Clinical trial NCT02586623
Conditions: Symptomatic Neurogenic Orthostatic Hypotension
Keywords: Parkinson's Disease Multiple System Atrophy Pure Autonomic Failure Primary Autonomic Failure Dopamine Beta Hydroxylase Deficiency
Sponsor: H. Lundbeck A/S
Start date: 2016-02-11; Completion date: 2022-09-09
Enrollment: 453 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the time to treatment intervention in patients with Parkinson's Disease (PD), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), Non-Diabetic Autonomic Neuropathy (NDAN) or Dopamine Beta Hydroxylase (DBH) Deficiency who have been previously stabilized with droxidopa therapy for symptoms of neurogenic orthostatic hypotension (NOH) (dizziness, light-headedness, or feelings that they are about to black out)

Detailed description:
This is a multi-site, placebo-controlled, double-blind, randomized withdrawal, time to intervention study with a duration of up to 36 weeks, consisting of 5 periods:

Screening Period: up to 4 weeks duration; Open-Label Titration Period (Titration Period): up to 4 weeks duration; Open-Label Treatment Period (Open-Label Period): 12 weeks duration; Double-Blind Treatment Period (Double-Blind Period): 12 weeks duration; Safety Follow-Up Period: 4 weeks duration

Arms: arm 1: Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open Label Titration Period, patients will first receive 100 mg TID and their dose will be raised (in 100 mg increments) at subsequent visits until optimal dose is determined. During the Open Label Treatment Period, patients will receive active droxidopa100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to the patient's individual dose at the end of the Open-Label Titration Period). arm 2: Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to patients individual dose at the end of the Open-Label Period) or matching placebo.
Interventions: intervention 1: Droxidopa capsules intervention 2: Placebo capsules
Intervention descriptions: intervention 1: 100, 200 or 300 mg intervention 2: None

Protocol documents:
Prot_000.pdf: 
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Page 1 
 
 
 
CLINICAL PROTOCOL 
 
RESTORE: A clinical study of patients with symptomatic neuRogenic orthostatic 
hypotEnsion to assess Sustained effecTs Of dRoxidopa thErapy 
 
Compound:  
 
 
 
 
23651-95-8 
Compound Name: 
 
 
 
 
Droxidopa 
Study Number: 
 
 
 
 
16306A 
US IND Number: 
 
 
 
 
077248 
Protocol Number: 
 
 
 
 
NOH402 
Version Number: 
 
 
 
 
Amendment 6.0 
Version Date: 
 
 
 
 
18 March 2021  
Phase:  
 
 
 
 
 
4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of Lundbeck NA (or under its control), and 
Lundbeck NA has provided this information to you in confidence as an investigator, potential investigator or consultant, for review by 
you, your staff and an applicable Ethics Review Committee. It is understood that this information will not be disclosed to others 
without written authorization from Lundbeck NA., except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. 
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PROTOCOL SYNOPSIS 
Title:  
A clinical study of patients with symptomatic neurogenic orthostatic hypotension to assess 
sustained effects of droxidopa therapy 
Indication: 
Symptomatic neurogenic orthostatic hypotension (NOH) in patients with Primary Autonomic 
Failure [Parkinson’s Disease (PD), Multiple System Atrophy (MSA) or Pure Autonomic Failure 
(PAF)], or Non-Diabetic Autonomic Neuropathy (NDAN) or Dopamine Beta Hydroxylase (DBH) 
deficiency. 
Rationale: 
Symptomatic NOH in patients is thought to be a consequence of norepinephrine (NE) 
neurotransmission dysfunction, leading to low systolic blood pressure (SBP) and cerebral 
hypoperfusion. Therapy with droxidopa results in increased levels of NE which should lead to 
improved SBP and cerebral perfusion thereby reducing the signs and symptoms of NOH.   
Droxidopa was approved in the US for the treatment of orthostatic dizziness,  light-headedness or 
the “feeling that you are about to black out” in patients with a clinical diagnosis of symptomatic 
NOH due to Parkinson’s disease, multiple system atrophy, pure autonomic failure, non-diabetic 
autonomic neuropathy, or dopamine-β-hydroxylase deficiency. Effectiveness was established in 
short-term (≤ 2 week) studies; effectiveness longer than 2 weeks has not yet been demonstrated.  
This long-term study will evaluate the durability of the clinical benefit in NOH patients treated 
with droxidopa in a randomized withdrawal design (time to treatment intervention study). 
Objectives: 
Primary objective:  
• To evaluate the time to treatment intervention in patients with PD, MSA, PAF, NDAN or 
DBH Deficiency who have been previously stabilized with droxidopa therapy for 
symptoms of NOH (dizziness, light-headedness, or feelings that they are about to black 
out) 
Secondary objectives:  
• To evaluate the long-term efficacy of droxidopa in patients with symptomatic NOH 
measured by 
o Discontinuation for any reason (all cause discontinuation) 
o Composite Orthostatic Hypotension Questionnaire (OHQ) scores 
o Clinicians’ and patients’ clinical global impression of severity (CGI-S) 
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• To evaluate the long-term safety and tolerability of droxidopa in patients with symptomatic 
NOH. 
Study Design:  
This is a multi-site, placebo-controlled, double-blind, randomized withdrawal, time to 
intervention study with a duration of up to 36 weeks, consisting of 5 periods (See Figure 1):   
• Screening Period: up to 4 weeks duration 
• Open-Label Titration Period (Titration Period): up to 4 weeks duration 
• Open-Label Treatment Period (Open-Label Period): 12 weeks duration 
• Double-Blind Treatment Period (Double-Blind Period): 12 weeks duration 
• Safety Follow-Up Period: 4 weeks duration 
 
Study Country Locations: 
United States 
Study Duration: 
The maximum duration of patient participation is 36 weeks.   
Number of Patients/Sites: 
Across approximately 125 study sites, a sufficient number of patients will be screened to 
randomize 240 patients into the Double-Blind Period (120 patients per treatment group). 
Study Population: 
Adult patients with symptomatic NOH associated with Primary Autonomic Failure [Parkinson’s 
Disease (PD), Multiple System Atrophy (MSA) or Pure Autonomic Failure (PAF)] or Non-
Diabetic Autonomic Neuropathy (NDAN) or Dopamine Beta Hydroxylase (DBH) deficiency.  
Inclusion Criteria (All Patients): 
1. 18 years or older and able to stand (with or without limited assistance) 
2. Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary 
Autonomic Failure (PD, MSA or PAF) or NDAN or DBH Deficiency 
3. Score of at least 4 or greater on Orthostatic Hypotension Symptom Assessment (OHSA) 
Item #1 (measured at Screening [Visit 1] and the first Titration Visit [Visit 2a] prior to 
dosing) 
4. A documented drop of at least 20 millimeters of mercury (mmHg) in SBP, within 3 minutes 
of standing.  This can either be documented in the patient history or assessed during 
Screening prior to the first Titration Visit (Visit 2a) 
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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  
Additional inclusion criteria for patients taking prescribed droxidopa prior to study entry: 
Patients who are taking prescribed droxidopa therapy are eligible to participate in the study if 
they meet the other inclusion criteria (1-5 above) and also have been on a stable dose of 
prescribed droxidopa for at least 2 weeks prior to the Screening Visit (Visit 1).  In addition, 
they must meet either of the following at the Screening Visit (Visit 1):  
6. The patient’s Visit 1 OHSA Item #1 score is ≥ 7 AND the prescribed dose is ≤ 300 mg 
three times daily (TID); OR 
7. The patient’s Visit 1 OHSA Item #1 score is ≤6 AND worsens by ≥ 2 units when retested 
after washing out of droxidopa for at least 3 days 
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 (DSM-5 
criteria) 
3. Women who are pregnant or breastfeeding 
4. Women of childbearing potential (WOCP) who are not using at least one method of 
contraception with their partner 
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 
(short-acting  antihypertensives to treat nocturnal supine hypertension are allowed in this 
study)  
8. Any significant uncontrolled cardiac arrhythmia 
9. History of myocardial infarction or stroke within the past 2 years  
10. Current unstable angina 
11. Congestive heart failure (NYHA Class 3 or 4) 
12. Diabetic autonomic neuropathy 
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 
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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 (Visit 2a) 
16. Currently receiving any investigational drug or have received an investigational drug 
within 28 days prior to the first Titration Visit (Visit 2a) 
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 discretion 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. In the Investigator’s opinion, the patient has increased risk of intracranial hemorrhage.  For 
example: history of brain aneurysm or current use of anticoagulants in the drug classes of 
Coumarins, Factor Xa Inhibitors, and Direct Thrombin Inhibitors 
 
End of Titration Criteria:  
At the end of the Titration Period (Visit 3), patients must have an Acute Dizziness score that is ≥ 
2 units lower (improved) than the Visit 2a OHSA Item #1 score.  Patients who do not meet this 
criterion will be withdrawn from the study.  
Randomization Criteria:  
At the end of the Open-Label Period (Visit 6), patients must have an OHSA Item #1 score that is 
≥ 2 units lower (improved) than the Visit 2a score.  Patients who do not meet this criterion will be 
withdrawn from the study. 
Treatment Intervention Criteria (Double-Blind Treatment Period): 
At each visit during the Double-Blind Period (Visits 7-12), patients will be evaluated for the 
following criteria: 
1. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) AND lack of efficacy as 
judged by the investigator; OR 
2. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) at 2 consecutive 
visits;OR 
3. OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early 
discontinuation; OR 
4. Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
If a patient meets any of these criteria for treatment intervention during the Double-Blind Period, 
the patient will be withdrawn from the study. 
 
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Investigational Medicinal Product and Formulation: 
Droxidopa (also known as L-threo-3,4-dihydroxyphenylserine, or L-DOPS) in 100, 200, and 300 
mg capsules 
Placebo capsules (to match droxidopa 100, 200, and 300 mg capsules) 
Dosage and Administration: 
During the Titration Period (Visits 2a-2f) and Open-Label Period (Visits 3-5), 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 is 100 mg TID. Doses 
will be titrated in 100 mg TID increments until the optimal dose is achieved. Four dose changes 
are permitted within the first two months of the Open-Label Period. No dose changes are allowed 
after Visit 5.  
Randomized patients will receive 100, 200, 300, 400, 500, or 600 mg TID of droxidopa or 
matching placebo (equal to their dose at the end of the Open-Label Period), orally at 
Randomization (Visit 6) and during the Double-Blind Period (Visits 7-12). No dose changes are 
permitted during the Double-Blind Period.  
Statistical Analysis: 
Sample Size Determination: 
The sample size and power calculations are based on the analysis of time to intervention in the 
Double-Blind Period. 
It is anticipated that event rates will be 0.15 for the droxidopa group and 0.25 for the placebo 
group 12 weeks post randomization. Assuming these event rates and a hazard ratio of 0.56 in 
favor of droxidopa, a 240-subject sample size would be expected to result in 48 events, providing 
~51% power to detect a difference between droxidopa and placebo.  A blinded review conducted 
in July 2020 indicated that the event rate may be higher than originally assumed and, if accurate, 
will result in a substantially higher power than 51%.  In addition, the study will contribute to the 
totality of results for the post-marketing requirement (PMR) evaluation, which justifies the 
reduced power given the circumstances.  
 Primary Efficacy Endpoint: 
Time-to-intervention.   Need for intervention is defined as meeting ANY of the following criteria 
during the Double-Blind Period: 
• 
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as 
judged by the investigator; OR 
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• 
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; 
OR 
• 
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early 
discontinuation; OR 
• 
Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
The timing of the need for intervention in the above criteria is defined as the first occurrence of a 
worsening of OHSA Item #1 by ≥ 2 units or when the patient stops taking IMP or withdraws due 
to a patient-reported lack of efficacy. Patients who withdraw without meeting criteria for treatment 
intervention will be censored at the time of withdrawal; patients who do not meet criteria for 
treatment intervention at the end of the Double-Blind Period (Visit 12) will be censored at the time 
of study completion.  
 
The primary endpoint will be summarized using Kaplan-Meier method. The primary analysis is 
the log-rank test to compare the two treatment groups. In addition, the Cox regression model will 
be used to estimate the hazard ratio.  Furthermore, the following sensitivity analyses using the 
same approach will be conducted: 
• Time-to-intervention defined as the criteria specified above; or OHSA Item #1 ≥2 unit 
worsening from Randomization (Visit 6) at the last visit of the Double-Blind Period (Visit 
12). 
• Cox regression analysis of time to intervention based on various definitions above. 
Secondary Endpoints: The Key Secondary Endpoint 
Time to all cause discontinuation is the key secondary endpoint.  
A gate keeping strategy will be applied in the testing of this key secondary endpoint. That is, the 
Log-rank test of this secondary endpoint will be performed at the nominal alpha level of 2-sided 
0.05 only if the primary endpoint reaches statistical significance in the primary analysis. This 
strategy ensures the overall type 1 error rate is preserved.  
Other Secondary Endpoints: 
Efficacy measures of droxidopa versus placebo: 
• Mean change in OHSA Item #1 score from Randomization (Visit 6) to all post-
Randomization visits  
• Mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from 
Randomization (Visit 6) to all post-Randomization visits (Visits 7-12) 
• Clinician-rated CGI-S at all post-Randomization visits (Visits 7-12) 
• Patient-rated CGI-S at all post-Randomization visits (Visits 7-12) 
• Proportion of patients who need intervention over the 12-week Double-Blind Treatment 
period 
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Adverse events, vital signs, and clinical safety laboratory assessments will be observed throughout 
the entire study.  Safety parameters from the open-label portions of the study (Titration Period and 
Open-Label Period) and the Double-Blind Period will be reported separately.  
Study Procedures: 
Refer to the Study Schedule/Flowchart (Table 1) on the following page for a summarization of the 
procedures and assessments conducted during this study. 
 
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Table 1: Study Schedule/Flowchart 
Study procedures 
 
Screening 
First 
Titration 
Visit 
Dose 
Titration 
Open-Label Treatment  End of Open-Label 
Treatment 
(Randomization) 
Double-Blind 
Treatment  
End of 
Treatment 
Safety 
Follow-Up 
Visit 1 
Visit 2a 
Visits 
2b...2f (f,g) 
Visit 3 
Visits 4-5 
Visit 6 
Visits 7-11(h) 
Visit 12 or 
Early 
Termination 
Visit 13 
Written informed consent 
✓ 
 
 
 
 
 
 
 
 
Review inclusion and exclusion criteria 
✓ 
✓ 
 
✓ 
 
✓ 
 
 
 
Demography 
✓ 
 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
 
Concomitant medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse events (continuous monitoring) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination 
✓ 
 
 
 
 
 
 
✓ 
 
Vital signs (BP, HR, RR, temp.) and weight 
✓(a, c) 
✓ (a) 
 
✓ (a) 
✓ (b) 
✓ (b) 
✓ (b, i) 
✓ (b) 
 
Orthostatic Standing Test 
✓ (d) 
 
 
 
 
 
 
 
 
Seated, pre-dose BP 
 
 
✓ 
 
 
 
 
 
 
Supine BP 
 
 
 
 
 
 
✓ (j) 
 
 
Supine, post-dose BP assessment 
 
✓ 
✓ 
 
 
 
 
 
 
Seated, post-dose BP assessment 
 
 
 
✓ 
 
 
 
 
 
Pregnancy test for WOCP (e) 
✓ 
 
 
 
 
✓ 
 
✓ 
 
12-lead ECG recording 
✓ 
 
 
 
 
 
 
 
 
Administer first daily dose of IMP on site 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Dose titration evaluation  
 
 
✓ 
 
 
 
 
 
 
Clinical symptoms–OHQ (OHSA & OHDAS) 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
 
Acute dizziness assessment 
 
 
 
✓ 
 
 
 
 
 
Patient-reported CGI-S 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Clinician-reported CGI-S 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Review Need For Intervention criteria 
 
 
 
 
 
 
✓ 
✓ 
 
Blood and urine samples (laboratory safety) 
✓ 
 
 
 
 
✓ 
 
✓ 
 
Randomization 
 
 
 
 
 
✓ 
 
 
 
IMP dispensed, as required 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
 
Capsule count/compliance check 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
IMP returned 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
(a) Seated BP assessed during Vital Signs  
 
 
 
 
 
(b) Supine BP assessed during Vital Signs 
(c)  Height recorded at Screening (V1) only 
 
 
 
 
 
(d) Only required if OH not documented in patient history   
 
(e) Local urine pregnancy test (on site dip-stick test; positive result to be verified by serum pregnancy test)  
(f) Patients anticipated to have up to 6 titration visits 
(g) Titration visits 2b-2f may be completed on site or via phone or video link  
 
 
(h) Double-blind visits 7, 9 & 11, will be completed via phone or video link 
(i) Visits 8 and 10 only   
 
 
 
 
 
(j) Visits 7, 9 and 11 only 
 
 
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Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
Note: Patients are anticipated to have up to 6 titration visits; the exact number of Titration Visits for a given patient will depend upon the number 
of Titration Visits required to reach their optimal dose. 
Double-Blind Period is 3 months in duration.  Week 0 of the Double-Blind Period begins with Randomization.  Visits in the Double-Blind Period 
will occur at Weeks 2, 4, 6, 8, 10, and 12. 
≤4 weeks 
500mg 
600mg 
200mg 
Optimal 
Dose 
Droxidopa 
OPEN-LABEL DOSE TITRATION 
V12 
V3 
V2b, 2c, 2d, 2e, 2f  
(Titration) 
≤4 weeks 
1 Month 
400mg 
Safety  
Follow-Up 
V1 
300mg 
DOUBLE BLIND TREATMENT 
OPEN-LABEL TREATMENT 
Month 1 
Month 2 
V5     
  Droxidopa 
Droxidopa 
Placebo 
V8     V9     V10    V11    
V4     
3 months 
V7     
 
6 
4 
2 
0 
8 
10 
12 
Weeks of Double-Blind Treatment 
V6 
100mg 
Randomization 
Month 3 
SCREENING 
V2a 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................ 19 
1.1 
Symptomatic Neurogenic Orthostatic Hypotension ....................................................... 19 
1.2 
Background .................................................................................................................... 19 
1.2.1 
Droxidopa ............................................................................................................... 19 
1.2.2 
Pharmacology ......................................................................................................... 20 
1.2.3 
Pre-clinical studies with Droxidopa ........................................................................ 20 
1.2.4 
Clinical studies with Droxidopa.............................................................................. 21 
1.2.5 
Efficacy Profile ....................................................................................................... 21 
1.2.6 
Safety Profile .......................................................................................................... 22 
1.3 
Study Rationale .............................................................................................................. 22 
1.3.1 
Selection of Droxidopa Dose and Schedule of Administration .............................. 23 
1.3.2 
Selection of Primary Efficacy Endpoint ................................................................. 24 
2. 
STUDY OBJECTIVES ......................................................................................................... 25 
3. 
STUDY METHODS ............................................................................................................. 25 
3.1 
Study Design .................................................................................................................. 25 
3.2 
Sites ................................................................................................................................ 26 
3.3 
Number of Patients and Assignment of Treatment Groups ........................................... 26 
3.4 
Study Population ............................................................................................................ 28 
3.4.1 
Inclusion Criteria (All Patients) .............................................................................. 28 
3.4.1.1 
Patients who are taking prescribed droxidopa therapy ................................................. 28 
3.4.2 
Exclusion Criteria (All Patients) ............................................................................. 28 
3.4.3 
End of Titration Criteria.......................................................................................... 29 
3.4.4 
Randomization Criterion ......................................................................................... 30 
3.4.5 
Treatment Intervention Criteria (Double-Blind Treatment Period) ........................ 30 
3.5 
Study Visit and Assessment Schedule ........................................................................... 30 
3.5.1 
Screening (Visit 1) .................................................................................................. 30 
3.5.1.1 
Patients who are taking prescribed droxidopa therapy ................................................. 31 
3.5.1.2 
Re-Screening of patients ................................................................................................. 31 
3.5.2 
Open-Label Dose Titration (Visits 2a-2f) ............................................................... 32 
3.5.2.1 
Initial Open-Label Dose Titration Visit (Visit 2a) ............................................................. 32 
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3.5.2.2 
Subsequent Open-Label Dose Titration (Visits 2b, 2c, 2d, 2e, 2f) .................................. 33 
3.5.2.3 
Titration Period Stopping Criteria ................................................................................... 34 
3.5.3 
Open-Label Treatment Period (Visits 3-6) ............................................................. 34 
3.5.3.1 
End of Titration / Initial Open-label Treatment Visit (Visit 3; Day 0) .............................. 34 
3.5.3.2 
Open-Label Treatment Period (Visits 4 & 5; Day 28 [+/- 7days] & Day 56 [+/ 7days]) ... 35 
3.5.3.3 
End of Open-label Treatment Period / Randomization (Visit 6; Day 84 [+/- 7 days]) ..... 36 
3.5.4 
Double-Blind Study Visits (Visits 7-11)................................................................. 37 
3.5.4.1 
Telephone / Video Link Double-Blind Study Visits (Visits 7, 9 & 11)............................... 37 
3.5.4.2 
On-Site Double-Blind Study Visits (Visits 8 & 10) ............................................................ 38 
3.5.5 
End of Treatment Visit (Visit 12; Day 84 [+/- 3 days] post Randomization)......... 39 
3.5.6 
Safety Follow-Up Visit (Visit 13)........................................................................... 40 
3.5.7 
Early Termination Visit .......................................................................................... 40 
3.5.8 
Unscheduled Visit ................................................................................................... 42 
3.5.9 
Guidance regarding Covid-19 ................................................................................. 42 
3.6 
Study Procedures and Assessments................................................................................ 42 
3.6.1 
General Study Procedures and Considerations ....................................................... 44 
3.6.1.1 
Supine Blood Pressure Assessments ............................................................................... 44 
3.6.1.1.1 Titration Period ......................................................................................................... 44 
3.6.1.1.2 Open Label Period and Double-Blind Period ............................................................ 44 
3.6.1.2 
Seated Blood Pressure Assessments ............................................................................... 44 
3.6.1.3 
Orthostatic Standing Test ............................................................................................... 44 
3.6.1.4 
Alcohol Consumption ...................................................................................................... 45 
3.6.1.5 
Hydration ........................................................................................................................ 45 
3.6.2 
Efficacy Assessments.............................................................................................. 45 
3.6.2.1 
Orthostatic Hypotension Questionnaire (OHQ) .............................................................. 45 
3.6.2.2 
Acute Dizziness Assessment ............................................................................................ 46 
3.6.3 
Safety Assessments ................................................................................................. 46 
3.6.3.1 
Adverse Events ................................................................................................................ 46 
3.6.3.2 
Blood Pressure Measurements ....................................................................................... 46 
3.6.3.3 
Physical Examination ....................................................................................................... 47 
3.6.3.4 
ECG .................................................................................................................................. 47 
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3.6.3.5 
Vital Signs and Weight .................................................................................................... 47 
3.6.3.6 
Clinical Safety Laboratory Tests ...................................................................................... 47 
3.7 
Study Endpoints ............................................................................................................. 49 
3.7.1 
Efficacy Endpoints .................................................................................................. 49 
3.7.1.1 
Primary Efficacy Endpoints ............................................................................................. 49 
3.7.1.2 
Secondary Efficacy Endpoints ......................................................................................... 49 
3.7.2 
Safety Endpoints ..................................................................................................... 50 
3.8 
Early Termination .......................................................................................................... 50 
3.9 
Study Termination .......................................................................................................... 50 
4. 
STUDY TREATMENTS ...................................................................................................... 51 
4.1 
Allocation to Study Treatments...................................................................................... 51 
4.2 
Emergency Blind Breaking ............................................................................................ 51 
4.3 
IMP Supplies .................................................................................................................. 52 
4.4 
Manufacturing, Formulation, Packaging and Labeling of IMP ..................................... 52 
4.4.1 
Formulation Details ................................................................................................ 52 
4.4.2 
Manufacturing, Packaging and Labeling Details .................................................... 52 
4.5 
Preparation, Administration and Dosing of Investigational Medicinal Product ............ 53 
4.5.1 
Preparation .............................................................................................................. 53 
4.5.2 
Route of Administration and Dose Schedule .......................................................... 54 
4.5.3 
Dose Increase / Dose Reduction ............................................................................. 55 
4.6 
Drug Storage and Accountability ................................................................................... 56 
4.7 
Treatment Compliance ................................................................................................... 56 
4.8 
Prior and Concomitant Medications ............................................................................... 57 
4.8.1 
Concomitant Medications ....................................................................................... 57 
4.8.2 
Prior Medications .................................................................................................... 57 
4.8.3 
Prohibited Medications ........................................................................................... 57 
4.8.4 
Allowed Medications .............................................................................................. 58 
5. 
ADVERSE EVENTS ............................................................................................................ 58 
5.1 
Definitions ...................................................................................................................... 58 
5.1.1 
Adverse Event Definitions ...................................................................................... 58 
5.1.1.1 
Adverse Events ................................................................................................................ 58 
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5.1.1.2 
Serious Adverse Events ................................................................................................... 59 
5.1.2 
Adverse Event Assessment Definitions .................................................................. 60 
5.1.2.1 
Assessment of Intensity .................................................................................................. 60 
5.1.2.2 
Assessment of Causal Relationship ................................................................................. 60 
5.1.2.3 
Assessment of Outcome ................................................................................................. 60 
5.2 
Pregnancy ....................................................................................................................... 61 
5.3 
Recording Adverse Events ............................................................................................. 61 
5.4 
Reporting Serious Adverse Events ................................................................................. 61 
5.5 
Treatment and Follow-Up of Adverse Events................................................................ 62 
5.6 
Warnings and Precautions .............................................................................................. 62 
6. 
DATA ANALYSIS / STATISTICAL METHODS .............................................................. 63 
6.1 
Sample Size Determination ............................................................................................ 63 
6.2 
Randomization ............................................................................................................... 63 
6.3 
Study Treatments............................................................................................................ 64 
6.4 
Analysis Population........................................................................................................ 64 
6.4.1 
Safety Set ................................................................................................................ 64 
6.4.2 
All Patients Treated Set .......................................................................................... 64 
6.4.3 
Per Protocol Set....................................................................................................... 64 
6.5 
Data Summary ................................................................................................................ 64 
6.5.1 
Summary of Efficacy Data ...................................................................................... 64 
6.5.1.1 
Analysis of Primary Endpoint .......................................................................................... 65 
6.5.1.2 
Analysis of Key Secondary Endpoint ............................................................................... 65 
6.5.1.3 
Analysis of Other Secondary Endpoints .......................................................................... 65 
6.5.2 
Summary of Safety Data ......................................................................................... 65 
6.6 
Interim Analysis ............................................................................................................. 66 
6.7 
Replacement Policy ........................................................................................................ 66 
7. 
DATA MONITORING COMMITTEE ................................................................................ 66 
8. 
STUDY DOCUMENTATION, eCRF AND RECORD KEEPING ..................................... 66 
8.1 
Investigator’s Files and Retention of Study Data........................................................... 66 
8.2 
Electronic Case Report Forms........................................................................................ 67 
8.3 
Background Data ............................................................................................................ 67 
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8.4 
Monitoring, Verification of Data, Audit, and Inspection ............................................... 67 
9. 
ADMINISTRATIVE PROCEDURES ................................................................................. 68 
9.1 
Compliance with Good Clinical Practice and Ethical Considerations ........................... 68 
9.2 
Informed Consent ........................................................................................................... 68 
9.3 
Confidentiality of Patient Information ........................................................................... 69 
9.4 
Protocol Compliance ...................................................................................................... 69 
9.5 
Conditions For Modification of the Protocol ................................................................. 69 
9.6 
Clinical Study Report and Publications ......................................................................... 70 
9.6.1 
Clinical Study Report .............................................................................................. 70 
9.6.2 
Data Ownership ...................................................................................................... 70 
9.6.3 
Publications ............................................................................................................. 70 
10. 
REFERENCES .................................................................................................................. 72 
11. 
APPENDICES ................................................................................................................... 73 
 
