Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism
Phase: PHASE2
Conditions: Parkinson Disease, Multiple System Atrophy, Progressive Supranuclear Palsy
Sponsor: Loma Linda University

 
 
 
 
PROTOCOL 
 
 
Safety and Efficacy of Droxidopa for Fatigue 
in Patients with Parkinsonism 
 
 
 
 
Principal Investigator: Khashayar Dashtipour, MD, PhD. 
Co- Investigator: Charles Kamen, MD 
 
 
 
 
 
 
 
February 13, 2018 
 
 
 
 
 
 
 
 
 
 

2 
 
Table of Contents 
Study Title   
 
 
 
 
 
 
 
 
 
3 
 
Background Rationale 
 
 
 
 
 
 
 
 
3 
Scientific Value 
 
 
 
 
 
 
 
 
 
3 
Primary Product                                                                                                        4 
Safety Profile 
 
 
 
 
 
 
 
 
 
4 
Primary Study Objective 
 
 
 
 
 
 
 
 
4 
Secondary Study Objective 
 
 
 
 
 
 
 
4 
Study Method/Design 
 
 
 
 
 
 
 
 
5-7 
Use of Concomitant, Prior, and Prohibited Medications   
 
 
 
8                               
Inclusion criteria 
 
 
 
 
 
 
 
 
 
9 
Exclusion criteria 
                                                                                            
9-10 
Exit Criteria                                                                                                              10 
Early Termination visit 
                                                                                      10-11 
Investigational Medicinal Product and Formulation                                                 11-12 
Dosage and Administration 
 
 
 
                            
 
12 
       
Safety Variables Measures 
 
 
 
 
 
 
 
12 
 
AE/SAE Reporting                                                                                                 
 
12-13 
 
Informed Consent  
 
 
 
 
 
 
 
 
14 
 
Confidentiality 
 
 
 
 
 
 
                                         14 
 
Data Collection 
 
 
 
 
 
 
 
 
 
14 
 
Statistics 
 
 
 
 
 
 
 
 
 
 
14 
References  
 
 
 
 
 
 
 
 
 
15 
Appendix 
 
 
 
 
 
 
 
 
 
 
15 
 

3 
 
Study Title: 
 
Safety and Efficacy of Droxidopa for Fatigue in Patients with Parkinsonism 
 
Background/Rationale: 
 
Fatigue is a common debilitating symptom in neurological disorders, and over 50% of 
Parkinson’s disease (PD) patients report fatigue as one of their top three debilitating 
symptoms. The definitions of fatigue are subjective, but they all focus on having an 
abnormal lack of energy that interferes with normal function [2]. Currently, there are no 
evidence-based guidelines for treating fatigue in PD, and no effective medications or 
therapeutic modalities exist for fatigue symptoms in patients with PD. Multiple 
mediations are being tried with no evidence in double-blind clinical trials. One study 
showed a statistically significant improvement with methylphenidate, but no effect was 
seen when data from other stimulant trials were pooled. A post hoc analysis of 
rasagaline showed statistically but clinically insignificant improvements, and levodopa 
showed small benefits for fatigue. However, non-motor symptoms were not the primary 
endpoints of the study, and further research is required to better understand and treat 
fatigue in PD. We hypothesize that fatigue is due to diminished levels of norepinephrine 
in PD. The locus coeruleus (LC), one of the major sources of norepinephrine, is affected 
during the preclinical phase of PD during stage 2 of Braak pathology staging. 
Norepinephrine is the final metabolite of dopamine, and we hypothesize that by adding 
exogenous norepinephrine, we can control some of the motor and non-motor symptoms 
of Parkinsonism. Norepinephrine is the final metabolite of droxidopa, and it is still 
unclear if it passes the blood-brain barrier. Here, we propose a pilot study to explore our 
hypotheses and to measure the efficacy and safety of droxidopa in Parkinsonism 
patients with fatigue. 
 
Scientific Value: 
 
Randomized control studies addressing fatigue in patients with Parkinsonism are an 
insufficiently addressed requirement to understand how to improve quality of life 
outcome measures. The lack of progress in understanding the pathophysiology and 
treatment of fatigue, along with the absence of effective therapy for fatigue in patients 
with Parkinsonism argues for a greater effort. The goal of the proposed pilot study is to 
follow patients over 6 month’s total (with 3 months of it being an open-label trial). The 
outcomes of our study will help determine the efficacy of droxidopa for fatigue in 
patients with Parkinsonism. Additionally, the outcomes of our study will provide us 
important information regarding the efficacy of droxidopa on other non-motor and motor 
symptoms of Parkinsonism. 
 
 
 
 
 

4 
 
Primary Product: 
 
Droxidopa  
 
(Droxidopa is also known as L-threo-3,4-dihydroxyphenylserine, or L-DOPS. Droxidopa 
is decarboxylated by 3,4-dihydroxyphenylalanine (DOPA) decarboxylase (DDC), and is 
directly converted to Nor Epinephrine .There are four stereoisomers of L-DOPS; 
however, only the L-threo-enantiomer (droxidopa) is biologically active. It is the 
International Non-proprietary Name (INN) for a synthetic amino acid precursor of NE, 
which was originally developed by Sumitomo Dainippon Pharmaceuticals Co., Limited, 
Japan (SDP). It has been approved for use in Japan since 1989 and in the United 
States (US) since February 2014).  
 
Safety Profile 
 
Droxidopa is safe and well tolerated in patients with symptomatic Neurogenic 
Orthostatic Hypotension associated with primary autonomic failure (PD, MSA and PAF), 
Dopamine Beta Hydroxylase Deficiency, or Non Diabetic Autonomic Neuropathy. Data 
from this program indicates that droxidopa treatment is associated with a small increase 
in supine hypertension (SBP >180 mmHg), and an increase in the incidence of 
headaches, dizziness, and nausea. Data from the SDP-sponsored clinical studies 
conducted in Europe and the large safety database of patients treated in Japan, where 
droxidopa has been marketed for over 20 years, further support the safety of droxidopa. 
Community standards do not require lab work, including pregnancy tests, when initiating 
or maintaining therapy with Droxidopa.   
 
