Conditions: Sialorrhea
Keywords: Cerebral Palsy ALS Stroke Neuroleptics
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 187
Healthy volunteers: no

Brief summary:
Multicenter, open-label, outpatient study of the safety and effectiveness of repeated doses of MYOBLOC over a 1-year duration in adult subjects with troublesome sialorrhea.

Detailed description:
Multicenter, open-label, outpatient study of the safety and effectiveness of repeated doses of MYOBLOC over a 1-year duration in adult subjects with troublesome sialorrhea. The primary goal is to determine the long-term safety and tolerability of MYOBLOC (administered intraglandularly as single total dose of 3,500 Units) treatments every 13 weeks over a maximum possible duration of 1 year in adult subjects with troublesome sialorrhea. The secondary goal is to assess the magnitude of therapeutic response of MYOBLOC (administered intraglandularly as a single total dose of 3,500 Units) using effectiveness assessments performed at intervals after treatments every 13 weeks over a maximum possible duration of 1 year.

Arms:
arm 1: After a screening period (up to 21 days), subjects who satisfy all eligibility criteria may receive single dose injections over the course of 1 year.

Interventions: intervention 1: MYOBLOC
Intervention descriptions: intervention 1: After a screening period (up to 21 days), subjects who satisfy all eligibility criteria may receive single dose injections of 3,500 Units of MYOBLOC every 13 weeks (±2 weeks) for a total of 4 treatments via injections into the submandibular and parotid glands. Subjects will undergo safety and effectiveness assessments at Weeks 4, 8, 13, 17, 26, 30, 39, 43, and 52, and telephone follow up will occur at Weeks 21, 34, and 47

Protocol document:
Prot_000.pdf: 
PRODUCT: MYOBLOC® (rimabotulinumtoxinB) Injection 
PROTOCOL NUMBER / AMENDMENT #: SN-SIAL-351 / 01 
SPONSOR: 
Solstice Neurosciences, LLC,  
a subsidiary of US WorldMeds, LLC 
4441 Springdale Rd, Louisville, KY 40241, USA 
TITLE: 
A Phase 3, Long-Term, Open-Label and Single-Arm Study of MYOBLOC® 
in the Treatment of Troublesome Sialorrhea in Adult Subjects 
DOCUMENT DATE: July 23, 2015 
IND NUMBER: 100,454 
NCT NUMBER: NCT02610868  


 
 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 3, Long-Term, Open-Label and Single-Arm Study of MYOBLOC®  
in the Treatment of Troublesome Sialorrhea in Adult Subjects 
 
Protocol Number: 
SN-SIAL-351 
Product: 
MYOBLOC® (rimabotulinumtoxinB) 
Injection 
Investigational New Drug (IND) Number: 
IND 100,454 
Development Phase of Study: 
Phase 3 
Medical Monitor: 
 
Sponsor: 
Solstice Neurosciences, LLC, 
a subsidiary of US WorldMeds, LLC 
4010 Dupont Circle, Suite L-07 
Louisville, KY  40207 
Protocol Date: 
February 12, 2015 
 
   Amendment No. 01 Date:  
 
      July 23, 2015 
 
Confidentiality Statement:  The information in this document contains trade secrets 
and commercial information that are privileged or confidential and that may not be 
disclosed without the written consent of Solstice Neurosciences, LLC (Sponsor).  
Acceptance of this document constitutes the agreement of the recipient that this 
information will not be disclosed to others, except to the extent necessary for 
Institutional Review Board procedures and to obtain written informed consent from 
those persons to whom test drug may be administered. 
Confidential Information 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
1 PROTOCOL AMENDMENT SUMMARY 
This section provides a summary of major changes made to the protocol for Study SN-SIAL-
351 in this current amendment (No. 01). Section 25 provides a detailed accounting of all 
amendment changes. 
• Protocol was revised by changing applicable inclusion/exclusion criteria to allow 
enrollment of subjects who have had prior botulinum toxin A or B injections to the 
salivary glands, provided that last administration was at least 24 weeks before 
screening, and previous botulinum toxin A or B exposure to other anatomical 
locations provided that last administration was at least 12 weeks before screening. 
Further, enrollment of subjects who previously received botulinum toxin injections 
would require that prior toxin exposure was well tolerated and without any significant 
long-term side effects, and subjects, in the Investigator’s opinion, must not have  
failed to respond to previous treatment with botulinum toxin. This change was 
implemented in order to improve enrollment and to facilitate the collection safety data 
on subjects who would be likely candidates for treatment with MYOBLOC for 
sialorrhea in clinical practice.    
 
