibility Criteria
All subjects will be evaluated to ensure they meet the eligibility criteria at Screening Visits 1 and 2 (V1 
and V2) and prior to enrollment on Day 1 (V3) as shown in Section 2.
3.3 Medical History
A complete medical history, including demographics and histories of alcohol or drug abuse, that in the 
investigator's judgment might impact compliance with study execution, will be taken at Screening Visit 1 
(V1) as shown in Section 2.  Additionally, chronic disorders (e.g., diabetes, hypertension, hay fever, 
polyneuropathy) that began prior to Screening Visit 1 (V1) and are still present at Screening Visit 1 (V1) 
should be recorded on the Medical History Form.  The medical history obtained at Screening Visit 1 (V1) 
will serve as the Baseline for clinical assessment.  All psychiatric, neurological, behavioral, and/or 
cognitive diagnoses should be reported.  Updates should be made to the medical/neurological/PD 
history with any findings from laboratories, dermatologists, etc. related to the period before initiation of 
study drug.  Medication (prescription or over-the-counter, including vitamins and herbal supplements) 
use from 30 days prior to informed consent form signature through the end of the study will also be 
recorded.
3.4 Clinical Assessments
A clinical assessment will be conducted on all subjects at Screening Visit 1 (V1) as shown in Section 2.  
This will include an assessment of the subject's PD treatment history, including the Advanced 
Parkinson's Disease (aPD) Clinician Assessment.1  To qualify for enrollment in the study, the subject 
should provide the investigator with a comprehensive history of their current and past (possibly up to 
5 years) PD medication.  This should be done according to the subject's recollection, as well as available 
history in a subject's chart.
The investigator or qualified designee will complete the aPD Clinician Assessment to determine if the 
subject has inadequate control of their motor symptoms despite treatment with PD medications and 
therefore requires advanced PD treatment.
3.5 Study Drug Prescription Record
Starting on Day 1 (V3) through the end of the study as shown in Section 2, the subject's pump settings 
(continuous infusion rate in mL/hr and extra dose volume in mL) should be recorded at the conclusion of 
each visit on the study drug prescription record.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
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3.6 Infusion Site Evaluation
The investigator or qualified designee will evaluate the infusion site area (abdomen) from Day 1 (V3) 
through the end of the study, as shown in Section 2.
At the time of each evaluation, the following rating scales will be used:2
Irritation – Numeric Grades
0 = No evidence of irritation
1 = Minimal erythema, barely perceptible
2 = Moderate erythema, readily visible; or minimal edema; or minimal papular response
3 = Erythema and papules
4 = Definite edema
5 = Erythema, edema, and papules
6 = Vesicular eruption
7 = Strong reaction spreading beyond the test site
Irritation – Letter Grades
A = No finding
B = Slight glazed appearance
C = Marked glazing
D = Glazing with peeling and cracking
E = Glazing with fissures
F = Film of dried serous exudates covering all or portion of the patch site
G = Small petechial erosions and/or scabs
Any observation of infusion site reaction with irritation criteria > 2 or > C must be recorded as an 
adverse event (AE).
Dermatologic Assessment
If any moderate to severe infusion site related AE, such as cellulitis/abscess formation, ecchymoses, 
subcutaneous nodules, or scarring occurs, or if any infusion site related reaction is assessed with an 
irritation numeric grade equal to 7 on the Infusion Site Evaluation scale, the investigator or designee is 
instructed to do the following, which will be documented in the eCRF:
1.
Photograph the skin reaction and follow the appropriate procedure for submission of 
photographs.  In rare situations where an assessment or visit cannot be completed onsite due to 
an extenuating event (e.g., COVID-19-related conditions), the subject may be asked to obtain 
and submit a self-captured photograph of the skin reaction.
2.
Refer the subject to a dermatologist for comprehensive evaluation (including skin biopsy, if 
applicable), treatment, and follow-up per standard practice.  The subject should be referred to a 
dermatologist within 2 business days after the photographs are taken.  The dermatologic visit 
should be completed within 2 weeks from identification of the AE or skin reaction that meets 
the above criteria.  While an in-person dermatology evaluation is preferred, this assessment 
may be performed as a telemedicine visit per the dermatologist's standard practice.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
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Photography data will be considered source documentation.  Dermatologic assessments may be 
performed during clinic visits (scheduled or unscheduled).
Sites will request medical records from the dermatologic visit.  Upon receipt of records or reports 
generated from the dermatologic visit, sites will promptly submit them to AbbVie or designee consistent 
with typical study data reporting requirements.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, the Infusion Site Evaluation (ISE) may be completed remotely via video 
conference at the study visits specified in Section 2 (provided the video is of sufficient quality).  If the ISE 
is completed via video conference, the subject will be asked to describe the reaction (swelling, redness, 
etc.).  Further, if the ISE meets the criteria for dermatologic assessment, request that a photo of the 
reaction be provided to the site in accordance with local regulations.  AEs should be reported per 
protocol.
3.7 Drug and Alcohol Screen
Subjects should have no history of clinically significant drug or alcohol abuse within the last 6 months 
that can preclude adherence to the protocol, in the opinion of the investigator.
Urine specimens will be tested at Screening Visit 1 (V1) as shown in Section 2 for the presence of drugs 
of abuse and for alcohol.  The panel for drugs of abuse will minimally include the drugs listed below.  
These analyses will be performed by the site or by the certified central laboratory.  If the screen is 
performed by the site, test kits and the confirmation of positive results will be provided by the central 
laboratory.  A positive confirmation will result in the subject's exclusion from the study only if in the 
opinion of the investigator, the subject's history of drug abuse could preclude adherence to the 
protocol.  Similarly, if there is documented proof that the detected drug is appropriately prescribed by a 
physician, the subject might be enrolled in the study.

Cannabinoids

Opiates

Barbiturates

Amphetamines*

Cocaine

Benzodiazepines
*
A positive confirmation of amphetamine use, even if appropriately prescribed by a physician, will result in the subject's 
exclusion from enrollment in the study, as amphetamines are dopamine depleting agents and therefore prohibited in this 
study.
3.8 Adverse Event Assessment
AEs will be assessed at every visit throughout the study as shown in Section 2.  The investigator will 
routinely monitor each subject for clinical and laboratory evidence of AEs throughout the study.  The 
investigator will assess and record any AE in detail including the date of onset, event diagnosis (if 
known) or sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the AE 
to study drug, and any action(s) taken.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
For serious adverse events (SAEs) considered as having "no reasonable possibility" of being associated 
with study drug or the study device components, the investigator will provide an "other" cause of the 
event.  For AEs to be considered intermittent, the events must be of similar nature and severity.  AEs, 
whether in response to a query, observed by clinical study personnel, or reported spontaneously by the 
subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
See also Section 4.1.
3.9 Prior and Concomitant Medications
Investigators and/or trained site staff will review and record all prior and concomitant medications at 
every visit throughout the study as shown in Section 2.
3.10 Patient-Reported Outcomes
Subjects will complete the self-administered patient-reported outcome (PRO) instruments.  Subjects 
should be instructed to follow the instructions provided with the PRO instrument and to provide the 
best possible response to each item.  Clinical study personnel shall not provide interpretation or 
assistance to subjects other than encouragement to complete the tasks.  Clinical study personnel will 
encourage completion of the PRO instrument at all specified visits and will ensure that a response is 
entered for all items.
Subjects will also complete rater-administered PRO instruments, such as the Columbia-Suicide Severity 
Rating Scale (C-SSRS), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease -
Rating Scale (QUIP-RS), and other assessments.  All applicable clinical, safety, health outcome, and 
cognition assessments will be administered only by individuals qualified by the sponsor.  Every effort 
must be made by the investigative sites to ensure that each subject is rated by the same rater 
throughout the subject's participation in the study.
Prior to administration of respective scale(s), designated raters will be trained on and certified (if 
appropriate) in the use of all the scales used in this study.  The objective of this certification/training is 
to ensure uniformity across sites in the administration and scoring of these assessments.
The sponsor, in conjunction with the selected rater training vendor, if applicable, will determine the 
minimum rater qualifications for each of the rating scales.  All raters must meet these qualifications 
prior to participation in the training process.  The names and qualifications of all clinical study personnel 
to be involved in rating scale administration will be submitted for approval upon site selection.  The 
qualifications of the raters will be verified through the training vendor.  Qualified raters will be trained 
and tested for competency and, if they meet established requirements, certified accordingly.  Individual 
exceptions to these requirements must be approved by the sponsor via the rater training vendor if 
applicable.
Only those persons who have been trained as raters for this study may rate subjects.  Raters who cannot 
participate in the initial pre-study training or who become involved in the study at a later time will not 
be permitted to perform study ratings until they have satisfactorily completed an individualized training 
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
program designed by the rater training vendor if applicable, approved by AbbVie, and supervised by the 
investigator or his/her designee.  Raters may be reassessed periodically throughout the study.
The PRO assessments are described below.  COVID-19 pandemic-related acceptable protocol 
modifications are described at the end of this section.
SLATE Device PRO (i.e., rater tablet):  The preferred method is to collect data using direct entry into the 
SLATE device, even when collected remotely.  Paper PROs may be used in certain cases; please discuss 
with the sponsor.  Specifications are outlined below.
Site rater-administered scales via SLATE Device PRO:  This includes MDS-UPDRS, C-SSRS, QUIP-RS, 
EQ-5D-5L, and PDQ-39, as applicable for each visit.  The qualified rater at the site can conduct those 
assessments remotely as specified by protocol except for the MMSE and MDS-UPDRS Part III (Motor 
Examination).  As default, the system does not allow raters to jump to the MDS-UPDRS Part IV without 
having completed Part III.  In this case, "Unable to Rate" is the response choice on the MDS-UPDRS 
Part III that should be used to skip through the questions.
Paper versions of certain scales may be available for remote administration.  Please discuss with the 
sponsor.

