The Role of the Noradrenergic System in the Nonmotor Symptoms of Parkinson's Disease: Orthostatic Hypotension and Other Nonmotor Symptoms
Phase: EARLY_PHASE1
Conditions: Parkinson Disease
Sponsor: Nathaniel M. Robbins

 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
THE ROLE OF THE NORADRENERGIC SYSTEM IN THE NONMOTOR SYMPTOMS 
OF PARKINSON’S DISEASE 
A single center study exploring the association between orthostatic hypotension and the 
neuropsychiatric and neurocognitive features of Parkinson’s disease  
 
 
 
PI: 
Nathaniel M. Robbins MD 
Department of Neurology  
One Medical Center Drive Lebanon, NH 03576 
Funding Sponsor: 
 
 
 
Protocol Number:  
The Alexander Reeves Endowment Fund  
Department of Neurology 
Dartmouth-Hitchcock Medical Center  
 
Velos: D19090 
D-HH IRB: 31685 
IND Number: 
146199  
 
 
 
 
 
 
 
 
Initial version: 11Apr2019 
Amended: 19Sep2019 
Amended: 14Nov2019 

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Table of Contents 
STUDY SUMMARY ..................................................................................................................... 1 
1 
INTRODUCTION................................................................................................................. 2 
1.1 BACKGROUND ...................................................................................................................... 2 
1.2 INVESTIGATIONAL AGENT ................................................................................................... 3 
1.3 PRECLINICAL DATA ............................................................................................................. 4 
1.4 CLINICAL DATA TO DATE .................................................................................................... 4 
1.5 DOSE RATIONALE ................................................................................................................ 6 
1.6    RISK/BENEFITS .................................................................................................................... 6 
 
2 
STUDY OBJECTIVES ......................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................... 8 
3.1 GENERAL DESIGN ................................................................................................................ 8 
3.2 PRIMARY STUDY ENDPOINTS ............................................................................................... 9 
3.3 SECONDARY STUDY ENDPOINTS .......................................................................................... 9 
4 
SUBJECT SELECTION AND WITHDRAWAL ............................................................ 10 
4.1 INCLUSION CRITERIA ......................................................................................................... 10 
4.2 EXCLUSION CRITERIA ........................................................................................................ 10 
4.3 SUBJECT RECRUITMENT AND SCREENING .......................................................................... 11 
4.4 EARLY WITHDRAWAL OF SUBJECTS .................................................................................. 11 
4.4.1 When and How to Withdraw Subjects ....................................................................... 11 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ......................................... 12 
5 
STUDY DRUG .................................................................................................................... 12 
5.1 DESCRIPTION ..................................................................................................................... 12 
5.2 TREATMENT REGIMEN ....................................................................................................... 12 
5.3 PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................... 12 
5.4 SUBJECT COMPLIANCE MONITORING ................................................................................. 12 
5.5 PRIOR AND CONCOMITANT THERAPY ................................................................................ 12 
5.6 PACKAGING ....................................................................................................................... 13 
5.7 RECEIVING, STORAGE, DISPENSING AND RETURN........ ERROR! BOOKMARK NOT DEFINED. 
5.7.1 Receipt of Drug Supplies .......................................................................................... 13 
5.7.2 Storage ...................................................................................................................... 13 
5.7.3 Dispensing of Study Drug ......................................................................................... 13 
5.7.4 Return or Destruction of Study Drug ........................................................................ 13 
6 
STUDY DEVICES .............................................................................................................. 13 
6.1 DESCRIPTION OF NEUROPTICS® PLR-3000 ...................................................................... 13 

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7 
STUDY PROCEDURES .................................................................................................... 15 
7.1 SCHEDULE OF ASSESSMENTS ....................................... ERROR! BOOKMARK NOT DEFINED. 
7.2 VISIT 1 ............................................................................................................................... 18 
7.3 VISIT 2 ............................................................................................................................... 20 
7.4 FOLLOW-UP PHONE CALL WITH STUDY COORDINATOR ..................................................... 21 
8 
STATISTICAL PLAN ........................................................................................................ 21 
8.1 SAMPLE SIZE DETERMINATION .......................................................................................... 21 
8.2 STATISTICAL METHODS ..................................................................................................... 22 
8.3 SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................... 22 
9 
SAFETY AND ADVERSE EVENTS ................................................................................ 22 
9.1 DEFINITIONS ...................................................................................................................... 22 
9.2 RECORDING OF ADVERSE EVENTS ..................................................................................... 25 
9.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................... 25 
9.3.1 Investigator reporting: notifying the Dartmouth IRB ............................................... 26 
9.3.2 Sponsor reporting: Notifying the FDA ..................................................................... 28 
9.4 MEDICAL MONITORING ..................................................................................................... 29 
10 DATA HANDLING AND RECORD KEEPING ............................................................. 29 
10.1 CONFIDENTIALITY ............................................................................................................. 29 
10.2 SOURCE DOCUMENTS ........................................................................................................ 29 
10.3 CASE REPORT FORMS ........................................................................................................ 30 
10.4 RECORDS RETENTION ........................................................................................................ 30 
11 STUDY MONITORING, AUDITING, AND INSPECTING ......................................... 30 
11.1 STUDY MONITORING PLAN ................................................................................................ 30 
11.2 AUDITING AND INSPECTING ............................................................................................... 30 
12 ETHICAL CONSIDERATIONS ....................................................................................... 30 
13 STUDY FINANCES............................................................................................................ 31 
13.1 FUNDING SOURCE .............................................................................................................. 31 
13.2 CONFLICT OF INTEREST ...................................................................................................... 31 
13.3 SUBJECT STIPENDS OR PAYMENTS ..................................................................................... 31 
14 ATTACHMENTS ............................................................................................................... 32 
 
14.1 REFERENCES……………………………………………………………………………………...  31 
 
14.2 DRUG INSERT………………………………………………………………………………………39 
 
 
 

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List of Abbreviations 
 
OH 
Orthostatic Hypotension 
NA 
Noradrenergic 
NP 
Neuropsychiatric 
PD 
Parkinson’s disease 
 
AR  
Adrenoceptor  
ED 
Erectile Dysfunction  
HUT 
Head Up Tilt 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
H&Y 
Hoehn & Yahr staging 
LDED 
Levodopa equivalent dose 
OVS 
orthostatic vital signs 
AVP 
arginine vasopressin 
NE 
norepinephrine 
SCOPA-AUT 
Scales For Outcomes In Parkinson’s Disease - Autonomic Dysfunction 
TOPF 
Test of Premorbid Functioning 
B-SIT 
Brief Smell Identification Test  
GDS 
Geriatric Depression Scale 
GAI 
Geriatric Anxiety Inventory 
FSS 
Fatigue Severity Scale 
AES 
Apathy Evaluation Scale 
AD-ACL 
Activation-Deactivation Checklist to assess arousal 
BRIEF-A 
Behavior Rating Inventory of Executive Function, Adult 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
VAS 
Visual Analogue Score 
CNS 
Central nervous system 
ANS 
Autonomic nervous system 
LC 
Locus coeruleus 

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HR 
Heart rate 
BP 
Blood pressure 
DB 
Deep breathing 
BMI 
Body mass index 
FDA 
Federal Drug Administration 
GMP 
Good Manufacturing Practice  
IND 
Investigational New Drug 
C-SSRS                 Columbia Suicide Severity Rating Scale 
CBC 
Complete Blood Count 
CMP  
      Complete Metabolic Panel 

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Study Summary 
 
Title 
The role of the noradrenergic system in the nonmotor symptoms of 
Parkinson’s disease 
Short Title 
NA in PD 
Protocol Number 
Velos: D19090  D-HH IRB: 31685 
IND 
146199 
Phase 
Phase 1 – Pilot 
Methodology 
Cross-sectional  
Study Duration 
12-24 months 
Study Center(s) 
Single-center: Dartmouth-Hitchcock Medical Center  
Objectives 
To explore the association between orthostatic hypotension (OH) and 
the neuropsychiatric (NP) and neurocognitive nonmotor features of 
Parkinson’s disease (PD) 
Number of Subjects 
22 patients total (11 patients with PD and OH (PD+OH) and 11 PD 
patients without OH (PD-OH)) 
Diagnosis and Main 
Inclusion Criteria 
Adults patients with a diagnosis of Parkinson’s Disease with and 
without OH 
Study Product, Dose, 
Route, Rationale 
Yohimbine (5mg) is administered orally during Visit 2 in order to 
manipulate the noradrenergic system to determine the association 
between OH and NP symptoms in those with PD. Yohimbine is not 
administered as a treatment in this study, but as a pharmacologic tool to 
study the adrenergic system.  
Statistical 
Methodology 
In the primary analysis, between group (PD+OH and PD-OH) 
differences in nonmotor symptoms of fatigue, apathy, depression, 
anxiety, and neurocognition will be compared using nonparametric tests 
for ordinal variables.  
 