LIST OF TABLES 
Table 1: Study Schedule/Flowchart .............................................................................................. 43 
Table 2: Capsule Combinations Per Dose .................................................................................... 54 
LIST OF FIGURES 
Figure 1: Biosynthesis of Norepinephrine from Droxidopa ......................................................... 20 
Figure 2: Study Design ................................................................................................................. 27 
APPENDICES 
Appendix 1: Questionnaires 
Appendix 1.1: Orthostatic Hypotension Questionnaire 
Appendix 1.2: Clinical Global Impressions - Severity 
 
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TERMS AND ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
AP 
alkaline phosphatase 
APTS 
all patients treated set 
AST 
aspartate transaminase (SGOT) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CGI-S 
Clinical Global Impressions - Severity 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CNS 
central nervous system 
CRO 
contract research organization 
CSR 
clinical study report 
DBH 
dopamine beta(β) hydroxylase 
DBP 
diastolic blood pressure 
DDC 
DOPA decarboxylase 
DMC 
data monitoring committee 
DOPA 
3,4-dihydroxyphenylalanine 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPV-US 
global pharmacovigilance – United States 
HDPE 
high-density polyethylene 
HR 
heart rate 
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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
investigational medicinal product 
INN 
international non-proprietary name 
IRB/IEC 
institutional review board/independent ethics committee 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
L-DOPS 
L-threo-3,4-dihydroxyphenylserine (droxidopa) 
MAOI 
monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MHPG 
3-methoxy-4-hydroxy-phenylglycol 
mmHg 
millimeters of mercury  
MSA 
multiple system atrophy 
NDAN 
non-diabetic autonomic neuropathy 
NE 
norepinephrine 
NOH 
neurogenic orthostatic hypotension 
NRIs 
norepinephrine reuptake inhibitors 
NYHA 
New York Heart Association 
OH 
orthostatic hypotension 
OHDAS 
Orthostatic Hypotension Daily Activity Scale 
OHQ 
Orthostatic Hypotension Questionnaire 
OHSA 
Orthostatic Hypotension Symptom Assessment 
OST 
orthostatic standing test 
PAF 
pure autonomic failure 
PD 
Parkinson’s disease 
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Abbreviation 
Definition 
PI 
Package Insert 
PK 
pharmacokinetic 
PPS 
per protocol set 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SNRIs 
serotonin–norepinephrine reuptake inhibitors 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TID 
three times per day 
TMF 
trial master file 
US 
United States 
WOCP 
women of child-bearing potential 
 
 
 
 
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1.  INTRODUCTION 
1.1 Symptomatic Neurogenic Orthostatic Hypotension 
Symptomatic neurogenic orthostatic hypotension (NOH) in patients is thought to be a consequence 
of norepinephrine neurotransmission dysfunction, leading to low systolic blood pressure (SBP) 
and cerebral hypoperfusion.  SBP is transiently and minimally decreased in healthy individuals 
upon standing.  Normal physiologic feedback mechanisms work through neurally-mediated 
pathways to maintain the standing blood pressure (BP), and thus maintain adequate cerebral 
perfusion.  The compensatory mechanisms that regulate BP upon standing are dysfunctional in 
patients with symptomatic NOH, a condition that may lead to inadequate cerebral perfusion with 
accompanying symptoms of syncope, dizziness or lightheadedness, unsteadiness and blurred or 
impaired vision, among other symptoms.  Symptomatic NOH may be a severely disabling 
condition which can seriously interfere with the quality of life of afflicted patients.   
Many of the currently available therapeutic options provide some symptomatic relief in a subset 
of patients, but are relatively ineffective and are often accompanied by severe side effects that limit 
their usefulness.  Support garments (e.g., tight-fitting leotards) may prove useful in some patients, 
but are difficult to don without family or nursing assistance, especially for older patients.  
Midodrine, fludrocortisone, methylphenidate, ephedrine, indomethacin and dihydroergotamine are 
some of the pharmacological interventions that have been used to treat orthostatic hypotension 
(OH), although, of these medications, only midodrine is specifically approved for this indication.   
The only other medication approved for this indication is droxidopa.  Therapy with droxidopa has 
been shown to result in increased levels of norepinephrine (NE) which leads to improved SBP and 
cerebral perfusion thereby reducing the signs and symptoms of symptomatic NOH.  As of 2014, 
droxidopa has been approved in the United States (US) for the treatment of orthostatic 
dizziness,  light-headedness or the “feeling that you are about to black out” in patients with a 
clinical diagnosis of symptomatic NOH due to Parkinson’s disease (PD), multiple system atrophy 
(MSA), pure autonomic failure (PAF), non-diabetic autonomic neuropathy (NDAN), or dopamine-
β-hydroxylase (DBH) deficiency. Effectiveness was established in short-term studies and efficacy 
beyond two weeks has not yet been demonstrated.  This long-term study will evaluate the durability 
of the clinical benefit in patients with symptomatic NOH treated with droxidopa.  
1.2 Background 
1.2.1 Droxidopa 
Droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, or L-DOPS] 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. 
Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a 
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variety of conditions including Shy-Drager syndrome (Multiple System Atrophy), Pure 
Autonomic Failure (PAF), and Parkinson’s disease (PD). There are four stereoisomers of L-DOPS; 
however, only the L-threo-enantiomer (droxidopa) is biologically active.   
1.2.2 Pharmacology 
Droxidopa is decarboxylated by 3,4-dihydroxyphenylalanine (DOPA) decarboxylase (DDC), and 
is directly converted to NE (see Figure 1). 
Figure 1: Biosynthesis of Norepinephrine from Droxidopa 
 
The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been 
precisely defined; however, its NE replenishing properties with concomitant recovery of decreased 
noradrenergic activity are considered to be of major importance. 
1.2.3 Pre-clinical studies with Droxidopa  
Numerous studies in animal models support central and peripheral mechanisms of action of 
droxidopa. Central nervous system (CNS) studies have shown the ability of droxidopa to increase 
the content of NE and 3-methoxy-4-hydroxy-phenylglycol (MHPG), the main metabolite of NE, 
in the brain of normal animals.  Droxidopa also replenished the levels of NE in the brain of NE-
Tyrosine hydroxylase
Dopamine-β-hydroxylase
DDC
Tyrosine
DOPA
Dopamine
Norepinephrine
Epinephrine
Droxidopa
Tyrosine hydroxylase
Dopamine-β-hydroxylase
DDC
Tyrosine
DOPA
Dopamine
Norepinephrine
Epinephrine
Droxidopa
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depleted animals. These results suggest that droxidopa acts as a NE precursor in the CNS.  
Droxidopa also increases the release of NE from nerve endings in experiments using brain 
synaptosomes and slices. 
Studies of the peripheral action of droxidopa show that droxidopa increased heart rate (HR) and 
elevated BP.  Inhibitors of DDC and -adrenoceptors blocked this effect, which suggests that these 
changes can be attributed to peripheral conversion of droxidopa to NE rather than a direct action 
of droxidopa itself.  Droxidopa inhibited the fall in BP associated with orthostatic changes, and 
accelerated the recovery from low BP in rats whose sympathetic nerves were chemically 
destroyed.  The efficacy of droxidopa in OH is, therefore, thought to be the result of a 
compensatory increase in the overall BP or a possible improvement in the BP reflex process. 
Further details of preclinical studies with droxidopa are provided in the Package Insert (PI). 
1.2.4 Clinical studies with Droxidopa 
To date, Lundbeck NA, Ltd. (Lundbeck; formerly Chelsea Therapeutics, Inc.) has completed three 
placebo-controlled Phase III studies and two long-term extension Phase III studies with droxidopa 
in patients with NOH.  Lundbeck has also sponsored a fed/fast pharmacokinetic (PK) study with 
healthy volunteers (NOH101), a bioequivalence study in healthy volunteers (NOH104), a 24-hour 
BP monitoring study (NOH305) and a dedicated thorough QTc study (NOH102).   
1.2.5 Efficacy Profile 
To date, Lundbeck has completed three Phase III studies of droxidopa for the treatment of 
symptomatic NOH: 
• A 
multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, 
induction-design study using the OHQ composite score as the prospectively-defined 
primary outcome variable to assess the clinical effect of droxidopa in patients with 
symptomatic NOH and PD, MSA, PAF, DBH Deficiency, or NDAN (Study NOH301)   
• A multi-center, double-blind, randomized, placebo-controlled, parallel-group, withdrawal-
design study using the Orthostatic Hypotension Symptom Assessment  (OHSA) Item 1 
(dizziness) as the prospectively-defined primary outcome variable and the OHQ composite 
score as a post-hoc analysis to assess the clinical effect of droxidopa in patients with 
symptomatic NOH and PD, MSA, PAF, DBH Deficiency, or NDAN and to study 
population PK/Pharmacodynamic parameters (Study NOH302) 
• A multi-center, double-blind, randomized, parallel-group, placebo-controlled study to 
assess the clinical effect of droxidopa in the treatment of symptomatic NOH in patients 
with PD (Study NOH306) 
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Lundbeck has also completed two Phase III, multi-center long-term open-label extension studies 
with droxidopa in patients with symptomatic NOH and PD, MSA, PAF, DBH Deficiency, or 
NDAN (Studies NOH303 and NOH304). 
In addition, numerous other studies have also shown droxidopa to be effective in the improvement 
of OH symptoms in PD patients (Birkmayer et al., 1983, Narabayashi et al., 1987, Yanagisawa et 
al., 1998), and in patients with PD or MSA (Sumitomo Pharmaceuticals Europe Limited CSR 
S10002, 2002).   
The collective data from Lundbeck’s clinical development program (further details of which are 
provided in the PI) demonstrate that treatment with droxidopa results in clinically meaningful 
improvements in the symptoms of NOH, including dizziness/light-headedness, vision, weakness, 
fatigue, trouble concentrating, head/neck discomfort, and their impact on patients’ ability to 
perform daily activities that require standing or walking. Treatment with droxidopa also results in 
significant increases in standing BP in patients with NOH. These increases in BP were generally 
similar when standing compared to when supine.   
Based on the results of Lundbeck’s clinical program, droxidopa was approved in the US in 2014 
for, “the treatment of orthostatic dizziness, light-headedness or the “feeling that you are about to 
black out” in patients with a clinical diagnosis of symptomatic NOH due to Parkinson’s disease, 
multiple system atrophy, pure autonomic failure, non-diabetic autonomic neuropathy, or 
dopamine-β-hydroxylase deficiency.”  However, durable clinical benefits with chronic use beyond 
2 weeks have not been demonstrated.   
1.2.6 Safety Profile 
The collective data from Lundbeck’s clinical development program demonstrate that droxidopa is 
safe and well tolerated in patients with symptomatic NOH associated with primary autonomic 
failure (PD, MSA and PAF), DBH Deficiency, or NDAN.  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.  For further information on the safety of droxidopa, refer to the PI. 
1.3 Study Rationale 
Symptomatic NOH in patients is thought to be a consequence of NE neurotransmission 
dysfunction, leading to low SBP and cerebral hypoperfusion. Therapy with droxidopa results in 
increased levels of NE which leads to improved SBP and cerebral perfusion, thereby reducing the 
signs and symptoms of symptomatic NOH.   
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Droxidopa was approved in the US for the treatment of orthostatic dizziness, light-headedness or 
the “feeling that you are about to black out” in patients with a clinical diagnosis of symptomatic 
NOH due to PD, MSA, PAF, NDAN, or DBH deficiency. Effectiveness was established in short-
term studies.  This long-term study will evaluate the durability of the clinical benefit in patients 
with symptomatic NOH treated with droxidopa in a randomized withdrawal design (time to 
intervention study). 
1.3.1 Selection of Droxidopa Dose and Schedule of Administration 
Single rising doses of droxidopa (100, 300, 600, and 900 milligrams (mg)) have been shown to be 
well tolerated in healthy male Japanese and Caucasian volunteers.  Droxidopa pharmacokinetics 
are roughly linear, but less than dose-proportional, for single doses between 100 and 2000 mg.  
The upper limit of individual doses for this study will not exceed 600 mg TID (1800 mg/day). 
In Japan, the recommended dosing regimen for NOH-associated indications is to administer the 
daily maintenance dose of droxidopa in divided doses three times a day. Pharmacokinetic 
modeling based on Phase I data in healthy volunteers indicate no accumulation of droxidopa with 
multiple doses of 100 mg or 300 mg administered three times per day.  Importantly, the reduced 
fluctuation in droxidopa plasma levels expected with three times a day dosing may help to maintain 
a therapeutic effect in NOH patients throughout the day, by maintaining a threshold NE level for 
beneficial pressor effects.  Maintenance of plasma plateau drug levels is supported by divided daily 
doses, especially for a drug like droxidopa, which has a half-life of approximately 1.5 hours in 
humans.   Increased dosing frequency is also supported by the findings of Kachi et al. (1988), who 
demonstrated decreased muscle sympathetic activity and reoccurrence of OH symptoms in a Shy-
Drager patient 3 hours post-dosing of droxidopa despite concomitant peak NE levels, suggesting 
a shorter duration of action than what might be predicted from plasma NE concentrations.  Lower 
peak plasma concentrations provided by split daily dosing should augment the drug’s safety by 
reducing the incidence of any peak concentration-related side effects.   
Lundbeck has conducted studies of droxidopa in more than 650 patients with pure autonomic 
failure (PAF) associated with symptomatic NOH and demonstrated that individually optimized 
doses from 100 to 600 mg TID are safe and effective for the treatment of symptomatic NOH 
associated dizziness or lightheadedness. 
The present study will utilize an open-label dose titration, during which patients are titrated on 
droxidopa, based on efficacy and tolerability as assessed by OHSA Item #1, BP measurements and 
adverse events (AEs).  The individual visits within the open-label dose titration period do not have 
fixed visit windows.  Investigators should tailor the titration schedule based on individual patients’ 
response to therapy and their own clinical judgment.  Patients should be up-titrated until they reach 
600mg TID or until a safety or tolerability concern prevent further up-titration.  The entire dose-
titration period will last for up to 4 weeks from the date of the initial titration visit (Visit 2a).  The 
initial dose will be 100 mg TID, and increase in 100 mg TID steps to a maximum dose of 600 mg 
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TID.  Once the optimized dose has been identified, patients will then enter a 12-week open-label 
dose treatment period, followed by a 12-week, double-blind, randomized withdrawal period on 
their individualized dose of investigational medicinal product (IMP). Doses are to be timed such 
that the first dose is taken upon waking and then taken approximately every 4 hours thereafter, 
with the final dose taken early enough (late afternoon) to minimize drug effects during night-time 
sleeping hours. 
1.3.2 Selection of Primary Efficacy Endpoint 
Time-to-intervention is the primary endpoint.  Since it is predominantly based on the OHSA Item 
#1 score, it is believed that the time-to-intervention endpoint requires corroboration to ensure that 
worsening OHSA Item #1 scores represent a true event. The criteria below represent a balanced 
approach to identify true events requiring treatment intervention. 
During the Double-Blind Period, eligible patients will be randomized 1:1 to either their stable 
regimen of droxidopa or matching placebo. Patients will be withdrawn from the study if they 
require treatment intervention for their NOH symptoms, defined by meeting ANY of the following 
criteria:   
1. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) AND lack of efficacy as 
judged by the Investigator; OR 
2. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) at 2 consecutive 
visits;OR 
3. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) at the visit before early 
discontinuation; OR 
4. Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
Time-to-intervention measures clinically relevant deterioration of the patient’s NOH symptoms. 
Importantly, patients are not required to remain on ineffective treatment. Patients will be 
withdrawn from the study if treatment fails.  
The criteria for treatment intervention are predominantly based on the OHSA Item #1 score. This 
instrument has both strengths and limitations. One limitation is that it is has high variability. 
Conditions such as poor hydration and diarrhea can cause worsening of OHSA Item #1 scores 
independent of treatment effects. Therefore, the time-to-intervention endpoint requires 
corroboration to ensure that worsening OHSA Item #1 scores represents a true event. Investigator 
judgment is one way, but not the only way, to corroborate worsening of dizziness symptoms. Thus:  
• If a patient has worsening OHSA Item #1 at any one visit and the investigator agrees that 
the worsening condition represents a treatment failure, then the patient is considered a 
treatment failure. If, however, the investigator does not consider the worsening OHSA 
Item #1 score at any one visit to be a true treatment failure, then the patient will continue 
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in the study. This gives the investigator the opportunity to ensure that non-pharmacologic 
care is optimized and any other medical conditions are treated appropriately.  
• If the patient continues to have worsening OHSA Item #1 at the second consecutive clinic 
visit, then the patient is considered a treatment failure. This criterion is independent of 
investigator judgment.  
• If the patient fails to return to the clinic after a visit with a worsened OHSA Item #1 
score, the patient is considered a treatment failure by definition. This criterion is 
independent of investigator judgment.  
• Also, a patient who stops study drug or withdraws from the study for patient-reported 
loss of efficacy is also a treatment failure. This criterion is also independent of 
investigator judgment.  
Altogether, these criteria represent a balanced approach in an attempt to identify true events of 
treatment failure. 
2. STUDY OBJECTIVES 
The study is designed to evaluate the clinical efficacy and safety of droxidopa versus placebo over 
a 12-week double-blind treatment period in patients with symptomatic NOH who have previously 
received up to 16 weeks of open-label treatment with an individually optimized dose of droxidopa 
(randomized withdrawal design).  
• Primary objective: 
o To evaluate the time to treatment intervention in patients with PD, MSA, PAF, 
NDAN or DBH Deficiency who have been previously stabilized with droxidopa 
therapy for symptoms of NOH (dizziness, light-headedness, or feeling that they are 
about to black out) 
 
• Secondary objectives:  
o To evaluate the long-term efficacy of droxidopa in patients with symptomatic NOH 
measured by 
▪ Discontinuation for any reason (all cause discontinuation) 
▪ Composite OHQ scores 
▪ Clinicians’ and patients’ clinical global impression of severity (CGI-S) 
▪ To evaluate the long-term safety and tolerability of droxidopa in patients 
with symptomatic NOH. 
3. STUDY METHODS 
3.1 Study Design 
This is a multi-site, placebo-controlled, double-blind, randomized withdrawal, time to intervention 
study with a duration of up to 36 weeks, consisting of 5 periods  
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• Screening period: up to 4 weeks duration 
• Open-Label Titration Period (Titration Period): up to 4 weeks duration 
• Open-Label Treatment Period (Open-Label Period): 12 weeks duration 
• Double-Blind Treatment Period (Double-Blind Period): 12 weeks duration 
• Safety Follow-Up Period: 4 weeks duration 
3.2 Sites 
The study will be conducted in approximately 125 study sites in the United States. 
3.3 Number of Patients and Assignment of Treatment Groups 
A sufficient number of patients will be screened to allow 240 patients to be randomized into the 
double-blind period (120 patients per treatment group).   
 