Source documentation should clearly indicate how each scale was obtained (e.g., in-person, 
phone, video conference) with time/date noted for each scale and with rater's initials.  Study 
personnel will transfer paper documentation to TrialManager (via SLATE device [i.e., rater 
tablet]) per instructions provided to the study site.
Subject Dosing Diary
Subjects will complete a dosing diary.  The time a new syringe dose is started, changes in the preset 
pump flow rate, self-administered extra dose times, stoppage in therapy (e.g., vial change-out, shower),
replacement of infusion sets, pump errors (e.g., occlusion alarm), and LD+DDCI tablets or levodopa 
inhalation powder self-administered by the subject during the study as possible rescue therapy should 
be recorded for 2 consecutive days prior to any study visits (as specified in Section 2).  Additionally, all 
instances of the use of rescue therapy, change in pump flow rates, and self-administered extra doses 
should be documented in the dosing diary throughout the study.  Completed dosing diaries should be 
submitted to the investigator at the first available occasion.
PD Diary
PD Diary Subject Training and Screening Requirements
The subject will be required to have PD Diary training that will include how to understand their PD 
symptomatology and how to complete the PD Diary.  Training will occur during Screening Visit 1 (V1).
Completion of the PD Diary
The core of the PD Diary is the questionnaire that the subject will use to record Parkinsonian symptoms.  
The subject will be prompted to record in the PD Diary whether he/she has been "On," "Off," or 
"Asleep" and what the severity of his/her dyskinesia (troublesome or not troublesome) was.  The PD 
Diary is to be completed for a full 24 hours of each day, reflecting both time awake and time asleep.  On 
PD Diary recording days, the subject will be instructed to make an entry upon waking and every 
30 minutes during their normal waking time and upon awakening from time asleep.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
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The PD Diary will be completed on 2 consecutive days prior to Day 1 (V3) during the Monitoring Period, 
and for 2 consecutive days immediately prior to the visits specified in Section 2.  Subjects should be 
reminded with a phone call prior to each visit to complete the PD Diary and to reinforce the importance 
of PD Diary completion.  If during the study, the subject incorrectly completes the PD Diary, they should 
receive re-training on PD Diary completion.
PD Diary Concordance Assessment
Following the initial PD Diary training during Screening Visit 1 (V1), the subject will complete a PD Diary 
over a minimum of 3 hours for a concordance evaluation while he/she is in the clinic at Screening Visit 1 
(V1) as shown in Section 2.  During this period, the subject must experience at least 1 transition from 
"Off" to "On" or from "On" to "Off," which must be observed by the investigator or a qualified rater.  
The investigator or an experienced and medically qualified study site designee (e.g., NP, PA, DO, MD, or 
PhD) assigned by the investigator will also complete a separate PD Diary for this period indicating their
assessment of the subject's motor state.  There must be at least 75% concordance between the subject's 
PD Diary and the PD Diary completed by the investigator or qualified designee.  If no transition from 
"Off" to "On" or from "On" to "Off" occurs during the time of concordance evaluation and/or the 
concordance is lower than 75%, the concordance testing may be prolonged at the discretion of the 
investigator or designee.  If the concordance is less than 75%, the subject will undergo re-training of PD 
Diary completion and repeat the concordance evaluation at Screening Visit 2 (V2).  Subjects previously 
enrolled in Study M15-739, for whom recognizable/identifiable "Off" and "On" state (motor 
fluctuations) have been already established and confirmed do not need to complete the concordance 
test.  The PD diary concordance test may also be omitted for subjects for whom 
recognizable/identifiable "Off" and "On" state (motor fluctuations) have been already established and 
confirmed, and for unforeseen circumstances, require rescreening.
EuroQol 5-Dimension Questionnaire
The EuroQol 5-dimension questionnaire (EQ-5D-5L) is a standardized instrument developed by the 
EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health 
conditions and treatments.  The EQ-5D-5L consists of 2 parts:  the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS).
The descriptive system comprises 5 dimensions:  mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  Impairment in each of the 5 dimensions is measured on a 5-level scale, where 
1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, and 5 = extreme 
problems.  The patient is asked to rate his/her current health by ticking the box next to the statement 
that most appropriately describes their health status in each of the 5 dimensions.  The patient's overall 
health can be described as a single number (formed by the combination of the levels of impairment 
across each of the 5 dimensions) that ranges from 11111 (full health/ no problems) to 55555 (extreme 
impairment in all dimensions).  The health status is converted to an index value using a country-specific 
weighted scoring algorithm.  The index value for the United States (US) ranges from a worst score of
–0.109 to a best score of 1.
In addition, the patient is also asked to self-rate their current health on a vertical visual analogue scale 
(VAS).  The scale ranges from 0 (labelled as "the worst health you can imagine") to 100 (labelled as "the 
best health you can imagine").  The VAS provides a complementary approach to the descriptive system 
for quantifying the patient's health based on their own judgment.
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Subjects will complete the EQ-5D-5L at the study visits specified in Section 2.
Columbia-Suicide Severity Rating Scale
The C-SSRS is a systematically administered instrument designed to assess suicidal behavior and 
ideation, track and assess all suicidal events, and assess the lethality of attempts.  Additional features 
assessed include frequency, duration, controllability, reason for ideation, and deterrents.
Answering "yes" to question 4 and/or question 5 of the suicidal ideation portion of the C-SSRS relative to 
the previous year, or to any category of the suicidal behavior portion of the C-SSRS relative to the last 
2 years, is considered as an indicator of high risk for suicide and subjects will need to be evaluated 
immediately by the investigator.  Similarly, if subjects express suicidal ideation or suicidal behavior at 
any time during the study, the investigator must evaluate the subjects immediately and consider 
whether they remain suitable for participation in the study.  The AbbVie therapeutic area medical 
director (TA MD) should be notified immediately.
Under no circumstances should a subject who has positively endorsed or expressed suicidal ideation be 
left alone, be allowed to exit the site, or go home before a qualified medical professional has evaluated 
the subject's risk.
A qualified rater will administer the C-SSRS at the visits specified in Section 2.  The C-SSRS will be 
administered prior to initiation of the continuous subcutaneous infusion (CSCI) of ABBV-951 on Day 1 
(V3).
Parkinson's Disease Questionnaire
The Parkinson's Disease Questionnaire (PDQ-39) is a disease-specific instrument designed to measure 
aspects of health that are relevant to subjects with PD, and which may not be included in general health 
status questionnaires.  Each item is scored on the following 5-point scale:  0 = never, 1 = occasionally, 
2 = sometimes, 3 = often, 4 = always (or cannot do at all, if applicable).
Higher scores are consistently associated with more severe symptoms of the disease such as tremors 
and stiffness.  The results are presented as 8 discrete domain scores and as a summary index.  The 
PDQ-39 domain scores and summary index range from 0 to 100, where lower scores indicate a better 
perceived health status.
A qualified rater will administer the PDQ-39 at the visits specified in Section 2.  The PDQ-39 will be 
administered prior to initiation of the CSCI of ABBV-951 on Day 1 (V3).
Movement Disorder Society-Unified Parkinson's Disease Rating Scale
The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is an 
investigator-used rating tool to follow the longitudinal course of PD.  Every effort should be made by the 
study sites to ensure that each subject is rated by the same rater throughout the subject's participation 
in the study.  The MDS-UPDRS assessment will be performed by an approved, trained rater.  To be 
qualified by the sponsor and the rater vendor, all raters must have participated in the rater training and 
have a current valid rater certificate.
The MDS-UPDRS consists of the following sections:

Part I:
Non-Motor Aspects of Experiences of Daily Living (nM-EDL)
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
Part II: Motor Aspects of Experiences of Daily Living (M-EDL)

Part III: Motor Examination (including Hoehn and Yahr stage)

Part IV: Motor Complications
Some sections require that multiple grades be assigned to each extremity.  The MDS-UPDRS total score 
(Parts I-III) ranges from 0 to 236 with 236 representing the worst (total) disability, and 0 representing no 
disability.
For the duration of the study, the MDS-UPDRS will be administered in the subjects' best "On" state with 
the exception of Day 1 (V3).  Before starting the infusion of the investigational drug, subjects will initially 
complete the MDS-UPDRS Part III in a practically defined "Off" state (i.e., without having taken any 
anti-PD medication since the evening of the day before the visit).  The assessment should be repeated 
after initiation of the infusion during the subject's best "On" state, which should be 1 to 2 hours after 
the beginning of the ABBV-951 infusion.  If possible, the MDS-UPDRS should be done at the same time of 
day at each visit throughout the trial by a qualified rater.  At all indicated visits specified in Section 2, a 
complete MDS-UPDRS (Parts I through IV) will be done during "On" time.
Unified Parkinson's Disease Rating Scale
In countries where a validated translation of the MDS-UPDRS scale is not available, the Unified 
Parkinson's Disease Rating Scale (UPDRS) version will instead be used.
The UPDRS is an investigator-used rating tool to follow the longitudinal course of PD.  Every effort 
should be made by the investigative sites to ensure that each subject is rated by the same rater 
throughout the subject's participation in the study.  The UPDRS assessment will be performed by an 
approved, trained rater.  To be qualified by the sponsor and the rater vendor, all raters must have 
participated in rater training and have a current valid rater certificate.
The UPDRS consists of the following sections:

Part I
Mentation, Behavior, and Mood

Part II
Activities of Daily Living

Part III Motor Examination

Part IV Complications of Therapy (including dyskinesias)