Primary Study Objective: 
 
 To determine the efficacy of droxidopa for fatigue in patients with Parkinsonism 
measured by the Visual Analog Fatigue Scale (VAFS). 
o Subjects will complete the VAFS which measures level of fatigue with zero 
being equivalent to energetic with no fatigue to ten being worst possible 
fatigue. The focus will be on change between baseline and 12 weeks, change 
between 13 weeks and 25 weeks, and at 29 weeks. 
 
Secondary Study Objectives: 
 
 To determine the efficacy of droxidopa on motor and non-motor symptoms of 
Parkinsonism using the Unified Parkinson’s Disease Rating Scale (UPDRS). 
o The UPDRS is a composite measurement of motor and non-motor symptoms 
divided into six domains. Domain I measures Mentation, Behavior and Mood. 
Domain II measures Activities of Daily Living. Domain III measures Motor 
Examination. Domain IV measures Complications of Therapy. Domain V is 
Modified Hoehn and Yahr Staging. Domain 6 is Schwab and Engladn 
Activities of Daily Living Scale. The focus will be on change between baseline 
and 12 weeks, change between 13 weeks and 25 weeks, and at 29 weeks. 
 

5 
 
 
Study Method/Design: 
 
This is a pilot study which will include 32 subjects total; with 16 Parkinsonism patients 
initially assigned to droxidopa treatment (group 1, experimental) and 16 Parkinsonism 
patients initially assigned to placebo (group 2, control). At no point during this study will 
there be any blood draws or urine collections. Patients will not be instructed to measure 
their blood pressure at home, and will instead be instructed to contact their primary 
doctor or study doctor if they experience any new symptoms. At the next study visit, 
these symptoms will be assessed and recorded.  
 
Within each group (n=16 per group), half (n=8 per group) will be Parkinsons Disease 
(PD) patients and half (n=8 per group) will be patients with atypical Parkinsonism to 
include multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). 
Overall, the study will recruit 16 PD patients and 16 patients with MSA or PSP. The 
Principal Investigator (PI)/ Sub Investigator will recruit subjects from the Faculty Medical 
Office (FMO) Movement Disorders Clinic at Loma Linda University, Loma Linda, 
California where several hundred patients who are clinically diagnosed with 
Parkinsonism are seen per year. Patients will not be recruited by phone.  
 
Table 1 (on Page 7 of this protocol) describes how the study will be conducted. This is a 
randomized, placebo-controlled, double-blind clinical trial for 3 months, and after a 
wash-out period of 7 days, every subject will receive droxidopa for another 3 months 
during the open-label phase. This approach will provide us with the chance to evaluate 
the efficacy of droxidopa for as long as 6 months. There will be one follow up visit that 
occurs 4 weeks after the final 6 month visit when Droxidopa has been withdrawn to 
evaluate fatigue in the absence of droxidopa. Subjects who meet the inclusion/exclusion 
criteria and consent to participating in the study will be randomized to the experimental 
group (droxidopa treatment for the entire 6 months) or control group (placebo for first 3 
months then droxidopa treatment for the remaining 3 months) by a random number 
generator. Subjects and the Principal Investigator/ Sub Investigator will be blinded to the 
group allocation for the first 3 months of the study. During the first 3 months of the 
double-blind phase, both groups will titrate (either droxidopa for the experimental group 
or placebo for the control group) then continue their optimal dose for 3 months. After a 
7-day wash-out period, both groups will titrate again (droxidopa only this time), then 
continue their optimal dose for another 3 months during the open-label phase.  
 
We will perform detailed assessments (see table 1) for the primary and secondary 
efficacy outcomes at 6 different visits, including the first screening/ baseline visit.  
 
Visit 1 will be screening/ baseline visit, where informed consent and demographics will 
be taken, it will also include a complete physical examination and vitals along with 
orthostatic standing test will also be taken. History of intake of concomitant medications, 
prohibited medications, and recent diagnostic, therapeutic or surgical procedures, will 
be taken. Medications taken in the 28 days prior to study will be recorded. It will be 

6 
 
during this visit that the droxidopa or placebo will be distributed and the titration will 
begin. VAFS and UPDRS will be completed at this visit. 
 
Visit 2 will occur 6 weeks from screening, and medication titration will finish prior to this 
day. History of intake of concomitant medications, any adverse events, physical exam, 
vital signs, adherence to treatment regimen including avoidance of prohibited 
medications, and recent diagnostic, therapeutic or surgical procedures, will be recorded 
and VAFS and UPDRS will be completed. IMP will be dispensed and compliance and 
capsule count will be done on this visit and remaining IMP will be returned. 
 
Visit 3 will occur 6 weeks from Visit 2 and correspond with the maintenance period. 
Again history of intake of concomitant medications, any adverse events, physical exam, 
vital signs, adherence to treatment regimen including avoidance of prohibited 
medications, and recent diagnostic, therapeutic or surgical procedures will be recorded, 
and VAFS and UPDRS will be completed. Compliance and capsule count will be done 
on this visit too and remaining IMP will be returned. Patients will be instructed to stop 
taking their IMP following this visit and IMP will be not be dispensed. 
 
Visit 4 will occur 1 week from Visit 3 and will begin the open-label titration. The patients 
will not be taking IMP for 7 days (plus 0-14 days) prior to visit 4 to create a washout 
period. Again history of intake of concomitant medications, any adverse events, physical 
exam, vital signs, adherence to treatment regimen including avoidance of prohibited 
medications, and recent diagnostic, therapeutic or surgical procedures will be recorded 
and VAFS and UPDRS will be completed. IMP (droxidopa only, no placebo) will be 
distributed and the titration will begin. 
 