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 Figure 2: Study Design 
 
 
 
 
 
 
 
 
 
 
 
Note: Patients are anticipated to have up to 6 titration visits; the exact number of Titration Visits for a given patient will depend upon the 
number of Titration Visits required to reach their optimal dose. 
Double-Blind Period is 3 months in duration.  Week 0 of the Double-Blind Period begins with Randomization.  Visits in the Double-Blind 
Period will occur at Weeks 2, 4, 6, 8, 10, and 12. 
≤4 weeks 
500mg 
600mg 
200mg 
Optimal 
Dose 
Droxidopa 
OPEN-LABEL DOSE TITRATION 
V12 
V3 
V2b, 2c, 2d, 2e, 2f  
(Titration) 
≤4 weeks 
1 Month 
400mg 
Safety  
Follow-Up 
V1 
300mg 
DOUBLE BLIND TREATMENT 
OPEN-LABEL TREATMENT 
Month 1 
Month 2 
V5     
  Droxidopa 
Droxidopa 
Placebo 
V8     V9     V10    V11    
V4     
3 months 
V7     
 
6 
4 
2 
0 
8 
10 
12 
Weeks of Double-Blind Treatment 
V6 
100mg 
Randomization 
Month 3 
SCREENING 
V2a 
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3.4 Study Population 
Adult patients with symptomatic NOH associated with primary autonomic failure [Parkinson’s 
Disease (PD), Multiple System Atrophy (MSA) or Pure Autonomic Failure (PAF)] or Non-
Diabetic Autonomic Neuropathy (NDAN) or Dopamine Beta Hydroxylase (DBH) deficiency. 
3.4.1 Inclusion Criteria (All Patients) 
1. 18 years or older and able to stand (with or without limited assistance) 
2. Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary 
Autonomic Failure (PD, MSA or PAF) or NDAN or DBH Deficiency 
3. Score of at least 4 or greater on Orthostatic Hypotension Symptom Assessment (OHSA) 
Item #1 (measured at Screening [Visit 1] and the first Titration Visit [Visit 2a] prior to 
dosing) 
4. A documented drop of at least 20 mmHg in SBP, within 3 minutes of standing.  This can 
either be documented in the patient history or assessed during Screening prior to the first 
Titration Visit (Visit 2a) 
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 
3.4.1.1 
Patients who are taking prescribed droxidopa therapy 
Patients who are currently taking prescribed droxidopa therapy are eligible to participate in the 
study if they meet the other inclusion criteria (1-5 above) and also have been on a stable dose of 
prescribed droxidopa for at least 2 weeks prior to the Screening Visit (Visit 1).  In addition, they 
must meet either of the following at the Screening Visit (Visit 1):  
6. The patient’s Visit 1 OHSA Item #1 score is ≥ 7 AND the prescribed dose is ≤ 300 mg 
three times daily (TID); OR 
7. The patient’s Visit 1 OHSA Item #1 score is ≤6 AND worsens by ≥ 2 units when retested 
after washing out of droxidopa for at least 3 days 
These patients will be required to wash out of their current droxidopa treatment regimen for at 
least 3 days and will be required to go through the same titration procedures as all other patients 
in the study (see Section 3.5.1.1). 
3.4.2 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 (DSM-5 
criteria) 
3. Women who are pregnant or breastfeeding 
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4. Women of childbearing potential (WOCP) who are not using at least one method of 
contraception with their partner 
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 
(short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this 
study)  
8. Any significant uncontrolled cardiac arrhythmia 
9. History of myocardial infarction or stroke within the past 2 years  
10. Current unstable angina 
11. Congestive heart failure (NYHA Class 3 or 4) 
12. Diabetic autonomic neuropathy 
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 (Visit 2a) 
16. Currently receiving any investigational drug or have received an investigational drug 
within 28 days prior to the first Titration Visit (Visit 2a) 
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 discretion 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. In the Investigator’s opinion, the patient has increased risk of intracranial hemorrhage.  For 
example: history of brain aneurysm or current use of anticoagulants in the drug classes of 
Coumarins, Factor Xa Inhibitors, and Direct Thrombin Inhibitors (see Prohibited 
Medications section 4.8.3) 
3.4.3 End of Titration Criteria 
At the end of the Titration Period (Visit 3), patients must have an Acute Dizziness score that is ≥ 
2 units lower (improved) than the Visit 2a OHSA Item #1 score.  Patients who do not meet this 
criterion will be withdrawn from the study. 
 
 
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3.4.4 Randomization Criterion 
At the end of the Open-Label Period (Visit 6), patients must have an OHSA Item #1 score that is 
≥ 2 units lower (improved) than the Visit 2a score.  Patients who do not meet this criterion will be 
withdrawn from the study. 
3.4.5 Treatment Intervention Criteria (Double-Blind Treatment Period) 
At each visit during the Double-Blind Period (Visits 7-12), patients will be evaluated for the 
following criteria: 
1. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) AND lack of efficacy as 
judged by the Investigator; OR 
2. OHSA Item #1 ≥ 2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; 
OR 
3. OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early 
discontinuation; OR 
4. Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
If a patient meets any of these criteria for treatment intervention during the Double-Blind Period, 
the patient will be withdrawn from the study. 
3.5 Study Visit and Assessment Schedule 
All study visits are to be conducted as out-patient visits. Titration Period visits 2b-2f and the Safety 
Follow-Up Visit (Visit 13) may be conducted via telephone or video link.  Double-Blind Period 
visits 7, 9, and 11 will be conducted via telephone or video link.  Written informed consent must 
be obtained before any study-specific procedures are undertaken. 
3.5.1 Screening (Visit 1) 
Screening assessments are to be conducted within 28 days of the patient’s initial Titration Visit 
(Visit 2a) to allow the Investigator sufficient time to review laboratory results and determine if the 
patient is eligible for study participation.   
The Investigator, or qualified designee, will conduct the following procedures at the visit and 
record the data in the eCRF provided: 
• Conduct of informed consent procedures  
• Assignment of patient identification number 
• Review of inclusion and exclusion criteria 
• Demography 
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• Medical history 
• Review of concomitant medications 
• Review of AEs  
• Physical examination 
• Vital signs (seated BP, HR, respiratory rate (RR), temperature), weight and height 
• Orthostatic Standing Test (required only if OH is not documented in medical history) 
• Pregnancy test for WOCP 
• 12-lead electrocardiogram (ECG) recording 
• Clinical Symptoms: OHQ 
• Blood samples for hematology and biochemistry 
• Urine sample for urinalysis  
Screening laboratory test results and ECG reports must be reviewed and assessed by the 
Investigator or designee prior to the initial Titration Visit (Visit 2a). 
3.5.1.1 
Patients who are taking prescribed droxidopa therapy 
Patients who are taking prescribed droxidopa therapy are eligible to participate in the study if they 
meet the additional inclusion criteria for this patient subgroup (see Section 3.4.1.1) in addition to 
all other inclusion / exclusion criteria. Discontinuation of prescribed droxidopa should not occur 
prior to signing the informed consent. It is permitted, based on the Investigator’s judgment, for 
patients to continue their prescribed droxidopa therapy while eligibility is being assessed in the 
screening period. However, it is required that patients discontinue droxidopa for at least 3 days 
before entering the Open Label Dose Titration Period at Visit 2a.  
Eligible patients will begin the Titration Period at 100 mg TID. Study procedures will be the 
same as patients who have not previously been prescribed droxidopa. 
3.5.1.2 
Re-Screening of patients 
Patients who Screen Fail may be re-screened at a later date if, in the Investigator’s opinion, 
circumstances have changed such that the patient may now be an appropriate candidate for the 
study.  Approval by the Lundbeck Medical Monitor must be obtained for a patient to be re-
screened. A patient will only be allowed to be re-screened once. 
At the time of re-screening, the patient must sign a new Informed Consent Form (ICF) and will 
be assigned a new screening number. A re-screened patient must complete a full new Screening 
Visit (Visit 1), and all eligibility criteria must be re-assessed when re-screened. 
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The following information will also be recorded in the eCRF at the time of re-screening: 
• That the patient has previously been screened for the study 
• That re-screening has been authorized by the Lundbeck Medical Monitor 
• The screening number that was assigned to the patient at the previous screening visit 
For a re-screened patient, none of the data from the original Screening Visit, where the patient 
failed to enter the study, will be used in the statistical analysis. 
3.5.2 Open-Label Dose Titration (Visits 2a-2f) 
It is anticipated that patients will have up to 6 visits during the Titration Period (Visits 2a-2f); some 
patients may have as few as 2 visits.  It is possible that a patient may have more than 6 visits during 
the Titration Period in order to properly ascertain their optimal dose of IMP. In these cases, 
subsequent visits would be considered as 2g, 2h, etc., and would be entered as Unscheduled visits 
in the eCRF. All open-label dose titration visits (except for Visit 2a) may be completed on site or 
via phone or video link. 
Visits within the Titration Period do not have fixed visit windows, although there should be a 
minimum of 1 day between each Titration Visit.  Patients should be titrated up until they reach 
600mg TID or until they reach one of the Titration stopping criteria (see Section 3.5.2.3).  Increases 
in dose must be at least 1 day apart.  The entire dose-titration schedule is to be completed, and the 
patient’s optimal dose reached, within the 4-week titration period, which begins with the initial 
Titration Visit (Visit 2a).  At the end of the Titration Period, patients will proceed to Visit 3 where 
their End of Titration criteria will be assessed (see Section 3.5.3.1).  If these criteria are met, they 
will proceed into the Open-Label Period. 
Dose titration will begin with an initial dose of 100 mg TID open-label droxidopa and will not 
exceed 600 mg TID. All doses of IMP during the open-label dose titration period will be 
administered using 100 mg and 200 mg capsule strengths of droxidopa (no 300 mg capsules will 
be used during the Titration Period).   Bottles of open-label IMP must be dispensed through the 
Interactive Web Response System (IWRS).  Patients are to be given IMP only from bottles 
dispensed specifically for them through the IWRS. 
3.5.2.1 
Initial Open-Label Dose Titration Visit (Visit 2a) 
The Investigator, or other qualified designee, will conduct the following procedures at the first 
dose titration visit (Visit 2a) and record the data in the eCRF provided: 
• Clinical Symptoms: OHQ (prior to initiating dosing) 
• Clinician- and Patient-recorded CGI-S (prior to initiating dosing) 
• Review of inclusion and exclusion criteria (prior to initiating dosing) 
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• Vital signs (seated BP, HR, RR, temperature) and weight (prior to initiating dosing) 
• Review of concomitant medications 
• Review of AEs  
• Use IWRS to dispense IMP for entire titration period 
• Administer 100 mg dose of droxidopa and record time of administration  
• Assessment of supine BP 3 hours (+/- 30 minutes) post-dose (as per section 3.6.1.1.1) 
• Schedule the next visit and instruct patient on appropriate dosing schedule until the next 
visit 
If the patient is found to be experiencing supine systolic blood pressure (SBP) greater than or 
equal to 180 mmHg or diastolic blood pressure (DBP) greater than or equal to 110 mmHg, 
when assessed ~3 hours after their initial dose of IMP, they will be withdrawn from the study. 
3.5.2.2 
Subsequent Open-Label Dose Titration (Visits 2b, 2c, 2d, 2e, 2f) 
At each subsequent Titration Visit, it is anticipated that the patient’s dose will be increased by 100 
mg higher than the previously evaluated dose (up to a maximum of 600 mg TID).  However, at the 
Investigator’s discretion the patient’s current dose may be maintained or reduced by 100 mg TID.  
The patient’s first dose of IMP on the day of a Titration Visit should be administered in the clinic, 
regardless of the time of day for which the visit is scheduled. Visits 2b-2f may be completed on 
site or via phone or video link. 
The Investigator, other qualified designee, will conduct the following procedures at each dose 
titration visit and record the data in the eCRF provided: 
• Seated BP (prior to dosing) 
• Time and dose of droxidopa taken on the day of the visit 
• Review of concomitant medications 
• Review of AEs  
• Assessment of supine BP 3 hours (+/- 30 minutes) post-dose (as per section 3.6.1.1.1) 
• Dose Titration Evaluation 
• Schedule the next visit and instruct patient on appropriate dosing schedule until the next 
visit   
If the visit is done via phone or video link, the patient (or their caregiver) will record the seated 
BP, time and dose of droxidopa and supine BP and report this information to the Investigator or 
qualified designee during the call, who will record this data in the eCRF provided. 
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If at any time during the study and / or the titration period a patient experiences sustained 
hypertension or if a patient becomes symptomatic for hypertension, the patient should be advised 
to immediately seek emergency medical attention and contact the investigator. 
3.5.2.3 
Titration Period Stopping Criteria 
Patients will be titrated upwards until either one of the following stopping criteria is met: 
1. The patient experiences supine SBP greater than or equal to 180 mmHg or DBP greater 
than or equal to 110 mmHg, when assessed ~3 hours after their initial dose of IMP; 
2. The patient is unable to tolerate side effects considered by the Investigator to be related to 
the IMP. 
If the initial supine BP measurement ~3 hours post-dose yields values greater than or equal to 180 
mmHg SBP or 110 mmHg DBP, two additional supine measurements should be conducted which 
are at least 10 minutes apart and for each of which the patient has been supine for at least 5 minutes 
(see Section 3.6.1.1.1).  If the average of these 3 supine measurements are either ≥180 mmHg 
systolic or ≥110 mmHg diastolic, the patient will be considered to have met stopping criterion #1.  
A patient’s optimal dose is defined as the highest dose at which they did not meet either of the 
titration stopping criteria.  If a patient does not meet either of the stopping criteria at 600 mg, this 
will be considered their optimal dose.   
Once the patient’s optimal dose has been established, the patient should be scheduled to return to 
the clinic for Visit 3 and instructed to continue taking their optimal dose until Visit 3.  This optimal 
dose will also be the dose assigned to the patient at the beginning of the Open-Label Period (Visit 
3). 
3.5.3 Open-Label Treatment Period (Visits 3-6) 
The windows for Visits 4-6 are anchored from the Visit 3 date, which is considered Day 0 of Open-
Label Treatment.  If the patient is required to return for a re-evaluation of the Open-Label entry 
criteria (see Section 3.5.3.1), the date of the re-evaluation will be considered Day 0 of Open-Label 
Treatment. 
3.5.3.1 
End of Titration / Initial Open-label Treatment Visit (Visit 3; Day 0) 
At Visit 3, in order to successfully complete the Titration Period and enter the Open-Label 
Period, patients must demonstrate an Acute Dizziness score ≥ 2 units lower (improved) than the 
Visit 2a OHSA Item #1 score. 
If a patient does not meet this criterion at Visit 3, they may, at the Investigator’s discretion, 
continue to take their assigned dose of droxidopa and then return to the clinic for a second 
evaluation of their Acute Dizziness score within 7 days (and within 28 days of Visit 2a).  This re-
evaluation would be recorded as an Unscheduled Visit.   
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If the patient is found to meet this criterion at either Visit 3 or the repeat assessment, they may be 
enrolled into the Open-Label Period of the study as outlined below.  If the patient fails to meet this 
criterion at both Visit 3 and the repeat evaluation, they are to be withdrawn from the study, and 
Early Termination procedures (see Section 3.5.7) should be conducted. 
The patient is to take their first dose at Visit 3 from the IMP dispensed for the Titration Period.  If 
the patient is required to return for a re-evaluation of the Open-Label entry criteria, they are to 
continue to take their assigned dose of droxidopa from the IMP dispensed for the Titration Period.  
Once a patient has been determined eligible to enter the Open-Label Period, the Investigator, or 
designee, will use the IWRS to dispense IMP for the Open-Label Period. 
The Investigator, or qualified designee, will conduct the following procedures at the visit and 
record the data in the eCRF provided: 
• Review of inclusion and exclusion criteria (prior to initiating dosing) 
• Vital signs (seated BP, HR, RR, temperature) and weight (prior to initiating dosing) 
• Clinician- and Patient-recorded CGI-S (prior to initiating dosing) 
• IMP return and capsule count/compliance check from Titration period 
• Record the time and dose of IMP taken on the day of the visit 
• Review of AEs  
• Review of concomitant medication 
• Clinical Symptoms: Acute Dizziness 2 hours (+/- 15 minutes post-dose) 
• Seated BP 2 hours (+/- 15 minutes post-dose) 
• Record optimal dose as determined during titration period 
• Use IWRS to dispense IMP, as required for next visit  
• Schedule the next visit and instruct patient on appropriate dosing schedule until next visit 
3.5.3.2 
Open-Label Treatment Period (Visits 4 & 5; Day 28 [+/- 7days] & Day 56 [+/ 
7days]) 
During the first 8 weeks of open-label treatment, the dose of droxidopa may be increased or 
decreased (by 100 mg TID increments) a maximum of four times at the Investigator’s discretion. 
The dose should remain stable between visits 5 and 6; no dose changes are allowed after Visit 5. 
The Investigator, or qualified designee, will conduct the following procedures at each visit and 
record the data in the eCRF provided: 
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• IMP return and capsule count/compliance check 
• Clinical Symptoms: OHQ  
• Clinician- and Patient-recorded CGI-S  
• Vital signs (supine BP, HR, RR, temperature) and weight 
• Review of AEs  
• Review of concomitant medication 
• Record the time and dose of IMP taken on the day of the visit 
• Use IWRS to dispense IMP, as required for next visit  
• Schedule the next visit and instruct patient on appropriate dosing schedule until next visit 
3.5.3.3 
End of Open-label Treatment Period / Randomization (Visit 6; Day 84 [+/- 7 
days]) 
The Investigator, or qualified designee, will conduct the following procedures and record the data 
in the eCRF provided: 
• Clinical Symptoms: OHQ (prior to first randomized dose)  
• Review of inclusion and exclusion criteria (prior to first randomized dose) 
• Clinician- and Patient-recorded CGI-S (prior to first randomized dose) 
• Vital signs (supine BP, HR, RR, temperature) and weight (prior to first randomized dose) 
• Pregnancy test for WOCP (prior to first randomized dose) 
• IMP return and capsule count/compliance check 
• Review of AEs  
• Review of concomitant medication 
• Blood samples for hematology and biochemistry 
• Urine sample for urinalysis  
• Randomize patient through the IWRS 
• Use IWRS to dispense IMP  
• Record the time and dose of IMP taken on the day of the visit 
• Schedule the next visit and instruct patient on appropriate dosing schedule until next visit 
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If a patient has a score on OHSA Item # 1 that is not ≥ 2 units lower than their Baseline Score (at 
Visit 2a), they will not be eligible to continue into the Double-Blind Period and will be withdrawn 
from the study (see Section 3.4.4).  
If a patient is deemed eligible to continue in the study, the Investigator, or their designee, after the 
completion of all procedures, will use the IWRS to randomize the patient to treatment with 
droxidopa or matching placebo (randomization is double-blind).  The patient’s daily dose will be 
the same as that at the end of the Open-Label Period.  Patients will be dispensed their bottle(s) of 
IMP (droxidopa or matching placebo capsules) and will be counseled on how to take their IMP for 
the rest of that day and also for the duration of their double-blind treatment.   
3.5.4 Double-Blind Study Visits (Visits 7-11) 
No dose changes of IMP are permitted during the Double-Blind Period. 
Visits 7, 9 and 11 will be completed via phone or video link; Visits 8 and 10 will be completed in-
clinic. 
The schedule for the visits in the Double-Blind portion of the study will be as follows (all visit 
windows are anchored from Visit 6, which is considered to be Day 0 of Randomization): 
• Visit 7: Day 14 (+/- 3 days) – via phone or video link   
• Visit 8: Day 28 (+/- 3 days) – clinic visit 
• Visit 9: Day 42 (+/- 3 days) – via phone or video link   
• Visit 10:  Day 56 (+/- 3 days) – clinic visit 
• Visit 11:  Day 70 (+/- 3 days) – via phone or video link   
3.5.4.1 
Telephone / Video Link Double-Blind Study Visits (Visits 7, 9 & 11) 
During the visits conducted via phone or video link during this period (Visits 7, 9 and 11), the 
patient or caregiver will record and report the information to the Investigator or qualified designee 
during the call or videoconference, who will record this data in the eCRF provided: 
• Record the time and dose of IMP taken on the day of the visit 
• Supine BP 
During the call, the Investigator or qualified designee will conduct the following procedures and 
record the data in the eCRF provided: 
• Review of AEs  
• Review of concomitant medication 
• Clinical Symptoms: OHQ  
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• Clinician- and Patient-recorded CGI-S  
• Review “Need For Intervention” Criteria: 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of 
efficacy as judged by the Investigator; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive 
visits; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before 
early discontinuation; OR 
o Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
• Schedule the next visit and instruct patient on appropriate dosing schedule until next visit 
If a patient meets the criteria to be withdrawn due to a need for intervention during a phone / video 
link visit (Visits 7, 9 or 11), the patient should be brought in for an Early Termination Visit (see 
Section 3.5.7) as soon as possible.   
3.5.4.2 
On-Site Double-Blind Study Visits (Visits 8 & 10) 
During the on-site visits during this period (Visits 8 and 10), the Investigator or other qualified 
designee, will conduct the following procedures at each dose titration visit and record the data in 
the eCRF provided: 
• Record the time and dose of droxidopa taken on the day of the visit 
• Review of AEs  
• Review of concomitant medication 
• Vital signs (supine BP, HR, RR, temperature) and weight  
• Clinical Symptoms: OHQ  
• Clinician- and Patient-recorded CGI-S  
• Review “Need For Intervention” Criteria: 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of 
efficacy as judged by the Investigator; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive 
visits; OR 
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o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before 
early discontinuation; OR 
o Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
• IMP return and capsule count/compliance check 
• Use IWRS to dispense IMP 
• Schedule the next visit and instruct patient on appropriate dosing schedule until next visit 
If a patient meets the criteria to be withdrawn due to a need for intervention while on-site at Visits 
8 or 10, the Early Termination procedures should be completed during the visit as outlined in 
Section 3.5.7 below.    
3.5.5 End of Treatment Visit (Visit 12; Day 84 [+/- 3 days] post Randomization) 
Patients will return to the site for an End of Treatment (completion of Double-Blind Period) visit 
(Visit 12).   
The Investigator, or qualified designee, will conduct the following procedures at each visit and 
record the data in the eCRF provided: 
• Record the time and dose of IMP taken on the day of the visit 
• Review of AEs  
• Review of concomitant medication 
• Clinical Symptoms: OHQ  
• Clinician- and Patient-recorded CGI-S  
• Review “Need For Intervention” Criteria: 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of 
efficacy as judged by the Investigator; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive 
visits; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before 
early discontinuation; OR 
o Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
• Physical Exam 
• Vital signs (supine BP, HR, RR) and weight.  
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• Pregnancy test for WOCP 
• Blood samples for hematology and biochemistry  
• Urine sample for urinalysis  
• IMP return and capsule count/compliance check 
• Schedule Follow-Up Visit (Visit 13) 
If a patient meets the criteria for a need for intervention at this visit, the patient is to be considered 
withdrawn due to a need for intervention, and their disposition recorded as such.  The Early 
Termination procedures should then be completed during the visit as outlined in Section 3.5.7 
below. 
3.5.6 Safety Follow-Up Visit (Visit 13) 
Sites will contact the patient 30 days (+5 days) after their final visit (Visit 12 or Early Termination 
Visit) to record any new AEs and follow-up on any AEs that were ongoing at the end of their 
previous visit.  This visit is to be conducted for all patients who have taken at least one dose of 
IMP; this visit is not required for patients who screen fail. 
The follow-up visit may be conducted via phone or video link.  In the event that the patient is 
unreachable, all reasonable efforts should be made and documented before considering the patient 
as unable to be contacted. 
3.5.7 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, including during the double-blind treatment period due to 
a need for intervention, the patient will be requested to return for an Early Termination 
Visit.  
If a decision is made to withdraw the patient from the study while on site due to: 
• a failure to meet criteria to enter the Open-Label Period at Visit 3 
• a failure to meet criteria to enter the Double-Blind Period at Visit 6 
• a need for intervention while on-site at Visits 8 or 10, OR 
• for any other reason 
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 
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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 
in the eCRF provided: 
• 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 
• Clinical Symptoms: OHQ  
• Clinician- and Patient-recorded CGI-S  
• Review “Need For Intervention” Criteria: 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of 
efficacy as judged by the Investigator; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive 
visits; OR 
o OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before 
early discontinuation; OR 
o Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
• Physical Exam 
• Vital signs (supine BP, HR, RR) and weight.  
• Pregnancy test for WOCP 
• Blood samples for hematology and biochemistry  
• Urine sample for urinalysis  
• IMP return and capsule count/compliance check 
• Schedule Follow-Up Visit (Visit 13) 
All patients who discontinue participation in the study are to have a Safety Follow-Up Visit 
(Visit 13) conducted 30 days (+5 days) after their final dose of IMP (see Section 3.5.6). 
 
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3.5.8 Unscheduled Visit 
A patient may return for an unscheduled visit at any time at the Investigator’s discretion.  The 
procedures conducted at the unscheduled visit may be limited, depending on the reason for the 
visit (for example, unscheduled visits for a repeat blood or urine sample, or for dispensing of 
new IMP to replace a lost bottle of IMP would only require those specific procedures relevant to 
the reason for the unscheduled visit to be done).  If an Unscheduled Visit is conducted between 
Visits 3-5 of the Open-Label Period for the purpose of modifying a patient’s dose of IMP, all 
procedures to be conducted during an Open-Label Treatment Visit (see Section 3.5.3.2) should 
be conducted. 
3.5.9 Guidance regarding Covid-19 
The protocol has always allowed the option of conducting Titration Visits 2b-2x remotely, via 
telephone or video chat.  In addition, Visits 7, 9 and 11 are required to be conducted remotely, as 
per the protocol.   
 
Due to the COVID-19 situation that developed in 2020, guidance was issued to all trial sites to 
temporarily allow all other study visits (except for Visits 1 and 2a) to be conducted remotely.  
This was done in the interest of patient safety as well to allow compliance with local and site 
regulations and guidance regarding COVID-19.  This guidance also included procedures to allow 
IMP to be sent to patients via courier, if required, and allowed for Visit 6 and 12 lab samples to 
be collected at a later date if such visits could not be conducted on site.  This guidance was 
placed into effect on 17 March 2020 and, as of the date of this version of the protocol, is still in 
effect.  This guidance may be rescinded by Lundbeck at any time in the future, once it is 
determined to be no longer needed. 
3.6 Study Procedures and Assessments 
Table 1 summarizes the procedures and assessments conducted during this study. 
 