Part V Modified Hoehn and Yahr Staging
For the duration of the study, the UPDRS will be administered in the subject's best "On" state with the 
exception of Day 1 (V3).  Before starting the infusion of the investigational drug, subjects will initially 
complete the UPDRS Part III in a practically defined "Off" state (i.e., without having taken any anti-PD 
medication since the evening of the day before the visit).  The assessment should be repeated after 
initiation of the infusion during the subject's best "On" state, which should be 1 to 2 hours after the 
beginning of the ABBV-951 infusion.  If possible, the UPDRS should be done at the same time of day at
each visit throughout the trial by a qualified rater.  At all indicated visits specified in Section 2, a 
complete UPDRS (Parts I through V) will be done during "On" time.
Parkinson's Disease Sleep Scale-2
Although a number of scales exist to evaluate sleep disturbances, only 3 are endorsed and 
recommended by the Movement Disorders Society.  One such scale specific for PD is the Parkinson's 
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Disease Sleep Scale (PDSS), which has been modified to the PDSS-2.  The purpose of the PDSS-2 is to 
characterize the various aspects of nocturnal sleep problems in patients with PD.  The PDSS-2 
instrument has been shown to be reliable, valid, precise, and a potentially treatment responsive tool for 
measuring nocturnal disabilities and sleep disorders in PD.  The PDSS-2 consists of 15 questions that 
evaluate motor and non-motor symptoms at night and upon wakening, as well as disturbed sleep 
grouped into 3 domains:  motor symptoms at night (5 items), PD symptoms at night (5 items), and 
disturbed sleep (5 items).  Specifically, the questions assess overall sleep quality, insomnia, sleep 
fragmentation, restless leg syndrome (RLS) and periodic leg movements of sleep (PLMS), rapid eye 
movement behavior disorder (RBD), hallucinations, nocturia, nocturnal immobility, pain and cramps, 
morning akinesia, tremor, and sleep apnea.  The PDSS-2 was developed from the PDSS based upon the 
need for a treatment measuring tool containing PD-specific sleep disorders; the instrument was 
extended to address specific sleep disturbances such as RLS, akinesia, pain, and sleep apnea.  Daytime 
sleepiness was removed from the PDSS-2, as it is a more complex PD symptom.
To increase ease of use, the visual analogue scale of the PDSS was transformed into a frequency 
measure in the PDSS-2.  The frequency is assessed for the 15 sleep problems based on a 5-point 
Likert-type scale (ranging from 0 [never] to 4 [very often] with the exception of Question 1 score ranging 
from 0 [very often] to 4 [never]).  Scores are calculated for each domain as well as a total score.  The 
recall period is for the past week.
A qualified rater will administer the PDSS-2 at the visits specified in Section 2.  The PDSS-2 will be 
administered prior to initiation of the CSCI of ABBV-951 on Day 1 (V3).
Mini-Mental State Examination
The Mini-Mental State Examination (MMSE) is a brief, 30-point questionnaire, administered by a trained 
rater, that provides a quantitative measure of cognitive mental status in adults and is used widely to 
screen for cognitive impairment and to estimate the severity of cognitive impairment at a given point in 
time, to follow the course of cognitive changes in a patient over time, and to document response to 
treatment.  The MMSE will be used in this study to screen for cognitive impairment.  The MMSE score 
ranges from 0 to 30 with lower scores indicating greater impairment.  The subject must have a score 
≥24 at Screening Visit 1 (V1) to be eligible for study participation.  Subjects with MMSE scores 19 to 23 
inclusive may still be enrolled in the study if, in the investigator's opinion, the cognitive impairment does 
not preclude the subject from completing study-required procedures.  Subjects with moderate or severe 
impairment (MMSE scores of 18 or below) may not be enrolled.  A qualified rater will administer the 
MMSE at Screening Visit 1 (V1) as shown in Section 2.
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale
The QUIP-RS is a brief, self-completed or rater-administered rating scale to assess the severity of 
symptoms of impulse control disorders (ICDs) and related behaviors reported to occur in PD.  In this 
study, QUIP-RS will be rater administered.  The QUIP-RS can also aid in supporting a diagnosis of ICDs 
and related disorders in PD.  The QUIP-RS uses a 5-point Likert scale that requires individuals to rate the 
severity of each symptom based on its frequency.  The potential advantages to using a rating scale 
include detection of subsyndromal behaviors, establishment of clear cutoff points with a good balance 
between sensitivity and specificity, and the ability to monitor changes in symptoms over time.
The QUIP-RS has 4 primary questions (pertaining to commonly reported thoughts, urges/desires, and 
behaviors associated with ICDs), each applied to the 4 ICDs (compulsive gambling, buying, eating, and 
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sexual behavior) and 3 related disorders (medication use, punding, and hobbyism).  It uses a 5-point 
Likert scale (score 0 – 4 for each question) to gauge the frequency of behaviors, and instructs patients to 
answer questions based on behaviors that occurred in the preceding 4 weeks (or any 4-week period in a 
designated time frame).  The QUIP-RS is administered with an instruction sheet that provides examples 
of the behaviors being assessed and a brief description of the Likert scale categories for frequency 
(i.e., never [0] = not at all, rarely [1] = infrequently or 1 day/week, etc.).  Scores for each ICD and related 
disorder range from 0 to 16, with a higher score indicating greater severity (i.e., frequency) of 
symptoms.  Due to overlap, hobbyism and punding were combined in the validation process to form a 
single diagnosis (hobbyism-punding), with a total score ranging from 0 to 32 for the combined disorder.  
The total QUIP-RS score for all ICDs and related disorders combined ranges from 0 to 112.
The behaviors can be described as:
(i)
Gambling (casinos, internet gambling, lotteries, scratch tickets, betting, or slot or poker machines);
(ii)
Sex (making sexual demands on others, promiscuity, prostitution, change in sexual orientation, 
masturbation, internet or telephone sexual activities, or pornography);
(iii)
Buying (too much of the same thing or things that you don't need or use);
(iv)
Eating (eating larger amounts or different types of food than in the past, more rapidly than normal, 
until feeling uncomfortably full, or when not hungry);
(v)
Hobbyism (specific tasks, hobbies or other organized activities, such as writing, painting, gardening, 
repairing or dismantling things, collecting, computer use, working on projects, etc.);
(vi)
Punding (repeating certain simple motor activities, such as cleaning, tidying, handling, examining, 
sorting, ordering, collecting, hoarding, or arranging objects, etc.);
(vii)
Medication use (consistently taking too much of your Parkinson's medications, or increasing on your 
own, without medical advice, your overall intake of Parkinson's medications)
The frequency of behaviors are described as never (0) = not at all, rarely; (1) = infrequently or 
1 day/week; sometimes (2) = at times or 2 to 3 days/week; often (3) = most of the time or 
4 – 5 days/week; very often (4) = nearly always or 6-7 days/week.
A qualified rater will administer the QUIP-RS at the times described in Section 2.
Parkinson's KinetiGraph
Developed by Global Kinetics Corporation, the Parkinson's KinetiGraph™ system (PKG™ or Personal 
KinetiGraph™as it is known in the US), is an innovative mobile health technology.  The PKG™ provides 
continuous, objective, ambulatory assessment of the symptoms of PD including tremor, bradykinesia, 
and dyskinesia.  The PKG™ also provides an assessment of daytime somnolence and an indication of 
propensity for impulsive behaviors.  The PKG™ system consists of a wrist-worn movement recording 
device known as the PKG™-Watch, proprietary algorithms, and a data-driven report known as the PKG™.  
Data are collected continuously by the PKG™-Watch during activities of daily living in the home 
environment.  The PKG™-Watch should be worn by the subject continuously except for recharging once 
a week (e.g., the night of the 7th day, every week).  The data are uploaded for processing at the time of 
recharging.
As allowed by local regulations, subjects will receive the PKG-watch following Visit 1 (V1), after being 
received by the study site, and prior to the Monitoring Period.  The Monitoring Period can occur any 
time before V3, as long as it lasts for 6 consecutive days.  Subjects will be required to wear the 
PKG-watch (refer to the currently approved manufacturer's directions) for at least the 6-day Monitoring 
Period during the Screening Period to at least the Week 26 Visit (V11); thereafter, wearing of the 
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PKG-watch will be optional.  "As allowed by local regulations" is applicable to all wearable device 
references throughout this protocol and its appendices.  The AbbVie TA MD should be consulted if, in 
the opinion of the Investigator, there are circumstances that might interfere with the use of the PKG 
device (e.g., religious reasons, atopic dermatitis).  A subject's inability to wear the PKG watch, due to 
logistics hindering the watch from being made available, will not preclude him/her from study 
participation.  During the 6-day Monitoring Period, subjects should be active (engaged in usual activities 
of daily living and not sitting or resting on a couch or chair or lying in bed) for at least 30 minutes before 
taking their first oral dose.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, PROs eligible for completion at the study visits for Weeks 1, 2, 3, 4, 13, 
and 39 may be conducted remotely.  In this situation, sites will read the PRO questions and response 
options to the subject and record the subject's responses.  The subject's ability to view the PRO to 
understand the questions and response options should be preserved.  Sites may share the questionnaire 
by video conference or send the questionnaires (email or hard copy) to the subjects to allow them to 
read/understand the questions and responses when the subject is providing responses over the phone.  
The date and time of PRO data collection should be recorded along with the name of the individual who 
collected the information.
3.11 Clinical Laboratory Tests
Samples for clinical laboratory tests will be collected at the visits specified in Section 2.  The Day 1 (V3) 
samples will be collected prior to initiation of the CSCI of ABBV-951.  The last laboratory test results 
prior to initiation of the CSCI will serve as the Baseline for clinical assessment for a particular test.
A certified central laboratory will be used to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.  Follow-up safety 
laboratory tests may be performed by a certified laboratory other than the site's local laboratory.
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory via the laboratory manual.
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Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Absolute platelet count 
Mean corpuscular hemoglobin
Mean corpuscular volume
concentration (MCHC)
Prothrombin time (PT)
Activated partial thromboplastin time
Blood urea nitrogen (BUN)
Creatininea
Creatine phosphokinase
Total bilirubin
Serum glutamic pyruvic
transaminase
Serum glutamic-oxaloacetic
transaminase
Lactate dehydrogenase (LDH)
Gamma-glutamyl transpeptidase
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Total protein
Albumin
Glucose
Sodium bicarbonate/CO2
Chloride
Triglycerides
Cholesterol
Magnesium
Special Laboratory Testsb
Vitamin B6
Vitamin B12
Folic acid
Methylmalonic acid (MMA)
Homocysteine
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Bilirubin
Microscopic examination,
if indicated
GFR = glomerular filtration rate
a.
GFR will be calculated one time at Screening Visit 1 (V1) according to the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation.
b.
Special laboratory tests to detect vitamin deficiencies, i.e., vitamin B12, vitamin B6, folic acid, homocysteine, and MMA 
levels will be performed at Screening Visit 1 (V1), on Day 1 (V3), and at Week 6 (V9), Week 26 (V11), and Week 52 (V13).  
An abnormal vitamin B12 level of questionable clinical significance (indeterminate or low normal results at Screening Visit 1 
[V1]), requires MMA and homocysteine laboratory assessments to be reviewed for determination of vitamin B12 deficiency 
prior to entry into the study.  If, at any time during the study, a subject displays symptoms of polyneuropathy, the 
investigator must perform this laboratory panel and any other assessment that the investigator feels is appropriate for 
further evaluation of polyneuropathy symptoms.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:

repeat the test to verify the out-of-range value;

follow the out-of-range value to a satisfactory clinical resolution; or
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
discontinue the subject from the study or require the subject to receive treatment; in this 
case, the laboratory result will be recorded as an AE.
All laboratory abnormalities that occur during the study must be evaluated by the investigator to 
determine if they indicate a new disease process, an exacerbation or worsening of an existing condition, 
or require further action and therefore may need to be reported as AEs.  Accordingly, for any values 
outside of the reference range, the investigator will indicate on the report if the result is clinically 
significant or not clinically significant.  If a laboratory abnormality meets criteria for a potentially 
clinically significant (PCS) laboratory value, the investigator must either report an associated AE or 
document in source the reason(s) the finding was not considered an AE.  See Appendix A.
Any laboratory value that remains abnormal at premature discontinuation/end of study and was judged 
to be clinically significant will be followed according to accepted medical standards until resolution of 
the abnormality.
Serum and Urine Pregnancy Tests
A pregnant or breastfeeding female subject will not be eligible for participation or continuation in this 
study.
Pregnancy testing is not required for females of non-childbearing potential.  Determination of 
post-menopausal status will be made during the Screening Period based on the subject's history.
A serum pregnancy test will be performed at V1 and a urine pregnancy test will be performed as shown 
in Section 2 for all women of childbearing potential.  The urine sample for the Day 1 (V3) urine 
pregnancy test will be collected prior to initiation of the CSCI of ABBV-951.
The serum pregnancy test will be performed by the central laboratory.  Urine pregnancy tests will be 
performed and analyzed at the site during the study visit if there is a scheduled visit.  If there is not a 
scheduled visit, subjects may either have a pregnancy test at the site as an unscheduled visit or at home 
with a pregnancy test kit provided by the site.  If a urine pregnancy test is performed at home, site 
personnel will contact the subject to capture the results of any study-related pregnancy tests and record 
these results in the source records only.  If a urine pregnancy test is positive, the results should be 
confirmed with a serum hCG test that will be performed by the central laboratory.
If the serum pregnancy test at V1 is positive, the subject is considered a screen failure.  If the result of 
the serum pregnancy test is borderline, it should be repeated to determine eligibility.
If the pregnancy test is:

Positive after the serum pregnancy confirmation, the subject is considered a screen failure;

Negative, the subject can be enrolled into the study;