• Revised exclusion criteria to remove specific exclusion of subjects with moderate to 
severe dysphagia and moderate to severe choking, and have revised exclusion criteria 
related to risk of aspiration (moderate to high risk of aspiration is exclusionary).  
Specific considerations have been provided which should be taken into account when 
the Investigator determines the subject’s level of risk of aspiration.  Moderate to high 
risk of aspiration is defined by any one of the following 
o History of aspiration pneumonia in the last 6 months before screening 
o Speech pathologist and/or formal swallowing test (e.g., with barium, 
endoscopy, dynamic swallowing study, imaging study, fiber-optic endoscopic 
swallowing evaluation or other imaging scan) that concludes that a  moderate 
to severe risk of aspiration exists 
o Due to perceived risk of aspiration, a health care professional has 
recommended PEG or G-tube but subject declined    
o In the investigator’s clinical judgment, the subject is at moderate to high risk 
of aspiration 
 
Subjects whose risk of aspiration are judged by the investigator to be satisfactorily 
controlled by placement of PEG or G-tube for nutritional support are eligible to 
participate. Specific criteria excluding subjects with moderate to severe dysphagia or 
choking within the last 6 months prior to screening have been removed, and instead 
the protocol focuses solely on the risk of aspiration, taking into consideration that 
those with a PEG or G-tube (in whom placement of either would mitigate the risk of 
aspiration associated with a moderate to severe risk dysphagia or choking) may 
participate.  The previous exclusion criteria could be considered too vague or 
restrictive as it focused on a symptom (dysphagia or difficulty with swallowing) that 
is common to many neurological disorders and especially frequent in ALS.  The 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
revised inclusion/exclusion criteria now focus on the baseline risk of aspiration 
because it is aspiration that can lead to significant morbidity and even mortality. 
 
• The requirement to administer the Visual Analog Scale (VAS) to subjects in order to 
rate severity for dysphagia and dry mouth at every clinic visit has been removed. 
Administering the scale at every visit, regardless of a reported event of dysphagia or 
dry mouth, is unnecessary and would result in an overreporting of events. Adverse 
events of dysphagia and dry mouth will continue to be collected based on subject 
report and severity will be determined by the Investigator.  
 
Study drug injections should not be administered if an adverse event of dysphagia or 
dry mouth of moderate to severe severity persists without prior consultation with the 
Medical Monitor. If the adverse event has not resolved or has not improved to a mild 
severity by the end of the per protocol window for injections to occur (every 13 ± 2 
weeks), the Medical Monitor should be contacted to discuss whether or not the 
subject should be dosed, discontinued, etc.  
 
• Administrative updates have been incorporated, including a change in the Medical 
Monitor information.  
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
3 PROCEDURES IN CASE OF EMERGENCY 
 
Table 1. 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Clinical Study Lead 
 
Solstice Neurosciences, LLC 
a subsidiary of US WorldMeds, LLC 
4010 Dupont Circle, Suite L-07 
Louisville, KY 40207 
 
 
 
Sr. Medical 
Monitor/ 
Safety Physician 
Back-up Medical 
Monitor/Safety 
Physician 
SAE Reporting 
 
 
 