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Table 1: Study Schedule/Flowchart 
Study procedures 
 
Screening 
First 
Titration 
Visit 
Dose 
Titration 
Open-Label Treatment  End of Open-Label 
Treatment 
(Randomization) 
Double-Blind 
Treatment  
End of 
Treatment 
Safety 
Follow-Up 
Visit 1 
Visit 2a 
Visits 
2b...2f (f,g) 
Visit 3 
Visits 4-5 
Visit 6 
Visits 7-11(h) 
Visit 12 or 
Early 
Termination 
Visit 13 
Written informed consent 
✓ 
 
 
 
 
 
 
 
 
Review inclusion and exclusion criteria 
✓ 
✓ 
 
✓ 
 
✓ 
 
 
 
Demography 
✓ 
 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
 
Concomitant medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse events (continuous monitoring) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination 
✓ 
 
 
 
 
 
 
✓ 
 
Vital signs (BP, HR, RR, temp.) and weight 
✓(a, c) 
✓ (a) 
 
✓ (a) 
✓ (b) 
✓ (b) 
✓ (b, i) 
✓ (b) 
 
Orthostatic Standing Test 
✓ (d) 
 
 
 
 
 
 
 
 
Seated, pre-dose BP 
 
 
✓ 
 
 
 
 
 
 
Supine BP 
 
 
 
 
 
 
✓ (j) 
 
 
Supine, post-dose BP assessment 
 
✓ 
✓ 
 
 
 
 
 
 
Seated, post-dose BP assessment 
 
 
 
✓ 
 
 
 
 
 
Pregnancy test for WOCP (e) 
✓ 
 
 
 
 
✓ 
 
✓ 
 
12-lead ECG recording 
✓ 
 
 
 
 
 
 
 
 
Administer first daily dose of IMP on site 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Dose titration evaluation  
 
 
✓ 
 
 
 
 
 
 
Clinical symptoms–OHQ (OHSA & OHDAS) 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
 
Acute dizziness assessment 
 
 
 
✓ 
 
 
 
 
 
Patient-reported CGI-S 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Clinician-reported CGI-S 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Review Need For Intervention criteria 
 
 
 
 
 
 
✓ 
✓ 
 
Blood and urine samples (laboratory safety) 
✓ 
 
 
 
 
✓ 
 
✓ 
 
Randomization 
 
 
 
 
 
✓ 
 
 
 
IMP dispensed, as required 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
 
Capsule count/compliance check 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
IMP returned 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
(a) Seated BP assessed during Vital Signs  
 
 
 
 
 
(b) Supine BP assessed during Vital Signs 
(c)  Height recorded at Screening (V1) only 
 
 
 
 
 
(d) Only required if OH not documented in patient history   
 
(e) Local urine pregnancy test (on site dip-stick test; positive result to be verified by serum pregnancy test)  
(f) Patients anticipated to have up to 6 titration visits 
(g) Titration visits 2b-2f may be completed on site or via phone or video link  
 
 
(h) Double-blind visits 7, 9 & 11, will be completed via phone or video link 
(i) Visits 8 and 10 only   
 
 
 
 
 
 
 
(j) Visits 7, 9 and 11 only 
 
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3.6.1 General Study Procedures and Considerations 
3.6.1.1 
Supine Blood Pressure Assessments 
3.6.1.1.1 
Titration Period 
During the Titration Period, BP assessments are to be performed 3 hours (+/- 30 minutes) after 
dosing at each visit during the open-label titration period (Visits 2a-2f; Sections 3.5.2.1 & 3.5.2.2).  
The initial BP reading should be taken following a 10 minute period of rest in the supine position 
(head and torso elevated at approximately 30 degrees from horizontal).  If the initial 
measurements are greater than or equal to 180 mmHg SBP or 110 mmHg DBP,  two 
additional supine measurements should be conducted which are at least 10 minutes apart and for 
each of which the patient has been supine for at least 5 minutes prior to the reading. 
These measurements will be conducted on site at Visit 2a.  If further titration visits are to be 
conducted via phone or video link, the Investigator will instruct the patient and / or caregiver at 
Visit 2a on how to conduct this BP reading at home and how to report the results during the phone 
call or videoconference. 
3.6.1.1.2 
Open Label Period and Double-Blind Period 
At Visits 4, 5, 6, 8, 10 and 12 (as well as during an Early Termination Visit): A supine BP reading 
will be taken as part of the Vital Signs, and does not need to be at any specified time following 
dosing.  This BP reading should be taken following a 10 minute period of rest in the supine position 
(head and torso elevated at approximately 30 degrees from horizontal).   
At Visits 7, 9 and 11, which are conducted via phone or video link, this supine BP reading will be 
conducted at home by the patient or caregiver.  The Investigator will instruct the patient and / or 
caregiver on how to conduct this BP reading at home and how to report the results during the 
phone call or videoconference. 
3.6.1.2 
Seated Blood Pressure Assessments 
A seated BP assessment is to be performed as part of the Vital Signs at the Screening Visit (Visit 
1), at all Titration Period Visits (Visits 2a-2f) and at Visit 3.  In addition, at Visit 3, a second seated 
BP is to be conducted 2 hours (+/- 15 minutes) post dose (see Section 3.5.3.1).  These BP readings 
should be taken following a 5 minute period of rest with the patient in the seated position in a chair 
(head and torso elevated at approximately 90 degrees from horizontal, feet flat on the floor). 
3.6.1.3 
Orthostatic Standing Test 
An Orthostatic Standing Test (OST) is to be conducted at the Screening Visit (Visit 1) if the patient 
does not have a documented history of OH.  The patient will lie supine for at least 5 minutes (head 
and torso elevated at approximately 30° from horizontal).  BP measurements will be taken 
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immediately prior to having the patient stand up, upon standing (minute 0) and after +3 minutes 
of standing.  If the Investigator considers that a patient cannot, or is unlikely to be able to stand for 
3 minutes, BP measurements should be taken as close to 3 minutes as possible.   
To calculate the decrease in BP, the “immediately prior to standing” SBP measurement is used as 
the baseline. The decrease in SBP is the difference between the baseline measurement and the 
lowest SBP measurement at a time point within 3 minutes of standing (between “minute 0” and 
“minute +3”).  
3.6.1.4 
Alcohol Consumption 
Patients are to be instructed not to drink any alcohol in the 24 hours prior to any study visits, and 
not to exceed a moderate consumption level of alcohol at all other times during the study.  
Moderate consumption is defined as no more than 2 standard drinks per day, with a standard drink 
containing 0.6 ounces of alcohol (e.g., 12 ounces of 5% beer, 6 ounces of 12% wine, or 1.5 ounces 
of 80 proof spirits per day). 
3.6.1.5 
Hydration 
Patients should be well hydrated on entry to the study, and should be encouraged to remain well 
hydrated throughout the study period. 
3.6.2 Efficacy Assessments 
3.6.2.1 
Orthostatic Hypotension Questionnaire (OHQ) 
The OHQ was developed by clinicians who treat disorders of the autonomic nervous system, in 
consultation with a psychometrician and statistician (Kaufmann et al., 2011; 0 et al., 2005).  The 
questionnaire includes specific instructions that are read aloud to the patients before the 
questions are answered, and is administered in two separate sections; a symptom assessment 
scale and a daily activity scale. 
The Orthostatic Hypotension Symptom Assessment (OHSA) scale was designed to rate symptoms 
occurring specifically as a result of low BP, using an 11-point scale (zero to 10), with more severe 
symptoms scoring higher.  A score of zero indicates that the symptom was not experienced.  The 
scale assesses six symptoms: 1) dizziness/lightheadedness, 2) problems with vision, 3) weakness, 
4) fatigue, 5) trouble concentrating, and 6) head/neck discomfort.  Scores for each activity and a 
composite score for all 6 activities are tabulated. 
The Orthostatic Hypotension Daily Activity Scale (OHDAS) was designed as a measure of quality 
of life.  It uses an 11-point scale to assess whether OH “interfered” with 4 types of activities:  1) 
standing for a short time, 2) standing for a long time, 3) walking for a short time, and 4) walking 
for a long time.  A zero rating means that over the preceding week the activity was performed with 
no interference and a 10 rating means that OH completely interfered with the activity.  As many 
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of these patients have difficulty walking or standing for reasons not directly related to their OH 
(e.g., parkinsonism or somatic neuropathy), patients are able to check a box in the questionnaire 
stating that they could not perform the activity for reasons other than OH.  Scores for each activity 
and a composite score for all 4 activities are tabulated. 
The OHQ composite score is a mean of the OHSA composite and the OHDAS composite scores. 
3.6.2.2 
Acute Dizziness Assessment 
At Visit 3, acute dizziness will be assessed by asking the patient to rate (on a scale from 0-10) the 
severity of their symptom of dizziness/lightheadedness/feeling faint/feeling like you might black 
out due to low blood pressure during the past 24 hours.   
3.6.3 Safety Assessments 
3.6.3.1 
Adverse Events 
All adverse events observed by the Investigator, elicited upon a non-leading question (such as 
“how do you feel?”), or reported spontaneously by the patient will be recorded, starting at the 
Screening Visit. The Investigator will assess the seriousness and the intensity of the adverse event 
and its relationship to the IMP. Refer to Section 5 for details on the definition of adverse events 
and the manner in which they are to be recorded and reported. 
3.6.3.2 
Blood Pressure Measurements 
Blood pressure should be taken on the same arm every visit. 
It is a recognized best practice that patients with symptomatic NOH are advised not to lay fully 
supine because of the associated risk of supine hypertension inherent with their condition (patients 
are advised to sleep in a semi-recumbent position).  Accordingly, for the purpose of this study, 
supine BP measurements are not to be conducted in the fully horizontal position, but should be 
done with patients positioned with their head and torso elevated at approximately 30 degrees from 
horizontal (see Section 3.6.1.1). 
Patients will be instructed by the Investigator or qualified designee how to take and report their 
BP for visits that take place via phone or video link (see Sections 3.6.1.1.1 and 3.6.1.1.2). 
If at any time during the study and / or the titration period a patient experiences sustained 
hypertension or if a patient becomes symptomatic for hypertension, the patient should be advised 
to immediately seek emergency medical attention and contact the investigator. 
 
 
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3.6.3.3 
Physical Examination 
A physical examination will be conducted at the screening visit (Visit 1) and at the End of 
Treatment Visit (Visit 12) / Early Termination Visit.  The physician conducting the physical exam 
must state whether or not any abnormal findings are of clinical significance. 
3.6.3.4 
ECG 
A 12-lead ECG will be conducted at the Screening Visit (Visit 1).  The Investigator, or a qualified 
designee, will be responsible for reviewing the results of this assessment, and must evaluate 
whether the results are normal or abnormal; the Investigator must also state whether or not any 
abnormal findings are of clinical significance.  
3.6.3.5 
Vital Signs and Weight 
Vital signs (seated BP, HR, RR, temperature) and weight will be measured at the Screening Visit 
(Visit 1), the first visit of the Titration Period (Visit 2a) and Visit 3.  At Visits 4-12 (and at the 
Early Termination Visit), the vital signs procedure will be modified to include a supine BP 
measurement (see Section 3.6.1.1.2) instead of a seated BP assessment.  Height will be measured 
only at the Screening Visit (Visit 1).  At Visit 3, a second, seated BP assessment will be taken ~2 
hours post-dose (see Section 3.5.3.3). 
3.6.3.6 
Clinical Safety Laboratory Tests 
All analytical tests will be performed by a central laboratory.  Urine pregnancy test will be assessed 
at sites.  Electronic copies of all results will be provided to the Investigator.   
The following laboratory tests will be performed at Screening (Visit 1), End of Open-label 
Treatment / Randomization (Visit 6) and End of Treatment (Visit 12) or Early Termination, as 
well as at any unscheduled visit if deemed appropriate by the Investigator: 
Hematology  
Hemoglobin 
 
 
 
Erythrocyte Count  
Hematocrit 
 
 
 
Total Leucocyte Count 
 
 
 
Neutrophils 
 
 
 
Eosinophils 
 
 
 
Basophils 
 
 
 
Lymphocytes 
 
 
 
Monocytes 
 
 
 
Thrombocyte Count 
 
Clinical Chemistry Total Bilirubin 
Alkaline phosphatase (AP) 
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Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
 
γ-glutamyl transferase (γGT) 
Sodium 
Potassium 
Calcium (Total) 
Bicarbonate 
Chloride 
Albumin 
Glucose 
Creatinine 
Blood Urea Nitrogen (BUN) 
Total Protein  
 
Urinalysis 
 
pH 
 
 
 
Specific Gravity 
Protein 
 
 
 
Glucose 
 
 
 
Ketones 
 
 
 
Blood 
 
 
 
Bilirubin 
Leukocytes  
Nitrites 
 
 
 
Microscopic sediment examination, only if dipstick is abnormal 
Female patients of childbearing potential will have a urine pregnancy test at the Screening Visit 
(Visit 1), End of Open-label Treatment / Randomization Visit (Visit 6) and End of Treatment Visit 
(Visit 12) or Early Termination Visit, as well as at any unscheduled visit if deemed appropriate by 
the Investigator.  The test will be done via an onsite dipstick test.  If the results of the urine test are 
positive, the results will be verified via a serum pregnancy test. 
Patients with a positive result on microscopic urinalysis should be brought back for a urine culture.  
Details of the procedures for blood and urine sample collection, handling and analysis are 
described in the laboratory manual provided by the central lab. 
 
 
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3.7 Study Endpoints 
3.7.1 Efficacy Endpoints 
3.7.1.1 
Primary Efficacy Endpoints 
Time to intervention.   Need for intervention is defined as meeting ANY of the following events 
that occur in the Double-Blind Period: 
• 
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as 
judged by the Investigator; OR 
• 
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; 
OR 
• 
OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early 
discontinuation; OR 
• 
Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
The timing of the need for intervention in the above criteria is defined as the first occurrence of a 
worsening of OHSA item 1 by ≥ 2 units or when the patient stops taking IMP, whichever comes 
first. 
The primary efficacy analysis will include all randomized patients who received at least one dose 
of double-blind IMP (all patients treated set (APTS)) and will be analyzed by the log-Rank test to 
compare treatment on time to intervention during the double-blind period. Patients who withdraw 
without meeting criteria for treatment intervention will be censored at the time of withdrawal; 
patients who do not meet criteria for treatment intervention at the end of the Double-Blind Period 
(Visit 12) will be censored at the time of study completion.    
3.7.1.2 
Secondary Efficacy Endpoints 
Efficacy of droxidopa versus placebo using patient- and clinician-rated endpoints on the APTS: 
• Time to all cause discontinuation  
• Mean change in OHSA item #1 score from Randomization (Visit 6; Week 0 of Double-
blind Period) to all post randomization visits  
• Mean change in OHQ composite score from Randomization (Visit 6; Week 0 of Double-
blind Period) to all post randomization visits  
• Clinician-rated CGI-S at all post randomization visits 
• Patient-rated CGI-S at all post randomization visits 
• Proportion of patients who need intervention over the 12 week double-blind period 
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3.7.2 Safety Endpoints 
Adverse events, vital signs, and clinical safety laboratory assessments will be observed through 
the entire study.  Safety parameters from the open-label portion of the study (Titration Period and 
Open-Label Period) and the Double-Blind Period will be reported separately.  
3.8 Early Termination 
An Early Termination occurs when an enrolled patient ceases participation in the study, regardless 
of the circumstances, prior to completion of the study.  The Investigator must determine the 
primary reason for discontinuation or withdrawal.  Patients withdrawing due to reasons other than 
a need for intervention will be censored at the time of withdrawal.   
Withdrawal due to an AE (see Section 5.1 for the definition of an AE) should correspond to the 
AE recorded on the appropriate eCRF page. 
When a patient is withdrawn due to a serious adverse event (SAE), the SAE must be reported in 
accordance with the reporting requirements defined below (see Section 5.4).  A withdrawal due to 
an SAE must be reported immediately to Lundbeck or the site’s Clinical Research Associate 
(CRA).  The decision to withdraw a patient from treatment for safety reasons may be made by the 
Medical Monitor, Lundbeck, and/or the Investigator.  In the event of discontinuation of treatment 
/ withdrawal from treatment, the Investigator will complete Early Termination procedures for the 
specified patient, as outlined in Section 3.5.7. 
If a subject becomes pregnant during the study, she will be withdrawn from study treatment 
immediately.  The pregnancy must be reported as detailed in Section 5.2. 
The patient may elect to withdraw from the study at any time and for any reason.  If the patient 
wishes to withdraw from treatment, they should return for a final, on-site visit, and the 
procedures outlined for an Early Termination Visit should be completed (see Section 3.5.7).  
Whenever practical, subjects should remain on IMP until the completion of the end of the 
Early Termination Visit. 
3.9 Study Termination 
Premature termination of this clinical study may occur as a result of a regulatory authority decision, 
change in opinion of the institutional review board/independent ethics committee (IRB/IEC), drug 
safety concerns, or at the discretion of Lundbeck.  In addition, Lundbeck retains the right to 
discontinue development of droxidopa at any time. 
The Investigator reserves the right to terminate the study, at his/her participating study site, at any 
time, for any reasons.  Should this be necessary, the procedures will be arranged on an individual 
site basis after review and consultation with Lundbeck.  In terminating the study, Lundbeck, the 
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contract research organization (CRO), and the Investigator will ensure that adequate consideration 
is given to the protection of the patients’ interests. 
4. STUDY TREATMENTS 
4.1 Allocation to Study Treatments 
In the Double-Blind Period, each patient will be randomized to receive study treatment (droxidopa 
or matching placebo; 1:1 ratio) according to a computer generated randomization schedule 
administered through a central IWRS. Neither the Investigator nor the patient will know the 
identity of the treatment that the patient will receive; however, the study will not be blinded with 
respect to (expected) dose.    
All bottles of IMP will be dispensed through the central IWRS. 
4.2 Emergency Blind Breaking 
In the case of an emergency where, in the opinion of the Investigator, discontinuation of IMP is 
not sufficient and the study treatment must be unblinded in order to evaluate a further course of 
action, the Investigator should make every effort to contact the Medical Monitor prior to 
unblinding.  The Investigator requesting the unblinding should be able to confirm that the 
unblinding of the patient is necessary and directly impacts the patient’s immediate medical 
management. 
In the rare event that contact with the Medical Monitor and/or sponsor is not possible prior to 
unblinding, the Investigator reserves the right to unblind a patient in a true medical emergency, 
where patient safety is at immediate risk. All instances of emergency unblinding must be reported 
to the Medical Monitor within 24 hours.  Upon breaking the blind, the patient must be withdrawn 
from the study, but should be followed up for safety purposes. 
The procedures described below will be followed in the event a request for emergency unblinding 
is received. 
The Medical Monitor will discuss the request with the Investigator and record the following 
information: 
• Protocol Number 
• Site Number 
• Patient Number and Initials 
• Reasons for Unblinding 
• Current Interventions 
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The Medical Monitor may contact the sponsor to discuss the request for emergency unblinding.  
The sponsor representative/Study Medical Monitor will follow up with the Investigator to 
communicate the decision regarding the request for unblinding.   
The Investigator will perform the emergency unblinding in accordance with the applicable 
procedure described in the IWRS procedures documentation. 
4.3 IMP Supplies 
IMP will be provided to the study site as open-label 100- and 200-mg capsules for the Titration 
Period, as open-label 100- 200-, and 300 mg capsules for the Open-Label Period, and as double-
blind 100-, 200-, and 300-mg capsules and matching placebo for the Double-Blind Period.  IMP 
is to be stored at room temperature (20°C-25°C).   
Patients must bring their IMP (including empty bottles) with them to each study visit, and must 
return all unfinished IMP to the Investigator at the end of each study period.  Inventory control of 
all IMP must be rigorously maintained throughout the duration of the study until final 
accountability procedures have been performed by the CRA, at which time the IMP may be 
destroyed on-site or returned to Lundbeck or the sponsor’s designee (see Section 4.6).  Any 
discrepancies noted between Drug Dispensing Records and the drug inventory must be reported to 
the sponsor. 
4.4 Manufacturing, Formulation, Packaging and Labeling of IMP 
4.4.1 Formulation Details 
Each active IMP capsule will contain 100 mg, 200 mg, or 300 mg droxidopa. 
Matching placebo capsules will contain the same ingredients as the active IMP capsules, except 
that droxidopa will be replaced by an equivalent quantity of mannitol. 
4.4.2 Manufacturing, Packaging and Labeling Details 
All IMP will be manufactured and packaged by Patheon, and will be labeled by Almac, and will 
be distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of Lundbeck.  Patheon will provide sufficient test formulations and the respective 
certificates of analysis, and will keep reference samples of the medication.   
IMP for the Titration, Open-Label and Double-Blind periods will be packaged and labeled to 
clearly identify the dose of the IMP.  All double-blind IMP will be packaged and labeled according 
to a randomization schedule generated by the Lundbeck BioStatistics department or their designee.  
For the IMP provided for the Double-Blind Period, the labels will be blinded with respect to 
treatment identity (but not dose) and will contain at least the following information (where 
required): 
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• Patient identification number/space for inserting  patient’s initials 
• Protocol number 
• Bottle number 
• Space for inserting Investigator name and phone number 
• Number of capsules in container 
• Capsule strength 
• Directions for use 
• Lot number 
• Expiration date of capsules 
• Denotation that the medication is “FOR CLINICAL TRIAL USE ONLY” 
• Denotation to “Keep out of the reach of children” 
• Storage conditions 
• Space for inserting dispensing date 
• Name of capsule manufacturer 
IMP for the Titration and Open-Label periods will be labeled in the same manner, with the 
exception of being unblinded with respect to treatment identity (all IMP used during the Titration 
and Open-Label periods will be active droxidopa). 
The wording on the labels will be in accordance with Good Manufacturing Practice (GMP) 
regarding labelling and national and/or local regulatory requirements. 
4.5 Preparation, Administration and Dosing of Investigational Medicinal Product 
4.5.1 Preparation 
Droxidopa 100 mg capsules will be presented as hard, gelatin capsules (size: No. 3) with an opaque 
light blue cap and an opaque white body.  Capsules will be imprinted with “Northera” and “100” 
for additional distinction of doses. 
Droxidopa 200 mg capsules will be presented as hard, gelatin capsules (size: No. 2) with an opaque 
light yellow cap and an opaque white body.  Capsules will be imprinted with “Northera” and “200” 
for additional distinction of doses. 
Droxidopa 300 mg capsules will be presented as hard, gelatin capsules (size: No. 1) with an opaque 
green cap and an opaque white body.  Capsules will be imprinted with “Northera” and “300” for 
additional distinction of doses. 
Placebo capsules will be identical in appearance to the droxidopa 100 mg, 200 mg, and 300 mg 
capsules. 
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The capsules for the Titration and Open-Label periods will be packaged in child-resistant high-
density polyethylene (HDPE) bottles, each containing 90 capsules of either 100 mg or 200 mg 
droxidopa (Titration Period), or 100 mg, 200 mg, or 300 mg droxidopa (Open-Label Period). The 
capsules for the Double-Blind Period will also be packaged in child-resistant high-density 
polyethylene (HDPE) bottles, each containing 90 capsules of either 100 mg, 200 mg, or 300 mg 
droxidopa or matching placebo. IMP will be stored in a secure, locked area, which is only 
accessible to authorized study personnel.  
4.5.2 Route of Administration and Dose Schedule 
Each patient will take 1 to 3 capsules three times daily during the Titration Period, and 1-2 capsules 
three times daily during the Open Label Period and during the Double-Blind Period.  Capsules will 
be taken orally with water (typically half a glass).  
Doses are to be timed such that the first dose is taken upon waking and then taken approximately 
every 4 hours thereafter, with the final dose taken early enough (i.e., late afternoon) to minimize 
drug effects during night-time sleeping hours.  However, on days when a patient has a study 
visit, the first dose should not be taken until the patient has arrived at the site for their visit. 
The combinations of capsules that patients may receive are shown in Table 2. 
 