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1 
Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 
Background 
Although Parkinson’s disease (PD) is traditionally considered a movement disorder resulting 
from dopamine deficiency, there is increasing recognition that nonmotor symptoms are prevalent 
and drastically impact quality of life.1-3 Orthostatic hypotension (OH) and symptoms of fatigue, 
depression, apathy, anxiety, and cognitive impairment (neuropsychiatric (NP) symptoms) are 
among the most bothersome symptoms in PD, and can occur early in the disease course.1,3,4 OH 
in PD is due to a combination of cardiac sympathetic denervation, peripheral vascular 
sympathetic denervation, and baroreflex failure. 5-7 Involvement of central nervous system 
(CNS) areas that mediate autonomic nervous system (ANS) function, such as the anterior 
cingulate and insular cortex, have also been radiologically and pathologically associated with 
OH in patients with PD.8, 9 Importantly, OH has been associated with depression, dementia, and 
poor prognosis in PD 5, 10-13, though not all studies agree14 - likely due to methodological 
differences.5  
 
The reasons for the association between OH and NP symptoms remains unknown.5 A disease 
progression hypothesis suggests that as α-synuclein inclusions spread, brain areas that mediate 
OH and NP symptoms degenerate simultaneously.15, 16 A neurochemical hypothesis suggests that 
since noradrenergic (NA) neurons are selectively damaged in PD, peripheral sympathetic 
degeneration is accompanied by degeneration of CNS NA areas such as the locus coeruleus 
(LC), which has been implicated in human cognition and arousal.17-19 A third hypothesis is that 
OH itself leads to cognitive decline, since both OH-induced cerebral hypoperfusion and OH-
associated supine hypertension can cause vascular brain injury,20, 21 though at least one study 
refutes this theory. 22 Determining reasons for the association between OH and NP symptoms is 
critical since treatment will differ significantly: the neurochemical explanation suggests that 
norepinephrine (NE) replacement should treat OH simultaneously with NP symptoms, while the 
causal explanation suggests that treating OH will then lead to better cognition and mood. In 
addition, understanding the association between OH, NP symptoms, and NA dysfunction may 
help improve prognostication for patients with PD, and may help to identify a PD subgroup with 
distinct pathophysiology that requires a different treatment approach.13 Unfortunately, studies to-
date have not distinguished between these hypotheses.   
 
In this study, we propose to test if NA dysfunction is associated with depression, cognition, 
apathy, anxiety, and fatigue in PD. First, we will test if OH in patients with PD is associated with 
other aspects of NP in which the adrenergic system plays a prominent role: fatigue/arousal, 

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Figure 1 - YOH chemical structure 
attention/cognition, and apathy/depression. We will then conduct a series of physiologic tests to 
elucidate the contributions of central and peripheral NA dysfunction in OH in PD, and use these 
results to see if NA dysfunction mediates any associations between OH and NP symptoms.  
 
These interrelated aims will help to determine if central NA dysfunction is associated with OH in 
PD, and whether NA dysfunction is associated with the NP symptoms in PD. These results may 
lead directly to treatment trials that target the NA system with the potential to significantly 
improve the lives of PD patients with bothersome nonmotor symptoms. 
1.2 
Investigational Agent 
During study visit 2, a single-dose of yohimbine will be used to manipulate the NA axis and 
investigate central nervous system NA function (aims 2 and 3 - see below). Yohimbine has been 
used numerous times in a similar fashion in order to pharmacologically manipulate the α2-
adrenoceptor (AR), as will be reviewed below.32, 34-39 In this study yohimbine is not being tested 
for any clinical indication, but only for its unique pharmacologic actions; nevertheless, since 
yohimbine is not approved by the Food and Drug Administration (FDA), an investigational new 
drug (IND) application will be required. Yohimbine is chosen due to its unique antagonistic 
activity at the α2-ARs. Alternative drugs that are relatively specific for the α2-ARs, such as 
clonidine, are agonists that decrease overall adrenergic output. This can lead to potentially 
dangerous hypotension in individuals at risk and is therefore not an acceptable alternative to 
yohimbine. 
 
Yohimbine (17α-hydroxyyohimban-16α-carboxylic acid methylester) (Fig. 1), an indole alkaloid 
found in a variety of botanical sources such as the Rauwolfia root, is the principal alkaloid 
extracted from the bark of the Pausinystalia 
yohimbe tree.23 It has also been called 
quebrachine, aphrodine, corynine, and 
hydroaerogotocin. Yohimbine is a potent 
selective α2-(AR) antagonist with weaker α1-
antagonist activity, as demonstrated by 
radioreceptor ligand binding assays and by 
pharmacological studies.24 The predominant use 
of yohimbine has been as a pharmacological tool 
to study the involvement of α2-ARs in the 
regulation of autonomic function, and for the 
treatment of impotence in males. As will be 
detailed below, yohimbine has a long history of 
safe use in clinical medicine and in clinical trials, including numerous recent studies.25-32 It is not 
currently commercially available in the United States as a drug, but it is widely distributed as a 
dietary supplement even though these supplements often contain pharmaceutical grades of 
yohimbine.33 Yohimbine is still available in several other countries including Canada.   

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1.3 
Preclinical Data 
Yohimbine is a nonspecific α2 NA antagonist. Its downstream effects are complex and include 
increasing sympathetic activity on blood vessels by way of negative feedback.23 In addition to its 
long track records in human studies, it has been used to manipulate the noradrenergic system in 
animals for decades.40  
 
Pertinent to this clinical investigation, yohimbine has been used to study animal models of stress, 
depression, cognition, arousal and pupillary function. Wang and colleagues used yohimbine to 
study the central release of norepinephrine from the locus coeruleus in a rat model of stress-
induced depression.41 Koss reviewed central α2 ARs in rats and cats and used yohimbine and 
clonidine, an α2 agonist, to study pupillary dynamics.42 Berridge et al. also studied pupillary 
dynamics using yohimbine in rats.43 Coull 44 and Arnsten et. al.45 reviewed the role of 
norepinephrine and α2-ARs in attentional and arousal aspects of cognition in animals. Verwaerde 
et al. tested yohimbine in a dog-model of neurogenic OH and found that yohimbine improved 
sympathetic tone and OH.46   
1.4 
Clinical Data to Date 
Over the last few decades, yohimbine has been used in hundreds of clinical trials around the 
world. In this clinical investigation, we will use yohimbine to manipulate the adrenergic system 
and not for a particular clinical indication. However, in order to focus on safety and its effects on 
the adrenergic system, we will review prior yohimbine studies that focused on the main subjects 
of the current investigation: pupillary pathways, neuropsychiatric symptoms, and PD and related 
disorders. We will also briefly review clinical trials of yohimbine for erectile dysfunction (ED), 
which is the most frequent indication, in order to illustrate yohimbine’s safety record.   
 
Pupillary dynamics 
Phillips et al. administered yohimbine in human subjects to investigate the role of central α2 AR 
receptors and pathways in pupillary dilation and constriction.35 They used a 22 mg dose, while 
we plan to use a 5 mg dose in case some of our patients with autonomic dysfunction have 
adrenergic denervation hypersensitivity47, 48 and have an exaggerated sympathomimetic effect.  
These authors found that yohimbine has a sympathomimetic effect on the pupils, most prominent 
in lighted conditions, concluding that it acts on central NA pathways.  No adverse events were 
reported, but neither was any safety data. While prior studies have looked at pupillary changes in 
Parkinson’s patients, 49 we are not aware of the use of yohimbine to study the NA pupillary 
system in this population.  
 
Neuropsychiatric and neurocognitive clinical data 
Halliday has shown that yohimbine can speed human processing time, likely through increasing 
norepinephrine.31, 50, 51 Yohimbine 21.6 mg has also been shown to increase anxiety and cocaine 
craving in cocaine abusers, but not healthy controls.29 High-dose (0.4 mg/kg) intravenous 

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yohimbine has been shown to increase impulsivity and blood pressure in 23 healthy controls, 
with no adverse events reported.31 A recent randomized clinical trial in 40 adults showed that 
yohimbine 10.8 mg is well-tolerated and may be useful to augment exposure therapy for social 
anxiety disorder.25 Another randomized controlled trial showed that 10 mg of yohimbine 
increases norepinephrine levels but does not augment exposure therapy for fear of flying in 67 
adults, and again the treatment was safe.27 A similar trial targeting specific phobias in 56 
individuals found that yohimbine 15 mg did not augment therapy but was safe.52 We are not 
aware of a study using yohimbine to study the role of the NA system in PD, as we propose to do. 
 
Erectile dysfunction 
Yohimbine has been widely used for erectile dysfunction (ED) and was one of the most widely 
prescribed agents prior to the age of sildenafil (Viagra) and other phosphodiesterase inhibitors. 
Vogt et al. tested over 80 patients in a double-blind trial using yohimbine at 30 mg per day for 8 
week for ED and found it to be well-tolerated with only few mild side effects.43 Lebret and 
colleagues also tested yohimbine for ED in 45 patients and again found it safe (and effective).53 
The use of yohimbine for ED was recently reviewed.54, 55 Aggregated evidence suggests that 
yohimbine is safe, and serious adverse events are infrequent and reversible. 
 