Still borderline, the AbbVie TA MD should be consulted.
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Clinical Chemistry
An 8-hour fast is recommended for blood samples to be drawn for clinical chemistry.  If a subject is not 
able to fast when necessary due to unforeseen circumstances, the nonfasting status will be recorded in 
study source documentation.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, 
or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 pandemic prevent the 
subject from having blood drawn for laboratory testing at the study site, if possible, arrange for subjects 
to have laboratory work done at a local laboratory, hospital, or other facility.  Local laboratory results 
should be obtained along with reference ranges and kept within the subjects' source documentation.  
The investigator should review local laboratory results as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued provided the 
investigator has reviewed all prior laboratory results and confirms and discusses with the subject that 
there is no safety concern for the subject to continue use of the study drug in the absence of current 
labs.  The subject should be scheduled for laboratory draws as soon as feasible.
3.12 Subject Withdrawal from Study
All attempts must be made to determine the date of the end of the infusion of study drug and the 
primary reason for discontinuation of study drug or study participation.  The information will be 
recorded on the appropriate electronic case report form (eCRF) page; however, these procedures should 
not interfere with the initiation of any new treatments or therapeutic modalities that the investigator 
feels are necessary to treat the subject's condition.  Following discontinuation of study drug, the subject 
will be treated in accordance with the investigator's best clinical judgment, irrespective of whether or 
not the subject decides to continue participation in the study.
3.13 Biomarker Sampling
Optional samples for biomarker testing will be collected at the visits specified in Section 2.  All samples 
should be labeled and shipped as outlined in the study-specific laboratory manual.
3.14 12-Lead Electrocardiogram
Single electrocardiograms (ECGs) will be recorded at the visits specified in Section 2 after the subject has 
been supine for at least 5 minutes.  Subjects will be instructed to remain stationary (no talking, laughing, 
deep breathing, sleeping, or swallowing) for approximately 10 seconds during the ECG recording.  When 
an ECG is recorded at a time near that of a blood collection, the ECG should be obtained prior to the 
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blood collection.  ECGs on Day 1 (V3) will be recorded after initiation of the CSCI of ABBV-951 prior to 
the end of the visit.
Clinical study personnel will transmit ECG data to an ECG central laboratory for processing and reading 
by a qualified cardiologist (central reader) who will independently review each ECG.  The central reader 
will evaluate a single ECG lead (Lead II, with V5 or V2 [in that order] evaluated if Lead II cannot be 
evaluated).  Heart rate, RR interval, PR interval, QRS duration, and QT interval will be measured for each 
ECG with 3 to 5 beats.  QT interval corrected for heart rate (QTc) will be determined using Fridericia's 
correction method (QTcF).
The central reader will also provide the interpretation of the ECG (i.e., "normal" or "abnormal").  The 
central ECG laboratory will send the ECG report to the site within 3 business days.  The investigator (or 
physician designee) will review the central reader's report/assessment and document his/her review by 
signing and dating the central ECG laboratory report.  Only the central ECG laboratory's data will be 
collected into the database.  The investigator should review and reconcile if necessary his/her 
interpretation of the ECG (normal/abnormal) with the central ECG laboratory in case of relevant 
divergent assessments and reconcile as he/she determines is appropriate.
The original ECG tracing and the central reader's interpretation, each with the investigator's signature 
and date, will be retained in the subject's records at the study site as source documents.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that an ECG may not be performed due to study modifications related to the COVID-19 
pandemic, perform the 12-lead ECG at the next earliest feasible visit or arrange to have an alternative 
acceptable local facility perform the ECG for the subject.
3.15 Vital Signs
Vital signs will be collected for both clino and orthostatism (supine and standing).  For clino vital signs, 
blood pressure and pulse rate will be measured after the subject has been supine for at least 5 minutes.  
For orthostatic vital signs, blood pressure and pulse rate will be measured after the subject has been 
supine for at least 5 minutes and then, after the subject has been standing for 2 minutes.  When vital 
sign measurements are scheduled at the same time as a blood collection, vital sign measurements 
should be obtained prior to blood collection.
Vital signs will be measured at the visits specified in Section 2.  Orthostatic vital signs will be measured 
on Day 1 (V3), and at Week 1 (V5), Week 6 (V9), Week 26 (V11), and Week 52 (V13) (or premature 
discontinuation).  Vital signs on Day 1 (V3) will be measured after initiation of the CSCI of ABBV-951 prior 
to the end of the visit.
See Appendix B for criteria for PCS vital sign values.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted remotely.  In these situations, vital 
signs may be obtained by the subject as needed and recorded in the subject's source documentation.  
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These data should not be recorded in EDC, as data are not obtained on calibrated devices and may not 
be obtained by medically trained individuals.
3.16 Height and Weight
Height and body weight will be measured at Screening Visit 1 (V1) as shown in Section 2.  Height will be 
measured at Screening Visit 1 (V1) only; weight will measured at the visits specified in Section 2.  The 
subject should not wear shoes during either measurement.
See Appendix B for criteria for PCS weight values.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted remotely.  In these situations, height 
and weight measurements may be performed by the subject as needed and recorded in the subject's 
source documentation.  These data should not be recorded in EDC, as data are not obtained on 
calibrated devices and may not be obtained by medically trained individuals.
3.17 Physical Examination
A complete physical examination will be performed at Screening Visit 1 (V1), on Day 1 (V3), and at 
Week 6 (V9), Week 26 (V11), and Week 52 (V13) as shown in Section 2.  The physical examination 
performed at Screening Visit 1 (V1) will serve as the baseline physical examination for clinical 
assessment.  A symptom-directed physical examination will be performed at each following visit when 
necessary.  Any significant physical examination findings after dosing will be recorded as AEs.
3.18 Neurological Examination
A neurological examination will be performed at the visits shown in Section 2.  Neurological findings 
beyond those related to PD should be reported in the eCRF.  The neurological examination performed at 
Screening Visit 1 (V1) will serve as the Baseline for clinical assessment.  Any significant neurological 
findings after dosing will be recorded as AEs.
The neurological examination will consist of the following:

Mental status – assessment of orientation, speech, and memory.

Cranial nerves – assessment of cranial nerves II – XII, including a funduscopic examination.

Motor system – assessment of tone and strength.

Sensory system – brief survey for light touch and temperature.

Reflexes – assessment of deep tendon reflexes and plantar responses (Babinski sign).

Coordination – assessment of upper and lower extremities.

Gait and station.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.19 Drug Delivery System Training
AbbVie personnel, or its delegate, will train the site how to calculate each subject's LED, to program the 
pump to administer the continuous dose and to titrate the dose for each subject as needed.  In addition, 
the site will be trained to prepare the drug delivery system by (i) loading the study drug into the syringe, 
(ii) placing it into the pump, (iii) attaching the infusion set to the subject and syringe, (iv) priming the 
syringe and infusion set, and (v) operating the pump.  Clinical study personnel will receive the ABBV-951 
System User Manual and the ABBV-951 System Programming Guide.
Subjects will receive training on the drug delivery system (e.g., pump, infusion set, syringe, vial, and vial 
adapter) at the visits specified in Section 2.  Training on Day 1 (V3) will occur prior to initiation of the 
CSCI of ABBV-951.  In addition to training, subjects will receive training materials for reference.
Subjects may be trained at Screening Visit 2 (V2) by site staff or nurses contracted by the sponsor on use 
of the drug delivery system.  These nurses must be trained on how to use the drug delivery system prior 
to training study subjects.  In addition, subjects may receive in-home visits from nurses to provide 
additional training and support with the drug delivery system.  During these in-home visits, the home 
health care nurse may ask questions about any problems or concerns the subject is having using the 
drug delivery system.  The home health care nurse will record the subject's answers and provide these 
to the study site for review.
3.20 Drug Delivery System Dispensing and Return
Study drug is intended to be dispensed to subjects every 2 weeks during the Treatment Period with or 
without a clinic visit being completed.  The drug delivery system, including tubing and other accessories 
will be dispensed as needed.
Additionally, a subject (or authorized representatives, if allowed per local regulations) may return to the 
clinic site for additional study drug or drug delivery system components or accessories.
For eligible subjects at participating sites, and as allowed by local regulations, the study drug, its delivery 
system and accessories may be directly delivered to the subject's preferred address by a third party 
vendor contracted by the sponsor.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All serious and nonserious AEs that could be related to study procedures will be collected from the time 
the subject signs the study-specific informed consent until the start of study drug infusion.  From the 
start of study drug infusion until 30 days after discontinuation of study treatment, all AEs and SAEs will 
be collected whether solicited or spontaneously reported by the subject.  After 30 days following 
completion of study treatment, all spontaneously reported SAEs will be collected (nonserious AEs will 
not be collected).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
If a subject has a confirmed or suspected COVID-19 infection and study drug was interrupted, the 
investigator should contact the sponsor emergency medical contact listed above before reintroducing 
study drug.
4.3 Product Complaint Reporting
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours day of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed to a satisfactory conclusion.
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.
Product complaints may require return of the product with the alleged complaint condition (infusion 
pump, infusion set, etc.).  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated within 30 days, 
the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to investigate and 
determine if any corrective actions are required (refer to Protocol Section 6.1, Complaints and Adverse 
Events for details).
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 Sample Retention Requirements
AbbVie (or people or companies working with AbbVie) will store the optional biomarker samples in a 
secure storage space with adequate measures to protect confidentiality.  The samples will be retained 
while research on ABBV-951 (or drugs of this class) or PD and related conditions continues, but for no 
longer than 20 years after study completion or according to local requirements.
5.2 SUSAR Reporting
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the IMP in accordance with global and local guidelines and Appendix A of the Investigator Brochure will 
serve as the Reference Safety Information (RSI).  The RSI in effect at the start of a Development Safety 
Update Report reporting period serves as the RSI during the reporting period.  For follow-up reports, the 
RSI in place at the time of occurrence of the "suspected" Serious Adverse Reaction will be used to assess 
expectedness.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.3 Treatment After End of Study
At the end of the study, subjects may continue on study treatment as part of an open-label extension 
study.  At the subject's last study visit, the investigator will discuss the appropriate subsequent 
treatment with the subject.
6 REFERENCES
1.
Antonini A, Schmidt P, Odin P, et al.  Development of a clinician-reported screening tool to 
identify patients with Parkinson's disease inadequately controlled on oral medications 
[abstract].  Mov Disord.  2017;32 (suppl 2).  Available from:  
http://www.mdsabstracts.org/abstract/development-of-a-clinician-reported-screening-tool-to-
identify-patients-with-parkinsons-disease-inadequately-controlled-on-oral-medications/.  
Accessed on:  June 19, 2017.
2.
Guidance for Industry:  Skin Irritation and Sensitization Testing of Generic Transdermal Drug 
Products.  US Dept of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER).  December 1999.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-741 VERSION 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. CRITERIA FOR POTENTIALLY CLINICALLY 
SIGNIFICANT VITAL SIGN VALUES AND WEIGHT 
VALUES
Variable Measured
Potentially Clinically Significant (PCS) Value
Vital Sign
Diastolic blood pressure decreased
≤ 50 mmHg and ≤ 40 mmHg below baseline value
Diastolic blood pressure increased
≥ 95 mmHg and ≥ 40 mmHg above baseline value
Orthostatic diastolic blood pressure
≥20 mmHg decrease from supine to standing
Pulse rate decreased
≤ 45 bpm and ≤ 35 bpm below baseline value
Pulse rate increased
≥ 120 bpm and ≥ 35 bpm above baseline value
Systolic blood pressure decreased
≤ 80 mmHg and ≤ 45 mmHg below baseline value
Systolic blood pressure increased
≥ 160 mmHg and ≥ 45 mmHg above baseline value
Orthostatic systolic blood pressure
≥30 mmHg decrease from supine to standing
Temperature increased
≥ 38.3°C and ≥ 1.1°C above baseline value
Weight decreased
≥ 7% decrease from baseline value
Weight increased
≥ 7% increase from baseline value
bpm = beats per minute
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SAP_001.pdf: 
ABBV-951
M15-741 – Statistical Analysis Plan
Version 4.0 – 10 March 2021
1
1.0
Title Page
Statistical Analysis Plan
Study M15-741
A 52-Week, open-label, single-arm study to evaluate 
the safety and tolerability of 24-hour daily exposure 
of continuous subcutaneous infusion of ABBV-951 in 
subjects with Parkinson's disease
Date:  10 Mar 2021
Version 4.0
 
NCT03781167


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Background...................................................................5
4.1
Objective....................................................................................................5
4.2
Study Design..............................................................................................5
4.2.1
Study Design and Design Diagram............................................................5
4.2.2
Variables Used for Stratification at Randomization ..................................7
4.3
Endpoint.....................................................................................................7
4.3.1
Primary Endpoints (Safety)........................................................................7
4.3.2
Secondary Endpoints .................................................................................8
4.3.3
Exploratory Endpoint.................................................................................9
4.4
Sample Size Justification ...........................................................................9
4.5
Interim Analysis.......................................................................................10
4.6
Multiplicity Testing Procedures for Type-I Error Control ......................10
4.7
Missing Data Imputation..........................................................................10
5.0
Analysis Populations and Important Subgroups ...............11
5.1
Analysis Population .................................................................................11
5.2
Subgroup..................................................................................................12
6.0
Demographics, Baseline Characteristics, Medical 
History, Prior/Concomitant Medications and Dosing .......12
6.1
Subject Disposition and Accountability...................................................12
6.2
Demographics and Baseline Characteristics............................................13
6.2.1
Medical History and Parkinson's Disease History...................................14
6.2.2
Prior and Concomitant Medications ........................................................14
6.3
Analysis of Dosing...................................................................................15
6.3.1
Analysis of Daily Prescribed Dose ..........................................................15
6.3.2
Analysis of Titration ................................................................................16
6.3.3
Analysis of Daily Levodopa Dose ...........................................................16
6.3.4
Other Dosing Analysis.............................................................................17
6.4
Other Descriptive Analyses .....................................................................17
 