 
 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
4 SYNOPSIS 
Title 
A Phase 3, Long-Term, Open-Label and Single-Arm Study of 
MYOBLOC® in the Treatment of Troublesome Sialorrhea in Adult 
Subjects 
Objectives 
Primary 
• To determine the long-term safety and tolerability of MYOBLOC 
(administered intraglandularly as a single total dose of 3,500 Units) 
treatments every 13 weeks over a maximum possible duration of 1 year 
in adult subjects with troublesome sialorrhea. 
Secondary 
• To assess the magnitude of therapeutic response of MYOBLOC 
(administered intraglandularly as a single total dose of 3,500 Units) 
using effectiveness assessments performed at intervals after treatments 
every 13 weeks over a maximum possible duration of 1 year. 
Study Design 
Multicenter, open-label, outpatient study of the safety and effectiveness of 
repeated doses (3,500 Units every 13 weeks) of MYOBLOC over a 1-year 
duration in adult subjects with troublesome sialorrhea.  The study 
population will be comprised of a mixture of patient populations including, 
but not limited to, subjects with Parkinson’s Disease (PD)-related 
sialorrhea, sialorrhea secondary to other non-PD conditions (e.g., adult 
cerebral palsy, amyotrophic lateral sclerosis [ALS], stroke, traumatic brain 
injury), or sialorrhea secondary to oral cancer or medications 
(e.g., neuroleptics). 
All MYOBLOC injections will be performed by Investigators who have 
prior experience or have been appropriately trained with injecting 
botulinum toxin.  Injections will be guided by external anatomical 
landmarks or by external anatomical landmarks with ultrasound-guided 
confirmation.  Sites designated as “ultrasound” sites will perform all their 
injections with ultrasound-guidance. 
After a screening period (up to 21 days), those subjects who satisfy all 
eligibility criteria may receive single dose injections of 3,500 Units of 
MYOBLOC every 13 weeks (±2 weeks) for a total of 4 treatments via 
injections into the submandibular and parotid glands.  Repeat injections at 
each treatment session will be done when subjects return to baseline status 
as determined by the Investigator, with a minimum interval of 11 weeks 
from the prior injection.  If after the first treatment of 3,500 Units the 
subject develops intolerable side effects, but still wishes to remain in the 
study, the Investigator has the discretion to decrease subsequent doses, but 
to no less than a total dose of 2,500 Units. 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
Study Design 
(continued) 
Subjects will undergo safety and effectiveness assessments at Weeks 4, 8, 
13, 17, 26, 30, 39, 43, and 52 as detailed below, and telephone follow up 
will occur at Weeks 21, 34, and 47. 
Sites 
20 or more (Target:  up to 1 subject/site/month.  Recruitment time: 6 to 
12 months) 
Inclusion 
Criteria 
1. Able to read and provide written informed consent before enrollment 
into the study, or the subject’s caregiver (Legally Authorized 
Representative) can provide written informed consent. 
2. Male or female, 18 to 85 years of age (inclusive). 
3. Seeking treatment for troublesome sialorrhea for at least 3 months that 
is occurring secondary to any disorder or related to any cause, 
including, but not limited to, Parkinson’s Disease (PD), adult cerebral 
palsy, amyotrophic lateral sclerosis (ALS), stroke, traumatic brain 
injury, oral cancer, and side effects of other medications.  Note:  A 
diagnosis of Parkinson’s Disease fulfills the UK Parkinson’s Disease 
Society Brain Bank diagnostic criteria.  A diagnosis of ALS fulfills the 
El Escorial World Federation of Neurology criteria. 
4. Minimum unstimulated salivary flow rate of 0.2 g/min at screening 
(unstimulated normal rate is 0.3 g/min) [Wang 1998]. 
 
5. Minimum Investigator’s Drooling Frequency and Severity Scale 
(DFSS) score of 4 (range 2-9, a score of 2 = “never drools”) at 
screening. 
6. Ability and availability to participate in the study for up to 1 year 
(ALS subjects:  ability and availability to participate in the study for at 
least 6 months), based on overall health of the subject and disease 
prognosis, as applicable, in the opinion of the Investigator, and able to 
comply with all requirements of the protocol, including completion of 
study questionnaires.  A caregiver may be designated to assist with 
assessments. 
Exclusion 
Criteria 
1. A moderate to high risk of aspiration will exclude participation in this 
study. Moderate to high risk of aspiration is defined by any one of the 
following: 
• History of aspiration pneumonia in the last 6 months before 
screening  
• Speech pathologist and/or formal swallowing test (e.g., with 
barium, endoscopy, dynamic swallowing study, imaging study, 
fiber-optic endoscopic swallowing evaluation or other imaging 
scan) that concludes that a  moderate to severe risk of aspiration 
exists 
• Due to perceived risk of aspiration, a health care professional has 
recommended PEG or G-tube but subject declined 
• In the Investigator’s clinical judgment, the subject is at moderate to 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
high risk of aspiration. 
Subjects whose risk of aspiration are judged by the Investigator to be 
satisfactorily controlled by placement of PEG tube or G-tube for 
nutritional support are eligible to participate. 
 