Parkinson’s disease and orthostatic hypotension 
Senard and colleagues tested whether yohimbine 2 mg three times daily of yohimbine was 
effective in treating orthostatic hypotension in individuals with PD.56 They found no effect on 
blood pressure, but yohimbine was deemed to be safe in individuals with PD. Onrot and 
colleagues tested yohimbine 5 mg daily to treat low blood pressure in patients with autonomic 
failure, and they found it to be effective and well-tolerated.38 Yohimbine has also been found to 
increase blood pressure in normal volunteers.48 Richard and colleagues tested yohimbine in 
Parkinson’s patients with a history of anxiety, depression, and panic attacks and found that 
yohimbine could induce panic or anxiety in susceptible individuals.57 No patients without a 
history of anxiety or panic attacks experienced panic with yohimbine, even at high doses of 21.6 
mg. As a result of this study and others, we will exclude patients with a history of panic attacks 
and warn subjects about this potential adverse event during consent. Petrie et al. tested 
yohimbine 0.65 mg/kg (a much larger dose than we plan to use) in a non-Parkinsonian 
population, including elderly individuals, to monitor the effects on plasma norepinephrine and 
found that yohimbine increases catecholamines.39 
Pharmacokinetics                                                                                                                    
Single-dose pharmacokinetics studies using yohimbine HCL demonstrated that yohimbine is 
rapidly absorbed and eliminated (both mean Tmax and elimination T1/2 < 1 hr).23 The average 
absorption half-life is 0.17 ± 0.11 hr, and absorption of yohimbine from the gut is generally 
complete in 45–60 min.23, 58 To ensure safety, our patients will be observed for at least 3 hours 
after yohimbine administration or until any adverse effects experienced during the visit are 

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completely resolved and blood pressure and heart rate have returned to the pre-yohimbine 
baseline. 
1.5 
Dose Rationale  
Oral and intravenous doses of between 5 mg and 30 mg have been used in prior clinical trials 
using yohimbine to manipulate the NA axis in human (see Section 1.4 Clinical Data to Date). 
Since patients with PD are prone to sympathetic degenerative neuropathies, 59 with 
accompanying sympathetic denervation hypersensitivity, 60, 61 we will be administering a low 
dose of 6 mg of oral yohimbine - similar to prior studies demonstrating safety in this 
population.62, 63, 64 
1.6 
Risk/Benefits 
Overall risks of this protocol are minimal. All risks will be spelled out in simple language on the 
consent form. All subjects must give informed consent prior to research participation.   
 
The surveys and interviews are non-invasive and minimal risk. There is a possibility that some 
questions might be embarrassing or uncomfortable. Patients will be reminded that they have the 
right to refuse to answer any questions they wish.  
 
With research participation, there is always a risk of data and privacy breach. All measures will 
be taken to protect the confidentiality of patients involved in the study by assigning a study 
identifier to each subject. Study data will be stored on a secure, web-based application called 
REDCap, and/or on a Department of Neurology computer or server managed by the Information 
Services department at Dartmouth-Hitchcock Medical Center. Paper records will be kept in 
Department of Neurology research offices, which are locked when not in use, and in long term 
storage managed by the Records Management/Health Information Services department. Ten 
years after completion of the study, all identifying information will be eliminated. 
 
Pupillometry, vibrotactile detection thresholds, and neurocognitive/neuropsychiatric tests are 
non-invasive and carry minimal risk. Cognitive questionnaires could conceivably be frustrating 
to the patient, or questionnaires may ask about troubling symptoms such as depression. Patients 
will be reminded they can withdraw at any time or choose not to answer certain questions they 
find bothersome. 
 
Venipuncture will be required to obtain blood samples as part of our protocol. Venipuncture is 
minimal risk but carries with it the risk of discomfort, bruising, bleeding, swelling, infection, and 
pain. Standard precautions will be followed during intravenous catheter placement and blood 
draws by trained personnel accustomed to these procedures as part of tilt-table testing.  
 
Both autonomic testing and tilt-table testing are minimally invasive but can precipitate 
hypotension, bradycardia or tachycardia, palpitations, anxiety, presyncope, or frank syncope with 

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accompanying cardiac arrhythmias. A study neurologist will be readily available during all 
autonomic tests, and a cardiac electrophysiologist and cardiac nurse will be physically present 
during all tilt-table tests. The protocol procedures will be stopped or paused for bothersome or 
worrisome symptoms. In the unlikely event of a dangerous arrhythmia or dangerous hypotension 
during the tilt-table test, the cardiologist will stop the test and administer the appropriate 
treatment. Known cardiac disease is a study exclusion criteria, to further minimize any potential 
risk.  
 
We will administer yohimbine as part of this protocol. Possible side effects of yohimbine may 
include, but are not limited to, hypertension, tachycardia, increased motor activity, irritability, 
anxiety, insomnia, tremor, increased chance of erection, dizziness, nausea, headache, and skin 
flushing. This medication has a long record of safety and use throughout the world, as reviewed 
above, so we do not anticipate any barrier to its use in this study. Prior research has documented 
its safety in PD and syncope.65, 66  
 
Subjects will be observed by research personnel while on yohimbine until the effects of the 
medication wear off.  
 
For participation in this study, participants will need to hold adrenergic medications for at least 
three half-lives and dopaminergic medications on the morning of the test.   
 
Holding levodopa and other dopaminergic medications for a morning presents minimal risk. This 
is not dangerous but may make subjects feel stiffer or more uncomfortable than normal. All 
subjects will agree to this as part of the informed consent process. This is not an uncommon 
practice for various clinical procedures such as deep brain stimulation evaluation so should not 
pose a problem.  
 
Subjects may have to wean off or hold medications that interfere with autonomic testing. This 
will be done with the guidance of their primary neurologists, with potential risks spelled out prior 
to patients agreeing to participate in this study. Subjects will only be enrolled if their primary 
neurologist feels that holding a medicine would represent minimal risk. Examples of medications 
that affect the noradrenergic axis and would have to be held for at least three half-lives include 
pyridostigmine, midodrine, stimulants (e.g. methylphenidate), venlafaxine, or droxidopa. 
Holding these medications could cause sleepiness, mild hypotension, increase appetite, anxiety, 
agitation, abnormal sweating, or other potentially bothersome symptoms, so their primary 
neurologists would need to approve participation when these medications are taken daily and 
need to be held. 
 
Subjects will also hold food and coffee the morning of their tilt-table test, which might present a 
nuisance but not any significance risk since we are excluding patients with diabetes. 

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2 
Study Objectives 
Primary Objective is to explore the association between orthostatic hypotension (OH) and 
several neuropsychiatric and neurocognitive nonmotor features of Parkinson’s disease (PD).  
 
Secondary objectives include the following: 
 To explore the association between central noradrenergic dysfunction, OH, and nonmotor 
symptoms of PD by measuring hormonal response to head up tilt-table (HUT) testing 
before and after administration of yohimbine 
 To explore the association between central noradrenergic dysfunction, OH, and nonmotor 
symptoms of PD by measuring pupillometric parameters before and after administration 
of yohimbine 
3 
Study Design 
3.1 
General Design 
This is a cross-sectional pilot study comparing 11 PD patients with OH to 11 PD patients without 
OH. OH will be defined as a drop in systolic BP of ≥ 20 mmHg or diastolic BP ≥ 10 mmHg 
within 5 minutes of standing (measured at 1, 2, and 5 minutes).59, 67 The study will include two 
clinical visits and a follow-up phone call 24-72 hours after the 2nd visit. Visits will last 
approximately 4-5 hours each. After consent has been signed, data from prior neurological 
exams, such as the H&Y staging, orthostatic vital signs (OVS) and UPDRS scores will be 
collected from a subject’s medical record as part of study data. 
 
For visit 1, subjects will be required to hold levodopa and other dopaminergic PD drugs on the 
morning of the visit, and other adrenergic medications for at least three half-lives. Subjects will 
bring their AM dopaminergic doses to be taken at the visit at the direction of study staff in order 
to coincide with the timing of procedures. Visit 1 will consist of reviewing informed consent and 
inclusion/exclusion criteria. The PI will confirm eligibility, (women of childbearing potential 
will undergo a serum pregnancy test as part of this eligibility review). Demographics, medical 
history, history and current use of alcohol, current and prior smoking status, and concomitant 
medications will be recorded. HR and BP response to deep breathing (DB) and Valsalva 
maneuvers, and vibrotactile detection thresholds, will also be tested. The subject will also 
undergo neurocognitive testing and neuropsychiatric assessments. OVS will be taken before 
administration of the subject’s dopaminergic medications, and at approximately 30 minutes and 
1 hour after dopamine administration. Dynamic pupillometry will be evaluated before and 
approximately 1 hour after administration of the subject’s dopaminergic medications. If the 
subject has not had a CBC and CMP in the past 6 months, the PI will order and review these 
blood levels for any clinically significant abnormalities. This visit will last approximately 4-5 
hours.  
 