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7.0
Study Drug Duration and Compliance................................17
8.0
Efficacy Analyses...................................................................18
8.1
General Considerations............................................................................18
8.2
Efficacy Analysis .....................................................................................19
8.3
Exploratory Efficacy Analysis.................................................................20
8.4
Efficacy Subgroup Analyses....................................................................20
9.0
Safety Analyses ......................................................................20
9.1
General Considerations............................................................................20
9.2
Analysis of Adverse Events.....................................................................21
9.2.1
Adverse Event Overview .........................................................................21
9.2.2
Adverse Event Summary .........................................................................23
9.2.3
Adverse Event by Maximum Severity.....................................................23
9.2.4
Adverse Event by Relationship to Study Drug ........................................24
9.2.5
Adverse Event by Relationship to Product Quality Complaints..............24
9.2.6
Adverse Event Leading to Study Drug Discontinuation, 
Interruption, and Dose Reduction............................................................25
9.2.7
Adverse Event Associated with Loading Dose Drug and Rescue 
Dose Drug ................................................................................................25
9.2.8
Serious Adverse Events ...........................................................................25
9.2.9
Adverse Events of Special Interest ..........................................................25
9.2.10
Adverse Events by Subgroup...................................................................26
9.2.11
Listings of Adverse Events ......................................................................26
9.2.12
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................26
9.3
Analysis of Laboratory Data....................................................................26
9.3.1
Analysis of Mean Changes for Laboratory Tests.....................................27
9.3.2
Analysis of Laboratory Tests by NCI CTC Criteria ................................27
9.3.3
Potentially Clinically Significant (PCS) Laboratory Values ...................27
9.4
Analysis of Vital Signs and Weight Variables ........................................28
9.4.1
Vital Sign and Weight Variable Mean Changes ......................................28
9.4.2
Potentially Clinically Significant (PCS) Vital Sign and Weight 
Variable Values........................................................................................28
9.5
Analysis of ECG Parameters....................................................................29
 


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9.5.1
ECG Mean Changes.................................................................................29
9.5.2
Potentially Clinically Significant (PCS) ECG Values .............................29
9.6
Infusion Site Evaluation Scale.................................................................29
9.7
Analysis of Questionnaire for Impulsive-Compulsive Disorders in 
PD-Rating Scale (QUIP-RS)....................................................................30
9.8
Analysis of Columbia-Suicide Severity Rating Scale (C-SSRS) ............30
10.0
References...............................................................................31
11.0
Summary of Changes ............................................................31
11.1
Summary of Changes Between the Previous Version and the 
Current Version........................................................................................31
11.2
Summary of Changes in Previous Versions.............................................32
12.0
Appendices .............................................................................33
List of Figures
Figure 1.
Study Design Schematic ............................................................................6
List of Appendices
Appendix A.
Activity Schedule.....................................................................................34
Appendix B.
Potentially Clinically Significant Laboratory Values ..............................41
Appendix C.
Criteria for Potentially Clinically Significant Vital Sign and
Weight Values..........................................................................................42
Appendix D.
Criteria for Potentially Clinically Significant ECG Values.....................43
Appendix E.
Definition of Adverse Events of Special Interest ....................................44
 


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses for ABBV-951 
Study M15-741.
This SAP provides high level summaries of the planned statistical analyses for key 
efficacy and safety endpoints, interim analysis and multiplicity control strategies where 
applicable.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Carry, NC 27513) under the UNIX operating system.
Pharmacokinetics/pharmacodynamics, pharmacogenetics, and selected biomarkers will be 
analyzed separately if applicable, and are not included in this SAP.
The SAP will not be updated in case of future administrative or minor amendments to the 
protocol unless the changes have any impact on the analysis of study data.
4.0
Study Background
4.1
Objective
The primary objective is to assess the local and systemic safety and tolerability of 
ABBV-951 delivered as a continuous subcutaneous infusion (CSCI) for 24 hours daily for 
up to 52 weeks.
The secondary objective is to assess the efficacy of ABBV-951 as measured by 
patient-reported and rater-measured efficacy endpoints.
4.2
Study Design
4.2.1
Study Design and Design Diagram
This is a 52-week, Phase 3, open-label, single-arm, multicenter study to assess the local 
and systemic safety and tolerability, as well as efficacy, of ABBV-951 administered as a 
 


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CSCI for 24 hours daily for up to 52 weeks.  At study completion, subjects may transition 
to a 24-hour CSCI of ABBV-951 open-label extension study.  Approximately 240 adult 
subjects with Parkinson's disease (PD) whose motor symptoms are inadequately 
controlled despite their current optimized PD therapy will be enrolled. 
A schematic of the study is shown in Figure 1.  Details regarding study procedures are 
located in Section 3 of the Operations Manual.
Figure 1.
Study Design Schematic
D = Day; V = Visit; W = Week
a.
The Screening Period may be extended up to a total of 90 days for extenuating circumstances, e.g., supply 
constraints.
b.
The Monitoring Period can occur any time before V3, as long as it lasts for 6 days.  PD Diaries will also be 
collected for at least 2 consecutive days during the Monitoring Period.  In countries where the PKG watch is not 
approved, the Monitoring Period may be reduced to at least 2 days to account for the collection of PD Diaries and 
pump training.
 
  
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening Period
The 10- to 42-day Screening Period will consist of 2 screening visits (V1 and V2) and a 
6-day Monitoring Period during which subjects will become familiar with the wearable 
device and the PD Diary.
Treatment Period
The Treatment Period starts with the initiation of ABBV-951 and consists of 2 parts:  a 
4-week Optimization Period and a 48-week Maintenance Period.
Post-treatment Period Activities
There are no post-treatment activities except for subjects who prematurely discontinue 
study participation.  See study protocol for additional information.
4.2.2
Variables Used for Stratification at Randomization
Since this is a single-arm study, there is no randomization.
4.3
Endpoint
4.3.1
Primary Endpoints (Safety)
The primary endpoints include the following safety variables:
1.
Percentage of subjects with adverse events (AEs) and serious adverse events 
(SAEs) during the study
2.
Percentage of subjects with AEs of special interest (AESI) during the study
3.
Percentage of subjects with numeric grade equal to or higher than 5 and percentage 
of subjects with letter grade equal to or higher than D on the Infusion Site 
Evaluation Scale at any time during the study
4.
Change in clinical laboratory test data from Baseline to end of study
5.
Change in vital sign measurements from Baseline to end of study
 


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6.
Change in electrocardiograms (ECGs) from Baseline to end of study
4.3.2
Secondary Endpoints
The efficacy endpoints are change from baseline to end of study for the following:
1.
Average normalized daily "Off" time and "On" times as assessed by the PD Diary
2.
PD symptoms as assessed by the Movement Disorder Society-Unified Parkinson's 
Disease Rating Scale (MDS-UPDRS) Parts I-IV scores and Hoehn and Yahr Stage
3.
Sleep symptoms as assessed by the PD Sleep Scale-2 (PDSS-2):  total score and 
domain scores
4.
Quality of life as assessed by the PD Questionnaire-39 items (PDQ-39):  summary 
index and domain scores
5.
Health-related quality of life as assessed by the EuroQol 5-dimensions 
questionnaire (EQ-5D-5L):  summary index and visual analogue scale (VAS)
6.
Early morning motor symptom derived from PD Diary
Canè pump-specific endpoints are as follows:
●
Safety
1.
Percentage of subjects with AEs and SAEs associated with pump-
specific product quality complaints.
2.
The percentage of pumps that were replaced due to pump malfunction
●
Effectiveness
1.
The number of times a subject was required to take rescue medication 
due to pump malfunction.
 


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Neria™ Guard infusion set-specific endpoints are as follows:
●
Safety
1.
Percentage of subjects with AEs and SAEs associated with Neria Guard 
infusion set-specific product quality complaints.
●
Effectiveness
1.
The number of product complaints associated with the Neria Guard 
infusion set that resulted in the subject replacing the infusion set.
4.3.3
Exploratory Endpoint
PD symptoms (including tremor, bradykinesia, dyskinesia and somnolence) as assessed 
by the Parkinson's KinetiGraph™/Personal KinetiGraph™ (PKG) wearable device (as 
allowed by local regulations).
●
Change from Baseline to Week 26 in median bradykinesia score (BK50)
●
Change from Baseline to Week 26 in interquartile range of bradykinesia score 
(BK75-BK25)
●
Change from Baseline to Week 26 in median dyskinesia score (DK50)
●
Change from Baseline to Week 26 in interquartile range of dyskinesia score 
(DK75-DK25)
●
Percent change from Baseline to Week 26 in time of tremor and somnolence
4.4
Sample Size Justification
Approximately 240 subjects will be enrolled to obtain exposure data from at least 100 
subjects treated with 24-hour daily CSCI of ABBV-951 for at least 12 months and to meet 
country requirements. With 240 subjects receiving ABBV-951, the probability to observe 
an AE with an annual incidence rate of 0.005, 0.01, and 0.02 is 70%, 91%, and 99%, 
respectively.
 


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4.5
Interim Analysis
Two interim analyses will be performed during the course of this study.  The first interim 
analysis will be performed after at least 100 subjects have completed 26 weeks of therapy; 
the second interim analysis will be performed after at least 100 subjects have completed 
52 weeks of therapy.  Interim locks will occur to preserve the clinical database to be used 
for these interim analyses.  All the analyses described in this SAP will be performed, 
except for analysis of change from baseline to the final visit.
4.6
Multiplicity Testing Procedures for Type-I Error Control
No multiplicity adjustment is needed since efficacy is not the primary objective.
4.7
Missing Data Imputation
PD Diary
If more than 2 valid diary days are available prior to Day 1 or post-baseline visits, the 
2 days closest to the clinical visit (or closet to Day 1 for Baseline) will be used.  If only 
1 valid diary day is available, that valid diary day will be used.  If no valid diary day is 
available for a visit, the average daily normalized "Off" or "On" times will be missing for 
that visit. 
MDS-UPDRS 
The MDS-UPDRS total score and score of each part will be calculated as long as no more 
than 15% of the answers are missing for that assessment.  The missing item will be 
imputed as the average of the non-missing items from the same MDS-UPDRS 
assessment.  Imputation for Part I, Part II, Part III or Part IV scores should use the non-
missing items within the particular part, but the imputation for the total score of Parts I-III 
should use the non-missing items from all 59 items across the 3 parts.
 