Visit 5 will occur 6 weeks from Visit 4 and will and medication titration will finish prior to 
this day. History of intake of concomitant medications, any adverse events, physical 
exam, vital signs, adherence to treatment regimen including avoidance of prohibited 
medications, and recent diagnostic, therapeutic or surgical procedures, will be recorded 
and VAFS and UPDRS will be completed. IMP will be dispensed and compliance and 
capsule count will be done on this visit and remaining IMP will be returned. 
 
Visit 6 will occur 6 weeks after Visit 5 and will correspond with the maintenance period. 
Again history of intake of concomitant medications, any adverse events, physical exam, 
vital signs, adherence to treatment regimen including avoidance of prohibited 
medications, and recent diagnostic, therapeutic or surgical procedures will be recorded, 
and VAFS and UPDRS will be completed. Compliance and capsule count will be done 
on this visit too and remaining IMP will be returned. Patients will be instructed to stop 
taking their IMP following this visit and IMP will be not be dispensed. 
 
Visit 7 will be final visit which will happen 4 weeks after visit 6 to evaluate fatigue in the 
absence of droxidopa. History of intake of concomitant medications, any adverse 
events, physical exam, vital signs, and recent diagnostic, therapeutic or surgical 
procedures, will be recorded, and VAFS and UPDRS will be completed at this visit. 
 

7 
 
Table 1 
Study Procedure 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5  
 
Visit 6 
 
Visit 7 
 
 
Screening/
Baseline 
Double 
blinded 
Titration 
Double blinded 
Maintenance   
Washout 
Open-Label 
Titration 
Open-Label 
Maintenance 
Final Visit 
Interval 
Time 0 
6 weeks  
(+ 0-14  days) 
6 Weeks  
(+ 0-14 days) 
1 week 
(+ 0-14 days) 
6 Weeks 
(+0-14 days 
days) 
6 Weeks 
(+0-14 days 
days) 
4 Weeks 
(+0-14 days 
days) 
Time from Baseline 
Time 0 
6 weeks 
from 
baseline  
12 weeks from 
baseline  
13 weeks from 
baseline 
16 weeks 
from 
baseline  
25 weeks 
from baseline  
29 weeks 
from 
baseline  
Written Informed 
consent 
X 
 
 
 
 
 
 
Review inclusion 
and exclusion 
criteria  
 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
x 
X 
x 
X 
X 
X 
Adverse events 
(continuous 
monitoring)  
 
x 
X 
x 
X 
X 
X 
Physical 
examination 
X 
x 
X 
x 
X 
X 
X 
Vital signs (BP, HR, 
RR, temp) and 
weight 
X 
x 
X 
x 
X 
X 
X 
Orthostatic Standing 
Test 
x 
 
 
 
 
 
 
Dose titration 
evaluation 
 
x 
 
 
x 
 
 
VAFS 
x 
 
x 
X 
x 
X 
X 
X 
UPDRS 
 
x 
x 
X 
x 
X 
X 
X 
Randomization 
 
x 
 
 
 
 
 
 
Unblinding 
 
 
x 
 
 
 
 
Blinding 
 
 
x 
 
 
 
 
 
 
IMP dispensed 
x 
 
x 
 
x 
x 
 
 
Capsule count / 
compliance check 
 
x 
X 
 
x 
x 
 
IMP returned 
 
 
x 
x 
 
x 
x 
 
 

8 
 
 
Use of Concomitant, Prior, and Prohibited Medications   
 
 Concomitant Medications  
 
No prescribed concomitant medication is to be taken without the knowledge of the 
Investigator. The Investigator may, at their discretion, prescribe any medication 
considered necessary for the patient’s welfare that is not expected to interfere with the 
evaluation of the IMP. All concomitant medications must be recorded. The generic 
name of the drug, dose, frequency of dose and the duration of treatment must be 
specified. In addition, any diagnostic, therapeutic or surgical procedure conducted 
during the study, that is not part of the study, should be recorded. The date, indication, 
description of procedure(s) and any clinical finding should be recorded.  
All concomitant medications should be maintained at stable doses during the study. If 
patients are already on other concomitant medications, which based on investigator 
judgment, would be expected to have side effect of hypertension, (e.g, amphetamine, 
amphetamine-like drugs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and 
norepinephrine reuptake inhibitors (NRIs), evaluate their continued use when 
introducing droxidopa.  
 
 Prior Medications  
 
Prior medication includes all medications (including herbal treatments and vitamins) 
taken within 28 days prior the Screening Visit . All prior medications taken within 28 
days of the Screening Visit must be recorded. 
 
 Prohibited Medications  
 
Administering droxidopa in combination with other agents that increase blood pressure 
(e.g, norepinephrine, ephedrine, midodrine, triptans) would be expected to increase the 
risk for supine hypertension. The following drugs must not be prescribed by the 
Investigator or taken by patients during the study:  
 
 Vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine;  
 Sumatriptan-like drugs, (for example, naratriptan, zolmitriptan, rizatriptan);  
 Cyclopropane or halothane, or other halogen-containing inhalational anesthetics;  
 Catecholamine-containing preparations (e.g. isoprenaline);  
 Non-selective monoamine oxidase inhibitors (MAOIs) including linezolid;  
 Ergotamine derivatives (except if anti-Parkinsonian medication);  
 Drugs that have anti-hypertensive properties and, in the Investigator’s opinion, 
significantly contribute to the patient’s orthostatic hypotension; and  
 Any investigational medication.  
 
Patients currently taking a prohibited medication at Screening may be enrolled into the 
study after a washout of at least 5 half-lives prior to first dose of IMP.  
 