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For Visit 2, subjects will again be required to hold levodopa and other medications that may 
interfere with autonomic testing. Women of childbearing potential will have a urine pregnancy 
test performed prior to the HUT. An IV will be placed as per HUT procedure. HUT testing will 
be conducted twice, once prior to and once after yohimbine administration.  The subjects will 
complete visual analogue sales measuring anxiety, mood, and fatigue prior to and after 
yohimbine administration. Dynamic pupillometry will also be evaluated prior to yohimbine 
administration and after yohimbine administration. Serum arginine vasopressin (AVP) and 
norepinephrine (NE) will be drawn twice prior to yohimbine administration and twice after 
yohimbine administration. One draw will be in the supine position, and the other will be during 
the head up tilt as outlined below, and then these two draws will be repeated after yohimbine (see 
Section 7.3, Figure 2).  
 
A follow up study phone call will be made by the study coordinator 24-72 hours after study visit 
2. Any adverse events which may have occurred since the study visit will be captured on the 
subject’s AE log. 
3.2 
Primary Study Endpoints 
The primary study endpoint will be between the group (OH verses non-OH) difference in fatigue 
(measured with the self-reported FSS), depression (measured with the self-reported GDS), 
apathy (measured with the AES and NPI-Q), anxiety (measured with the GAI and NPI-Q), and 
cognitive impairment (measured as an average composite z-score on the neurocognitive battery).  
3.3 
Secondary Study Endpoints  
Secondary study endpoints will be:  
 Difference between OH and non-OH group in change in supine and orthostatic 
catecholamine and AVP levels before and after yohimbine administration 
 Difference between OH and non-OH group in change in time to pupillary redilation 
before and after yohimbine 
 Change in self-reported anxiety, mood and fatigue before and after yohimbine  
 Between group difference in baseline BP rise with yohimbine administration 
 Difference in time to recovery of BP after 60 degree HUT before and after yohimbine 
administration 
 Correlation between sympathetic function (measured with pupillary redilation and beat-
to-beat BP) and levodopa use 

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4 
Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
 
1. Participant able to provide informed consent  
2. Diagnosis of Parkinson’s disease confirmed by a DH neurologist according to Movement 
Disorder Society criteria, with the exception that “Red flag” 5a will not be used (severe 
autonomic failure within five years of disease onset).68  
3. All subjects must have CMP and CBC drawn within 6 months of study visit 1, with 
results in the normal range or with abnormal results not considered to be clinically 
significant in the investigator’s opinion. If CMP, CBC have not been drawn within 6 
months of study enrollment, they will be ordered, drawn and reviewed for abnormalities 
of clinical significance as part of the screening process.  
4. Female patients must be post-menopausal (at least one year) or have undergone surgical 
sterilization or hysterectomy at least 3 months before Visit 1. Women of childbearing 
potential must not be breastfeeding, have a negative pregnancy test at study entry and 
prior to yohimbine administration, have no intention to become pregnant during the 
course of study participation, and use contraceptive drugs or devices for the two weeks 
prior to and after yohimbine administration. Male patients with partners of child-bearing 
potential, must agree to use adequate contraception for 2 weeks before and after 
yohimbine administration. Adequate contraception includes oral, transdermal, or 
injectable (depot) estrogen and/or progestogen, selective estrogen receptor modulator 
therapy, intrauterine contraceptive device, double barrier method (e.g., condom and 
diaphragm or spermicidal gel) or vasectomy. 
 
4.2 
Exclusion Criteria 
 
1. Diagnosis or previous history of diabetes of any kind  
2. Known autonomic neuropathy unrelated to PD 
3. History of or current cardiac, liver or renal disease that, in the opinion of the investigator, 
may put the patient at risk because of participation in the study 
4. Known condition that in the investigator’s opinion would be a contraindication to HUT 
testing or yohimbine challenge (e.g. decompensated cardiac disease, severe positional 
vertigo; severe anxiety, known panic disorder69)  
5. Current use of catecholaminergic medications (e.g. stimulants, droxidopa, midodrine) 
that cannot be held for at least three half-lives 
6. Inability to hold PD medications for at least 12 hours 
7. History of major depressive or bipolar disorder preceding the diagnosis of PD,69 or 
diagnosis or previous history of psychiatric illness that in the investigator’s opinion 
would affect the subject’s ability to successfully participate in the study. 

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8. Any history (other than PD) that could affect neurocognitive function, such as history of 
traumatic brain injury (head injury with loss of consciousness > 1 hour), known dementia 
unrelated to Parkinson’s or related diseases; developmental delay, multiple sclerosis, 
epilepsy, intellectual deficit, diagnosed and untreated sleep apnea; untreated syphilis; 
HIV; or other conditions that, based on the investigators opinion, could interfere with 
neurocognitive evaluation.  
9. Known ophthalmologic disease such as untreated cataract, glaucoma, optic neuritis, 
orbital trauma, or other neuroretinal disease that might impact pupillary function 
10. Severe illness within 30 days prior to enrollment.  
11. Use of opiate, procholinergic, or other medications influencing pupillary function that 
cannot be held for three half-lives 
12. In the Investigator’s opinion, subject would be unable to successfully participate in the 
study for any reason. 
4.3 
Subject Recruitment and Screening 
 
Participation in this research requires informed consent according to Institutional Review Board 
(IRB) guidelines. A signed IRB approved Consent Form is the means of documenting this 
understanding. Subjects must be able to consent for themselves to be able to participate in this 
study and have received an exact copy (at point of signature acquisition). Potential recruits are 
instructed that their participation is voluntary and that their medical care will not be altered in 
any way should they elect not to participate. 
 
Initial recruitment will take place during routine clinic visits with a DH neurologist caring for 
patients with PD. The study will be briefly described to the patient. If the patient is interested, a 
study coordinator will contact them to explain the study in detail and confirm eligibility. 
Interested subjects will then be sent informed consent information (i.e. study procedure, risks, 
and benefits) to review at home, and they will have the opportunity to ask questions prior to 
scheduling the first study visit. Completion of the informed consent process will then take place 
face-to-face at the onset of Study Visit 1, prior to any data collection. Data regarding the 
subject’s UPDRS, H&Y standing and OVS will be gathered from the subject’s medical record 
after consent has been obtained. All study visits and procedures will take place at Dartmouth-
Hitchcock Medical Center, Lebanon, NH.  
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
A subject may be withdrawn from the study prior to the expected completion of that subject for 
safety reasons, failure of subject to adhere to protocol requirements, subject consent withdrawal, 
or subject is lost to follow up. Subjects will be deemed lost to follow up after a minimum of 3 
documented phone calls, emails, or certified letters of a physician or designee at the study site to 

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the subject or emergency contact. If a participant is deemed lost to follow up, the PI or designee 
will mail a signed letter to the patient to inform them of their withdrawal from the study. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
All study procedures will be discontinued for the subject at the point of being classified as 
“Withdrawn.” Data collected up to the point of subject withdrawal may be used for analysis. If a 
patient is terminated early from the study as a result of an adverse event related to study 
procedures, every effort will be made to follow the patient until the adverse event resolves.  
5 
Study Drug  
5.1 
Description 
Yohimbine is a potent selective α2-adrenoceptor (AR) antagonist with weaker α1-antagonist 
activity.  
5.2 
Administration Regimen 
One yohimbine tablet (5mg) will be dispensed to the subject and administered orally at Visit 2.  
5.3 
Preparation and Administration of Study Drug  
Yohimbine will be produced in a GMP compliant facility by CHEPLAPHARM ARZNEIMITTEL 
GMBH (ZIEGELHOF 24 GREIFSWALD 17489 GERMANY). The appropriate dose will be dispensed by the 
Investigational Pharmacy at Dartmouth-Hitchcock Medical Center and administered to the 
subject by a licensed clinician during Visit 2.   
5.4 
Subject Compliance Monitoring 
Subjects will be asked to hold dopaminergic medications on the morning of Visits 1 and 2 and 
adrenergic medications for at least three half-lives on the mornings of Visit 1 and 2. If subjects 
do not comply with this, the visit will be rescheduled.  
5.5 
Prior and Concomitant Therapy 
As part of each study visit, concomitant medications will be recorded and then reviewed.  
Subjects will be asked to hold levodopa and other dopaminergic medications for the morning of 
Visits 1 and 2. In addition, subjects may have to wean off or hold medications that interfere with 
autonomic testing and pupillary testing for Visits 1 and 2.  Examples of medications that affect 
the NA axis and would have to be held for at least three half-lives include pyridostigmine, 
midodrine, stimulants (e.g. methylphenidate), venlafaxine, or droxidopa. This will be done with 
the guidance of their primary neurologists, with potential risks explained prior to patients 
agreeing to participate in this study. Subjects will only be enrolled if their primary neurologist 
feels that holding a medicine would represent minimal risk. 