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PDSS-2
There is no imputation of missing responses.  If any item score is missing, the total score 
and the corresponding domain scores will not be calculated.
PDQ-39
The PDQ-39 summary index will be calculated as long as no more than 15% (i.e., 5) of 
the answers are missing for that assessment.  It will be imputed as the average of the non-
missing items from the same PDQ-39 assessment.  The domain score will only be 
calculated if all the questions for that domain are answered.
EQ-5D-5L
The EQ-5D-5L summary index will only be calculated if answers are provided for all 
5 individual questions.  The EQ-5D-5L VAS is a single value collected and there is no 
imputation if the VAS value is missing.
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Population
The Full Analysis Set (FAS) consists of all subjects who receive any ABBV-951 infusion 
and have a baseline and treatment observation for at least 1 efficacy outcome measure.
The Treatment Naive Analysis Set (TNAS) consists of all subjects in the FAS who have 
the initial exposure to ABBV-951 in Study M15-741, i.e., subjects who had received 
ABBV-951 in another study prior to participating in Study M15-741 are excluded from 
the TNAS.
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5.2
Subgroup
Unless otherwise noted, all analyses will be conducted by subgroup defined by dose 
category (low dose or high dose) according to total daily levodopa dose from levodopa 
phosphate (LDP) by molecular weight calculated from dosing diary.  Each subject will be 
categorized to a dose subgroup based on the modal total daily dose over the treatment 
period.
Other subgroups are: 
●
Gender
●
Race (White, Asian, Other).  Analysis of Other race will be conducted if at 
least 3 subjects had races other than White or Asian.
●
Age category (< 65, ≥ 65)
●
Geographic region (North America, Europe and Australia, or Japan)
●
PD duration (time since diagnosis) category (< 10 years, ≥ 10 years)
Additional subgroup analyses may be conducted as appropriate.
6.0
Demographics, Baseline Characteristics, Medical 
History, Prior/Concomitant Medications and Dosing
6.1
Subject Disposition and Accountability
All enrolled subjects will be used for the subject disposition summaries.  Number and 
percentage of subjects for each of the following categories will be provided:
●
Analysis Population
○
Full Analysis Set
○
Treatment Naïve Analysis Set
○
Safety Analysis Set
●
Prematurely discontinued ABBV-951
●
Prematurely discontinued from study
 


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●
ABBV-951 ongoing
●
Study ongoing
●
Completed study
The number of subjects screened, enrolled, screen failure, prematurely discontinued 
ABBV-951 and prematurely discontinued from study will be provided by country and 
investigational site.
In addition, the number of sites and countries that screened and enrolled at least 1 subject 
will be summarized.  The number and percentage of subjects who screen failed, 
prematurely discontinued ABBV-951, and prematurely discontinued study will be 
summarized by reason (primary and all reasons).  Subject disposition will also be 
summarized by Sample 1 (Subjects enrolled prior to 08-Jul-2020) and Sample 2 (Subjects 
enrolled on or after 08-Jul-2020).
6.2
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized for the Safety Analysis 
Set. Categorical variables will be summarized with the number and percentage of 
subjects.  Continuous variables will be summarized with descriptive statistics (number of 
observations, mean and standard deviation [SD], median, minimum [min] and maximum
[max]). Missing observations are excluded from all summary statistics.
Variables to be included in this analysis are listed below.
●
Continuous variables:  Age (years), Weight (kg), Height (cm), Body mass 
index (BMI) (kg/m2), Mini-Mental State Examination (MMSE) total score
●
Categorical variables:  Country, Geographic Region (North America, Europe 
and Australia or Japan), Age (< 65 years, ≥ 65 years), Age (< 75 years, ≥ 75 
years), BMI category (< 18.5, 18.5 - < 25.0, 25.0 - < 30.0, ≥ 30.0), Sex 
(Female, Male), Ethnicity (Hispanic or Latino, Not Hispanic or Latino), Race 
(White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other pacific islander), Tobacco (Current, Former, Never, 
 


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Unknown), Alcohol (Current, Former, Never, Unknown), and all Brief 
Neurological Examination variables.
Additional variables may be included given sufficient data.
6.2.1
Medical History and Parkinson's Disease History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class [SOC] and preferred term
[PT]) will be summarized. The SOC will be presented in alphabetical order, and the PT
will be presented in alphabetical order within each SOC. Subjects reporting more than 
one condition/diagnosis will be counted only once in each row (SOC or PT).
Parkinson's Disease history will be summarized with the following variables:
●
Continuous variables:  Age at PD onset (years), Duration of PD since onset 
(years), Age at PD diagnosis (years), Duration of PD since diagnosis (years), 
Age at onset of motor fluctuation (years), Duration since onset of motor 
fluctuation (years), MDS-UPDRS – Part III score during "Off" state.
●
Categorical variables:  Duration of PD since diagnosis (< 10 years, 
≥10 years), History of levodopa induced dyskinesia (Yes, No), Levodopa 
response for more than 5 years (Yes, No), and Hoehn and Yahr Stage.
The Advanced Parkinson's Disease (APD) tool will be summarized for each question as a 
categorical variable and for each domain score as a continuous variable.
6.2.2
Prior and Concomitant Medications
Prior and concomitant PD medications and non-PD medications will be summarized 
separately.  A prior medication is defined as any medication taken prior to the date of first 
ABBV-951 infusion and collected in the electronic case report form (eCRF).  A 
concomitant medication is defined as:
 


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●
Any medication that started prior to the date of first ABBV-951 infusion and 
continued to be taken after ABBV-951 infusion started.
OR
●
Any medication that started on or after the date of first ABBV-951 infusion, 
but not after the date of the last ABBV-951 infusion.
The number and percentage of subjects who take at least one medication will be 
summarized by generic drug name based on the World Health Organization (WHO) Drug 
Dictionary for both concomitant PD medications and non-PD medications.  For 
summaries of concomitant medications, if an incomplete start date or end date was 
collected for a medication, the medication will be assumed to be a concomitant 
medication unless there is evidence that confirms that the medication was not a 
concomitant medication (e.g., the medication end date was prior to the first dose of study 
drug).
Parkinson's disease medications use at Screening (V1) and at baseline (on Day –2) will be 
summarized, respectively, by the number of PD medications taken.
6.3
Analysis of Dosing
Based on molecular weight, 100 mg of LDP is equivalent to 71 mg of levodopa.
Unless otherwise noted, all analyses of dosing diary data will be performed on valid 
dosing diary days.  A valid dosing diary day is defined as one in which ABBV-951 has 
been infused ≥ 80% of the entire 24-hour period (i.e., ≥ 19.2 hours).
6.3.1
Analysis of Daily Prescribed Dose
Summary statistics (mean, SD, median, min and max) will be provided for prescribed 
dose information, including levodopa oral loading dose, F1 (Base), F2 (High) and F3 
(Low) continuous infusion rates, and extra dose.
 


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In addition, daily total prescribed dose based on Base rate infused for entire 24-hour 
period will be calculated and summarized.  High and Low infusion rates as percentage of 
Base infusion rate will also be summarized for the subjects that these alternative infusion 
rates were enabled by the investigator.
When available, the summary statistics will be provided at initial prescription, 
first maintenance prescription following the Optimization Period, final prescription in the 
48-week Maintenance Period and final prescription in study.  Change from initial to 
first maintenance, initial to maintenance final, initial to final and maintenance first to final 
will also be summarized.
6.3.2
Analysis of Titration
Duration of Initial Titration is defined as the number of days from Day 1 to the first day 
where there is no change to F1 rate for at least 15 days.
Duration of Initial Titration will be summarized by the following interval (days):  1, 2, 3 -
7, 8 - 14, 15 - 21, 22 - 28, and > 28. When applicable, the summary statistics will include 
mean, SD, median, min and max.
6.3.3
Analysis of Daily Levodopa Dose
Daily levodopa dose will be summarized for ABBV-951 and other levodopa at each 
protocol defined visit.  Extra dose (ABBV-951), oral loading dose and oral rescue dose 
will also be summarized.  The summary statistics include mean, SD, median, min and 
max.
The modal total daily levodopa dose during the study will be determined for each subject 
by first assigning the subject's total daily levodopa doses to narrow dose ranges in 100-mg 
increments (e.g., 1000 to < 1100 mg, 1100 to < 1200 mg) and then take the most frequent 
narrow dose range for the subject.  If two or more dose ranges are of the same highest 
frequency, the highest dose range will be selected.
 


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The modal pump infusion rate (i.e., Base, High, Low) will be similarly defined for each 
subject.
The modal total daily dose and modal pump infusion rate will be summarized for the 
Safety Analysis Set.
6.3.4
Other Dosing Analysis
The frequency of subjects taking extra dose, rescue dose and switching among 3 pump 
flow rates will be summarized by 0 time, 1 time, 2 times and ≥ 3 times categories for each 
planned visit.  In addition, number of subjects with at least one occurrence and the total 
number of occurrences will be summarized by mean, SD, median, min and max.
In addition, during the 52-week ABBV-951 CSCI, the percentage of time that the 
ABBV-951 was infused with each rate (Base, High and Low) will be summarized 
separately.  The summary statistics include mean, SD, median, min and max.
6.4
Other Descriptive Analyses
A summary of protocol deviation will be provided.
7.0
Study Drug Duration and Compliance
For the Safety Analysis Set, study drug duration will be calculated in the following two 
ways and will be summarized by mean, SD, median, min and max:
1.
Duration of ABBV-951 exposure: Date of ABBV-951 discontinued/completed –
Date of ABBV-951 started + 1
2.
Duration of ABBV-951 exposure without interruption: Date of ABBV-951 
discontinued/completed – Date of ABBV-951 started + 1 – total duration of 
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In addition, the number and percentage of subjects in each study drug duration interval 
(1 to 7, 8 to 14, 15 to 21, 22 to 28, 29 to 42, 43 to 91, 92 to 182, 183 to 273, and ≥ 274) 
will be summarized.
For each subject, study drug compliance will be summarized and is defined as the number 
of hours the pump is infusing per day relative to the 24-hour/day goal and averaged across 
all dosing diary days.
Compliance categories are defined as:
●
Low compliance:  study drug compliance < 60%
●
Medium compliance:  study drug compliance ≥ 60% to < 80%
●
High compliance:  study drug compliance ≥ 80% to 100%
Study drug compliance will be summarized for each visit that dosing diary is collected for 
the Safety Analysis Set by compliance category.  In addition, number of subjects with 
non-missing observations, mean, SD, median, min and max of study drug compliance will 
be summarized for the entire study period.
In addition, patient-years of exposure will also be summarized.
8.0
Efficacy Analyses
8.1
General Considerations
This is a single-arm, open-label study.  Unless stated otherwise, all analyses on efficacy 
variables will be performed with the FAS using data collected no more than 1 day after 
the end of the infusion of ABBV-951.  Paired-sample t-test will be performed for testing 
the change from baseline.
Variables Derived from PD Diary
A PD Diary recording day is defined as a full 24-hour period across two calendar days,
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On PD diary recording days, the subject will be instructed to make an entry upon waking 
and every 30 minutes during their normal waking time and upon awakening from time 
asleep for a full 24-hour PD diary day from 6:00 am to 5:30 am of the next day (48 entries 
with each entry representing 0.5 hour).  Each entry could be in one of 5 categories:  
Asleep, "Off," "On" without dyskinesia, "On" with non-troublesome dyskinesia, and "On" 
with troublesome dyskinesia.  For each PD diary recording day, the absolute time spent in 
each category will be summed.  The daily awake time will be the sum of the absolute time 
spent in the 4 non-asleep categories.  The daily "Off" and "On" times will be normalized 
to a typical waking day (16 hours) to account for different sleep patterns across subjects, 
e.g., 
Normalized "Off" time = (Absolute "Off" time/Awake time) × 16
Daily normalized "Off" and "On" times are averaged over valid diary days for each visit 
to obtain the average daily normalized "Off" and "On" times.
A valid PD diary day is defined as a PD diary recording day with no more than 2 hours of 
missing data (4 or less missing entries) OR at least 12 awake hours (i.e., at least 24 "Off"
or "On" time entries)for the entire 24-hour diary.
Only valid PD diary days are used in the analysis for "Off" and "On" times.
The early morning motor symptom will also be summarized and is defined to be the 
first non-sleep entry between 0:00 am and 12:00 pm within a calendar day, after at least 
4 consecutive entries of "Asleep" (i.e., at least 2 hours of continuous sleep).
The analysis of early morning motor symptoms will be performed if there are ≤ 2 missing 
entries during the period between 0:00 am and 12:00 pm.
8.2
Efficacy Analysis
For all efficacy endpoints, the change from baseline to each planned visit and to the final 
visit will be summarized in a descriptive manner for each dose category subgroup and 
 