9 
 
 
Inclusion Criteria (All Patients)  
 
1. Age of 50 years or older.  
 
2. Clinical diagnosis of Parkinsons Disease or Atypical Parkinsonism (including MSA, 
PSP) 
 
3. Patients should be fluent and be able to understand and converse freely in English. 
 
4. Patient should report fatigue as a symptom and must have a mean VAFS score of 4 
or more at baseline. 
 
5. Provide written informed consent to participate in the study and understand that they 
may withdraw their consent at any time without prejudice to their future medical care. 
 
Exclusion Criteria (All Patients)  
 
1. In the Investigator’s opinion, the patient is not able to understand or cooperate with 
study procedures.  
 
2. Known or suspected alcohol or substance use disorder within the past 12 months (as 
per DSM-5 criteria)  
 
3. Women who are pregnant or breastfeeding  
 
4. Women of childbearing potential (WOCP)  
 
5. Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 
mmHg diastolic. Sustained is defined as the average of 3 observations each at least 10 
minutes apart with the patient having been supine and at rest for at least 5 minutes prior 
to each measurement.  
 
6. Untreated closed angle glaucoma  
 
7. Diagnosis of hypertension that requires treatment with antihypertensive medications  
 
8. Any significant uncontrolled cardiac arrhythmia. 
 
9. History of myocardial infarction, within the past 2 years. 
 
10. Current unstable angina. 
 
11. Congestive heart failure (NYHA Class 3 or 4). 
 
12. Diabetic autonomic neuropathy.   

10 
 
 
13. History of cancer within the past 2 years other than a successfully treated, non-
metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ. 
 
14. Gastrointestinal condition that may affect the absorption of Investigational Medicinal 
Product (e.g. ulcerative colitis, gastric bypass). 
 
15.  Any major surgical procedure within 30 days prior to the first titration visit. 
 
16. Currently receiving any investigational drug or have received an investigational drug 
within 28 days prior to the first titration visit. 
 
17. Any condition or laboratory test result, which in the Investigator’s judgment, might 
result in an increased risk to the patient, or would affect their participation in the study. 
 
18. The Investigator has the direction to exclude a patient if, for any reason, they feel 
the patient is not a good candidate for the study or will not be able to follow study 
procedures.    
 
19. We will also exclude patients with dementia or non-treated depression, because 
fatigue may be associated with these conditions, and these patients may be less 
reliable at completing assessments and with medication compliance.  
 
20. Subjects who have a mean VAFS score of less than 4 at baseline will be excluded 
from the study.  
 
21. We will exclude vulnerable populations from this study.  
 
22. Patients with uncontrolled intercurrent illnesses including, but not limited to severe 
lung disease, ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, symptomatic cardiac arrhythmia, and situations that would limit 
compliance with study requirements will be excluded. 
 
23. Orthostatic hypotension (OH) will be excluded from this study. 
 
Exit Criteria 
 
Patients will be removed from the study if the patient has any side effects, or the patient 
feels uncomfortable continuing the study for any reason or physician feels patient is not 
safe to continue study.   
 
 
Early Termination Visit  
 
If at any time during the study a patient requests to withdraw from treatment, or if a 
decision is made to withdraw the patient, the patient will be requested to return for an 

11 
 
early termination visit. A decision will be made to withdraw the patient from the study 
while on site due to non-adherence to the plan as detailed in the protocol, the 
development of any adverse effects, the development of any of the above stated 
exclusion criteria, or due to starting any of the prohibited medications for this study. 
The early termination procedures should be completed during that visit. The patient 
should not be brought back for an Early Termination Visit at a later date.  
 
Whenever practical, patients should be encouraged to remain on IMP until the 
completion of the early termination procedures. This is particularly important for patients 
who withdraw from the study during the double-blind treatment period. As the primary 
efficacy endpoint is time to intervention, it is critical that the date of withdrawal (which 
will be the date of the patient’s last dose) due to a need for intervention during the 
double-blind period is accurately recorded.  
 
The Investigator or qualified designee will conduct the following procedures and record 
the data.  
 
 Record the time and dose of IMP taken on the day of the visit  
 Record the reason for withdrawal  
 Review of AEs  
 Review of concomitant medication  
 Patient stops IMP or withdraws from study for patient-reported lack of efficacy:  
 
 Physical Exam  
 
 Vital signs (supine BP, HR, RR) and weight.  
 
 IMP return and capsule count/compliance check  
 
 Schedule Follow-Up Visit  
 
All patients who discontinue participation in the study are to have a Safety Follow-Up 
Visit conducted 30 days (+5 days) after their final dose of IMP. 
 
Investigational Medicinal Product and Formulation 
 Droxidopa (also known as L-threo-3,4,-dihyrdoxyphenylserine, or L-DOPS) in 100, 
200, and 300mg capsules. 
 Placebo capsules (to match Droxidopa 100, 200m, and 300mg capsules 
 Both Placebo and Droxidopa will be titrated in the same schedule 

12 
 
Both Droxidopa and Placebo will be provided by Lundbeck. Both will be stored at 
ambient temperature in a locked room, in the clinic where the trial is taking place. 
Medication count and medication temperature will be logged.  
Dosage and Administration 
During the Titration Period and Open-Label Period, patients will receive 100, 200, 300, 
400, 500, or 600 mg TID of droxidopa, orally. 
 
The droxidopa starting dose for all eligible patients in the Titration Period in 100mg TID. 
Doses will be titrated by 100mg TID; increments will be made weekly until the optimal 
dose is achieved. Five dose changes are permitted within the first two months of the 
Open-Label Period. No dose changes are allowed after Visit 3. Optimal dose will be 
based on patient’s subjective response to medication. Patients will be instructed 
continue increasing medication until they either A) achieve the maximal dose which is 
600mg TID, or B) they do not notice an improvement in their subjective fatigue on a 
higher dose compared to the most recent dose. Patients will be instructed to measure 
their blood pressure at least once weekly while titrating the medication. If they do not 
have a way to measure their blood pressure at home, they will be given the option to 
come to the clinic for such measurement. If their systolic blood pressure is 140 or 
above, they will be instructed to contact the study doctor, who will adjust the dose 
appropriately.  
 