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5.6 
Packaging 
Yohimbine preparation will be conducted in a GMP facility, CHEPLAPHARM ARZNEIMITTEL 
GMBH. Each package containing yohimbine will be pre-numbered with a lot number by the 
manufacturer prior to shipment and delivery to DHMC. The yohimbine hydrochloride tablets 
will be shipped to the Dartmouth-Hitchcock Investigational Pharmacy as 50 or 100 tablets in 
platelets (PVC / Aluminum) of 10 tablets  
5.6.1 Receipt of Drug Supplies 
Yohimbine will be shipped directly from CHEPLAPHARM ARZNEIMITTEL GMBH (ZIEGELHOF 24 
GREIFSWALD 17489 GERMANY) to the Investigational Pharmacy at Dartmouth-Hitchcock Medical 
Center. Upon receipt of the study treatment supplies by the receiving pharmacy, the designated 
study staff will count and verify that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study drug in a given shipment will be documented in the 
study files.  
5.6.2 Storage 
Yohimbine will be stored at the Investigational Pharmacy at Dartmouth-Hitchcock Medical 
Center in a dry, cool location.  
5.6.3 Dispensing of Study Drug 
The yohimbine tablet will be dispensed at Visit 2. The Dartmouth-Hitchcock Investigational 
Pharmacy will keep record of all study drug issued. Notation will also be made in the 
participants’ electronic medical records regarding the dispensation of the study drug 
5.6.4 Return or Destruction of Study Drug 
At the completion of the trial, a final reconciliation of study drug shipped, consumed, and 
remaining will be performed.  This reconciliation will be logged on the drug reconciliation form, 
signed and dated.  Any discrepancies noted will be investigated, resolved, and documented prior 
to destruction of unused study drug. All drug remaining at the completion of the study will 
destroyed on site and will be documented in the study files. 
6 
Study Devices  
6.1 
Description of NeurOptics® PLR-3000 
 
All subjects will undergo pupillometric evaluation with the NeurOptics® PLR-3000. The PLR-
3000 system automatically measures monocular resting pupillary size using infrared light in a 
dark room, and then uses a brief light flash to measure minimum post-contraction pupillary size, 
contraction velocity, contraction latency, redilation velocity, and time of pupillary redilation. 
Pupillometric methods have been described previously 70-72 and will modified for use with the 
NeurOptics system. Testing will be done twice in each eye. Binocular pupillometric data 
collection will take less than 5 minutes to obtain. Bilateral results will be averaged for final 

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comparison. If there is a unilateral preexisting condition (e.g. untreated cataract), pupillometric 
evaluation will be limited to the unimpaired side with no averaging. We will measure these 
parameters at baseline with the patient at rest and room lights as dim as possible, then again with 
lights on. Pupillometry will be performed in the same room to maintain minimal variation in 
luminance. We will repeat these studies after yohimbine administration at the time of the second 
HUT.  
 
 
 
 
 
 
 
 
 
 
 

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7 
Study Procedures 
7.1 
Schedule of Assessments 
 
Event/Assessment Visit 1 
Visit 2 
(occurs no more than 
30 days after  V1) 
Follow-Up 
Phone Call  
(24-72 hours 
after Visit 2) 
Informed consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
History and current 
use of alcohol 
X 
 
 
 
 
 
Current and prior 
smoking status 
X 
 
 
 
 
 
UPDRS, Hoehn & 
Yahr staging  
X 
 
 
 
 
 
Orthostatic vital signs 
(OVS) 
X 
Baseline: 
holding L-dopa 
 
X 
30 min after  
L-dopa 
administration 
 
X 
1 hour after  
L-dopa 
administration 
X 
pre yohimbine 
administration 
X 
post yohimbine 
administration 
 
Serum Pregnancy Test 
(WOCBPO)i 
X 
 
 
 
 
 
 

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Event/Assessment 
Visit 1 
Visit 2 
 
Follow-Up Phone 
Call (12 to 72 
hours after Visit 2) 
Urine Pregnancy 
Test (WOCBPO) 
 
 
 
X 
 
 
Concomitant 
medications 
X 
 
 
X 
 
X 
Adverse Events 
X 
 
 
X 
 
X 
SCOPA-AUT 
X 
 
 
 
 
 
HR and BP response 
to DB and Valsalva 
X 
 
 
 
 
 
Vibrotactile 
detection thresholds 
X 
 
 
 
 
 
Neurocognitive 
testing 
X 
 
 
 
 
 
Neuropsychiatric 
assessment 
X 
 
 
 
 
 
Neuropsychiatric 
assessment 
(Informant)  
X 
 
 
 
 
 
Dynamic 
pupillometry 
X  
(holding levodopa) 
 
X 
(1 hour after  
levodopa 
administration) 
X 
(pre yohimbine 
administration) 
X 
(post yohimbine 
administration) 
 
 
C-SSRS Baseline 
Version 
X 
 
 
 
 
 

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Event/Assessment 
Visit 1 
Visit 2 
 
Follow-Up Phone 
Call (12 to 72 
hours after Visit 2) 
CSSRS- Since Last 
Visit Version 
 
 
X 
 
 
IV placement 
 
 
X 
 
 
HUT  
 
 
X 
(pre yohimbine 
administration) 
X 
(post yohimbine 
administration) 
 
Visual analogue 
scales measuring 
anxiety, mood, 
fatigue  
 
 
X  
pre -yohimbine 
administration 
X  
post- yohimbine 
administration 
 
Serum AVP ii and 
NE iii 
 
 
X Pre Yohimbine 
administration 
X  
Post Yohimbine 
administration 
 
Safety Labs (CBC, 
CMP)iv 
X 
 
 
 
 
 
i Women of Child Bearing Potential Only 
ii AVP will be draw after approximately 30 minutes supine and again at approximately 15 minutes upright tilt to 60 degrees. 
iii NE drawn after approx.30 minutes supine and again at approximately 5 minutes after upright tilt to 60 degrees 
iv If labs have been drawn within past 6 months and are WNL or with abnormalities that are NCS; those can be utilized for inclusion 
 

18 
 
CONFIDENTIAL 
 
 
7.2 
Visit 1 
 Informed consent 
 Confirmation of Inclusion/Exclusion 
 Demographic collection 
 Medical History data collection 
 Vital Signs 
 Serum Pregnancy Test (women of childbearing potential only) 
 Serum Safety Labs for CBC, CMP (if not completed in past 6 months) 
 Orthostatic Vital Signs 
o Baseline, (holding AM dopamine) 
o Approx 30 minutes after dopamine administration 
o Approx 1 hour after dopamine administration 
 Peripheral Nerve Testing 
o HR and BP response to DB and Valsalva 
o Vibrotactile detection thresholds 
o SCOPA-AUT survey 
 Dynamic Pupillometry 
 
 
 
Prior to dopamine administration 
 
 
Approximately 60 minutes post-dopamine administration 
 Neuropsychiatric and neurocognitive testing (approx. 1.5 hours in length) 
 Columbia Suicide Severity Rating Scale, (Baseline) 
 
Patients will be informed to hold dopaminergic medications on the morning of Visit 1 and 
adrenergic medications for at least three half-lives. After providing informed consent and 
meeting inclusion/exclusion criteria, subjects will be asked to complete a structured interview 
using a standardized questionnaire/data abstraction form to obtain demographic and clinical data. 
Information that the patient does not know will be obtained from the medical record and the 
patient’s primary neurologist and entered into the standardized questionnaire/data abstraction 
form.  
 
The following demographics and disease characteristics will be captured:  
 Age, sex, race and ethnicity 
 Income 
 BMI 
 Highest level of education completed 
 H&Y staging 
 Concomitant medications including levodopa and LDED 

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 Years since PD diagnosis 
 Comorbidities (Charleston Comorbidity Index) 
 Current and prior alcohol use 
 Current and prior smoking status.  
 
Subjects will also have their OVS done at baseline (holding AM dopamine) and then again at 
approximately 30 minutes and 1 hour after dopamine administration. 
 
Neuropsychiatric and neurocognitive testing 
Patients will complete on one occasion a battery of neurocognitive measures.   
This will include: 
 The Test of Premorbid Functioning (TOPF) , a word reading based estimate of premorbid 
IQ 74 
 Montreal Cognitive Assessment (MoCA) 70 
 Brief University of Pennsylvania Smell Identification Test (B-SIT) 75 
 Digit Span subtest from the Wechsler Adult Intelligence Scale – IV 76 
 Symbol Digit Modalities Test (Smith, 1968) 77 
 Trail Making Test 78 
 California Verbal Learning Test – II 79 
 Rey Complex Figure Test 80 
 DKEFS Color-Word Interference Test 81 
 Phonemic and Semantic Verbal Fluency 82 
 Behavior Rating Inventory of Executive Function – Adult 83 
 
Patient neuropsychiatric characteristics will be assessed by having them complete on one 
occasion:  
 The Geriatric Depression Scale (GDS) 84, 85 
 Geriatric Anxiety Inventory (GAI) 86, 87 
 Fatigue Severity Scale (FSS) 88 
 Apathy Evaluation Scale (AES) 89, 90 
 Activation-Deactivation Checklist to assess arousal (AD-ACL) 91  
 
Patients will also complete a visual analogue scale before and after yohimbine to assess for acute 
changes in symptoms such as anxiety, fatigue, and concentration/attention [VAS; score ranging 
from 0% (no symptoms) to 100% (most severe symptom possible)]. 95 
An informant (when available) will complete informant report versions of the BRIEF-A, AES, as 
well as the Neuropsychiatric Inventory Questionnaire (NPI-Q). 92 
 
The total time for neurocognitive and neuropsychiatric testing will be approximately 1.5 hours. 