 
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Table 1: Capsule Combinations Per Dose 
Medication for Open-Label 
Titration 
TID Dose (mg) 
100 
200 
300 
400 
500 
600 
 
# of Droxidopa 100 mg capsules  
 
1 
 
1 
 
1 
 
# of Droxidopa 200 mg capsules  
 
1 
1 
2 
2 
3 
 
Medication for Open-Label 
Treatment and Double blind 
period* 
TID Dose (mg) 
100 
200 
300 
400 
500 
600 
 
# of Droxidopa 100 mg capsules  
 
1 
 
 
 
 
 
# of Droxidopa 200 mg capsules  
 
1 
 
2 
1 
 
 
# of Droxidopa 300 mg capsules  
 
 
1 
 
1 
2 
 
 
* The medication for the double-blind period will include matching placebo treatments for each 
of the dose options. 
4.5.3 Dose Increase / Dose Reduction 
During the Titration Period, the dose of IMP will be up-titrated from 100 mg TID to 600 mg TID 
(see Section 3.5.2).  It is anticipated that this will take up to 6 Titration visits, within the 4-week 
Titration Period. 
During the initial 8 weeks of the Open-Label Period, the Investigator may elect to increase or 
decrease an individual patient’s dose, in increments of 100 mg TID, a maximum of four times (see 
Section 3.5.3.2).  The dose should remain stable during the last four weeks of the Open-Label 
Period (between Visits 5 and 6). 
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4.6 Drug Storage and Accountability 
A central IWRS will be used to manage on-site IMP supplies.  The Investigator or a qualified 
designee (e.g., pharmacist) will receive IMP supplies and keep records of their receipt, storage, 
and dispensing in accordance with current International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines.  A Drug Dispensing Log must be kept current and should 
contain, at a minimum, the following information: 
• The identification/randomization number of the patient to whom the IMP was dispensed; 
• The date(s) and quantity of IMP dispensed to the patient. 
The inventory must be available for inspection by the study’s CRA or Lundbeck.  During the study, 
the Investigator or a qualified designee will liaise with the CRO to ensure that supplies of IMP are 
maintained. 
Unused or partially used IMP may be destroyed by the Investigator only after authorization from 
the CRA (after verification with Lundbeck), provided such disposition does not expose humans to 
risk from the drug.  The Investigator or their designee should maintain records of any such 
alternative disposition of the IMP.  These records must show the identification and quantity of 
each unit that has been disposed, the method of destruction (taking into account the requirements 
of local law and the site’s standard operating procedures [SOPs]), and the person who disposed of 
the IMP.  Alternatively, Investigators may elect to return unused or partially used drug supplies to 
Lundbeck, or the sponsor’s designee, instead of destroying them on-site. 
4.7 Treatment Compliance 
At each visit at which IMP is dispensed, patients will be given sufficient IMP to supply them until 
their next clinic visit. 
Patients will be required to bring their IMP to all in clinic visits, and compliance will be monitored 
by capsule counts.  The number of returned capsules will be counted by the Investigator, or a 
designee, and recorded in the Drug Dispensing Log and eCRF.  The study CRA will review the 
compliance documentation during routine monitoring visits.  
At least 80% compliance will be defined as acceptable in this study during the Open-Label and 
Double-Blind periods.  If a patient is found to be below 80% compliance during a treatment visit, 
the patient should be counseled on the proper dosing regimen and the counseling should be 
documented in the patient’s chart.  If a patient is found to be non-compliant at a second treatment 
visit, the Investigator is to discuss this issue with the Medical Monitor in order to determine the 
patient’s eligibility to continue in the study.  In the event of over-compliance (i.e., a patient who 
is found to be over 120% compliant with their IMP), the patient will be treated in the same manner 
as a patient with compliance below 80%. 
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4.8 Prior and Concomitant Medications 
4.8.1 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 in the eCRF.  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 in the eCRF.  The date, indication, description of procedure(s) and any clinical finding 
should be recorded. 
All concomitant medications (including permitted medications given concomitantly for 
symptomatic NOH) should be maintained at stable doses during the study.  Any proposed changes 
in a patient’s treatment for symptomatic NOH considered necessary by the Investigator must be 
discussed with the Study Medical Monitor prior to implementation to determine its impact on the 
patient’s participation in 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. 
4.8.2 Prior Medications 
Prior medication includes all medications (including herbal treatments and vitamins) taken within 
28 days prior the Screening Visit (Visit 1).  All prior medications taken within 28 days of the 
Screening Visit must be recorded in the appropriate eCRF page. 
4.8.3 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); 
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• 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 
• Oral Anticoagulants in the drug classes of Coumarins: Coumadin (warfarin); Factor Xa 
Inhibitors: Xarelto (rivaroxaban), Eliquis (apixaban), Savaysa (edoxaban); and Direct 
Thrombin Inhibitors: Pradaxa (dabigatran etexilate mesylate) 
• 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 at Visit 2a.  Patients taking 
midodrine at Screening are required to washout of this drug for at least 2 days prior to first dose 
of IMP at Visit 2a. 
4.8.4 Allowed Medications 
Concomitant treatment for symptomatic NOH (with the exception of vasoconstricting agents) will 
be permitted during the study. This includes fludrocortisone, which is permitted during the study. 
Medications for the treatment of PD will be permitted during the study. Fludrocortisone and 
medications for treatment of the patient’s primary diagnosis should remain stable during the 
Double-Blind Period.  Short-acting anti-hypertensive medications taken at bedtime to reduce the 
risk of nocturnal supine hypertension may be taken during the study. 
The concomitant use of drugs that inhibit the re-uptake of NE at nerve terminals (e.g. tricyclic 
antidepressants) is permitted during the study.  However, due to a potential interaction with 
droxidopa, patients are not allowed to either initiate treatment with NE re-uptake inhibitors or 
modify the dose of any such medications during the study (the combined action of both drugs can 
increase NE concentrations at the nerve terminal). 
5. ADVERSE EVENTS 
5.1 Definitions 
5.1.1 Adverse Event Definitions 
5.1.1.1 
Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a clinical study patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
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An AE can therefore be any unfavorable and unintended sign (including clinically significant out-
of-range values from relevant tests, such as clinical safety laboratory tests, vital signs, ECGs), 
symptom, or disease temporally associated with the use of a medicinal product, regardless of 
whether it is considered related to the medicinal product. 
All AEs, including pre-treatment AEs (those that start after the patient has signed the ICF and prior 
to the first dose of IMP) will be collected and recorded up until 30 days after the last dose of IMP.  
Worsening of NOH is related to the primary endpoint in the Double-Blind Period.  As such, 
“worsening of NOH” is not to be considered an AE in the Double-Blind Period of this study unless 
the worsening meets the criteria for an SAE (see Section 5.1.1.2). 
5.1.1.2 
Serious Adverse Events 
A serious adverse event (SAE) – is any AE that: 
• 
results in death 
• 
is life-threatening (this refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above) 
SAE’s are collected 30 days after the last dose of IMP. 
Examples of medically important events are intensive treatment in an emergency room for allergic 
bronchospasm; blood dyscrasia or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse. 
Planned hospitalizations or surgical interventions for a condition that existed before the patient 
signed the ICF and that did not change in intensity are not SAEs. 
A non-serious adverse event is any AE that does not meet the definition of an SAE. 
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative viewpoint 
must be taken, and the adverse event must be reported as an SAE. 
A suspected unexpected serious adverse reaction (SUSAR) is any AE that is assessed as serious, 
unexpected (its nature or intensity is not consistent with the current version of the reference safety 
information) and related to an investigational product by either the Investigator or the sponsor. 
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An overdose is a dose taken by a patient that exceeds the dose prescribed to that patient. Any 
overdose (and associated symptoms) must, at a minimum be recorded as a non-serious adverse 
event.  
5.1.2 Adverse Event Assessment Definitions 
5.1.2.1 
Assessment of Intensity 
The Investigator must assess the intensity of the adverse event using the following definitions, and 
record it on the Adverse Event Form: 
• 
Mild: the AE causes minimal discomfort and does not interfere in a significant manner 
with the subject’s normal activities. 
• 
Moderate: the AE is sufficiently uncomfortable to produce some impairment of the 
subject’s normal activities. 
• 
Severe: the AE is incapacitating, preventing the subject from participating in his or her 
normal activities. 
5.1.2.2 
Assessment of Causal Relationship 
The Investigator must assess the causal relationship between the AE and the IMP using the 
following definitions, and record it on the Adverse Event Form (and on the Serious Adverse Event 
Report Form, if applicable): 
• 
Probable: the AE has a strong temporal relationship to the IMP or recurs on rechallenge, 
and another aetiology is unlikely or significantly less likely. 
• 
Possible: the AE has a suggestive temporal relationship to the IMP, and an alternative 
aetiology is equally or less likely. 
• 
Not related: the AE has no temporal relationship to the IMP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event). 
An AE is considered causally related to the use of the IMP when the causality assessment is 
probable or possible. 
5.1.2.3 
Assessment of Outcome 
The Investigator must assess the outcome of the AE using the following definitions, and record it 
on the Adverse Event Form (and on the Serious Adverse Event Report Form, if applicable): 
• 
Recovered: the subject has recovered completely, and no symptoms remain. 
• 
Recovering: the subject’s condition is improving, but symptoms still remain. 
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• 
Recovered with sequelae: the subject has recovered, but some symptoms remain (for 
example, the subject had a stroke and is functioning normally, but has some motor 
impairment). 
• 
Not recovered: the subject’s condition has not improved and the symptoms are unchanged 
(for example, an atrial fibrillation has become chronic). 
• 
Death 
5.2 Pregnancy 
Although not necessarily considered an AE, a pregnancy in a patient in the study must be recorded 
on an Adverse Event Report Form, as well as on a Pregnancy Form, even if no adverse event associated 
with the pregnancy has occurred. Pregnancies must be reported to Lundbeck using the same 
expedited reporting timelines as those for SAEs. 
An uncomplicated pregnancy should not be considered an SAE. If, however, the pregnancy is 
associated with an SAE, the appropriate serious criterion (for example, hospitalization) must be 
indicated on the Serious Adverse Event Report Form. Examples of pregnancies to be reported as SAEs 
(medically important) are spontaneous abortions, stillbirths, and malformations. 
The Investigator must follow up on the outcome of the pregnancy and report it on a Pregnancy 
Form.  The follow-up must include information on the neonate at least up until the age of 1 month. 
5.3 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, start and stop time; 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, 
NA immediately (within 24 hours) after becoming aware of it (refer to section 5.4). 
Adverse events, including clinically significant out-of-range clinical safety laboratory test values, 
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. 
5.4 Reporting Serious Adverse Events 
The Investigator must report SAEs to Lundbeck immediately (within 24 hours) after becoming 
aware of them by completing a Serious Adverse Event Form in the EDC system. 
 
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As much information as possible must be entered when initially completing the EDC form.  If 
more information about the patient’s condition becomes available at a later date, the Serious 
Adverse Event Form in the EDC system must be updated with the additional information. 
If the investigator cannot report the SAE in the EDC System, then he or she must complete and 
sign the Serious Adverse Event Fallback Form and send to: 
Global Pharmacovigilance – US (GPV-US) 
Fax:       +1 (847) 282-1003 
e-mail:   luinc_safety@lundbeck.com 
 
The signed (original) Serious Adverse Event Fallback Form must be collected by the CRA and 
filed in the sponsor TMF.  
Any Serious Adverse Event information provided on the Serious Adverse Event Fallback Form 
must be entered into the EDC system in a timely manner. 
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 IEC or IRB and to act accordingly. 
Lundbeck will assess expectedness and inform the Investigators about suspected unexpected 
serious adverse reactions (SUSARs) via individual blinded CIOMS in accordance with local 
requirements.  
5.5 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 (Visit 13), 
whichever comes first. At the safety follow-up visit (Visit 13), 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 GPV database. 
5.6 Warnings and Precautions 
Patients will be informed in a language that is understandable to them, that the following clinically 
significant adverse reaction was reported in post-marketing data: neuroleptic malignant syndrome 
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(symptoms include hyperpyrexia, disturbance of consciousness, marked muscle rigidity, 
involuntary movements, and elevation of serum CPK).  If these adverse reactions should occur, 
the Investigator should contact the medical monitor to discuss. 
Other adverse reactions that have been reported with droxidopa can be found in the PI. 
6. DATA ANALYSIS / STATISTICAL METHODS 
Continuous variables will be summarized using descriptive statistics including the number of 
observations, mean, standard deviation, minimum, median, and maximum values.  Categorical 
values will be summarized using number of observations and percentages. 
All other statistical tests will be done at the two-sided, 5% significance level, unless otherwise 
specified.  The assumptions underlying the statistical tests will be evaluated as appropriate and 
documented in the study report. 
Unless otherwise specified, efficacy endpoints will be evaluated using the full analysis set (FAS).  
In order to control the overall type I error, statistical significance of the secondary endpoints (see 
Section 3.7.1.2) will be evaluated using a hierarchical testing procedure that will be described in 
the Statistical Analysis Plan (SAP). 
A detailed description of all planned analyses will be provided in the SAP before the study is 
unblinded.  Any deviations from the protocol or SAP will be documented in the study report. 
6.1 Sample Size Determination 
The sample size and power calculations are based on the analysis of time to intervention in the 
Double-Blind Period.   
It is anticipated that event rates will be 0.15 for the droxidopa group and 0.25 for the placebo 
group 12 weeks post randomization. Assuming these event rates and a hazard ratio of 0.56 in 
favor of droxidopa, a 240-subject sample size would be expected to result in 48 events, providing 
~51% power to detect a difference between droxidopa and placebo.  A blinded review conducted 
in July 2020 indicated that the event rate may be higher than originally assumed and, if accurate, 
will result in a substantially higher power than 51%.  In addition, the study will contribute to the 
totality of results for the post-marketing requirement (PMR) evaluation, which justifies the 
reduced power given the circumstances.  
6.2 Randomization 
The study randomization schedule will be computer generated by the Lundbeck BioStatistics 
department or their designee, and provided to the IWRS programmers prior to the opening of site 
enrollment.  Randomization will be on a one to one basis with no additional stratification factors.  
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Neither the Investigator nor the patient will know the identity of the treatment that the patient will 
receive; however, the study will not be blinded with respect to (expected) dose. 
6.3 Study Treatments 
Summaries of efficacy and safety data for this study will be presented in terms of randomized 
treatment group (i.e., droxidopa or placebo) as well as for all open-label periods of the study. 
6.4 Analysis Population 
6.4.1 Safety Set 
The Safety Set will consist of all patients who received at least one dose of IMP.  This includes 
patients who received IMP during the open label titration.  All safety analyses will be based on the 
Safety Set unless otherwise specified. 
6.4.2 All Patients Treated Set 
The APTS will be a modified intent to treat (ITT) set, consisting of all randomized patients who 
take at least one dose of study drug in the double-blind period of the trial.  Patients will be included 
in the analysis according to the treatment to which they were randomized. 
6.4.3 Per Protocol Set 
The per protocol set (PPS) will consist of patients in the FAS who do not have major protocol 
violations and are compliant with study treatment.  Compliance will be defined as taking at least 
80% of the planned study doses during the 12-week Double-Blind Period, from the date of 
Randomization (Visit 6) to the date of their final visit (Visit 12 or Early Termination Visit).  In 
order to minimize the potential for bias, the review of protocol violations and assignment of 
patients to analysis sets will be performed prior to unblinding.  Protocol violations will be defined 
in the SAP and will be listed by treatment group. 
The primary efficacy analysis will be based on the APTS, although a secondary analysis will also 
be performed based upon the PP Set, to assess the sensitivity of the analysis to the choice of 
analysis population.  Analysis of all other efficacy endpoints will be based upon the APTS.  
Selected secondary efficacy parameters may be evaluated using the PP Set.  All safety analyses 
will be based on the Safety Set. 
6.5 Data Summary 
6.5.1 Summary of Efficacy Data 
Details of the analysis of these endpoints, as well as exploratory endpoints, will be further 
described in the SAP. 
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6.5.1.1 
Analysis of Primary Endpoint 
The primary endpoint is time to treatment intervention defined in section 1.3.2. The event time is 
measured as the time from randomization to the time of occurrence of the earliest event, as defined 
in the treatment intervention criteria. Patients withdrawing and without need for intervention will 
be censored at the time of withdrawal; patients without need for intervention before the end of the 
study will be censored at the time of study completion.  
The primary endpoint will be summarized using Kaplan-Meier method. The primary analysis is 
the Log-rank test to compare the two treatment groups. In addition, the cox regression model will 
be used to estimate the hazard ratio.  Furthermore, the following sensitivity analysis using the same 
analysis approach will be conducted: 
1 Time to treatment intervention according to the treatment intervention criteria (see Section 
3.7.1.1) or OHSA Item #1 ≥ 2 unit worsening from randomization at the last visit of the 
study 
2 Time to treatment intervention defined as discontinuation due to lack of efficacy as judged 
by the Investigator. 
3 Cox regression analysis of time to treatment intervention based on various definitions 
above.     
6.5.1.2 
Analysis of Key Secondary Endpoint 
A gate keeping strategy will be applied in the testing of the key secondary endpoint, time to all 
cause discontinuation. That is, the Log-rank test of this endpoint will be performed at the nominal 
alpha level of 2-sided 0.05 only if the primary endpoint reaches the statistical significance in the 
primary analysis. This strategy ensures the overall type 1 error rate is preserved.  
6.5.1.3 
Analysis of Other Secondary Endpoints 
Proportion of patients with need for treatment intervention will be summarized by treatment groups 
and treatment difference will be tested using Chi-square test. 
Descriptive statistics will be used to summarize mean change of OHSA item 1 score as well as 
OHQ composite score from randomization to each post randomization visit. 
Categorical analysis will be used to summarize both clinician and patient reported CGI-S at each 
post-randomization visit. 
6.5.2 Summary of Safety Data 
The safety data will be presented in two separate periods of the study.  The Titration Period and 
the 12 week Open-Label Period will be presented as appropriate in standard tabulations and 
listings. The changes from Randomization (Visit 6) to Week 12 of the Double-Blind Period (Visit 
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12) in the safety parameters will be summarized separately using standard tabulations and listings.  
Further details will be provided in the SAP. 
Clinical laboratory tests will be summarized using descriptive statistics by visit and treatment 
group.  Changes from randomization and shift tables will also be presented as appropriate. Vital 
signs will be summarized by treatment group using descriptive statistics and/or listed. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) AE 
dictionary.  Treatment-emergent AEs will be summarized by system organ class, preferred term, 
and by treatment group.  Severity of the AE and the relationship to IMP will also be summarized.  
Serious AEs and events leading to discontinuation of IMP will be summarized by body system, 
preferred term and treatment group. 
6.6 Interim Analysis 
There will be no interim efficacy analysis for this study.  Accordingly, no formal stopping rules 
will be applied. 
An interim analysis of safety data will be prepared annually. 
6.7 Replacement Policy 
A sufficient number of patients will be screened to allow 240 patients to be randomized into the 
study and receive at least one dose of double-blind IMP (120 randomized to droxidopa and 120 
randomized to placebo).   
Patients who fail to qualify prior to receiving their first dose of IMP may be rescreened once, with 
approval of the Medical Monitor (see Section 3.5.1.2). 
7. DATA MONITORING COMMITTEE 
Safety data from this study will not be reviewed by an independent Data Monitoring Committee 
(DMC).    
8. STUDY DOCUMENTATION, eCRF AND RECORD KEEPING 
8.1 Investigator’s Files and Retention of Study Data 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be separated into two categories: Investigator’s study file and patient clinical source documents. 
1. The Investigator’s study file will contain the protocol and protocol amendments (if 
applicable), eCRF guidelines, eCRF query forms, IRB/IEC and governmental regulatory 
approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms and other appropriate documents and correspondence. 
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2. Patient clinical source documents (which are usually defined by the project in advance to 
record key efficacy and/or safety parameters independent of the eCRF) may include patient 
and/or hospital clinical records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG, X-ray, pathology and special assessment reports, consultant’s 
letters, screening and enrollment log, etc. 
The patient’s involvement in the study should be clearly documented in the study site’s clinical 
records. Details should include the study protocol number, the patient’s screening and 
randomization number, the patient’s consent to take part in the study (including the date of 
consent), the dates of all study visits, details of any treatments withdrawn because of study 
participation, the dates of dispensing IMP, details of any AEs (including any SAEs), and changes 
in concomitant medications. 
The documents in these two categories must be kept on file by the Investigator for at least 15 years 
after completion or termination of the study. 
Study documents should not be destroyed without prior written agreement between Lundbeck and 
the Investigator. If the Investigator wishes to assign the study records to another party or move 
them to another location, Lundbeck must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement for any or all the documents at the 
investigational site, arrangements must be made between the Investigator and Lundbeck to store 
these in a sealed container(s) outside the site. The sealed container(s) can therefore be returned to 
the Investigator in case of a regulatory audit. Where source documents are required for the 
continued care of the patient, appropriate copies should be made for storing outside the site. 
8.2 Electronic Case Report Forms 
The Investigator is to record all data with respect to protocol procedures, drug administration, local 
laboratory data, safety data and efficacy ratings in the eCRF.  The Investigator must sign the final 
eCRF pages to attest to the accuracy and completeness of all data.   
8.3 Background Data 
The Investigator will supply Lundbeck and the CRO, on request, with any required background 
data from the study documentation or clinic records.  This is particularly important when errors in 
data transcription are suspected.  In case of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary to have direct access to the completed study 
records, provided that patient confidentiality is protected. 
8.4 Monitoring, Verification of Data, Audit, and Inspection 
The Lundbeck monitor, or assigned CRA, will periodically visit each site that has enrolled patients 
into the study to discuss the progress of the study and review eCRFs and original source documents 
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with the study personnel, for accuracy of data recording, IMP accountability, and correspondence.  
Periodically, some/all of the facilities used in the study (e.g., laboratory, pharmacy) may be 
reviewed or inspected by Lundbeck, the IRB/IEC and/or regulatory authorities. 
The Investigator is to ensure that the study participants are aware of and consent that personal 
information may be reviewed during the data verification process as part of monitoring/auditing 
by properly authorized agents of Lundbeck or subject to inspection by regulatory authorities.  In 
addition, participation and personal information is treated as strictly confidential to the extent the 
applicable law permits and not publicly available.  The audit or inspection may include, for 
example, a review of all source documentation, drug records, original medical notes, some or all 
of the facilities used in the study. 
The Investigator must notify Lundbeck, without delay, of an announced inspection by a regulatory 
authority. During audits and inspections, the Investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.  
During audits and inspections, the auditors and inspectors may copy relevant parts of medical 
records. No personal identification apart from the screening or randomisation number will appear 
on these copies. Patient data will not be disclosed to unauthorised third parties, and patient 
confidentiality will be maintained at all times. 
9. ADMINISTRATIVE PROCEDURES 
9.1 Compliance with Good Clinical Practice and Ethical Considerations 
This study must be conducted in compliance with Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) and International Committee on Harmonization (ICH) GCP Guidelines.  In 
addition, all local regulatory requirements will be adhered to, in particular those which afford 
greater protection to the safety of the study participants. 
This study will be conducted in general according to the Declaration of Helsinki and with local 
laws and regulations relevant to the use of new therapeutic agents in the country of conduct. 
Before initiating a study, the Investigator/institution will have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol, written informed consent 
form, patient recruitment procedures (e.g., advertisements), and data collection instruments which 
will be completed by patients.  Protocol amendments, consent form updates, and any amendments 
to the documents described before must be approved by the IRB/IEC prior to implementation 
unless such changes are necessary to address immediate safety concerns. 
9.2 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.  The informed consent procedure needs to be documented at 
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each study site.  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, according to 
current ICH GCP Guidelines. 
A sample copy of the patient information sheet and consent form will be provided by the sponsor. 
These documents may, however, be subject to country specific changes and the IRB/IECs may ask 
for them to be altered.  In this case, any modifications are to be approved by Lundbeck.  A copy 
of the patient information sheet and consent form that is approved for this study by each IRB/IEC 
and Lundbeck will be kept by the CRO in the trial master file (TMF). 
9.3 Confidentiality of Patient Information 
All patients who provide written informed consent will be assigned a patient number.  
Subsequently, patients will be identified in the eCRFs 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. 
9.4 Protocol Compliance 
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate from 
the protocol. If deviations occur, the Investigator must inform the CRA and they must review, 
discuss, and document the implications of the deviation. 
9.5 Conditions For Modification of the Protocol 
Protocol modifications to an ongoing study that could potentially adversely affect the safety of 
participating patients, or that alter the scope of the investigation, the scientific quality of the study, 
the experimental design, dosages, duration of therapy, assessment variables, the number of patients 
treated or patient selection criteria must be made only after consultation with appropriate 
representatives of Lundbeck, the CRO, and the Investigator. 
Protocol modifications will be prepared, and reviewed by Lundbeck, and reviewed and signed by 
the Investigator.   
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Any modifications to the protocol that are made after receipt of the IRB/IEC approval must be 
submitted by the Investigator to the IRB/IEC in accordance with local procedures and regulatory 
requirements, before the changes can be implemented.  Modifications to the protocol that eliminate 
an apparent immediate hazard to patients do not require pre-approval by the IRB/IEC. 
9.6 Clinical Study Report and Publications 
9.6.1 Clinical Study Report 
Upon completion of the study, a Clinical Study Report will be prepared by Lundbeck or the 
company’s designee. 
9.6.2 Data Ownership 
The data collected in this study are the property of Lundbeck. 
9.6.3 Publications 
The results of this study will be submitted for publication. 
The primary publication based on this study must be published before any secondary publications 
are submitted for publication. 
Authors of the primary publication must fulfil the criteria defined by the International Committee 
of Medical Journal Editors (ICMJE). 
 