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overall subjects.  The statistics include the number of observations, mean, SD, median, 
min and max.
8.3
Exploratory Efficacy Analysis
The change from baseline to each planned visit and to the final visit in normalized daily 
"Off" time and "On" times will be summarized on the TNAS. The analysis of PKG 
related exploratory endpoints defined in Section 4.3.3 will also be performed on the FAS.
In addition, a sensitivity analysis will be performed for average normalized daily "Off"
time and "On" times by modifying the definition of the valid PD diary day as "a PD diary 
recording day with no more than 2 hours of missing data (4 or less missing entries) for the 
entire 24-hour diary."
The change from baseline to each planned visit and to the final visit in normalized daily 
"Off" time and "On" times will also be summarized by Sample 1 (Subjects enrolled prior 
to 08-Jul-2020) and Sample 2 (Subjects enrolled on or after 08-Jul-2020).
8.4
Efficacy Subgroup Analyses
The change from baseline to each planned visit and to the final visit on the average 
normalized "Off" time and "On" times will be summarized for each of the subgroups 
defined in Section 5.2.
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will be performed using the Safety Analysis Set.  All analyses on safety 
variables, with the exception of Adverse Events and Infusion Site Evaluation Scale, will 
be performed using data collected no more than 1 day after the end of the infusion of 
ABBV-951.  For continuous safety outcomes, the change from baseline will be analyzed 
in a descriptive manner by visit for each dose category subgroup and overall subjects.  For 
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summarized by visit for each dose category subgroup and overall subjects.  Hypothesis 
testing will not be performed.
9.2
Analysis of Adverse Events
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The MedDRA version will be noted on the statistical tables and in the CSR.  
Treatment Emergent Adverse Events (TEAE) will be defined as all events that begin or 
worsen on or after CSCI initiation through 30 days after the last infusion.  Adverse events 
will be summarized by primary MedDRA system organ class (SOC) and preferred term 
(PT).  Subjects reporting more than one adverse event for a given PT will be counted only 
once for that term.  Subjects reporting more than one adverse event within an SOC will be 
counted only once for the SOC total.  Subjects reporting more than one adverse event will 
be counted only once in the overall adverse event total.  For summaries by SOC and PT, 
the SOCs will be presented in alphabetical order and the PTs will be presented in 
alphabetical order within each SOC.
Adverse events will be summarized by time interval for the Optimization Period, the 
Maintenance Period, and the entire Treatment Period.  For subjects who received less than 
29 days of ABBV-951 infusion, all TEAEs will be assigned to the Optimization Period.  
For subjects who received at least 29 days of ABBV-951 infusion, adverse events with 
onset from Study Day 1 through Study Day 28 will be assigned to the Optimization 
Period and all other TEAEs will be assigned to the Maintenance Period.
9.2.1
Adverse Event Overview
The number and percentage of subjects experiencing one or more TEAEs in the following 
adverse event categories will be summarized for the Optimization Period, the 
Maintenance Period and the entire study:
●
Any TEAE
●
Any severe TEAE
●
Any TEAE that are considered associated with study drug
 


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Any TEAE that are considered associated with product complaint:  ABBV-951
●
Any TEAE that are considered associated with product complaint:  Infusion 
Pump
●
Any TEAE that are considered associated with product complaint:  Vial 
Adapter
●
Any TEAE that are considered associated with product complaint:  Syringes
●
Any TEAE that are considered associated with product complaint:  Cleo 90 
Infusion Set 6 mm
●
Any TEAE that are considered associated with product complaint:  Cleo 90 
Infusion Set 9 mm
●
Any TEAE that are considered associated with product complaint:  Neria 
Guard Infusion Set 6 mm
●
Any TEAE that are considered associated with product complaint:  Neria 
Guard Infusion Set 9 mm
●
Any TEAE that are considered associated with product complaint:  PKG 
Wearable Watch
●
Any TEAE that are considered associated with loading dose
●
Any TEAE that are considered associated with rescue dose
●
Any TEAE that are considered associated with COVID-19 infection
●
Any TEAE leading to prematurely discontinuation of study drug
●
Any TEAE leading to death (fatal TEAE)
●
Any serious TEAE
●
Any TESAE that are considered associated with infusion pump
●
Any TESAE that are considered associated with Neria Guard infusion set
●
Any TESAE that are considered associated with Cleo90 infusion set
●
All Deaths
●
Death related to COVID-19
●
AESI:  infusion site related infections
●
AESI:  infusion site related non infection reactions
●
AESI:  polyneuropathy
 


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AESI:  weight loss
●
AESI:  hallucinations/psychosis
●
AESI:  somnolence
●
AESI:  falls and associated injuries
In addition, the number and percentage of subjects experiencing one or more TEAEs in 
the above adverse event categories will also be summarized by Sample 1 (Subjects 
enrolled prior to 08-Jul-2020) and Sample 2 (Subjects enrolled on or after 08-Jul-2020).
9.2.2
Adverse Event Summary
The number and percentage of subjects experiencing one or more TEAEs, one or more 
TESAEs, one or more TEAEs leading to premature discontinuation of study drug will be 
summarized by primary SOC and PT by time interval for the Optimization period, the 
Maintenance Period and the entire Treatment Period.
A listing contains all subjects numbers associated with each PT will be presented for all 
TEAEs.
9.2.3
Adverse Event by Maximum Severity
The number and percentage of subjects experiencing one or more TEAEs will also be 
summarized by maximum severity category (mild, moderate, severe, or unknown) and 
primary SOC and PT for the entire study.  Subjects reporting more than one TEAE for a 
given PT will be counted only once for that term in the most severe category reported.  If 
a subject has an adverse event with unknown severity, then the subject will be counted in 
the severity category of "unknown," even if the subject has another occurrence of the 
same event with a severity present.  The only exception is if the subject has another 
occurrence of the same adverse event with the most extreme severity – "Severe."  In this 
case, the subject will be counted under the "Severe" category.
 


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9.2.4
Adverse Event by Relationship to Study Drug
The number and percentage of subjects experiencing one or more TEAEs will also be 
summarized by maximum relationship category (reasonable possibility, no reasonable 
possibility, or unknown), as assessed by the investigator, and primary SOC and PT for the 
entire study.  Subjects reporting more than one TEAE for a given PT will be counted only 
once for that term in the most related category reported.  If a subject has an adverse event 
with unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same adverse event with a relationship assessment of "reasonable possibility."  In this 
case, the subject will be counted under the "reasonable possibility" category.
9.2.5
Adverse Event by Relationship to Product Quality 
Complaints
The number and percentage of subjects experiencing one or more TEAEs that are 
associated with Product Quality Complaints will also be summarized by the products 
listed below:
●
ABBV-951
●
Infusion Pump
●
Vial Adapter
●
Syringes
●
Cleo 90 Infusion Set 6 mm
●
Cleo 90 Infusion Set 9 mm
●
Neria Guard Infusion Set 6 mm
●
Neria Guard Infusion Set 9 mm
●
PKG Wearable Watch
 


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9.2.6
Adverse Event Leading to Study Drug Discontinuation, 
Interruption, and Dose Reduction
The number and percentage of subjects experiencing one or more TEAEs leading to study 
drug discontinuation, interruption, and dose reduction will also be summarized by primary 
system organ class and preferred term, respectively.
9.2.7
Adverse Event Associated with Loading Dose Drug and 
Rescue Dose Drug
The number and percentage of subjects experiencing one or more TEAEs associated with 
oral loading dose drug, and rescue dose drug will also be summarized by primary system 
organ class and preferred term, respectively.
9.2.8
Serious Adverse Events
In addition to Section 9.2.2, the number and percentage of subjects experiencing one or 
more serious adverse events related to infusion pump and Neria Guard infusion set will be 
summarized by primary SOC and PT, respectively.
9.2.9
Adverse Events of Special Interest
Adverse events of special interest (AESIs) include:
●
Infusion Site Related Infections
●
Infusion Site Related Non Infection Reactions
●
Polyneuropathy
●
Weight loss
●
Hallucinations/psychosis
●
Somnolence
●
Falls and associated injuries
The search strategy for each AESI is defined in Appendix E.
 


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The analysis of AESI includes an overview summary of each AESI and for each AESI, 
the number and percentage of subjects experiencing one or more adverse events will be 
summarized in descending frequency by PT.
9.2.10
Adverse Events by Subgroup
The number and percentage of subjects in each of the subgroups (defined in Section 5.2) 
experiencing one or more TEAEs during the study will be summarized by primary SOC 
and PT.
9.2.11
Listings of Adverse Events
The following additional summaries of adverse events will be prepared.
●
Listing of all deaths for all subjects screened
●
Listing of all serious TEAEs
●
Listing of all TEAEs that led to discontinuation of study treatment
●
Listing of all AESIs (As defined in Section 9.2.9)
9.2.12
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for baseline where SAE-related 
laboratory assessments on or before the date of first ABBV-951 infusion will be excluded. 
The clinical laboratory tests defined in the protocol operations manual (e.g., hematology 
and clinical chemistry) will be summarized.
 


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9.3.1
Analysis of Mean Changes for Laboratory Tests
Change from baseline to each planned visit and to the minimum, maximum and final 
value will be summarized in a descriptive manner for each continuous hematology, 
chemistry, urinalysis, and special laboratory variable.
For each change from baseline analysis, the following summary statistics will be 
presented:  sample size, baseline mean, visit mean, and the summary statistics (i.e., mean, 
SD, and median) of the change from baseline.  The summary statistics of the change from 
baseline will only be calculated for subjects who have both baseline and visit values.
9.3.2
Analysis of Laboratory Tests by NCI CTC Criteria
Changes in laboratory parameters will be tabulated using shift tables either by Common 
Terminology Criteria for Adverse Events (CTCAE) criteria or categorized as low, normal, 
or high based on the normal ranges of the laboratory used for each sample. A shift table 
from baseline either to the worse value (based on CTCAE criteria) or to minimum and 
maximum value (based on normal range) during study, will be created.
A similar shift table will be provided to summarize shifts from baseline to the final post-
baseline value during study.
9.3.3
Potentially Clinically Significant (PCS) Laboratory Values
Criteria for potentially clinically significant (PCS) values have been predefined for 
selected laboratory variables as outlined in Appendix B.  For each variable, a summary of 
the number and percentage of subjects who have at least one post-baseline observation 
that meets the PCS criteria and is more extreme than their baseline value will be provided.
A listing will also be prepared that will include, for each variable, all observations for 
each subject that met the PCS criteria for that variable at any time during the study.
In addition, a summary of the number and percentage of subjects who have at least one 
observation that meets the HY's Law criteria will be provided.
 


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A listing will also be prepared that will include, for each variable, all observations for 
each subject that met the HY's Law criteria for that variable at any time during the study.
9.4
Analysis of Vital Signs and Weight Variables
Vital sign variables include:  body temperature, pulse (supine, standing and orthostatic), 
diastolic blood pressure (supine, standing and orthostatic), and systolic blood pressure 
(supine, standing and orthostatic).
Weight variables include:  weight and BMI.
Orthostatic variables will be calculated as the change from supine to standing (standing 
measurement minus supine measurement).
9.4.1
Vital Sign and Weight Variable Mean Changes
Change from baseline to each planned visit and to the minimum, maximum and final
value will be summarized in a descriptive manner for each vital sign and weight variable.
For each change from baseline analysis, the following summary statistics will be 
presented:  sample size, baseline mean, visit mean, and the summary statistics (i.e., mean, 
SD, and median) of the change from baseline.  The summary statistics of the change from 
baseline will only be calculated for subjects who have both baseline and visit values.
9.4.2
Potentially Clinically Significant (PCS) Vital Sign and Weight 
Variable Values
Criteria for PCS values have been predefined for selected vital sign and weight variables 
as outlined in Appendix C.  For each variable, a summary of the number and percentage 
of subjects who have at least one post-baseline observation that meets the PCS criteria and 
is more extreme than their baseline value will be provided.  A listing will also be prepared 
that will include, for each variable, all observations for each subject that met the PCS 
criteria for that variable at any time during the study.
 