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Peripheral nerve testing:  
This following peripheral nerve testing will performed by trained autonomic technicians and 
interpreted by the PI or a sub-I. 
 HR and continuous BP variability monitoring with deep breathing and Valsalva. 
 Patients will  answer a validated survey to quantify their autonomic symptoms (the 
SCOPA-AUT).93  
 Measurement of vibrotactile detection thresholds.94   
 Dynamic pupillometry testing prior to subjects taking their levodopa-, and then again 
approximately 60 minutes after ingestion. See section 6.1 for pupillometry protocol. 
7.3 
Visit 2 
HUT will be done first thing in the morning, since subjects will be holding their levodopa and 
other medications that could interfere with autonomic testing. Subjects will fast and abstain from 
coffee the morning of testing but will be encouraged to hydrate exuberantly.  
 
Prior to beginning the HUT, the following will occur:  
 Collection of adverse events since consent was signed /changes in medical history 
 Collection of changes in concomitant medication will be collected.  
 A C-SSRS, (Since Last Visit), will be also be performed.  
 Urine pregnancy test will be performed prior to starting the HUT, (if a women is of 
childbearing potential,). 
 
The following procedures will be performed as part of the HUT and measured per HUT protocol 
6, 22, while under the supervision of a cardiac electrophysiologist, cardiology nurse and study 
coordinator.  
 
 IV will be placed per standard HUT procedure.  
 After approximately 30 minutes of supine rest:  
o Serum AVP and NE levels draw for baseline level 
o VAS scale completion for baseline/resting anxiety, fatigue and mood, ([VAS; 
score ranging from 0% (no symptoms) to 100% (most severe symptom 
possible)]95).  
 Pupillometric evaluations (see Figure 2).  
 Tilt table to approximately 60 degrees for approximately 15 minutes; return to supine 
 Yohimbine administration  
 VAS scale completion for baseline/resting anxiety, fatigue and mood, ([VAS; score 
ranging from 0% (no symptoms) to 100% (most severe symptom possible)]95). 
 Patients will then be tilted to 60 degrees for a second time and remain in that position 
for approximately 15 minutes. 
 NE will be drawn approximately 5 minutes after being tilted up to 60 degrees. 
 AVP will be drawn approximately 15 minutes after being tilted up to 60 degrees.  

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Figure 2. Timeline of Visit 2 
 
 
 
The total time for Visit 2 will be approximately 4-6 hours, pending observation time post 
yohimbine administration (see Figure 2 above). 
 
A cardiac electrophysiology sub-investigator, who will be trained in the protocol and drug 
effects, will monitor the tilt test, as well as halt the test in the unlikely case of dangerous 
syncope, arrhythmia, or intolerable symptoms. Yohimbine may even improve orthostasis.65, 66 
  
Dr. Robbins, or a designated sub-investigator, will be available via pager during all scheduled 
visit 2 activities. In the event of any adverse events during yohimbine administration and HUT, 
he will be available to assess and document any adverse effects clinically and identify a plan for 
clinical treatment, should any be necessary.   Any adverse events occurring during yohimbine 
administration and HUT involving autonomic nervous system function and vital signs will be 
monitored for at least 3 hours post event to assure stable vital signs/condition.  
7.4 
Follow-up Phone Call  
24-72 hours after Visit 2 has been completed, the subjects will be contacted over the phone and 
will be enquired about any adverse events following research procedures.  
8 
Statistical Plan 
8.1 
Sample Size Determination 
Our primary study objective is to compare the nonmotor symptoms of fatigue, anxiety, 
depression, apathy, and cognitive impairment between the OH and non-OH groups. If we aim to 
detect a clinically significant difference of 2 points on an 11 point visual analogue fatigue scale, 
only 4 patients in each group are needed, using a 1-way test of means and assuming a population 
standard deviation of 1, α = 0.05 and β=0.80. However, it is important to recognize that this is an 
investigative pilot study; since little research has been done in this area and we cannot be certain 

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of these assumptions, it is entirely possible the study will be underpowered for at least some of 
our primary and secondary outcomes. 
8.2 
Statistical Methods 
Primary analysis plan: 
To test whether OH correlates with the nonmotor symptoms of fatigue, anxiety, depression, 
apathy, and cognitive impairment, we will compare these variables between the PD (+OH) group 
to the PD (-OH) group using the Mann-Whitney U test. Although this pilot study is likely 
underpowered for additional analyses, we will then construct several linear regression models 
with each nonmotor variable as an outcome, and also include important clinical (e.g. disease 
duration, total LDED) and demographic variables in the models in order to test if OH is 
independently associated with these nonmotor outcomes. 
 
Secondary analysis plan: 
To test whether central NA dysfunction is involved in these nonmotor symptoms, we will 
correlate each variable (i.e. quantified scores of depression, apathy, anxiety, fatigue, and 
cognition) with the difference before and after yohimbine in the change in catecholamine and 
AVP levels supine and at 60 degree tilt. We will also correlate the nonmotor scores with 
pupillary redilation speed, which measures sympathetic function, before and after yohimbine.   
We will compare change in anxiety, mood, and fatigue scores (measured on a visual analogue 
scale) before and after yohimbine between the PD (OH+) and PD (OH-) groups using the Mann-
Whitney U test. We will also compare the changes in BP parameters before and after yohimbine 
between groups. 
 
After these initial correlations and comparisons, we will construct linear regression models 
incorporating clinical and demographic variables of interest in order to test if our measures of 
NA dysfunction independently predict the nonmotor symptoms of PD, though we expect these 
analyses to be underpowered. Finally, we will test if central NA dysfunction (measured through 
changes in catecholamines and pupillary response to yohimbine, as above) explains the 
relationship between OH and the nonmotor symptoms of PD by incorporating our measures of 
central NA dysfunction into the linear regression models described above, and testing whether 
the relationship between OH and nonmotor symptoms persist. 
8.3 
Subject Population(s) for Analysis 
All subjects who complete at least one study visit will be subjected to the study analysis. 
9 
Safety and Adverse Events 
9.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  

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 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
 Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  

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Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, the end of study treatment follow-up is defined as the completion of the follow-up phone 
call.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
 

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Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
9.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period and are determined to be possibly related to the study treatment or 
study participation must be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately. 
9.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a minimum 
those events that must be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  

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(See definitions, section 9.1).   
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
 Study identifier 
 Study Center 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study treatment was discontinued 
 The reason why the event is classified as 
serious 
 Investigator assessment of the association 
between the event and study treatment 
 
9.3.1 Investigator reporting: notifying the Dartmouth IRB 
 
This section describes the requirements for safety reporting by investigators who are Dartmouth 
faculty, affiliated with a Dartmouth research site, or otherwise responsible for safety reporting to 
the Dartmouth IRB. The Dartmouth Hitchcock Health IRB requires expedited reporting of those 
events related to study participation that are unforeseen and indicate that participants or others 
are at increased risk of harm.  The Dartmouth IRB will not acknowledge safety reports or bulk 
adverse event submissions that do not meet the criteria outlined below: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or 
off-site) that occurs any time during or after the research study, which in the opinion of 
the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and package 
inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.) 
 
1. Unanticipated problems that are serious adverse events should be reported to the IRB within 1 
week of the investigator becoming aware of the event. 
2. Any other unanticipated problem should be reported to the IRB within 2 weeks of the 
investigator becoming aware of the problem. 

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Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Dartmouth IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others 
Including Reportable Adverse Events” or as a written report of the event (including a description 
of the event with information regarding its fulfillment of the above criteria, follow-up/resolution 
and need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 
Reporting Deaths:   
Concerning deaths that occur during the course of a research study:   
 Report the event when the death is unforeseen (unexpected) and possibly related 
indicating participants or others may be at increased risk of harm.  The AE/Unanticipated 
Problem Form is required. 
 Report the event at the time of continuing review, for all other deaths, regardless of 
whether the death is related to study participation. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Dartmouth IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 
 Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
– A paper is published from another study that shows that an arm of your research study 
is of no therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
 Breach of confidentiality 

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 Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
 Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk, or affects the rights or welfare of subjects. 
9.3.2 Sponsor reporting: Notifying the FDA 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of 
event: 
 
 Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected, and 
– fatal or life-threatening 
 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the previous 
reports. 