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INVESTIGATOR SIGNATURE 
I, the undersigned, certify that I have reviewed and approve the protocol, the appropriate informed 
consent form, and other associated documents and agree to abide by their terms and to comply 
with current ICH GCP Guidelines.  I fully understand that any changes initiated by the Investigator 
without prior agreement in writing from Lundbeck would constitute a deviation from the protocol.  
 
 
 
………………………………………… 
…………………….. 
Investigator Signature  
 
 
Date 
 
………………………………………… 
Investigator Name (Print) 
 
………………………………………… 
………………………………………… 
………………………………………… 
Address 
 
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10. 
REFERENCES 
Birkmayer, W., Birkmayer, G., Lechner, H., Riederer, P.  D,L-3,4-threo-DOPS in Parkinson's 
disease: Effects on orthostatic hypotension and dizziness.  J. Neural Transm. 1983; 58:305-313. 
Kachi, T., Iwase, S., Mano, T., Saito, M.,  Kunimoto, M., Sobue, I.  Effect of L-threo-3,4-
dihydroxy-phenylserine on muscle sympathetic nerve activities in Shy-Drager syndrome.  
Neurology. 1988; 38:1091-1094 
Kaufmann, H, Malamut R, Norcliffe-Kaufmann L, Rosa K FR. The Orthostatic Hypotension 
Questionnaire (OHQ): validation of a novel symptom assessment scale. Nov 2. Clin Auton Res. 
2011. 
Kaufmann, H., Saadia, D., Voustianiouk, A., Goldstein, D.S., Holmes, C., Yahr, M.D., Nardin, 
R., Freeman, R.    Norepinephrine precursor therapy in neurogenic orthostatic hypotension.  
Circulation. 2003; 108:724-728. 
Malamut, R., Freeman, R., Gilden, J., Tulloch, J., Kaufmann, H. A multi-center, double-blind, 
randomized, placebo controlled, cross-over study to assess the clinical benefit of midodrine in 
patients with neurogenic orthostatic hypotension. Clin. Auto. Res. 2005; 15 (5) 337[abstract]. 
Narabayashi, H., Nakanishi, T., Kanazawa, I., Yoshida, M., Mizuno, Y., Yanagisawa, N., 
Kondo, T.   Clinical effects of L-threo-3,4-dihydroxyphenylserine in Parkinson’s disease and 
Parkinson syndrome:  Results of multi-center open study at 45 institutions.  Yakuri To Chiryo 
(Jpn. Pharmacol. Ther.) 1987; 15(Suppl. 2):411 to 443. 
Yanagisawa, N, Ikeda S, Hashimoto T, Hanyu N, Nakagawa S, Fujimori N,Ushiyama M.  
Effects of L-threo-Dops on orthostatic hypotension in Parkinson's  disease (Article in Japanese).  
No To Shinkei. 1998; 50(2):157-63 
 
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11. 
APPENDICES 
Appendix 1:    Questionnaires 
Appendix 1.1:  Orthostatic Hypotension Questionnaire (OHQ) 
Appendix 1.2:  Clinical Global Impressions – Severity  
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Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: NOH402 
                               Version: Final 3.0, Date: 12 May 22 
Page 1 of 46 
 
Sponsor: 
H. Lundbeck A/S (Lundbeck) 
Study title: 
RESTORE: A clinical study of patients with symptomatic neuRogenic 
orthostatic hypotEnsion to assess Sustained effecTs Of dRoxidopa 
thErapy 
Study number: 
16306A 
ICON ID:  
0546/0093 
SAP version: 
Final 3.0 - 12 May 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________                                      ________________ 
Signature                                                                        Date 
 
 
Function: 
 
Company: ICON Clinical Research Services 
City: Beijing 
Country: China 
 
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PPD
PPD
PPD


 
 
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Statistical Analysis Plan 
Protocol Number: NOH402 
                               Version: Final 3.0, Date: 12 May 22 
Page 2 of 46 
 
Sponsor's representative: 
 
 
 
 
 
 
 
 
 
 
 
________________________                                      ________________ 
Signature                                                                        Date 
 
 
Function: 
 
Company: H. Lundbeck A/S 
City: Valby/Copenhagen 
Country: Denmark 
 
 
 
 
 
 
 
 
 
 
Confidentiality statement: 
▪ 
The information provided in this document is strictly confidential.  
▪ 
The Recipients of the SAP must not disclose the confidential document and any 
related information to other persons. 
▪ 
In addition, they must keep this confidential document in a controlled 
environment which prevents unauthorized access to the document. 
 
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Statistical Analysis Plan 
Protocol Number: NOH402 
                               Version: Final 3.0, Date: 12 May 22 
Page 3 of 46 
 
REVISION HISTORY 
 
 
Version/ 
Date 
Version name Section 
Changes implemented 
Version 1.0/ 
11-Jul-2017 
Initial 
approved 
version 
N/A 
N/A 
Version 2.0/ 
08-Dec-2017 
Amendment 1 
of the Final 
SAP 
Section 5.1.9.1  
Primary 
Efficacy 
Endpoints 
Provided a detailed definition of 
"consecutive visits" and clarified how to 
classify patients who are missing the next 
or all OHSA Item 1 
scores after having a worsening OHSA 
item 1 ≥ 2 units (and not meeting criteria 
1, 3 or 4). 
 
Section 6.2.1.1 
– Primary 
analysis 
Removed the definition of time-to-
intervention as already in section 5.1.9.1 
Version 3.0/ 
06 Apr-2022 
Amendment 2 
of the Final 
SAP 
Throughout the 
document 
Language edits. 
Removed listings to align with the needs 
for the CSR.  
Clarifications. 
Corrections. 
 
 
Section 3.3.2 – 
Planned sample 
size 
Sample size update, incl rationale 
 
 
Section 4.3 – 
All Patients 
Treated Set 
(APTS) 
Title of the section updated to Full analysis 
set (FAS) 
 
 
Section 4.4 – 
Per Protocol set 
(PP) 
Removed the section, no PP analyses to 
be performed 
 
 
Section 4.5 – 
Clinical review 
of protocol 
violations and 
Removed the section, no PP analyses to 
be performed  
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Page 4 of 46 
 
exclusions from 
analysis sets 
 
 
Section 5.2.1 – 
Missing data 
analysis 
methods 
Added modified BOCF 
 
 
Section 6.1.2 – 
Population 
membership 
and protocol 
deviations   
Section removed as patients will not be 
excluded from any analyses 
 
 
 
New section 6.1.2 Protocol Deviations 
added 
 
 
Section 6.2.1.3 
-  
Removed PP analyses, removed 
competing risks analysis 
 
 
Section 6.2.3 – 
Analysis of 
other secondary 
endpoints 
Added mBOCF 
Added ANCOVA 
Removed competing risks 
 
 
Section 6.3.4 – 
Physical 
examination 
Removed section, to be included in 
datasets only 
 
 
Section 6.3.5 – 
12-lead ECG 
Removed section, to be included in 
datasets only 
 
 
Throughout the 
document 
Language edits. 
Clarifications: For Safety Set Outputs 
“Droxidopa” treatment column will be 
presented instead of “Overall” column 
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Page 5 of 46 
 
 
 
 
 
 
Section 6.1.2 
Protocol deviation outputs will be based on 
All-enrolled Set 
 
 
Section 6.2.3 
Removed figure  
“A bar chart illustrating the need for 
treatment intervention and per criterion” 
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Page 6 of 46 
 
TABLE OF CONTENTS 
 
REVISION HISTORY ..................................................................................................................................... 3 
1 
List of abbreviations ................................................................................................................................ 8 
2 
Introduction ........................................................................................................................................... 10 
3 
Study objectives, endpoints and study design ...................................................................................... 10 
3.1 
Objectives.................................................................................................................................... 10 
3.1.1 
Primary objective............................................................................................................ 10 
3.1.2 
Secondary objectives ..................................................................................................... 10 
3.2 
Endpoints .................................................................................................................................... 11 
3.2.1 
Primary efficacy endpoint ............................................................................................... 11 
3.2.2 
Secondary endpoints ..................................................................................................... 11 
3.2.2.1 Key secondary endpoint ................................................................................ 11 
3.2.2.2 Other secondary endpoints ........................................................................... 11 
3.3 
Study design................................................................................................................................ 12 
3.3.1 
Assessments and study duration ................................................................................... 12 
3.3.2 
Planned sample size ...................................................................................................... 16 
3.4 
Interim analysis ........................................................................................................................... 16 
4 
Analysis populations ............................................................................................................................. 16 
4.1 
All-enrolled set ............................................................................................................................ 16 
4.2 
Safety set .................................................................................................................................... 16 
4.3 
Full analysis set (FAS) ................................................................................................................ 16 
5 
Statistical Considerations and analysis ................................................................................................ 17 
5.1 
Derived variables ........................................................................................................................ 17 
5.1.1 
Period ............................................................................................................................. 17 
5.1.2 
Baseline.......................................................................................................................... 17 
5.1.3 
Definitions relative to study days ................................................................................... 17 
5.1.3.1 Study days for the Open-Label titration period (Visits 2a-3)......................... 17 
5.1.3.2 Study days for the Open-Label treatment period(Visits 3-6) ........................ 18 
5.1.3.3 Study days for the Double-Blind treatment period (Visits 6-12) ................... 18 
5.1.4 
Age ................................................................................................................................. 18 
5.1.5 
Weight, height and BMI .................................................................................................. 18 
5.1.6 
Temperature ................................................................................................................... 18 
5.1.7 
Orthostatic hypotension ................................................................................................. 18 
5.1.8 
Primary disease duration ............................................................................................... 18 
5.1.9 
NOH duration ................................................................................................................. 19 
5.1.10 Definitions relative to IMP exposure and compliance .................................................... 19 
5.1.10.1 Exposure to IMP ............................................................................................ 19 
5.1.10.2 IMP compliance ............................................................................................. 19 
5.1.11 Definitions relative to efficacy criteria ............................................................................ 19 
5.1.11.1 Primary efficacy endpoint .............................................................................. 19 
5.1.11.2 Secondary efficacy endpoints ....................................................................... 20 
5.1.11.3 Orthostatic Hypotension Questionnaire (OHQ) ............................................ 20 
5.1.11.4 Clinical Global Impression - Severity (CGI-S) ............................................... 21 
5.1.12 Definitions relative to safety parameters........................................................................ 22 
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5.1.12.1 Adverse Event (AE) ....................................................................................... 22 
5.1.12.2 Serious Adverse Event (SAE) ....................................................................... 22 
5.1.12.3 Duration of AEs ............................................................................................. 22 
5.1.12.4 Relationship of AEs ....................................................................................... 22 
5.1.12.5 Intensity of AEs .............................................................................................. 23 
5.2 
Handling of missing data and/or invalid data and outliers .......................................................... 23 
5.2.1 
Missing data analysis methods ...................................................................................... 23 
5.2.2 
Handling of missing or incomplete dates ....................................................................... 24 
5.2.2.1 Concomitant medications definition and handling of missing or incomplete 
dates 24 
5.2.2.2 Definition of treatment-emergent AEs and handling of missing or incomplete 
dates 24 
5.2.3 
Handling of Early Termination (ET) data ....................................................................... 25 
5.2.3.1 Handling of ET data during the Titration Period............................................ 25 
5.2.3.2 Handling of ET data during the Open-Label Period ...................................... 25 
5.2.3.3 Handling of ET data during the Double-Blind Period .................................... 26 
6 
Statistical plan and methods ................................................................................................................. 26 
6.1 
Background characteristics ......................................................................................................... 28 
6.1.1 
Patient disposition .......................................................................................................... 28 
6.1.2 
Protocol Deviation .......................................................................................................... 28 
6.1.3 
Demographic and baseline characteristics .................................................................... 29 
6.1.4 
Medical condition ........................................................................................................... 29 
6.1.5 
Prior and concomitant medications and procedures .............................................. 29 
6.1.6 
IMP exposure and compliance....................................................................................... 30 
6.1.6.1 IMP exposure................................................................................................. 30 
6.1.6.2 IMP compliance ............................................................................................. 30 
6.2 
Efficacy analysis .......................................................................................................................... 30 
6.2.1 
Analysis of primary endpoint .......................................................................................... 30 
6.2.1.1 Primary analysis ............................................................................................ 30 
6.2.1.2 Descriptive analyses...................................................................................... 31 
6.2.1.3 Sensitivity analyses ....................................................................................... 31 
6.2.2 
Analysis of key secondary endpoint .............................................................................. 32 
6.2.2.1 Testing strategy for key secondary endpoint ................................................ 32 
6.2.3 
Analysis of other secondary endpoints .......................................................................... 32 
6.3 
Safety analysis ............................................................................................................................ 33 
6.3.1 
Adverse events .............................................................................................................. 34 
6.3.2 
Clinical safety laboratory tests ....................................................................................... 35 
6.3.3 
Vital signs and weight .................................................................................................... 37 
7 
Changes from the planned analysis in study protocol .......................................................................... 37 
8 
References ............................................................................................................................................ 39 
APPENDIX A - Orthostatic Hypotension Questionnaire (OHQ) .................................................................. 40 
APPENDIX B - Clinical Global Impressions - Severity (CGI-S) .................................................................. 42 
APPENDIX C – algorithms/sas reference codes ........................................................................................ 43 
APPENDIX D – Lundbeck PCS Criteria ...................................................................................................... 44 
 
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1 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase (SGPT) 
AP 
Alkaline Phosphatase 
AST 
Aspartate Transaminase (SGOT) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CGI-S 
Clinical Global Impressions - Severity 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
DBH  
Dopamine Beta Hydroxylase 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FAS 
Full Analysis Set 
γGT 
γ-glutamyl transferase 
GCP 
Good Clinical Practice 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
LLN 
Lower limit of the reference range 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mmHg 
Millimetres of mercury 
MSA 
Multiple System Atrophy 
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n 
Number of non-missing observations 
N 
Number of patients in the population 
NDAN 
Non-Diabetic Autonomic Neuropathy 
NOH 
Neurogenic Orthostatic Hypotension 
OH 
Orthostatic Hypotension 
OHDAS 
Orthostatic Hypotension Daily Activity Scale 
OHQ 
Orthostatic Hypotension Questionnaire 
OHSA 
Orthostatic Hypotension Symptom Assessment 
PAF 
Pure Autonomic Failure 
PCS 
Potentially Clinically Significant 
PD 
Parkinson’s Disease 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TID 
three times per day 
TLFs 
Tables, Listings and Figures 
ULN 
Upper limit of the reference range 
WHO 
World Health Organization 
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2 
INTRODUCTION 
This statistical analysis plan (SAP) describes the detailed procedures for performing statistical 
analyses and for producing tables, listings, and figures (TLFs) for Study 16306A. 
The SAP will be finalized before database lock (DBL).  
This study consists of an Open-Label Titration Period, and Open-Label Treatment Period, and a 
Double-Blind Treatment Period. In the Double-Blind Treatment Period patients will be randomized 
(1:1) to either droxidopa or placebo using an Interactive Web Response System (IWRS). 
Unblinding is permissible after DBL or on an individual patient basis in case of emergency only. 
Emergency unblinding (via IWRS) should only be undertaken when it is essential to treat the 
patient safely and efficaciously.  
3 
STUDY OBJECTIVES, ENDPOINTS AND STUDY DESIGN 
3.1 
Objectives 
The objectives of the study are to evaluate the clinical efficacy and safety of droxidopa versus 
placebo over a 12-week Double-Blind treatment period in patients with symptomatic neurogenic 
orthostatic hypotension (NOH) who have previously received up to 16 weeks of Open-Label 
treatment with an individually optimized dose of droxidopa (randomized-withdrawal design). 
3.1.1 Primary objective 
The primary objective is to evaluate the time to treatment intervention in patients with Parkinson’s 
disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), non-diabetic 
autonomic neuropathy (NDAN) or dopamine beta hydroxylase (DBH) deficiency who have been 
previously stabilized with droxidopa therapy for symptoms of NOH (dizziness, light-headedness, 
or feeling that they are about to black out). 
3.1.2 Secondary objectives 
The secondary objectives are: 
• 
To evaluate the long-term efficacy of droxidopa in patients with symptomatic NOH 
measured by: 
o Discontinuation for any reason (all-cause discontinuation) 
o Composite orthostatic hypotension questionnaire (OHQ) scores 
o Clinician- and patient-rated clinical global impression of severity (CGI-S) scores 
• 
To evaluate the long-term safety and tolerability of droxidopa in patients with symptomatic 
NOH 
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3.2 
Endpoints 
3.2.1 Primary efficacy endpoint 
The primary efficacy endpoint is the “time-to-intervention”.  
The need for intervention is defined as meeting ANY of the following events during the Double-
Blind period: 
• 
Orthostatic hypotension symptom assessment (OHSA) Item 1 ≥2 units worsening from 
randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR 
• 
OHSA Item 1 ≥2 units worsening from randomization (Visit 6) at 2 consecutive visits; OR 
• 
OHSA Item 1 ≥2 units worsening from randomization (Visit 6) at the visit before early 
discontinuation; OR 
• 
Patient stops investigational medicinal product (IMP) or withdraws from study for patient-
reported lack of efficacy 
The timing of the need for intervention in the above criteria is defined as the first occurrence of a 
worsening of OHSA Item 1 by ≥2 units, or when the patient stops taking IMP or withdraws due 
to a patient-reported lack of efficacy, whichever comes first. 
Note: a patient that fulfils the criterion ‘Patient stops IMP or withdraws from study for patient-
reported lack of efficacy’ has a final status ‘Discontinued’ on the ‘Subject Disposition’ Form in the 
eCRF.  
3.2.2 Secondary endpoints 
3.2.2.1 Key secondary endpoint 
Time to all-cause discontinuation 
3.2.2.2 Other secondary endpoints 
• 
Efficacy measures of droxidopa versus placebo on the: 
o Mean change in OHSA item 1 score from randomization (Visit 6) to all post-
randomization visits (Visits 7-12) 
o Mean change in OHQ composite score from randomization (Visit 6) to all post-
randomization visits (Visits 7-12) 
o Clinician-rated CGI-S score at all post-randomization visits (Visits 7-12) 
o Patient-rated CGI-S score at all post-randomization visits (Visits 7-12) 
o Proportion of patients who need intervention over the 12-week Double-Blind 
treatment period 
• 
Adverse events (AEs) 
• 
Absolute values and changes from baseline in clinical safety laboratory tests and vital 
signs 
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• 
Potentially clinically significant safety laboratory test values and vital signs 
3.3 
Study design 
This is a multi-site, placebo-controlled, Double-Blind, randomized-withdrawal, time-to-intervention 
study with a duration of up to 36 weeks and consists of 5 periods: 
• 
Screening period: up to 4 weeks duration 
• 
Open-Label titration period (Titration Period): up to 4 weeks duration 
• 
Open-Label treatment period (Open-Label Period): 12 weeks duration 
• 
Double-Blind treatment period (Double-Blind Period): 12 weeks duration 
• 
Safety follow-up period: 4 weeks duration 
Adult patients with symptomatic NOH associated with primary autonomic failure (PD, MSA or 
PAF), NDAN or DBH deficiency will be enrolled. Across approximately 125 study sites in the 
United States, a sufficient number of patients will be screened to allow 240 patients (120 patients 
per treatment group) to be randomized in the Double-Blind Period. 
The study design is presented in Figure 1. 
Figure 1: Study Design 
 
3.3.1 Assessments and study duration 
The maximum duration of patient participation is 36 weeks. 
All eligible patients will enter the Titration Period (Visit 2a). Patients are anticipated to have up to 
6 titration visits. The exact number of titration visits for each patient will depend on the number of 
titration visits required to reach his/her optimal dose. At the end of the Titration Period (Visit 3), 
patients who have an acute dizziness score that is ≥2 units lower (improved) than the Visit 2a 
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OHSA item 1 score will enter the Open-Label Period. At the end of the Open-Label Period (Visit 
6), patients who have an OHSA item 1 score that is ≥2 units lower (improved) than the Visit 2a 
score will enter the Double-Blind Period and be randomized to receive either droxidopa or 
placebo. Week 0 of the Double-Blind Period begins with randomization (Visit 6). Visits in the 
Double-Blind Period will occur at Weeks 2, 4, 6, 8, 10 and 12 (Visits 7-12). 
During the Titration Period (Visits 2a-2f) and the Open-Label Period (Visits 3-5), patients will 
receive 100, 200, 300, 400, 500 or 600 mg three times daily (TID) of droxidopa, orally. The 
droxidopa starting dose for all eligible patients in the Titration Period is 100 mg TID. Doses will 
be titrated in 100 mg TID increments until the optimal dose is achieved. Four dose changes are 
permitted within the first two months of the 3-month Open-Label Period. No dose changes are 
allowed between Visit 5 and Visit 6. Randomized patients will receive 100, 200, 300, 400, 500 or 
600 mg TID of droxidopa or matching placebo (equal to their dose at the end of the Open-Label 
Period), orally at randomization (Visit 6) and during the Double-Blind Period (Visits 7-12). Dose 
changes are not permitted during the Double-Blind Period. 
A detailed description of the procedures and assessments to be conducted during the study is 
provided in Sections 3.5 and 3.6 of the Protocol and summarized in the Study Schedule/Flowchart 
in Table 1 below. 
 