Safety Variables/Measures 
Safety will be assessed by reported Adverse Events (AE) and Serious Adverse Events 
(SAE) and vital signs. Subjects will be asked to monitor their blood pressure at home 
and report any abnormal changes. 
 
AE/SAE Reporting 
Any serious and unexpected adverse events (SAE’s) will be reported to the sponsor, 
FDA, and Loma Linda University (LLU) ethical review board in writing immediately 
(within 5 days) of the event. Any fatal or life-threatening AEs will be reported to the 
sponsor, FDA, and LLU ethical review board within 5 days of the event.  
 
 Recording Adverse Events  
 
Adverse events (including pre-treatment AEs) must be recorded on an Adverse Event 
Form. The Investigator must provide information on the AE, preferably with a diagnosis, 
or at least with signs and symptoms; start and stop dates, intensity; causal relationship 
to IMP; action taken; and outcome. If the AE is an overdose, the nature of the overdose 
must be stated (for example, medication error, accidental overdose, or intentional 
overdose). If the intensity changes during the course of an adverse event, this must be 
recorded on the Adverse Event Intensity Log. If the AE is serious, this must be indicated 
on the Adverse Event Form. Furthermore, the Investigator must fill out a Serious 
Adverse Event Report Form and report the SAE to Lundbeck, immediately within 5 

13 
 
days, after becoming aware of it. Adverse events, must be recorded individually, except 
when considered manifestations of the same medical condition or disease state; in such 
cases, they must be recorded under a single diagnosis.  
 
 Reporting Serious Adverse Events  
 
The Investigator must report SAEs to Lundbeck immediately (within 5 days) after 
becoming aware of them by completing a Serious Adverse Event Form.  
 
As much information as possible must be entered when initially completing the Serious 
Adverse Event Form. If more information about the patient’s condition becomes 
available at a later date, the Serious Adverse Event Form must be updated with the 
additional information.  
 
The Serious Adverse Event Form will be mailed to: 
 
Global Pharmacovigilance – US  
Fax: +1 (847) 282-1003  
e-mail: luinc_safety@lundbeck.com 
 
 
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance 
with local regulations. It is the Investigator’s responsibility to be familiar with local 
requirements regarding reporting SAEs to the IRB and to act accordingly.  
Lundbeck will assess expectedness and inform the Investigators about suspected 
unexpected serious adverse reactions (SUSARs) in accordance with local 
requirements.  
 
 Treatment and Follow-Up of Adverse Events  
 
Patients with AEs must be treated in accordance with usual clinical practice at the 
discretion of the Investigator. Non-serious AEs must be followed up until resolution or 
the follow-up assessment whichever comes first. At the safety follow-up visit information 
on new SAEs, if any and stop dates for previously reported AEs must be recorded. It is 
the responsibility of the Investigator to follow up on SAEs until the patient has 
recovered, stabilized, or recovered with sequelae, and to report to Lundbeck all relevant 
new information using the same procedures and timelines as those for the initial report. 
Relevant information includes discharge summaries, autopsy reports, and medical 
consultations. SAEs that are spontaneously reported by a patient to the Investigator 
after the follow-up assessment must be handled in the same manner as SAEs that 
occur during the study. These SAEs will be captured in the Global Pharmacovigilance 
database. 
 
 
 
 

14 
 
Informed Consent 
 
It is the responsibility of the Investigator to obtain written informed consent from each 
patient participating in this study, after adequate explanation of the aims, methods, 
potential benefits and any potential hazards of the study. No study-related procedures, 
including washout of any medications, may be performed prior to obtaining written 
informed consent.  
 
The Investigator must explain that the patients are completely free to refuse to enter the 
study or to withdraw from it at any time and for any reason. Similarly, the Investigator or 
Lundbeck is free to withdraw the patient from the study at any time for safety reasons. 
Any other requirements necessary for the protection of the human rights of the patient 
will also be explained. 
 
Confidentiality 
 
All patients who provide written informed consent will be assigned a patient number. 
Subsequently, patients will be identified in the records only by their initials, date of birth, 
and their patient number (as allowed by local country regulations). Any information 
published as a result of the study will be such that it will not permit identification of any 
patient. The information from this study will be available within Lundbeck and may be 
shared with regulatory authorities. It may also be the subject of an audit by a regulatory 
agency, such as the Food and Drug Administration (FDA), within the local government. 
The patient’s identity will remain protected except as required for legal or regulatory 
inquiries. 
 
Data Collection 
 
At each visit, using a data collection form, visit #, subject ID, age, sex, concomitant 
medication medications, medications taken within 28 days of screening visit, avoidance 
of prohibited medications, diagnostic, therapeutic or surgical procedure conducted 
during the study, adherence to regimen vital signs, physical exam, UPDRS score and 
VAFS score will be recorded and saved in a locked cabinet in a locked room at the 
neurology clinic where this study is taking place. If Lundbeck requests, they will be 
provided with protocol, statistical analysis plan, clinical study report, and any other data 
they request. This material will be provided to Lundbeck in person, not electronically.  
 
Statistics 
 
For VAFS and UPDRS data, mean change from randomization to the end of study in 
the droxidopa and placebo groups will be compared using analysis of covariance, with 
value at randomization as covariate and treatment group as main effect. The VAFS and 
UPDRS are attached to the end of the protocol. 
 
 
 

15 
 
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Parkinsons disease: Report from a multidisciplinary symposium. Npj Parkinsons 
Disease 2016; 2:15025. 
 