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Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. If supplied as in 
a narrative format, the minimum information to be supplied is noted above at the beginning of 
section 8.3. The contact information for submitting IND safety reports is noted below: 
 
Division of Neurology Products  
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
Building 22, Suite 4346   
Phone: (301) 796-2250 Fax: (301) 796-9842 
9.4 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above. In addition to PI oversight, a medical monitor external to the study team 
will be identified.  Medical monitoring will include a regular assessment of the number and type 
of serious adverse events. 
10 Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 

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diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
10.3 Case Report Forms 
Both written study case report forms (CRF) and RedCap will be data collection instruments for 
this study. All data requested on the CRF must be recorded.  All missing data must be explained. 
If a space on the CRF is left blank because the procedure was not done or the questions was not 
asked, a written notation will be made. If an item is not applicable to the individual case, written 
notation will be made. All changes made to written CRF’s will be initialed and dated. Changes 
made to data recorded in RedCap will be recorded by an audit trail. 
10.4 Records Retention 
Records will be retained for 10 years following publication of results from the study.  
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan.  The investigator will allocate 
adequate time for such monitoring activities.  The Investigator will also ensure that the monitor 
or other compliance or quality assurance reviewer is given access to all the above noted study-
related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and 
has adequate space to conduct the monitoring visit. 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and Dartmouth compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable Dartmouth compliance and quality assurance 
offices. 
12 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 

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This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent 
form, must be obtained before that subject undergoes any study procedure.  The consent form 
must be signed by the subject and the investigator-designated research professional obtaining the 
consent.  
13 Study Finances 
13.1 Funding Source 
This study is being funded by the Dartmouth-Hitchcock Department of Neurology.  
13.2 Conflict of Interest 
All Dartmouth investigators will follow the Dartmouth conflict of interest policy. 
13.3 Subject Stipends or Payments 
Subjects will be paid $60 after all study visits have been completed.  

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Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 
2016;31:270-279. 
88. 
Friedman JH, Alves G, Hagell P, et al. Fatigue rating scales critique and 
recommendations by the Movement Disorders Society task force on rating scales for Parkinson's 
disease. Movement disorders : official journal of the Movement Disorder Society. 2010;25:805-
822. 
89. 
Lueken U, Evens R, Balzer-Geldsetzer M, et al. Psychometric properties of the apathy 
evaluation scale in patients with Parkinson's disease. International journal of methods in 
psychiatric research. 2017. 

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90. 
Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy 
Evaluation Scale. Psychiatry research. 1991;38:143-162. 
91. 
Thayer RE. The biopsychology of mood and arousal. . New York: Oxford University 
Press; 1989. 
92. 
Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form 
of the Neuropsychiatric Inventory. The Journal of neuropsychiatry and clinical neurosciences. 
2000;12:233-239. 
93. 
Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment of autonomic 
dysfunction in Parkinson's disease: the SCOPA-AUT. Movement disorders : official journal of 
the Movement Disorder Society. 2004;19:1306-1312. 
94. 
Gerr F, Letz R, Hershman D, Farraye J, Simpson D. Comparison of vibrotactile 
thresholds with physical examination and electrophysiological assessment. Muscle & nerve. 
1991;14:1059-1066. 
95. 
Wolz M, Hauschild J, Koy J, et al. Immediate effects of deep brain stimulation of the 
subthalamic nucleus on nonmotor symptoms in Parkinson's disease. Parkinsonism & related 
disorders. 2012;18:994-997. 

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14.2 Drug Insert 
 
 
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SUMMARY OF PRODUCT CHARACTERISTICS 
1. NAME OF THE MEDICINAL PRODUCT 
YOCORAL 5 mg tablets 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Yohimbine hydrochloride ............................................... .................................................. ............... 5 mg per tablet. 
For the full list of excipients, see section 6.1. 
3. PHARMACEUTICAL FORM 
Tablet 
4. CLINICAL DATA 
4.1. Therapeutic indications 
Adjunctive treatment of erectile dysfunction. 
4.2. Dosage and method of administration 
Dosage 
3 to 4 tablets a day in 3 doses. 
The dosage will be adapted according to the individual results, without exceeding 4 tablets per day 
(ie 20 mg / day).  
A delay of 2 to 3 weeks may be necessary to see the first effects of treatment appear. 
In patients with renal and / or hepatic impairment 
Patients with mild to moderate renal and / or hepatic impairment should use 
Yocoral with caution (see section 4.4). Yocoral is contraindicated in patients with 
Hepatic and / or severe renal impairment (see section 4.3). 
In the geriatric patient 
There is great variability in the plasma distribution of yohimbine. Peak plasma concentration and the AUC of the 
active 11-OH-yohimbine metabolite may be decreased in elderly patients (see section 5.2). The clinical relevance of 
the use in geriatric patients 
is not known. 
Pediatric population 
Yocoral is not indicated for patients under 18 years of age. 
Women 
Yocoral is not indicated for sexual dysfunction in women. 
Administration mode 
The tablets should be taken with a glass of water, preferably removed from meals. 
4.3. Contraindications 
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• Severe hepatic and / or renal insufficiency,  
• Heart disease (including coronary heart disease, tachyarrhythmia), 
• Hypertension, hypotension 

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• Psychiatric disorders, particularly emotional and panic disorder, 
• gastrointestinal ulcer, 
• Glaucoma, 
• Concomitant use of products acting on the central nervous system (eg drugs treating psychiatric or neurological 
disorders, some antihypertensives, alcohol). 
4.4. Special warnings and precautions for use 
• It is not recommended to use yohimbine for erectile dysfunction caused by 
serious psychological or organic illness, or if the disease is of organic origin clearly correctable. 
• There has been a report of increased epileptic seizures when yohimbine was used with concomitant treatment for 
epilepsy. Therefore, it can not be excluded that yohimbine might promote epileptic seizures in epileptic patients. 
• Yohimbine may aggravate existing renal dysfunction. 
• Impairment of liver function may influence the biotransformation of yohimbine and 
thus reinforce its clinical effects or its undesirable effects. 
• The effect of the combination of yohimbine with other drugs used in the treatment of 
Erectile insufficiency is not known. As a result, an interaction potentiating the effects 
undesirable effects can not be excluded. 
4.5. Interactions with other drugs and other forms of interactions 
Associations advised against 
+ 
Central antihypertensives 
Possible inhibition of antihypertensive activity by antagonism at the receptors. The 
Yohimbine and clonidine should not be administered concurrently as their effects may be 
neutralize. 
Associations to take into account 
+ 
antidepressants 
Concomitant use of yohimbine and antidepressants may enhance effects and effects 
adverse effects of both drugs.  
It has been reported an interaction with imipramine antidepressants, clomipramine, 
amitriptyline and fluoxetine. Clomipramine increases plasma levels of yohimbine and can 
potentiate the effects of drugs. 
+ 
alprazolam 
Yohimbine antagonizes the effects of alprazolam on behavior, biochemistry and pressure 
arterial at the healthy subject. 
+ 
phenothiazine 
An interaction with phenothiazine is possible. 
+ 
amphetamines 
Concomitant use of yohimbine and amphetamines should be avoided due to 
potentially strengthened. 
+ 
opioids 
Yohimbine may enhance the effect of opioids. 
+ 
sibutramine 
Patients with cardiovascular risk factors should avoid use 
concomitant with anorectics containing sibutramine. This can lead to tachycardia and 
hypertension.  

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4.6. Fertility, pregnancy and lactation 
Pregnancy 
YOCORAL has no indication in women. 
feeding 
YOCORAL has no indication in women. 
Fertility 
The effect of yohimbine on fertility has not been studied. Preclinical data did not show 
effects on fertility (see section 5.3). 
4.7. Effects on ability to drive and use machines 
Due to the variability of the individual reaction of yohimbine on the central nervous system, 
Yocoral may impair the ability to drive and use machines, including 
association with alcohol consumption. 
4.8. Side effects 
Adverse effects are predominantly dose-dependent and attributed to pharmacological effects 
of the drug. 
The side effects listed below are classified according to their frequency of occurrence: 
• very common (≥ 1/10) 
• common (≥ 1/100, <1/10)  
• uncommon (≥ 1/1000, <1/100)  
• rare (≥ 1/10 000, <1/1000)  
• very rare (<1 / 10,000) 
• indefinite frequency (can not be estimated based on available data) 
Blood and lymphatic system disorders 
• Not known : agranulocytosis 
Immune system disorders 
• Uncommon: allergic reactions 
Psychiatric disorders 
• Common: insomnia, anxiety, agitation, irritability, impatience 
• Uncommon: nervousness, decreased libido 
Nervous system disorders 
• Common : headache 
• Uncommon : dizziness, cold feet, paresthesia 
• Very rare : tremors 
Heart conditions 
• Uncommon: palpitations, tachycardia, increased heart rate 
Vascular disorders 
• Uncommon: increased blood pressure, hypotension 
• Not known : persistent priapism 
Respiratory, thoracic and mediastinal disorders 
• Very rare : bronchospasm  