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Table 1: 
Study Schedule/Flowchart 
 
 
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3.3.2 Planned sample size 
The sample size and power calculations are based on the analysis of time to intervention in the 
Double-Blind Period. 
It is anticipated that event rates will be 0.15 for the droxidopa group and 0.25 for the placebo 
group 12 weeks post randomization. Assuming these event rates and a hazard ratio of 0.56 in 
favour of droxidopa, a sample size of 240 patients would be expected to result in 48 events, 
providing ~51% power to detect a difference between droxidopa and placebo.  A blinded review 
of overall study events conducted in July 2020 indicated that the rate may be higher than 
originally assumed and, if maintained and the anticipated differential between droxidopa and 
placebo is an accurate assumption, will result in a substantially higher power than 51%.  In 
addition, the study will contribute to the totality of results for the post-marketing requirement 
(PMR) evaluation, which justifies the reduced power given the circumstances.  
3.4 
Interim analysis 
There will be no interim efficacy analysis. Accordingly, no formal stopping rules will be applied. 
4 
ANALYSIS POPULATIONS 
4.1 
All-enrolled set 
All patients who were enrolled into the study (i.e. patients who entered the Open-Label titration 
period at Visit 2a). 
Unless otherwise stated, data listings will be based on the all-enrolled set. 
4.2 
Safety set 
The Safety set will consist of all patients who received at least one dose of IMP. This includes 
patients who received IMP during the Open-Label titration period. All safety analyses will be based 
on the Safety set unless otherwise specified. 
Patients who did not receive the planned randomized treatment during the Double-Blind Period 
will be analysed according to the actual treatment received for >50% of the treatment duration of 
the randomized treatment period. 
4.3 
Full analysis set (FAS) 
The FAS will be a modified intent-to-treat set, consisting of all randomized patients who took at 
least one dose of IMP in the Double-Blind period. Patients will be included in the analysis 
according to the treatment to which they were randomized. 
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5 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
5.1 
Derived variables 
5.1.1 Period 
• 
Titration Period - treatment started on or after first dose in the Titration Period (Visit 2a) 
and before first dose in the Open-Label period (Visit 3); 
• 
Open-Label Period - treatment started on or after first dose in the Open-Label period (Visit 
3) and before first dose in the Double-Blind period (Visit 6); 
Entire Open label portion includes Titration period and Open-Label period. 
• 
Double-Blind Period - treatment started on or after first dose in the Double-Blind period 
(Visit 6). 
• 
Follow-Up: After visit 12. 
5.1.2 Baseline 
• 
Baseline in the Titration Period - The Visit 2a date (initial dose of IMP) is considered Day 
0 of the Titration Period. Baseline assessment for the Open-Label titration period is the 
assessment from visit 2a. If this value is missing, then the latest available value from the 
screening period will be used. Baseline in the Titration Period is also used for analysis of 
the entire open label portion (Titration and Open-Label Period combined). 
• 
Baseline in the Open-Label Period – The Visit 3 date is considered Day 0 of the Open-
Label Treatment Period. Baseline assessment for the Open-Label treatment period is the 
assessment from visit 3. If this value is missing, then the latest available value from the 
Open-Label titration period will be used. 
• 
Baseline in the Double-Blind Period - The Visit 6 date (randomization) is considered Day 
0 of the Double-Blind Period. Baseline assessment for the Double-Blind Period is the 
assessment from visit 6. 
• 
 
5.1.3 Definitions relative to study days 
5.1.3.1 Study days for the Open-Label titration period (Visits 2a-3) 
Visits within the Titration Period do not have fixed visit windows, although there should be a 
minimum of 1 day between each Titration Visit. The Visit 2a date (initial dose of IMP) is considered 
Day 0 of the Titration Period. 
Therefore, study days for the Open-Label titration period will be calculated as: 
 <visit/examination date> minus <date of Visit 2a>. Visit 3 is the last visit in the titration period and 
will be included in the calculations.  
All assessments made prior to dosing at visit 3 will be part of the Open-Label titration period 
assessments. 
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5.1.3.2 Study days for the Open-Label treatment period(Visits 3-6) 
The windows for Visits 4-6 are anchored from the Visit 3 date, which is considered Day 0 of the 
Open-Label Period. If the patient is required to return for re-evaluation of the Open-Label entry 
criterion, the date of the repeat assessment (recorded as an Unscheduled Visit) will be considered 
Day 0 of the Open-Label Period.  
Therefore, study days for the Open-Label treatment period will be calculated as: 
<visit/examination date> minus <date of Visit 3 or repeat assessment (if any)>. 
For changes from baseline in efficacy or safety endpoints in the Open-Label treatment period, the 
last value obtained prior to the Open-Label titration period will be used as baseline value. 
5.1.3.3 Study days for the Double-Blind treatment period (Visits 6-12) 
The windows for Visits 7-12 are anchored from the Visit 6 date (randomization), which is 
considered Study Day 0 of the Double-Blind Period. 
Therefore, study days for the Double-Blind treatment period will be calculated as: 
<visit/examination date> minus <date of Visit 6>. 
For changes from baseline in efficacy or safety endpoints in the Double-Blind treatment period, 
the visit 6 value will be used as baseline value. 
5.1.4 Age 
Age at informed consent will be calculated in years as:  
integer part of ([date of informed consent - date of birth + 1]/ 365.25) 
5.1.5 Weight, height and BMI 
Weight, recorded in pounds on the eCRF, will be converted to kilograms (1 pound = 0.45359 kg). 
Height, recorded in inches on the eCRF, will be converted to centimeters (1 inch = 2.54 cm). 
Body mass index (BMI) will be calculated as: weight (kg)/(height [m])2 
5.1.6 Temperature 
Temperature, recorded in degree Fahrenheit on the eCRF, will be converted to degree Celsius: 
(degree Fahrenheit - 32) x (5/9) 
5.1.7 Orthostatic hypotension 
Orthostatic hypotension (OH) is defined as a fall in SBP ≥ 20 mmHg or in diastolic blood pressure 
(DBP) ≥ 10 mmHg between the supine and standing measurements. 
5.1.8 Primary disease duration 
Primary disease (PD, MSA, PAF, NDAN, or DBH deficiency) duration will be calculated in 
months as: (date of informed consent - date of primary clinical diagnosis of NOH + 1)/ 30.4375 
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5.1.9 NOH duration 
NOH duration will be calculated in months as:  
(date of informed consent - date of diagnosis of NOH + 1)/ 30.4375 
5.1.10 Definitions relative to IMP exposure and compliance 
5.1.10.1 Exposure to IMP 
Exposure to IMP (number of days) for the Open-Label titration period will be calculated between 
the Visits 2a-3 and will be defined in that period as:  
(date of last dose of IMP – date of first dose of IMP) 
Exposure to IMP (number of days) for the Open-Label treatment period will be calculated between 
the Visits 3-6 and will be defined in that period as:  
(date of last dose of IMP – date of first dose of IMP) 
Exposure to randomized IMP (number of days) for the Double-Blind treatment period will be 
calculated between the Visits 6-12 and will be defined in that period as:  
(date of last dose of IMP – date of first dose of IMP) + 1 
5.1.10.2 IMP compliance 
At each visit at which IMP is dispensed, patients will be given sufficient IMP to last them until their 
next clinic visit. 
Patients will be required to bring their IMP to all clinic visits, and compliance will be checked by 
capsule counts. The number of returned capsules will be counted by the Investigator or a 
designee and recorded in the eCRF. The compliance score (expressed in %) will also be recorded 
in the eCRF (Visits 3, 4, 5, 6, 8, 10 and 12). 
In case of missing IMP compliance data for a patient at a clinic visit (due to IMP bottles 
missing/lost since last visit), the worst-case scenario will apply, i.e. the IMP compliance will be 
considered as 0% for that clinic visit. 
At least 80% compliance will be defined as acceptable during the Open-Label and Double-Blind 
Treatment Periods.  
5.1.11 Definitions relative to efficacy criteria 
5.1.11.1 Primary efficacy endpoint 
The primary efficacy endpoint is Time to intervention. Since it is predominantly based on the 
OHSA item 1 score, it is believed that the time-to-intervention endpoint requires corroboration to 
ensure that worsening OHSA item 1 scores represent a true event. The criteria below represent 
a balanced approach to identify true events requiring treatment intervention. 
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During the Double-Blind treatment period, eligible patients will be withdrawn from the study if they 
require treatment intervention for their NOH symptoms, defined by meeting ANY of the following 
criteria: 
• 
Criterion 1: OHSA item 1 ≥2 units worsening from randomization and lack of efficacy as 
judged by the investigator; OR 
• 
Criterion 2: OHSA item 1 ≥2 units worsening from randomization at 2 consecutive visits; 
OR 
• 
Criterion 3: OHSA item 1 ≥2 units worsening from randomization at the visit before early 
discontinuation; OR 
• 
Criterion 4: Patient stops IMP or withdraws from study for patient-reported lack of efficacy  
A consecutive visit for OHSA item 1 will be defined as the next non-missing OHSA item 1 result, 
including the results from unscheduled visit.  If a patient has all OHSA item 1 missing after having 
a worsening OHSA item 1 ≥2 units (and not in Criterion 1, 3 and 4) then this patient is considered 
a treatment failure. See below an example for four patients who have an unscheduled visit 
between Visit 10 and 12. ‘Yes’ means that OHSA item 1 ≥2 units worsening from randomization 
(and not in Criterion 1, 3 and 4). ‘No’ means that OHSA item 1 <2 units worsening from 
randomization. ‘Missing’ means that OHSA item 1 is missing for this patient for this particular visit. 
 
Patient 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Unsche-
duled 
Visit 
Visit 
11 
Visit 
12 
Outcome 
001 
Yes 
No 
Yes 
No 
Yes 
No 
No 
This patient is not 
considered a treatment 
failure 
002 
No 
Yes 
missing 
missing 
Yes 
No 
No 
This patient is considered 
a treatment failure at the 
unscheduled visit 
003 
No 
No 
No 
Yes 
No 
Yes 
No 
This patient is not 
considered a treatment 
failure  
004 
Yes 
missing 
missing 
missing 
missing 
missing 
missing 
This patient is considered 
a treatment failure at visit 
7 
 
The timing of the need for intervention in the above criteria is defined as the first occurrence of a 
worsening of OHSA item 1 by ≥ 2 units, or when the patient stops taking IMP or withdraws due 
to a patient-reported lack of efficacy, whichever comes first. 
5.1.11.2 Secondary efficacy endpoints 
5.1.11.3 Orthostatic Hypotension Questionnaire (OHQ) 
The severity of NOH symptoms in patients is assessed using the Orthostatic Hypotension 
Questionnaire1. The questionnaire consists of two separate sections: an Orthostatic Hypotension 
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Symptom Assessment (OHSA) scale and an Orthostatic Hypotension Daily Activity Scale 
(OHDAS) (see Appendix A). 
The OHSA scale is designed to rate symptoms occurring specifically as a result of low blood 
pressure (BP), using an 11-point scale (0 to 10), with more severe symptoms scoring higher. A 
score of zero indicates that the symptom was not experienced. The scale assesses six symptoms: 
1) dizziness/lightheadedness, 2) problems with vision, 3) weakness, 4) fatigue, 5) trouble 
concentrating, and 6) head/neck discomfort. Scores for each symptom and a composite score for 
all 6 symptoms are tabulated. The OHSA composite score is calculated as the average of the 
individual OHSA item score not rated zero at baseline. 
The OHDAS is designed as a measure of quality of life. It uses an 11-point scale to assess 
whether OH “interfered” with 4 types of activities in the preceding week: 1) standing for a short 
time, 2) standing for a long time, 3) walking for a short time, and 4) walking for a long time. A 
score of zero means that in the preceding week, the activity was performed with no interference 
and a score of 10 means that OH completely interfered with the activity. As many of these patients 
have difficulty walking or standing for reasons not directly related to their OH (e.g., parkinsonism 
or somatic neuropathy), patients are able to check a box in the questionnaire stating that they 
could not perform the activity for reasons other than OH. Scores for each activity and a composite 
score for all 4 activities are tabulated. The OHDAS composite score is calculated as the average 
of the individual OHDAS item score not rated zero at baseline. 
An overall OHQ composite score is calculated as the average of the OHSA and OHDAS 
composite scores. 
The OHSA item 1 score and the OHQ composite score will be analysed at 2, 4, 6, 8, 10, and 12 
weeks post-randomization (Visits 7-12) by comparing with scores at randomization (Visit 6). 
5.1.11.4 Clinical Global Impression - Severity (CGI-S) 
The CGI-S2 is a one-item scale evaluating the severity of the patient’s illness on a 7-point scale: 
1=normal, no OH; 2=borderline OH; 3=mild OH; 4=moderate OH; 5=marked OH; 6=severe OH; 
7=most extremely ill with OH (see Appendix B). 
The clinician-reported CGI-S asks the clinician the question: “Considering your total clinical 
experience with this particular population, how severe is the patient’s orthostatic hypotension 
(OH) at this time?”. The patient-reported CGI-S asks the patient the question: “How severe is your 
orthostatic hypotension (OH) at this time?”. 
The clinical- and patient-rated CGI-S scores will be analysed at 2, 4, 6, 8, 10, and 12 weeks’ post-
randomization (Visits 7-12) by comparing with the scores at randomization (Visit 6). 
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5.1.12 Definitions relative to safety parameters 
To assess the long-term safety and tolerability of Droxidopa in patients with symptomatic NOH, 
adverse events, clinical safety laboratory assessments, vital signs, and physical examination 
were performed throughout the study. 
5.1.12.1 Adverse Event (AE) 
An AE is any untoward medical occurrence in a clinical study patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including clinically significant out-
of-range values from relevant tests, such as clinical safety laboratory tests, vital signs, ECGs), 
symptom, or disease temporally associated with the use of a medicinal product, regardless of 
whether it is considered related to the medicinal product.  
All AEs, including pre-treatment AEs (those that start after the patient has signed the ICF and 
prior to the first dose of IMP) will be collected and recorded until 30 days after the last dose of 
IMP. 
5.1.12.2 Serious Adverse Event (SAE) 
An SAE is any AE that: 
• 
results in death 
• 
is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenial anomaly/birth defect  
• 
is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above) 
5.1.12.3 Duration of AEs 
The duration of an AE will be calculated as the resolution date minus the date at which it first 
appeared plus 1. 
In the case of an AE still continuing at the end of the study, the duration will be considered as 
unknown. 
5.1.12.4 Relationship of AEs 
The Investigator will assess the causal relationship between an AE and the IMP using the 
following definitions: 
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• 
Probable: the AE has a strong temporal relationship to the IMP or recurs on re-challenge, 
and another aetiology is unlikely or significantly less likely. 
• 
Possible: the AE has a suggestive temporal relationship to the IMP, and an alternative 
aetiology is equally or less likely. 
• 
Not related: the AE has no temporal relationship to the IMP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event). 
Adverse events will be considered causally related to the use of the IMP when the causality 
assessment is probable or possible, or if the relationship is not recorded.  
5.1.12.5 Intensity of AEs 
The Investigator will assess the intensity of AEs using the following definitions:  
• 
Mild: the AE causes minimal discomfort and does not interfere in a significant manner with 
the subject’s normal activities 
• 
Moderate: the AE is sufficiently uncomfortable to produce some impairment of the subject
’s normal activities 
• 
Severe: the AE is incapacitating, preventing the subject from participating in his or her 
normal activities. 
5.2 
Handling of missing data and/or invalid data and outliers 
5.2.1 Missing data analysis methods 
Exploratory analyses of the following secondary efficacy endpoints (quantitative variables) in the 
Double-Blind treatment period will be performed using the FAS using descriptive methods: 
• 
OHSA item 1 score from randomization (Visit 6) to all post-randomization visits (Visits 7-
12) 
• 
OHQ composite score from randomization (Visit 6) to all post-randomization visits (Visits 
7-12) 
• 
Clinician-reported CGI-S score from randomization (Visit 6) to all post-randomization visits 
(Visits 7-12) 
• 
Patient-reported CGI-S score from randomization (Visit 6) to all post-randomization visits 
(Visits 7-12) 
Missing change from randomization (Visit 6) to each post-randomization visit (Visits 7-12) will be 
imputed using LOCF, which is assumed to be a conservative approach in a 
randomized-withdrawal study, as the majority of the patients will be withdrawn when response is 
lost based on the OHSA item 1 score. Missing post-baseline data will be imputed using the last 
non-missing observation prior to calculating change from baseline. 
In addition, due to the study design, missing data due to meeting the treatment intervention criteria 
are categorized as missing not at random (MNAR), and a modified baseline observation carried 
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forward (BOCF) method will be applied, where missing data (due to any reason) will be imputed 
with the last available post-randomization OHSA Item 1 score. When no post-randomization score 
is available, the baseline value obtained before the start of treatment in the titration period (Visit 
2a) will be used for imputations during the Double-Blind treatment period rather than the score at 
randomization (Visit 6), which is the baseline for the Double-Blind treatment period. The score at 
Visit 6 should not be missing, as OHSA Item 1 is part of the randomization criteria. However, in 
the unlikely event that it is missing, the score will be imputed with the last-obtained score from the 
Open-Label period. This method is assumed to provide a conservative estimate of the treatment 
difference. 
5.2.2 Handling of missing or incomplete dates 
5.2.2.1 Concomitant medications definition and handling of missing or 
incomplete dates 
Medications will be assigned as being prior to the IMP or concomitant with IMP, based on the 
start and stop dates of the medication and the date of the first IMP dose (Visit 2a). If the medication 
stop date is before the date of the first dose of IMP, the medication will be assigned as being prior 
to IMP. Otherwise, the medication will be assigned as being concomitant with IMP. Concomitant 
medications that continued after first dose of IMP or that started after first dose of IMP will be 
tabulated separately and will be split into Open-Label period and Double-Blind period. 
Prior medications – medications that stopped before visit 2a.  
Concomitant medications during Titration period – medications that continued after first dose of 
IMP or that started after first dose of IMP.  
Concomitant medication during Open Label period – medications that continued on or after visit 3 
or started after visit 3.  
Concomitant medication during Double-Blind Period – medications that continued after visit 6. 
If the start date or stop date for a medication is missing or incomplete to the extent that it could 
be before or after the first IMP dose, then it will be assumed that the medication was started or 
stopped after the start of IMP (i.e. reported as a concomitant medication). 
5.2.2.2 Definition of treatment-emergent AEs and handling of missing or 
incomplete dates 
A treatment-emergent AE (TEAE) is defined as an AE occurring or worsening on or after the date 
of first IMP dose (Visit 2a). Events with an onset date or end date prior to the start of IMP will be 
classified as pre-treatment AEs. 
If the onset date of an AE is partially or completely missing (such that it cannot be determined if 
the event onset was prior to the start of IMP), the AE will be assumed to be treatment-emergent, 
unless the AE stop date indicates otherwise (worst-case approach). 
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Tabulations of AEs will be split into Titration Period, Open-Label period, and Double-Blind period. 
For AEs listings, dates will be presented as they have been recorded (missing and partial dates 
will not be replaced). 
5.2.3 Handling of Early Termination (ET) data 
If, at any time during the study, a patient requests to withdraw from treatment or if a decision is 
made to withdraw the patient, including during the Double-Blind treatment period due to a need 
for intervention, the patient will be requested to return for an Early Termination Visit. Whenever 
practical, patients should be encouraged to remain on IMP until the completion of the early 
termination procedures. Such assessments are recorded on the ‘Visit 12 - End of Treatment/Early 
Termination Visit’ CRF pages. 
5.2.3.1 Handling of ET data during the Titration Period 
In patient listings and summary tabulations, the following time point will be presented to reflect 
this data: 
• 
‘Visit 3/ET’: If the ET Visit occurred during the Open-Label titration period, the ET Visit 
data will be labelled ‘Visit 3/ET’ and summarized separately from the other scheduled time 
points for that period. 
5.2.3.2 Handling of ET data during the Open-Label Period 
Descriptive summary statistics based on absolute values and changes (relative to visit 2a) from 
baseline will be used to present the visits in the Open-Label treatment period (Visits 3-6) for the 
secondary efficacy endpoints (quantitative variables) using all available data. 
For patients who withdrew during the Open-Label treatment period, the Early Termination visit 
will be reassigned for the OHSA item 1 score, the OHQ composite score, and both the clinician- 
and patient-reported CGI-S scores tabulation by visit using the actual visit/assessment dates and 
the following visit windows, based on baseline date (date of Visit 3 or repeat assessment on Day 
0): 
Visit 
Visit Window 
Baseline (Open-Label) 
0 (no window) 
Visit 4 (Day 28) 
1 to 42 
Visit 5 (Day 56) 
43 to 70 
Visit 6 (Day 84) 
71 
In summary tabulations, the ET data will be presented at the visit determined by the above rules. 
Within patient listings, this time point will be labeled as ‘Visit 6/ET’. In the event that a patient’s 
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ET Visit is assigned (using the above rules) to a visit where he/she had attended (and thus, 
already had data), the data collected at the ET Visit will not be tabulated. 
5.2.3.3 Handling of ET data during the Double-Blind Period 
Descriptive summary statistics will be used to present the visits in the Double-Blind treatment 
period for the secondary efficacy endpoints (quantitative variables) using all available data 
between Visit 6 and Visit 12/Early Termination. 
For patients who withdrew during the Double-Blind treatment period, the Early Termination visit 
will be reassigned for the OHSA item 1 score, the OHQ composite score, and both the clinician- 
and patient-reported CGI-S scores tabulation by visit using the actual visit/assessment dates and 
the following visit windows, based on baseline date (date of randomization on Day 0): 
Visit 
Visit Window 
Baseline (Double-Blind) 
0 (no window) 
Visit 7 (Week 2) 
1 to 21 
Visit 8 (Week 4) 
22 to 35 
Visit 9 (Week 6) 
36 to 49 
Visit 10 (Week 8) 
50 to 63 
Visit 11 (Week 10) 
64 to 77 
Visit 12 (Week 12) 
78 
In summary tabulations, the ET data will be presented at the visit determined by the above rules. 
Within patient listings, this time point will be labeled as ‘Visit 12/ET’. In the event that a patient’s 
ET Visit is assigned (using the above rules) to a visit where he/she had attended (and thus, 
already had data), the data collected at the ET Visit will not be tabulated. 
6 
STATISTICAL PLAN AND METHODS 
All data analyses and generation of TLFs will be performed using the SAS® software package 
version 9.4 or higher. 
Descriptive statistical methods will be used to summarize the data, with statistical testing 
performed for the primary efficacy endpoint (time-to-intervention) and the key secondary endpoint 
(time to all-cause discontinuation). To control the overall type I error, statistical significance of the 
key secondary endpoint will be evaluated using hierarchical testing.  
Analyses of the other secondary efficacy endpoints will be considered supportive and no 
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confirmatory statistical testing will be performed. Nominal P-values will be calculated for 
presentation purpose.  
Unless otherwise stated, all statistical testing will be two-sided using a significance (alpha) level 
of 0.05.  
Continuous variables will, as a minimum, be summarized by number of non-missing observations 
(n), arithmetic mean (Mean), standard deviation (SD), minimum (Minimum), median (Median), 
and maximum (Maximum). One additional decimal point for mean and median and 2 additional 
decimal points for SD will be used.  
Categorical variables will be summarized using the number of non-missing observations (n) or 
the number of patients in the population (N), as applicable, and percentages (%). Percentages 
will be rounded to one decimal place. Two-sided 95% confidence intervals (CI) will be provided, 
when relevant.  
Unless otherwise stated, the baseline in each study period as per section 5.1.2. The change from 
baseline value at each post-baseline assessment (scheduled and unscheduled assessments) will 
be calculated as post-baseline value minus the baseline value for each post-baseline time point. 
Unless otherwise stated, only scheduled assessment change from baseline values (including ET 
Visits windowed per Section 5.2.3) will be tabulated; however, all changes from baseline in safety 
assessment values will be included when listed. 
The term “treatment group” refers to randomized treatment assignment for the Double-Blind 
Period. Summaries of efficacy and safety data will be presented in terms of randomized treatment 
group (Droxidopa and Placebo separately and overall) as well as for the Open-Label periods. 
Unless otherwise stated, unscheduled/repeat visit results will be included in date/time 
chronological order in patient listings only. All listings will be sorted by study site, patient number, 
date/time and visit. For the Double-Blind Period, the treatment group (Droxidopa and Placebo) 
will be stated in each listing. Unless otherwise stated, data listings will be based on the 
All-Enrolled set. 
Subgroup investigations will be performed to assess the potential impact of COVID-19 on the 
recruited patient population. The subgroup analyses will include demographics and baseline 
characteristics as well as efficacy subgroup analyses and/or sensitivity analyses stratified on the 
cut-off date (time-to-event) or adjusted for the cut-off date (ANCOVA). The cut-off date for these 
subgroup analyses will be 17 March 2020, which is the date when Lundbeck issued formal 
guidance to investigators on the COVID-19 pandemic. The cut-off date will be applied to the 
enrolment date, the randomization date and/or the withdrawal date, as further specified in sections 
6.1 and 6.2. Comparisons between groups will be done based on visual inspections, if not 
otherwise stated. 
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6.1 
Background characteristics 
6.1.1 Patient disposition 
All patients who provided informed consent will be included in a summary of patient disposition. 
The number of patients screened, the number of screening failures, the frequency and percentage 
of patients enrolled, in enrolled and treated in the Open-Label period, in the Safety set randomized 
(by treatment group and overall), in the FAS (by treatment group and overall) will be summarized. 
The frequency and percentage of patients who completed/withdrew in the Titration Period, in the 
Open-Label Period, and in the Double-Blind Period (by treatment group and overall) will also be 
tabulated with the primary and all reasons for withdrawal. The reasons for screening failure will 
also be tabulated. 
In addition, the number of enrolled, the number of randomized patients, and the main reason for 
withdrawal before and on/after 17 March 2020 will be included in the tabulations. 
Patient disposition will be summarized by study periods (Titration Period, Open-Label Period, and 
the Double-Blind Period).  Each study period summarizes (as appropriate) the number of patients 
screened, enrolled, randomized, completed, withdrawn, and the number of patients in each 
analysis sets.  Withdrawal from the study will be summarized by primary reason and all reasons 
for withdrawal for each study period. 
Patients withdrawn from the study will be listed, including last dose of IMP received prior to 
withdrawal and study period for withdrawal. 
For all patients randomized, listings will be provided displaying screening number, randomization 
number, site ID, and treatment group, sorted by screening number. A similar list will be created 
sorted by randomization number, screening number, site ID, and treatment group. 
6.1.2 Protocol Deviation 
All major protocol deviations will be identified at the Classification Meeting prior to study 
unblinding using the following sources of information: 
• 
Patient listings, based on data recorded on the eCRF 
• 
Protocol Deviation Logs 
The list of protocol deviations to be identified for the CSR is defined as: 
• 
Failure to obtain informed consent (to be excluded from all analyses) 
• 
ICF not dated correctly, not witnessed, wrong version signed, pages missing or no 
documentation that copy was provided to patient 
• 
Patient does not meet one or more of the inclusion criteria 
• 
Patient meets one or more of the exclusion criteria 
• 
Non-compliance with randomization or other randomization error. Includes patient 
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randomization when not meeting criteria for randomization 
• 
Non-compliance with IMP (<80% or >120% of planned doses) during the Open-Label 
treatment period or the Double-Blind treatment period 
• 
Disallowed medications, as per Sections 4.8.3 and 4.8.4 of the protocol 
• 
Serious breach of GCP 
• 
Patient/Investigator unblinded to treatment 
• 
Incorrect treatment or dosing allocation 
• 
Patient did not meet End of Titration criteria but entered the Open-Label treatment period 
• 
Patient did not have an OHSA item 1 score meeting the randomization criterion (≥2 units 
lower [improved] than the Visit 2a score) but was randomized 
The number of patients with major protocol deviation will be summarized by treatment group (if 
applicable) and overall based on the All-enrolled Set.  
All protocol deviations will be listed based on data recorded on the eCRF and/or protocol deviation 
Logs (from ICON Medical). 
6.1.3 Demographic and baseline characteristics 
Descriptive statistics of demographic variables (age, sex, ethnicity, race, baseline height, weight 
and BMI) and baseline characteristics including medical history past/ongoing at Screening, 
primary disease diagnosis (PD, MSA, PAF, NDAN, or DBH deficiency) and duration, NOH 
duration at the Screening visit and severity at the Screening and baseline visits (prior to initial 
dose titration) (OHSA item 1 score, OHSA, OHDAS, and OHQ composite scores), both clinician- 
and patient-reported CGI-S scores at baseline (prior to initial dose titration) will be presented for 
the Safety set and the FAS by treatment group . Demographics and baseline characteristics will 
also be presented by enrolment date into the study before versus on or after 17 March 2020, and 
by randomization date before versus on or after 17 March 2020 in order to assess the potential 
impact of the COVID-19 pandemic.  
6.1.4 Medical condition 
Summaries of medical history will be presented by system organ class (SOC) and preferred term 
(PT) using Medical Dictionary for Regulatory Activities® (MedDRA) Version 24.1 or higher. 
Concurrent medical conditions will be tabulated based on the Safety set (Open-Label period) and 
the FAS (Double-Blind Period).  
6.1.5 Prior and concomitant medications and procedures 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (March 2015 or later).  
Prior and concomitant medications will be summarized according to WHO drug class and 
preferred term for each study period (Titration Period, Open-Label Period, and Double-Blind 
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Period). This analysis will be based on the Safety set (Open-Label period) and the FAS 
(Double-Blind Period). 
6.1.6 IMP exposure and compliance 
6.1.6.1 IMP exposure 
IMP exposure will be summarized for the Titration Period and the Open-Label Period (Safety Set), 
and by treatment group for the Double-Blind Period (FAS).  
Exposure to IMP in the Open-Label Titration Period will be categorized by intervals (1-10 days, 
11-20 days, ≥21 days) and summarized using quantitative and categorical variables. The sum 
of patient days of IMP exposure will also be tabulated. 
Exposure to IMP in the Open-Label Treatment Period will be categorized by intervals (1-30 days, 
31-60 days, ≥61 days) and summarized using quantitative and categorical variables. The sum 
of patient days of IMP exposure will also be tabulated.  
The distribution of IMP dose administered (100, 200, 300, 400, 500, or 600 mg TID) will be 
tabulated upon entry into the Open-Label Treatment Period (Visit 3). 
Exposure to IMP in the Double-Blind Treatment Period will be categorized by intervals (1-30 days, 
31-60 days, ≥61 days) and summarized by treatment group using quantitative and categorical 
variables. The sum of patient days of randomized IMP exposure will also be tabulated by 
treatment group. 
The distribution of randomized IMP dose administered (100, 200, 300, 400, 500, or 600 mg TID) 
will be tabulated by treatment group upon entry into the Double-Blind Treatment Period (Visit 6). 
6.1.6.2 IMP compliance 
IMP compliance will be summarized for the Titration Period and the Open-Label Treatment Period 
(Safety Set), and by treatment group for the Double-Blind Treatment Period (FAS).  
IMP compliance in the Open-Label Treatment Period will be categorized as <80% compliant, 80 
to 120% compliant, or >120% compliant and summarized using quantitative and categorical 
variables, both by scheduled visit. 
Compliance with randomized IMP will be categorized as <80% compliant, 80 to 120% compliant, 
or >120% compliant and summarized by treatment group using quantitative and categorical 
variables, by scheduled visit for the Double-Blind Treatment Period. 
6.2 
Efficacy analysis 
6.2.1 Analysis of primary endpoint 
6.2.1.1 Primary analysis 
The primary efficacy analysis will be based on the FAS. 
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The time-to-intervention is the primary endpoint and will be summarized using the Kaplan-Meier 
method3.  
The primary efficacy analysis is the Log-rank test to compare the two treatment groups on time 
to treatment intervention during the Double-Blind treatment period. 
A Kaplan-Meier survival curve for time to treatment intervention in the 12 weeks post-
randomization will be displayed by treatment group. The p-value of the Log-rank test comparing 
the treatment groups will be displayed in the survival curve. 
Patients who withdrew or were lost to follow-up without meeting the criteria for treatment 
intervention will be censored at the time of withdrawal or last contact date; patients who did not 
meet the criteria for treatment intervention at the end of the Double-Blind Period (Visit 12) will be 
censored at the date of study completion. 
6.2.1.2 Descriptive analyses 
The number and percentage of patients who presented a need for treatment intervention, the 
number and percentage of patients still at risk for treatment intervention, and the number and 
percentage of censored patients will be tabulated. The treatment-intervention-free rate estimate 
and the corresponding two-sided 95% CI (using log-log methodology) will be presented at the 
upper limit of the visit window. The time window for the 12-week treatment-intervention-free rate 
is ≤84 + 3 days post-randomization. The median and quartiles time until treatment intervention 
will also be summarized with the corresponding 95% CIs. 
6.2.1.3 Sensitivity analyses 
A Cox proportional hazards model4 will be used, including treatment as a factor and baseline 
OHSA item 1 score (prior to initial dose titration) as a covariate in order to compare the probability 
of need for treatment intervention between the two treatment groups. Treatment effect will be 
presented as a hazard ratio (HR) with the corresponding 95% Wald CI and p-value based on the 
Wald chi-square test. 
Furthermore, both Kaplan-Meier and Cox regression analyses will also be performed as part of 
the following sensitivity analyses based on the FAS: 
• 
Time to treatment intervention according to the treatment intervention criteria (Section 
5.1.11.1) or OHSA item 1 ≥2 units worsening from randomization at the last visit of the 
Double-Blind Period (Visit 12) 
See Appendix C for SAS code used to implement Kaplan-Meier method and Cox proportional 
hazards model. 
To assess the potential impact of the COVID-19 pandemic, a sensitivity analysis will be performed 
based on the primary analysis model, but stratified by randomization date before or on/after 17 
March 2020.  In addition, a subgroup analysis based on the primary analysis model will be 
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performed using the same cut-off for the randomization date subgroups. 
6.2.2 Analysis of key secondary endpoint 
Time to all-cause-discontinuation is the key secondary endpoint. 
Analysis of the key secondary endpoint will be based on the FAS.  
During the Double-Blind treatment period, the time to all-cause-discontinuation is defined as the 
time from randomization to withdrawal or last contact date. 
Patients who did not withdraw at the end of the Double-Blind Period (Visit 12) will be censored at 
the date of study completion. 
Sensitivity analyses of the potential impact of the COVID-19 pandemic will be performed the same 
way as described in Section 6.1.2.3.  
6.2.2.1 Testing strategy for key secondary endpoint 
A gate keeping strategy will be applied in the testing of the key secondary endpoint. The Log-rank 
test will be performed at the nominal alpha level of two-sided 0.05 and will be considered part of 
the testing strategy only if the primary efficacy endpoint reached the statistical significance in the 
primary analysis. This is to ensure that the overall type I error rate is preserved. The key 
secondary analysis will be performed similar to the primary efficacy analysis (Log-rank test of 
treatment difference, Kaplan-Meier plot, Cox regression analysis). 
6.2.3 Analysis of other secondary endpoints 
Analysis of all other secondary endpoints (described in Section 3.2.2.2) will be based on the FAS 
using observed cases, LOCF, and modified BOCF.  
For exploratory purposes, Droxidopa will be compared to placebo. Nominal P-values will be 
calculated. Early Termination data will be utilized for data summarizations as specified in Section 
5.2.3.3. 
Summary tables including summary statistics by treatment group and visits and change from 
baseline summaries will be provided for: 
• 
Analysis of OHSA item 1 score from randomization (Visit 6) to all post-randomization visits 
(Visits 7-12) 
• 
Analysis of OHQ composite score from randomization (Visit 6) to all post-randomization 
visits (Visits 7-12) 
• 
Analysis of clinician-reported CGI-S score from randomization (Visit 6) to all post-
randomization visits (Visits 7-12) 
• 
Analysis of patient-reported CGI-S score from randomization (Visit 6) to all post-
randomization visits (Visits 7-12) 
For each of the secondary endpoint, graphical representations of the data distribution using plots 
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of mean change from baseline (mean and 95% CI) will be provided over time by treatment group. 
Additionally, the change from randomization to Week 12 in OHSA Item 1 score will be analysed 
using an analysis of covariance (ANCOVA) model that includes the treatment group, the pooled 
site (based on US state), and the OHSA Item 1 score at randomization. Additionally, the change 
from randomization (Visit 6) to all other visits (Visits 7-12) will be analysed using the same model. 
A sensitivity analysis will also be performed, including the change in OHSA Item 1 score from pre-
treatment baseline (Visit 2a) to randomization (Visit 6) rather than having the OHSA Item 1 score 
at randomization as a covariate. In case of missing value at any post-randomization visit (Visits 
7-12), the missing values will be imputed using LOCF as well as modified BOCF. Another 
sensitivity analysis will be performed with an indicator of randomization before or on/after 17 
March 2020 included in the model to adjust for potential impact of the COVID-19 pandemic. 
The number and proportion of patients who needed treatment intervention will be summarized by 
treatment group: 
• 
over the 12-week Double-Blind treatment period (between Visit 6 and Visit 12/Early 
Termination) 
• 
For each of the criteriaa defining the need for treatment intervention 
The need for treatment intervention during the 12-week Double-Blind treatment period will be 
compared between treatment groups using Chi-square test (of Fisher’s exact test). A similar 
comparison between treatment groups will be performed for each of the criteriaa defining the need 
for treatment intervention. 
For quantitative variables, summary tables including summary statistics by scheduled visits and 
change from baseline will be provided for OHSA item 1 score, OHQ composite score, and both 
clinician- and patient-reported CGI-S scores in the Titration Period and Open-Label Treatment 
Period. 
6.3 
Safety analysis 
All the safety analyses will be based on the Safety set. 
Adverse events, vital signs, and clinical safety laboratory assessments will be performed 
throughout the study. Adverse events will be assessed for the Titration Period, the Open-Label 
Period, and for Double-Blind Period separately. Vital sign and clinical safety laboratory 
assessments will be assessed in two periods of the study: the entire Open-Label portion of the 
study (Titration Period and Open-Label Period) and the Double-Blind Period. The Titration and 
 