4. Medonca DA, Menezes K, Jog MS. Methylphenidate improves fatigue scores in 
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5. Smith KM, Eyal E, Weintraub D, ADAGIO Investigators. Combined rasagiline and 
antidepressant use in Parkinson disease in the ADAGIO study: Effects on nonmotor 
symptoms and tolerability. JAMA Neurol. 2015; 72(1):88-95. 
 
6. Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, et al. Droxidopa 
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Neurology 2014; 83(4):328-335. 
 
7. Tseng BY, Gajewski BJ, Kluding PM. Reliability, Responsiveness, and Validity of the 
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Appendix I 
Questionnaires: 
1. Visual Analog Fatigue Scale (VAFS) 
2. Unified Parkinson’s disease Rating Scale (UPDRS). 
 

Visual Analog Fatigue Scale (VAFS) 
 
 

Unified Parkinson’s 
Disease Rating Scale
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD RATING SCALE | ©WE MOVE 2006 
23
I. Mentation, Behavior and Mood
1. Intellectual Impairment
0 = None.
1 = Mild. Consistent forgetfulness with partial recollection  
of events and no other difficulties.
2 = Moderate memory loss, with disorientation and 
moderate difficulty handling complex problems. Mild 
but definite impairment of function at home with need 
of occasional prompting.
3 = Severe memory loss with disorientation for time and 
often to place. Severe impairment in handling problems.
4 = Severe memory loss with orientation preserved to person 
only. Unable to make judgements or solve problems. 
Requires much help with personal care. Cannot be left 
alone at all.
2. Thought Disorder (Due to dementia or drug 
intoxication)
0 = None.
1 = Vivid dreaming.
2 = “Benign” hallucinations with insight retained.
3 = Occasional to frequent hallucinations or delusions; 
without insight; could interfere with daily activities.
4 = Persistent hallucinations, delusions, or florrid psychosis. 
Not able to care for self.
3. Depression
1 = Periods of sadness or guilt greater than normal, never 
sustained for days or weeks.
2 = Sustained depression (1 week or more).
3 = Sustained depression with vegetative symptoms 
(insomnia, anorexia, weight loss, loss of interest).
4 = Sustained depression with vegetative symptoms and 
suicidal thoughts or intent.
4. Motivation/Initiative
 0 = Normal.
1 = Less assertive than usual; more passive.
2 = Loss of initiative or disinterest in elective (nonroutine) 
activities.
3 = Loss of initiative or disinterest in day to day (routine) 
activities.
4 = Withdrawn, complete loss of motivation.
II. Activities of Daily Living  
(for both “on” and “off”)
5. Speech
 0 = Normal.
1 = Mildly affected. No difficulty being understood.
2 = Moderately affected. Sometimes asked to repeat 
statements.
3 = Severely affected. Frequently asked to repeat statements.
4 = Unintelligible most of the time.
6. Salivation
 0 = Normal.
1 = Slight but definite excess of saliva in mouth; may have 
nighttime drooling.
2 = Moderately excessive saliva; may have minimal drooling.
3 = Marked excess of saliva with some drooling.
4 = Marked drooling, requires constant tissue or 
handkerchief.
7. Swallowing
0 = Normal.
1 = Rare choking.
2 = Occasional choking.
3 = Requires soft food.
4 = Requires ng tube or gastrotomy feeding.
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham 
Park, NJ. Macmillan Health Care Information 1987, 153-163, 293-304.

8. Handwriting
0 = Normal.
1 = Slightly slow or small.
2 = Moderately slow or small; all words are legible.
3 = Severely affected; not all words are legible.
4 = The majority of words are not legible.
9. Cutting Food and Handling Utensils
0 = Normal.
1 = Somewhat slow and clumsy, but no help needed.
2 = Can cut most foods, although clumsy and slow; some 
help needed.
3 = Food must be cut by someone, but can still feed slowly.
4 = Needs to be fed.
10. Dressing
0 = Normal.
1 = Somewhat slow, but no help needed.
2 = Occasional assistance with buttoning, getting arms in sleeves.
3 = Considerable help required, but can do some things 
alone.
4 = Helpless.
11. Hygiene
0 = Normal.
1 = Somewhat slow, but no help needed.
2 = Needs help to shower or bathe; or very slow in hygienic 
care.
3 = Requires assistance for washing, brushing teeth, 
combing hair, going to bathroom.
4 = Foley catheter or other mechanical aids.
12. Turning in Bed and Adjusting Bed Clothes
0 = Normal.
1 = Somewhat slow and clumsy, but no help needed.
2 = Can turn alone or adjust sheets, but with great difficulty.
3 = Can initiate, but not turn or adjust sheets alone.
4 = Helpless.
13. Falling (Unrelated to Freezing)
0 = None.
1 = Rare falling.
2 = Occasionally falls, less than once per day.
3 = Falls an average of once daily.
4 = Falls more than once daily.
14. Freezing when Walking
0 = None.
1 = Rare freezing when walking; may have start hesitation.
2 = Occasional freezing when walking.
3 = Frequent freezing. Occasionally falls from freezing.
4 = Frequent falls from freezing.
15. Walking
0 = Normal.
1 = Mild difficulty. May not swing arms or may tend to drag 
leg.
2 = Moderate difficulty, but requires little or no assistance.
3 = Severe disturbance of walking, requiring assistance.
4 = Cannot walk at all, even with assistance.
16.  Tremor (Symptomatic complaint of tremor in any part  
of body.)
0 = Absent.
1 = Slight and infrequently present.
2 = Moderate; bothersome to patient.
3 = Severe; interferes with many activities.
4 = Marked; interferes with most activities.
17. Sensory Complaints Related to Parkinsonism
0 = None.
1 = Occasionally has numbness, tingling, or mild aching.
2 = Frequently has numbness, tingling, or aching; not 
distressing.
3 = Frequent painful sensations.
4 = Excruciating pain.
Unified Parkinson’s Disease Rating Scale
24  
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD RATING SCALE | ©WE MOVE 2006
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham 
Park, NJ. Macmillan Health Care Information 1987, 153-163, 293-304.