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Gastrointestinal disorders 
• Common : nausea 
• Uncommon : vomiting, anorexia, gastrointestinal disturbances (epigastric pain, diarrhea, reflux, constipation, 
flatulence) 
Skin and subcutaneous tissue disorders 
• Uncommon: redness of the skin, rash, hives, hirsutism 
• Very rare: exanthem 
Renal and urinary disorders 
• Frequent: increased urinary frequency. 
• Very rare: dysuria, decreased urinary urgency, genital pain 
General disorders 
• Uncommon: Sweating, chills, fever, fatigue 
Reporting of suspected adverse reactions  
The reporting of suspected side effects after approval of the drug is important. It 
allows continuous monitoring of the benefit / risk ratio of the drug. Please 
report any suspected adverse reactions via the national reporting system: National Agency 
of medicines and health products (ANSM) and a network of regional centers for 
Pharmacovigilance - Website: www.ansm.sante.fr. 
4.9. Overdose 
The following symptoms appeared after a massive overdose (0.2 - 5 g) of yohimbine: toxic symptoms with nausea, 
epigastric pain, vomiting, diarrhea, tingling, chills,flushing, psycho-organic syndrome with anxiety, confusion, 
unconsciousness, incoordination, seizures, somnolence, hypertension and / or hypotension, tachycardia, retrosternal 
pain, atrial fibrillation, retrograde amnesia, vegetative disorders, cyanosis, urinary retention, systemic lupus 
erythematosus.  
Treatment of overdose: 
After ingestion of high doses, in the acute phase, detoxification with gastric lavage is recommended followed by the 
administration of medicinal charcoal, and a medicinal support therapy according to the clinical course: 
anticonvulsant treatment, benzodiazepines in case of administration massive. Clonidine can inhibit psychovegetative 
symptoms. If necessary, intubation, 
mechanical ventilation and catheterization of the bladder. 
5. PHARMACOLOGICAL PROPERTIES 
5.1. Pharmacodynamic properties 
Pharmacotherapeutic group: DRUGS USED IN ERECTILE DISORDERS, ATC code: G04BE04 
(genitourinary system and sex hormones). 
Yohimbine hydrochloride is a competitive antagonist of alpha-2-adrenergic receptors with 
a low affinity for alpha-1-adrenergic α1 receptors, depending on its location. The affinity for 
Alpha-2 receptor subtypes can vary between tissues / organs and species. The action of yohimbine hydrochloride 
on other receptors known for their activity on erection is discussed below, including antagonistic properties at 
dopamine D2 receptors, and receptor activity Serotoninergic 5-HT1A, B, D, and vaso-intestinal cholinergic and 
polypeptic receptors. 
The mechanism of erection and the precise mode of functioning of yohimbine in erectile dysfunction is not yet fully 
understood. Action on the central nervous system responsible for erection through effects on the autonomic nervous 
system is discussed. In addition, yohimbine seems to act on the dilation of the blood vessels of the penis and directly 
on the penile tissue.  

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Norepinephrine binding to pre-junctional adrenergic receptors on adrenergic, cholinergic and on non-adrenergic / 
non-cholinergic 
nerves 
that 
regulate 
negatively 
the 
release 
of 
norepinephrine 
and 
nitric 
oxide, 
respectively. Inhibition of this 
feedback from yohimbine hydrochloride, a alpha2 receptor antagonist, leads to an increase in the release of 
norepinephrine and nitric oxide respectively. 
In smooth muscle tissue, the binding of adrenaline and norepinephrine to  
adrenergic 2 receptors induces contraction via inhibition of adenylate cyclase by a G-protein coupled receptor.  
Inhibition of 2 penile adrenergic receptors by yohimbine hydrochloride 
and stimulation of nitric oxide release increases the relaxation of smooth muscle and decreases contraction, resulting 
in erection. 
Due to the norepinephrine stimulating effect of yohimbine hydrochloride, it may 
influence or aggravate (pre-existing) pathologies related to the noradrenergic system. In this 
context, yohimbine hydrochloride is psychoanaleptic and can cause anxiety. Furthermore, 
increased noradrenaline release and sympathetic activation affect the cardiovascular system. A rise in blood pressure 
and heart rate has been described, with an increase in impulse errors and accelerated reaction times after the increase 
in the release of norepinephrine associated with yohimbine. Norepinephrine leads to activation 
of β1 receptors in the heart and peripheral vessels, respectively, with aconsequence of vasoconstriction. Notably, the 
individual response seems to depend on physiology, because yohimbine hydrochloride caused a lower rate increase 
plasma levels of noradrenaline in hypertensive patients than in normotensive subjects, but 
the vasopressive response was stronger in hypertensive patients. An alteration of the balance of 
 adrenergic receptors, for example, with desensitization of 2 adrenergic receptors pre- 
synaptic activity and hyperreactivity of post-synaptic 1 receptors, which may lead to 
development of hypertension, and could be an explanation of these different responses. In 
some patients with severe orthostatic hypotension, significant increases in 
systolic blood pressure could be observed after the administration of hydrochloride yohimbine (5.4 mg). 
However, patients with panic disorders can have an anxiety and cardiovascular response to yohimbine 
hydrochloride, probably because of the noradrenergic dysregulation and the higher density and sensitivity of 2 
receptors. 
In addition, the activation of 2 receptors results in the inhibition of various gastrointestinal functions, 
including gastric motility and emptying, gastrointestinal secretions, and acetylcholine release 
by the vagus nerve. Therefore, yohimbine hydrochloride as a competitive inhibitor of 
a2 adrenergic receptors could increase the release of acetylcholine and gastric secretion. 
Finally, yohimbine hydrochloride could influence the release of vasopressin 
antidiuretic, ADH) induced by the noradrenergic system. On the one hand, it has been shown that 
Yohimbine hydrochloride inhibits catecholamine-induced ADH release. On the other hand, it is  
known that yohimbine hydrochloride increases the plasma level of noradrenaline and that it can 
inhibit diuresis induced by medetomidine, a 2-adrenergic agonist. Therefore, an effect 
on urination in humans is possible but has not yet been elucidated. In accordance with the heterogeneous effect on 
the inhibition of norepinephrine binding while increasing the concentration of noradrenaline, the reactions may 
depend on the individual initial state.  
5.2. Pharmacokinetic properties 
Absorption 
Yohimbine hydrochloride is completely absorbed in about one hour. Mmaximum blood levels are reached after 45 
to 120 minutes. The bioavailability varies enormously with between individuals and in the same individual, 
primarily because of a first-pass effect hepatic. 
Distribution 
The distribution of yohimbine hydrochloride indicates a high tissue binding capacity. Yohimbine has a plasma 
protein binding of approximately 82%. Only a small amount of 
yohimbine hydrochloride and the active metabolite 11-hydroxyyohimbine is detectable in cerebrospinal fluid.  

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biotransformation 
Two hydroxyl metabolites could be determined: 10-hydroxyyohimbine and the active metabolite 11- 
hydroxyyohimbine. 
Elimination 
The product is eliminated by the hepatic and extra-hepatic metabolic pathways. The half-life 
varies between 0.25 and 2.5 hours after a single dose. The active metabolite 11- 
hydroxyyohimbine has a higher elimination half-life of about 6 hours.  
Special characteristics in elderly subjects 
Maximum plasma concentrations and area under the curve (AUC) of the active 11-OH-metabolite 
yohimbine were significantly lower in 10 elderly subjects (71.2 ± 3.5 years), compared with 
to 11 young volunteers (26.3 ± 4.8 years), and 10 patients with Alzheimer's disease (69.5 ± 7.9 
years). There is great variability in the plasma distribution of yohimbine. Clinical relevance 
of use in the elderly is not assessable. 
5.3. Preclinical safety data 
Very limited preclinical data on chronic toxicity showed an absence of 
organic lesions in the rat, although dose-dependent weight gain was observed. 
The tests in vitro and in vivo for genotoxic potential of yohimbine were negative. 
Yohimbine showed no effect on fertility or reproductive behavior in male rats 
as part of a fertility study. At doses greater than 6 mg / kg body weight, a 
reduction of testes and epididymal weight was observed. 
6. PHARMACEUTICAL DATA 
6.1. List of excipients 
Calcium hydrogen phosphate dihydrate, povidone K25, microcrystalline cellulose, corn starch, 
magnesium stearate, colloidal anhydrous silica. 
6.2. incompatibility 
Not applicable. 
6.3. The duration of the conversation 
3 years 
6.4. Special precautions for storage 
Store at a temperature not exceeding 25 ° C. 
6.5. Nature and contents of the pack 
50 or 100 tablets in platelets (PVC / Aluminum) of 10 tablets. 
6.6. 
Special precautions for disposal and handling 
No special requirements. 
7. HOLDER OF THE MARKETING AUTHORIZATION 
CHEPLAPHARM ARZNEIMITTEL GMBH 
ZIEGELHOF 24 
GREIFSWALD 17489 
GERMANY  

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8. MARKETING AUTHORIZATION NUMBER (S) 
• 34009 353 730 9 0: 50 tablets in platelets (PVC / Aluminum). 
• 34009 353 731 5 1: 100 tablets under pads (PVC / Aluminum). 
9. DATE OF FIRST AUTHORIZATION / RENEWAL OF AUTHORIZATION 
Date of first authorization: March 28, 2000 
Last renewal date: March 28, 2010 
10. DATE OF REVISION OF THE TEXT 
04/2018 
11. DOSIMETRY 
Not applicable. 
12. INSTRUCTIONS FOR THE PREPARATION OF RADIOPHARMACEUTICALS 
Not applicable.