2. Respiratory forced vital capacity (FVC) of <20% of predicted.  FVC 
will be tested in all ALS subjects, and also in other subjects at 
Investigator discretion if warranted. 
 
3. Prior botulinum toxin type A or B treatment in the salivary gland(s) 
identified for treatment in this study within 24 weeks before screening. 
Prior botulinum toxin type A or B treatment into other anatomical 
regions not selected for treatment in this study is not exclusionary, but 
must have occurred at least 12 weeks before screening. 
• In the Investigator’s assessment, prior toxin exposure must have 
been well tolerated and without any significant long-term side 
effects in the case of repeated prior exposure. Subjects should be 
excluded if, in the Investigator’s opinion, the subject failed to 
respond to previous treatment with botulinum toxin. Subjects 
should not receive nor have any plans for receiving any botulinum 
toxin treatment, other than the study drug (MYOBLOC), during 
the entire course of the study (from the point the informed consent 
is signed until subject’s participation is complete). 
4. Prior salivary gland surgery. 
5. Concomitant use, or exposure within 5 half-lives of screening, of 
aminoglycoside antibiotics, curare-like agents, or other agents that 
interfere with neuromuscular function. 
Exclusion 
Criteria 
(continued) 
6. Current treatment or treatment at any time during the study with 
Coumadin® (warfarin) or similar anti-coagulant medications.  Anti-
platelet medications are not specifically exclusionary. 
7. Anticipated or scheduled surgery during the study period. A PEG 
tube/G tube may be placed for nutritional support at any time during 
the study and will not exclude the subject from continued study 
participation. 
8. Major surgery (requiring general anesthesia, except PEG tube/G tube 
placement) within the previous 6 months before screening.  If surgery 
occurred more recently than 6 months before screening, Investigator 
must have sufficient documentation to demonstrate the subject has 
fully recovered and stabilized.  Prior movement disorder-related 
surgery (e.g., pallidotomy, thalamic/subthalamic/pallidal deep brain 
stimulation) will not exclude the subject, provided the surgery was 
performed at least 6 months before screening. 
9. Anticholinergic and antihistamine medication eligibility restrictions: 
 