III. Motor Examination
18. Speech
0 = Normal.
1 = Slight loss of expression, diction and/or volume.
2 = Monotone, slurred but understandable; moderately 
impaired.
3 = Marked impairment, difficult to understand.
4 = Unintelligible.
19. Facial Expression
0 = Normal.
1 = Minimal hypomimia, could be normal “Poker Face.”
2 = Slight but definitely abnormal diminution of facial 
expression
3 = Moderate hypomimia; lips parted some of the time.
4 = Masked or fixed facies with severe or complete loss of 
facial expression; lips parted 1/4 inch or more.
20. Tremor at Rest (head, upper and lower extremities)
0 = Absent.
1 = Slight and infrequently present.
2 = Mild in amplitude and persistent. Or moderate in 
amplitude, but only intermittently present.
3 = Moderate in amplitude and present most of the time.
4 = Marked in amplitude and present most of the time.
21. Action or Postural Tremor of Hands
0 = Absent.
1 = Slight; present with action.
2 = Moderate in amplitude, present with action.
3 = Moderate in amplitude with posture holding as well  
as action.
4 = Marked in amplitude; interferes with feeding.
22. Rigidity (Judged on passive movement of major joints 
with patient relaxed in sitting position. Cogwheeling to  
be ignored.) 
0 = Absent.
1 = Slight or detectable only when activated by mirror or 
other movements.
2 = Mild to moderate.
3 = Marked, but full range of motion easily achieved.
4 = Severe, range of motion achieved with difficulty.
23. Finger Taps (Patient taps thumb with index finger in 
rapid succession.) 
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing.  
May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating 
movements or arrests in ongoing movement.
4 = Can barely perform the task.
24. Hand Movements (Patient opens and closes hands  
in rapid succesion.) 
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing.  
May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating 
movements or arrests in ongoing movement.
4 = Can barely perform the task.
25. Rapid Alternating Movements of Hands  
(Pronation-supination movements of hands, vertically 
and horizontally, with as large an amplitude as possible, 
both hands simultaneously.) 
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing.  
May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating 
movements or arrests in ongoing movement.
4 = Can barely perform the task.
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD RATING SCALE | ©WE MOVE 2006 
25
Unified Parkinson’s Disease Rating Scale
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham 
Park, NJ. Macmillan Health Care Information 1987, 153-163, 293-304.

26. Leg Agility (Patient taps heel on the ground in rapid 
succession picking up entire leg. Amplitude should be  
at least 3 inches.)
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing.  
May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating 
movements or arrests in ongoing movement.
4 = Can barely perform the task.
27. Arising from Chair (Patient attempts to rise from a 
straightbacked chair, with arms folded across chest.)
0 = Normal.
1 = Slow; or may need more than one attempt.
2 = Pushes self up from arms of seat.
3 = Tends to fall back and may have to try more than one  
time, but can get up without help.
4 = Unable to arise without help.
28. Posture
0 = Normal erect.
1 = Not quite erect, slightly stooped posture; could be 
normal for older person.
2 = Moderately stooped posture, definitely abnormal;  
can be slightly leaning to one side.
3 = Severely stooped posture with kyphosis; can be 
moderately leaning to one side.
4 = Marked flexion with extreme abnormality of posture.
29. Gait
0 = Normal.
1 = Walks slowly, may shuffle with short steps, but no 
festination (hastening steps) or propulsion.
2 = Walks with difficulty, but requires little or no assistance; 
may have some festination, short steps, or propulsion.
3 = Severe disturbance of gait, requiring assistance.
4 = Cannot walk at all, even with assistance.
30. Postural Stability (Response to sudden, strong 
posterior displacement produced by pull on shoulders 
while patient erect with eyes open and feet slightly apart. 
Patient is prepared.)
0 = Normal.
1 = Retropulsion, but recovers unaided.
2 = Absence of postural response; would fall if not caught  
by examiner.
3 = Very unstable, tends to lose balance spontaneously.
4 = Unable to stand without assistance.
31. Body Bradykinesia and Hypokinesia (Combining 
slowness, hesitancy, decreased arm swing, small 
amplitude, and poverty of movement in general.)
0 = None.
1 = Minimal slowness, giving movement a deliberate 
character; could be normal for some persons. Possibly 
reduced amplitude.
2 = Mild degree of slowness and poverty of movement 
which is definitely abnormal. Alternatively, some reduced 
amplitude.
3 = Moderate slowness, poverty or small amplitude of 
movement.
4 = Marked slowness, poverty or small amplitude of 
movement.
26  
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD RATING SCALE | ©WE MOVE 2006
Unified Parkinson’s Disease Rating Scale
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham 
Park, NJ. Macmillan Health Care Information 1987, 153-163, 293-304.

PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD RATING SCALE | ©WE MOVE 2006 
27
Unified Parkinson’s Disease Rating Scale
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham 
Park, NJ. Macmillan Health Care Information 1987, 153-163, 293-304.
IV. Complications of Therapy  
(In the past week)
A. Dyskinesias
32. Duration: What proportion of the waking day are 
dyskinesias present? (Historical information.)
0 = None
1 = 1–25% of day.
2 = 26–50% of day.
3 = 51–75% of day.
4 = 76–100% of day.
33. Disability: How disabling are the dyskinesias? 
(Historical information; may be modified by office 
examination.)
0 = Not disabling.
1 = Mildly disabling.
2 = Moderately disabling.
3 = Severely disabling.
4 = Completely disabled.
34. Painful Dyskinesias: How painful are the 
dyskinesias?
0 = No painful dyskinesias.
1 = Slight.
2 = Moderate.
3 = Severe.
4 = Marked.
35. Presence of Early Morning Dystonia  
(Historical information.)
0 = No
1 = Yes
B. Clinical Fluctuations
36. Are “off” periods predictable?
0 = No
1 = Yes
37. Are “off” periods unpredictable?
0 = No
1 = Yes
38. Do “off” periods come on suddenly, within a  
few seconds?
0 = No
1 = Yes
39. What proportion of the waking day is the patient 
“off” on average?
0 = None
1 = 1–25% of day.
2 = 26–50% of day.
3 = 51–75% of day.
4 = 76–100% of day.
C. Other Complications
40. Does the patient have anorexia, nausea, or vomiting?
0 = No
1 = Yes
41. Any sleep disturbances, such as insomnia or 
hypersomnolence?
0 = No
1 = Yes
42. Does the patient have symptomatic orthostasis? 
(Record the patient’s blood pressure, height and weight 
on the scoring form)
0 = No
1 = Yes 

28  
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD RATING SCALE | ©WE MOVE 2006
V. Modified Hoehn and Yahr Staging
STAGE 0 = No signs of disease.
STAGE 1 = Unilateral disease.
STAGE 1.5 = Unilateral plus axial involvement.
STAGE 2 = Bilateral disease, without impairment of balance.
STAGE 2.5 = Mild bilateral disease, with recovery on pull test.
STAGE 3 = Mild to moderate bilateral disease; some postural instability; physically independent.
STAGE 4 = Severe disability; still able to walk or stand unassisted.
STAGE 5 = Wheelchair bound or bedridden unless aided.
VI. Schwab and England Activities of Daily Living Scale
100% = Completely independent. Able to do all chores without slowness, difficulty or impairment. Essentially normal. 
Unaware of any difficulty.
90% = Completely independent. Able to do all chores with some degree of slowness, difficulty and impairment.  
Might take twice as long. Beginning to be aware of difficulty.
80% = Completely independent in most chores. Takes twice as long. Conscious of difficulty and slowness.
70% = Not completely independent. More difficulty with some chores. Three to four times as long in some.  
Must spend a large part of the day with chores.
60% = Some dependency. Can do most chores, but exceedingly slowly and with much effort. Errors; some impossible.
50% = More dependent. Help with half, slower, etc. Difficulty with everything.
40% = Very dependent. Can assist with all chores, but few alone.
30% = With effort, now and then does a few chores alone or begins alone. Much help needed.
20% = Nothing alone. Can be a slight help with some chores. Severe invalid.
10% = Totally dependent, helpless. Complete invalid.
0% = Vegetative functions such as swallowing, bladder and bowel functions are not functioning. Bedridden.
Unified Parkinson’s Disease Rating Scale
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham 
Park, NJ. Macmillan Health Care Information 1987, 153-163, 293-304.

Name __________________________________________________________________________________   Unit Number ______________________________________________________
Unified Parkinson’s 
Disease Data Form
	
Date
 dopa mg/day        hrs dopa lasts
                          |
	
1. Mentation
	
2. Thought Disorder
	
3. Depression
	
4. Motivation/Initiative
	
Subtotal 1 – 4 (maximum = 16)
	
5. Speech
	
6. Salivation
	
7. Swallowing
	
8. Handwriting
	
9. Cutting food
	
10. Dressing
	
11. Hygiene
	
12. Turning in bed
	
13. Falling
	
14. Freezing
	
15. Walking
	
16. Tremor
	
17. Sensory symptoms
	
Subtotal 5  – 17 (maximum = 52)
	
18 Speech
	
19. Facial expression
	
20. Tremor at rest: face,lips,chin
	
Hands: right
	
left
	
Feet: right
	
left
	
21. Action tremor: right
	
left
	
22. Rigidity: neck
	
Upper extremity: right
	
left
	
Lower extremity: right
	
left
on   off   on   off   on   off   on  off   on   off   on   off   on  off   on   off 
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD DATA FORM | ©WE MOVE 2006 
29

Unified Parkinson’s Disease Data Form
Fahn S, Elton R, Members of the updrs Development Committee. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol 2. Florham Park, NJ. 
Macmillan Health Care Information 1987, pp 153-163, 293-304
	
Date
 
	
23. Finger taps: right
	
left
	
24. Hand grips: right
	
left
	25. Hand pronate/supinate: right
	
left
	
26. Leg agility: right
	
left
	
27. Arise from chair
	
28. Posture
	
29. Gait
	
30. Postural stability
	
31. Body bradykinesia
	Sub-total:18 –31 (maximum = 108)
	
Total points: 1 –31 (max = 176)
	
32. Dyskinesia (duration)
	
33. Dyskinesia (disability)
	
34. Dyskinesia (pain)
	
35. Early morning dystonia
	
36. “Offs” (predictable)
	
37. “Offs” (unpredictable)
	
38. “Offs” (sudden)
	
39. “Offs” (duration)
	 40. Anorexia, nausea, vomiting
	
41. Sleep disturbance
	
42. Symptomatic orthostasis
	
Blood Pressure: seated
	
supine
	
standing
	
Weight
	
Pulse: seated
	
standing
	
Name of Examiner
	
Hoehn & Yahr Stage
	
% ADL Score (PD)
	
% ADL (with dyskinesia)
best   worst   best   worst   best   worst   best   worst   best   worst   best   worst   best   worst   best   worst
on   off   on   off   on   off   on  off   on   off   on   off   on  off   on   off 
30  
PD WORKBOOK — THE WE MOVE CLINICIANS’ GUIDE TO PARKINSON’S DISEASE | UNIFIED PD DATA FORM | ©WE MOVE 2006