a Criterion 1: OHSA item 1 ≥2 units worsening from randomization and lack of efficacy as judged by the investigator; 
Criterion 2: OHSA item 1 ≥2 units worsening from randomization at 2 consecutive visits; Criterion 3: OHSA item 1 ≥2 
units worsening from randomization at the visit before early discontinuation; Criterion 4: Patient stops IMP or withdraws 
from study for patient-reported lack of efficacy. 
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Open-Label Periods will be presented as appropriate in standard tabulations and listings. The 
absolute values and the changes from randomization to Week 12 in the Double-Blind Treatment 
Period will be summarized separately using standard tabulations and listings. The two treatment 
groups will be analysed separately during the Double-Blind Treatment Period. The analysis of 
safety endpoints during the Double-Blind Treatment Period will be based on the FAS. Patients 
who did not receive the planned randomized treatment during the Double-Blind Period will be 
analysed according to the actual treatment received for >50% of the treatment duration. 
6.3.1 Adverse events 
All AEs will be coded according to the MedDRA, Version 24.1 or higher. 
The incidence of adverse events will be summarized for the Titration Period, the Open-Label 
Period, and for Double-Blind Period separately. 
Summary presentations will be produced by treatment group (Double-Blind Period) and period 
(Titration Period, Open-Label Period and Double-Blind Period separately), for the number and 
percentage of patients in each of the following categories: at least one TEAE, TEAEs related to 
the IMP, severe TEAEs, TEAEs leading to IMP withdrawal, SAEs, SAEs related to the IMP and 
SAEs leading to IMP withdrawal.  
Serious AEs and AEs that lead to IMP withdrawal will be listed. 
Additional summaries will be produced for TEAEs (Titration Period, the Open-Label Period and 
Double-Blind Period separately) showing number and percentage of patients for: 
• 
Incidence of TEAEs by treatment group (Double-Blind Period), SOC and PT 
• 
Incidence of TEAEs related to the IMP by treatment group (Double-Blind Period), SOC 
and PT 
• 
Incidence of TEAEs leading to IMP withdrawal by treatment group (Double-Blind Period), 
SOC and PT 
• 
Incidence of SAEs by treatment group (Double-Blind Period), SOC and PT 
The incidence of TEAEs by the maximum severity overall and by SOC and PT will be presented 
by treatment group (Double-Blind Period), and similarly for TEAEs related to IMP. TEAEs with an 
incidence ≥5% will be summarized. 
All AEs will be listed by site/patient and will include verbatim and PT and SOC, onset and 
resolution date/time, study day of onset, the number of days since the last IMP dose prior to onset, 
duration, severity, seriousness, outcome, relationship to IMP, and action taken with IMP. The 
number of days since the last IMP dose prior to the AE onset will be calculated based on the 
difference in dates between the IMP dose and the onset date of the AE. 
Pre-treatment AEs and TEAEs will be listed (Safety Set). 
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6.3.2 Clinical safety laboratory tests 
All analytical tests will be performed by ICON Central Laboratories. The laboratory’s set of 
reference ranges will be listed. The Lundbeck’s set of potentially clinically significant (PCS) criteria 
will be listed. Urine pregnancy test will be assessed at sites. 
The following clinical safety laboratory tests will be performed at Screening (Visit 1), at the End of 
Open-Label Treatment/Randomization (Visit 6), and at the End of Treatment Visit (Visit 12/Early 
Termination), as well as at any unscheduled visit if deemed appropriate by the Investigator: 
• 
Hematology: 
o Haemoglobin 
o Erythrocyte Count 
o Haematocrit 
o Total Leucocyte Count 
o Neutrophils 
o Eosinophils 
o Basophils 
o Lymphocytes 
o Monocytes 
o Thrombocyte Count 
• 
Clinical Chemistry: 
o Total Bilirubin 
o Alkaline phosphatase (AP) 
o Alanine Aminotransferase (ALT) 
o Aspartate Aminotransferase (AST) 
o γ-glutamyl transferase (γGT) 
o Sodium 
o Potassium 
o Calcium (Total) 
o Bicarbonate 
o Chloride 
o Albumin 
o Glucose 
o Creatinine 
o Blood Urea Nitrogen (BUN) 
o Total Protein 
• 
Urinalysis: 
o pH 
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o Specific Gravity 
o Protein 
o Glucose 
o Ketones 
o Blood 
o Bilirubin 
o Leukocytes 
o Nitrites 
o Microscopic sediment examination, only if dipstick is abnormal 
The clinical safety laboratory data will be reported in Standard International (SI) units. 
Clinical safety laboratory parameters (haematology and clinical chemistry) will be summarized 
using descriptive statistics by scheduled visits by treatment group (Double-Blind Period) and 
Droxidopa (Open-Label portions). Change from baseline to each post-baseline visit will also be 
produced.  
Urinalysis dipstick results will be summarized categorically by visit for each test and microscopy 
results will be summarized by visits according to the dipstick results by treatment group (Double-
Blind Period) and Droxidopa (Open-Label portions). 
Shift tables (haematology and clinical chemistry) will be presented as appropriate, showing the 
shift from baseline to post-baseline, categorized as below, within or above the reference range, 
presented by treatment group (Double-Blind Period) and Droxidopa (Open-Label portions).  
The number and percentage of patients with PCS values will be summarised by parameter 
(haematology, clinical chemistry and urinalysis), visit, treatment group (Double-Blind Period) and 
Droxidopa (Open-Label portions). All available assessments will be included in the evaluation of 
PCS values (scheduled, reassessments, and unscheduled). See Appendix D for the Lundbeck 
PCS Criteria.  
The number and percentage of patients with at least one post-baseline PCS value will be 
summarized by parameter (haematology, clinical chemistry), treatment group (Double-Blind 
Period) and Droxidopa (Open-Label portions). All available assessments will be included in the 
evaluation of PCS values (scheduled, reassessments, and unscheduled).  
For patients with post-baseline PCS values, listings of all PCS laboratory values sorted by 
site/patient will be provided including all available values for the specific parameter, with flagging 
of PCS values. Listings will include out-of-range flags (“H” for a value higher than the upper limit 
of the reference ranges, “L” for a value lower than the lower limit of the laboratory reference 
ranges).    
If a lab value is reported using a nonnumeric qualifier e.g., less than (<) a certain value, or greater 
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than (>) a certain value, the given numeric value will be used in the summary statistics, ignoring 
the nonnumeric qualifier. 
The clinical safety laboratory data will be based on the Safety Set. 
6.3.3 Vital signs and weight 
Vital signs (seated BP, heart rate, respiratory rate, temperature) and weight will be measured at 
Screening (Visit 1), at the first visit of the Titration Period (Visit 2a) and at Visit 3; at Visit 3, a 
second seated BP will be measured ~2 hours post-dose. At Visits 4-12 (and at the Early 
Termination Visit), supine BP will be measured instead of seated BP. 
Vital signs will be summarized by visits by treatment group (Double-Blind Period) and Droxidopa 
(Open-Label portions). The change from baseline to each scheduled post-dose assessment will 
also be summarized. 
The number and percentage of patients with PCS value will be summarized by parameter, visit, 
treatment group (Double-Blind Period) and Droxidopa (Open-Label portions). All available 
assessments will be included in the evaluation of PCS values (scheduled and unscheduled). See 
Appendix D for the Lundbeck PCS Criteria.  
The number and percentage of patients with at least one post-dose PCS value will be summarized 
by parameter, treatment group (Double-Blind Period) and Droxidopa (Open-Label portions). All 
available assessments (scheduled and unscheduled) will be included in the evaluation of PCS 
values.  
For patients with post-baseline PCS values, listings of all PCS values sorted by site/patient will 
be provided including all available values for the specific parameter, with flagging of PCS values.  
The vital signs data will be based on the Safety Set. 
7 
CHANGES FROM THE PLANNED ANALYSIS IN STUDY PROTOCOL 
• 
Both clinician- and patient-reported CGI-S ratings will be analysed as quantitative 
variables instead of a categorical analysis. Quantitative analysis will be used to summarize 
both clinician- and patient-reported CGI-S scores at each scheduled visit as well as 
changes from baseline. 
• 
The APTS has been renamed to FAS to avoid confusion (all patients were treated with 
droxidopa in the initial Open-Label part of the study). 
• 
The per protocol analyses have been removed as they add no value to a late stage study. 
• 
A modified BOCF has been introduced for imputation of missing data. 
• 
The changes in the OHSA item 1 score during the Double-Blind treatment period will be 
explored using ANCOVA, with missing data imputed with LOCF as well as mBOCF.  
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• 
Subgroup based on the cut-off date 17 March 2020 has been added to assess the 
potential impact of the COVID-19 pandemic. 
 
 
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8 
REFERENCES 
1. 
Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic 
Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale. Clin 
Auton Res. 2012; 22(2):79-90. 
2. 
Busner J, Targum SD. The Clinical Global Impressions Scale: applying a research tool in 
clinical practice. Psychiatry. 2007; 4(7):28-37. 
3. 
Goel MK, Khanna P, Kishore J. Understanding survival analysis: Kaplan-Meier estimate. 
Int J Ayurveda Res. 2010; 1(4):274-278. 
4. 
Cox DR. Regression Models and Life-Tables. J R Stat Soc. 1972; 34(2):187-220. 
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APPENDIX A - ORTHOSTATIC HYPOTENSION QUESTIONNAIRE (OHQ) 
 
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APPENDIX B - CLINICAL GLOBAL IMPRESSIONS - SEVERITY (CGI-S) 
 
CLINICAL GLOBAL IMPRESSIONS - CLINICIAN 
1) Severity of Illness 
Considering your total clinical experience with this particular population, how severe 
is the patient’s orthostatic hypotension (OH) at this time? 
0 - Not assessed 
1 - Normal, no OH 
2 - Borderline OH 
3 - Mild OH 
4 - Moderate OH 
5 - Marked OH 
6 - Severe OH 
7 - Among those patients most extremely ill with OH 
 
CLINICAL GLOBAL IMPRESSIONS - PATIENT 
1) Severity of Illness 
How severe is your orthostatic hypotension (OH) at this time? 
0 - Not assessed 
1 - Normal, no OH 
2 - Borderline OH 
3 - Mild OH 
4 - Moderate OH 
5 - Marked OH 
6 - Severe OH 
7 - Most extremely ill with OH 
 
 
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APPENDIX C – ALGORITHMS/SAS REFERENCE CODES 
• 
Tables that require Kaplan-Meier estimates and log-rank test: 
PROC LIFETEST data=dataset timelist=(0 2 4 6 8 10 12) alpha=.05 outsurv=estim reduceout; 
TIME time*event(0); 
STRATA trt; 
RUN; 
 
Notes:  
– 
Time represents the time to event or time to censoring; 
– 
Event represents the censoring indicator (0 = censored); 
– 
Trt represents the treatment group; 
 
• 
Tables that require Cox proportional hazards model and 95% CIs of hazard ratios 
between treatments: 
PROC PHREG data=dataset; 
CLASS trt OHSA_1_score; 
MODEL time*event(0) = trt OHSA_1_score / ties=exact; 
CONTRAST 'a vs b' trt 1 -1 / estimate=exp; 
RUN; 
 
Notes:  
– 
Trt represents the treatment group; 
– 
OHSA_1_score represents the OHSA item #1 score (quantitative) prior to initial dosing 
at the first Titration Visit (Visit 2a); 
– 
Time represents the time to event or time to censoring; 
– 
Event represents the censoring indicator (0 = censored); 
– 
Treatment order: 1 = Droxidopa, 2 = Placebo; 
 
 
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Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: NOH402 
                         Version: Final 3.0, Date: 12 May 22 
Page 44 of 46 
 
APPENDIX D – LUNDBECK PCS CRITERIA 
The Lundbeck PCS criteria are presented on the next page for clinical safety laboratory tests and 
vital signs. 
The PCS criteria are either absolute, relative to the lower limit of the reference range (LLN) or the 
upper limit of the reference range (ULN), or relative to the baseline value. 
 
 
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Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: NOH402 
                         Version: Final 3.0, Date: 12 May 22 
Page 45 of 46 
 
Lundbeck PCS Criteria for Clinical Safety Laboratory Tests 
 
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Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: NOH402 
                         Version: Final 3.0, Date: 12 May 22 
Page 46 of 46 
 
Lundbeck PCS Criteria for Clinical Safety Laboratory Tests (continued) 
 
Lundbeck PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference 
 
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