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9.5
Analysis of ECG Parameters
Electrocardiogram (ECG) variables include:  heart rate (HR), PR interval, QRS interval, 
uncorrected QT interval, and QT interval corrected for heart rate using Fridericia's 
formula (QTcF).
9.5.1
ECG Mean Changes
Change from baseline to each planned visit and to the minimum, maximum and final 
value will be summarized in a descriptive manner for each ECG variable.
For each change from baseline analysis, the following summary statistics will be 
presented:  sample size, baseline mean, visit mean, and the summary statistics (i.e., mean, 
SD, and median) of the change from baseline.  The summary statistics of the change from 
baseline will only be calculated for subjects who have both baseline and visit values.
9.5.2
Potentially Clinically Significant (PCS) ECG Values
Criteria for PCS values have been predefined for selected ECG variables as outlined in 
Appendix D.  For each variable, a summary of the number and percentage of subjects who 
have at least one post-baseline observation that meets the PCS criteria and is more 
extreme than their baseline value will be provided.  A listing will also be prepared that 
will include, for each variable, all observations for each subject that met the PCS criteria 
for that variable at any time during the study.
9.6
Infusion Site Evaluation Scale
All observations from the Infusion Site Evaluation Scale will be included in the analysis, 
regardless the date of assessment relative to the last date of study drug infusion.  The 
number and percentage of subjects with each category for numeric and letter grade will be 
presented at each planned visit.  The number and percentage of subjects with numeric 
grade equal or higher than 5 or letter grade equal or higher than D at any time during the 
study will be presented.
 


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A listing will also be prepared that includes all subjects with numeric grade equal or 
higher than 5 and letter grade equal or higher than D at any time during the study.
9.7
Analysis of Questionnaire for Impulsive-Compulsive 
Disorders in PD-Rating Scale (QUIP-RS)
The QUIP-RS is a brief, self-completed or rater-administered rating scale to assess the 
severity of symptoms of impulse control disorders (ICDs) and related behaviors reported 
to occur in PD.
Change from Baseline to each planned visit and to the final value will be summarized in a 
descriptive manner for QUIP-RS total score and domain scores.
For each change from baseline analysis, the following summary statistics will be 
presented:  sample size, baseline mean, visit mean, and the summary statistics (i.e., mean, 
SD, and median) of the change from baseline.  The summary statistics of the change from 
baseline will only be calculated for subjects who have both baseline and visit values.
9.8
Analysis of Columbia-Suicide Severity Rating Scale
(C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a systematically administered 
instrument developed to track suicidal adverse events across a treatment study.  At 
Screening (V1) the C-SSRS will be administered to collect lifetime history as well as 
experience during the past year.  At all other visits, the C-SSRS will collect experience 
since the last visit.  Affirmative responses on the C-SSRS will be summarized for the 
initial screening and each subsequent visit.
Each summary will include the number and percentage of subjects with one or more 
affirmative responses to each of the 5 suicidal ideation questions, each of the 6 suicidal 
behavior questions, any of the 5 suicidal ideation questions, any of the 6 suicidal behavior 
questions, any suicidal ideation or behavior question, and the non-suicidal self-injurious 
behavior question.
 


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A listing will also be prepared that includes all subjects with 1 or more affirmative 
responses.
10.0
References
1.
U.S. Department of Health and Human Services, National Institutes of Health, 
National Cancer Institute, Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0 Published:  May 28, 2009 (v4.03:  June 14, 2010) [accessed 
03 December 2018].  Available from:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf.10.0 References.
11.0
Summary of Changes
11.1
Summary of Changes Between the Previous Version and the 
Current Version
The following changes are made in SAP Version 4.0 since SAP Version 3.0, consistent 
with updates in protocol Version 4.0, 4.1, 4.1.1, 5.0, 6.0, 6.1, 6.2 and 7.0:
●
Sample size increased.
●
Added analysis by Sample 1 and Sample 2.
●
Added a second planned interim analysis.
●
Updated Figure 1.
●
Updated language in 'Post-treatment Period Activities'
●
Updated language in Section 4.3.2.
●
Added Canè pump-specific endpoints.
●
Added Neria Guard-specific endpoints.
●
Updated language in Section 4.3.3.
●
Updated language in Section 4.5.
●
Updated language in Section 4.7
●
Renamed the analysis population:
 


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○
ITT data set is renamed as Full Analysis Set (FAS)
○
TN ITT data set is renamed as Treatment Naïve Analysis Set (TNAS)
○
Safety data set is renamed as Safety Analysis Set. 
●
Renamed subgroup and updated language in Section 5.2.
●
Added 'Descriptive Analyses' section as Section 6.0.
●
Added 'Study Drug Duration and Compliance' section as Section 7.0
●
Added missing data imputation method for efficacy endpoints.
●
Added the derivation algorithm for variables derived from PD diary. 
●
Added the analysis of early morning symptom from PD diary.
●
Added a new AESI: Falls and related injuries.
●
Adjusted analysis for AESI and SAE. 
●
Added a new summary analysis for subjects who met HY's Law.
●
Updated language in Section 8.4.
●
Updated language in Section 9.1, Section 9.2 and Section 9.3.
●
Added reference for CTCAE criteria.
●
Added sensitivity analysis by using a different definition for valid PD diary 
day.
●
Added COVID-19 related analysis.
●
Change 'average dose' to 'modal dose' for low/high dose subgroup definition.
●
Added analysis for modal dose.
11.2
Summary of Changes in Previous Versions
The following changes were made in SAP Version 2.0 since SAP Version 1.0:
●
Added one efficacy endpoint EQ-5D-5L
●
Added an analysis population TN ITT data set for exploratory efficacy 
analysis.
●
Added subgroup analysis for race.
 


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The following changes were made in SAP Version 3.0 since SAP Version 2.0, consistent 
with updates in protocol Version 3.0:
●
Hallucinations/psychosis and somnolence were added as AESIs.
●
The Minnesota Impulsive Disorders Interview (MIDI) was replaced with the 
QUIP-RS.
●
The sample size could be increased up to 160 if needed.
12.0
Appendices
 


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Appendix A.
Activity Schedule
The required study activities are shown in the following table.  Individual activities are 
described in detail in the Operations Manual.
 












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b.
Urine pregnancy tests will be performed monthly for women of childbearing potential.  If there is a scheduled visit, the test will be performed on site; if there is not a 
scheduled visit, the test may be performed at an unscheduled visit or at home.
c.
Dispensing visits may occur with or without a clinic visit being completed.
d.
If the subject is willing, the post-treatment follow-up call will occur 30 days after premature discontinuation from the study or 30 days after completion of Week 52 for 
subjects not enrolling in the extension study.
 


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Appendix B.
Potentially Clinically Significant Laboratory Values
Clinical Laboratory Tests
Very Low (VL)
Very High (VH)
Hematology
Activated partial thromboplastin 
time 
NA
> ULN
Hemoglobin
< 100 g/L (6.2 mmol/L)
> 40 g/L above ULN
Prothrombin Intl. Normalized 
Ratio
NA
> ULN
Leukocytes (white blood cell)
< 2 × 109/L
> 100 × 109/L
Lymphocyte 
< 0.5 × 109/L
> 20 × 109/L
Neutrophil 
< 1 × 109/L
NA
Platelets 
< 75 × 109/L
NA
Chemistry
Bilirubin
NA
> 1.5 × ULN
Cholesterol
NA
> 12.92 mmol/L (500 mg/dL)
Creatinine
NA
> 1.5 × ULN
Calcium (corrected serum)
< 1.75 mmol/L (7.0 mg/dL)
> 3.1 mmol/L (12.5 mg/dL)
Glucose (fasting)
< 2.2 mmol/L (40 mg/dL)
> 13.9 mmol/L (250 mg/dL)
Potassium
< 3.0 mmol/L
> 6.0 mmol/L
Magnesium
< 0.4 mmol/L (0.9 mg/dL)
> 1.23 mmol/L (3 mg/dL)
Triglycerides
NA
> 5.7 mmol/L (500 mg/dL)
Uric acid
NA
> 590 umol/L (10 mg/dL)
Albumin
< 20 g/L
NA
Sodium
< 130 mmol/L
> 155 mmol/L
Inorganic phosphorus
< 0.6 mmol/L (2 mg/dL)
NA
Enzymes
Alanine aminotransferase (ALT)
NA
> 3 × ULN
Alkaline phosphatase
NA
> 2.5 × ULN
Aspartate aminotransferase (AST)
NA
> 3 × ULN
Creatine phosphokinase (CPK)
NA
> 5 × ULN
NA = not applicable; ULN = upper limit of normal
Adapted from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published:  May 28, 2009 
(v4.03:  June 14, 2010).
 


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Appendix C.
Criteria for Potentially Clinically Significant Vital Sign and Weight 
Values
Vital Signs
Unit
Very Low (VL)
Very High (VH)
Systolic blood pressure 
(supine and standing)
mmHg
≤ 80 and decreased 
≥45 from baseline
≥ 160 and increased 
≥45 from baseline
Orthostatic systolic 
blood pressure 
mmHg
Decrease ≥ 30 from 
supine to standing
NA
Diastolic blood pressure 
(supine and standing)
mmHg
≤ 50 and decreased 
≥40 from baseline
≥ 95 and increased 
≥40 from baseline
Orthostatic diastolic 
blood pressure
mmHg
Decrease ≥ 20 from 
supine to standing
NA
Pulse rate
(supine and standing)
bpm
≤ 45 and decreased 
≥35 from baseline
≥ 120 and increased 
≥35 from baseline
Orthostatic pulse rate
bpm
Increase ≥ 30 from 
supine to standing
Temperature
degrees C
NA
≥ 38.3 and increase 
≥1.1 from baseline
Weight
kg
Decreased ≥ 7% from 
baseline
Increased ≥ 7% from 
baseline
 


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Appendix D.
Criteria for Potentially Clinically Significant ECG Values
ECG Parameters
Unit
Very Low (VL)
Very High (VH)
Heart rate
bpm
≤ 45 and decreased 
≥35 from baseline
≥ 120 and increased 
≥35 from baseline
PQ (PR)
ms
≤ 120
≥ 220
QTcF Interval
ms
NA
≥ 480 OR
Increased ≥ 60 from baseline
 


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Appendix E.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria:
Area of Safety Interest
Search Criteria
Infusion Site Related 
Infections
Infusion Site Related Infections (AbbVie ABBV-951 product-specific) 
Company MedDRA Query (CMQ) (code 80000194)
Infusion Site Related Non 
Infection Reactions
Infusion Site Related Non Infection Reactions (AbbVie ABBV-951 
product-specific) CMQ (code 80000193)
Polyneuropathy
Broad search and narrow search of the Standardized MedDRA Queries 
(SMQ)

SMQ Peripheral Neuropathy (code 20000034)
Weight Loss
Weight Loss CMQ (code 80000109)
Hallucinations/Psychosis
Search of combined terms in:

CMQ Hallucinations (code 80000088)

SMQ Psychosis and Psychotic Disorders (code 20000117).  
Note:  all terms in this SMQ are narrow search.
Somnolence
Preferred terms (PT) "Somnolence." "Hypersomnia," "Microsleep," 
"Sudden onset of sleep," "Sleep disorder due to general medical 
condition, hypersomnia type," "sleep attacks"
Falls and associated injuries
Separate and combined searches:

Falls and Associated Injuries (ABBV-951 product-specific) 
CMQ (code 80000204)

Orthostatic Hypotension PTs "blood pressure ambulatory 
decreased," "blood pressure orthostatic," "blood pressure 
orthostatic decreased," "dizziness," "dizziness postural," 
"orthostatic hypotension," "syncope"