• Oral/transdermal pharmacologic treatment (specifically 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
antihistamines and those medications with anticholinergic 
properties) for troublesome sialorrhea must be discontinued during 
the 30-day period before screening and are not allowed in the entire 
duration of the study, except ALS subjects as allowed herein.  For 
ALS subjects only: such medications for the treatment of sialorrhea 
are allowed; however, conversion to, or continuation of, a short-
acting medication (duration of action of approximately 8 hours or 
less) is required at a stable dose/regimen at least 2 weeks before the 
first injection of study drug (i.e., Day 1 of Treatment Session 1).  
The short-acting anti-cholinergic medication for the treatment of 
sialorrhea may be continued throughout screening and study 
participation provided that the ALS subject agrees to hold the 
medication for at least 8 hours before the screening, baseline, and 
all subsequent study visits, so that the effectiveness and safety of 
the study drug can be properly evaluated. 
• Antihistamines and anticholinergic medications taken for a
non-sialorrhea condition should be avoided as much as possible,
but are not exclusionary.
Exclusion 
Criteria 
(continued) 
10. Evidence of any clinically significant neurologic disease
(e.g., myasthenia gravis, Lambert-Eaton syndrome), cardiovascular, 
hematologic (including bleeding diathesis), hepatic, renal, 
gastrointestinal, endocrine, pulmonary, musculoskeletal, psychiatric 
disease or condition, or dental condition, which in the judgment of the 
Investigator or screening dentist would put the subject at risk while in 
the study, could influence the results of the study, or negatively impact 
the subject’s ability to participate in the study
11. Pregnancy or lactation
•
As assessed by the Investigator, females of childbearing potential
must agree to practice a medically acceptable method of
contraception (e.g., intrauterine device, hormonal contraception
started at least one full cycle before study enrollment or barrier
method in conjunction with spermicide) for the duration of the
study (including 2 months after study completion).  For the
purposes of this study, all females are considered to be of
childbearing potential unless they are confirmed by the
Investigator to be post-menopausal (at least 1 year since last
menses), biologically sterile, or surgically sterile (e.g., s/p
hysterectomy, bilateral oophorectomy, tubal ligation).
12. History of drug or alcohol abuse currently or within the previous
6 months, as determined by the Investigator.
13. Current infection at the sialorrhea treatment injection site(s).
14. Participation in another clinical drug, device, or biological agent study
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
within 30 days of screening or while participating in this study. 
15. Any other condition or clinical finding that, in the opinion of the 
Investigator and/or the Sponsor, is determined to be unsuitable for 
enrollment into this study. 
Number of 
Subjects 
Approximately 120 to 200 subjects or until requirements of safety database 
are met. 
Safety 
Endpoints 
• Occurrence, seriousness, severity, and causality assessment of adverse 
events at each study visit; 
• Occurrence of adverse events of special interest (i.e., aspiration, 
aspiration pneumonia, choking, dysphagia) at each study visit as 
assessed by the Investigator; 
• Columbia Suicide Severity Rating Scale (C-SSRS) at each study visit; 
and 
• Occurrence of dental adverse events. 
Effectiveness 
Endpoints 
• Unstimulated salivary flow rate (USFR) (Assessor) at each study visit; 
• Clinical Global Impression of Severity (CGI-S) and Change (CGI-C) 
(Assessor) at each study visit; 
• DFSS-I (Assessor) at each study visit;  
• DFSS-S as assessed via subject’s diary at each assessment time point; 
• Patient Global Impression of Severity (PGI-S) and Change (PGI-S) 
at each study visit; and 
• Drooling Impact Score (DIS) (Subject) at each study visit. 
Duration 
The planned duration of participation for each subject is a minimum of 
26 weeks and a maximum of 52 weeks (excluding up to a 21-day screening 
period), including: 
• Up to four 13-week (±2 weeks) treatment sessions over a 1-year period.  
Note that Treatment Sessions 3 and 4 are likely, but may not be 
necessary as the study progresses because the study may be stopped 
early once enough subjects have completed the study to meet FDA 
safety database requirements.  Any subject that enters the study, 
however, is required to participate at least through 6 months (i.e., 
complete Treatment Sessions 1 and 2). 
Study Visits 
Screening Period:  up to 21 days 
Treatment Session 1 
Day 1 (day of injection of study drug) and 4 weeks (±3 days), 8 weeks 
(±3 days), and 13 weeks (±2 weeks) post-injection, and a telephone 
follow up 24 hours (±1 day) post-injection. 
Treatment Sessions 2, 3, and 4 
For each 13-week treatment session: 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
• 4 weeks (±5 days) and 13 weeks (±2 weeks) after each treatment, with a 
telephone follow up 1 week (±1 day) and 8 weeks (±5 days) after each 
treatment.  Note that the last visit of a prior treatment session will serve 
as the first day of the next treatment session. 
Safety 
Assessments 
The following safety assessments will be performed as follows: 
• Occurrence, seriousness, severity, and causality assessment of 
adverse events at each study visit or, if applicable, at discontinuation 
from the study; 
• Occurrence of adverse events of special interest (i.e., aspiration, 
aspiration pneumonia, choking, dysphagia) at each study visit or, if 
applicable, at discontinuation from the study; 
• Occurrence of dental-related adverse events; 
• Vital signs at each study visit or, if applicable, at discontinuation from 
the study; 
• Complete physical exam at Weeks 4, 13, 26, 39, and 52 (brief at other 
study visits) or, if applicable, at discontinuation from the study; 
• FVC in all ALS subjects, and in other subjects if warranted at the 
discretion of the Investigator, at screening, before the first injection of 
study drug on Day 1, and at Weeks 4, 8 (as clinically warranted), and 
13.  Thereafter, FVC will be checked as clinically warranted. 
• Clinical laboratory safety tests (fasting) at screening and Weeks 13, 26, 
and 52 or, if applicable, at discontinuation from the study.  Laboratory 
testing will also be done as clinically warranted throughout the study. 
• Neurologic exam at screening, Day 1 (before first injection of study 
drug), and Weeks 13 and 52 or, if applicable, at discontinuation from 
the study.  Additional neurologic exams will be performed as clinically 
warranted. 
• Dental exam by a licensed dentist at screening and Weeks 4, 13, 26, 
and 52 or, if applicable, at discontinuation from the study.  Four bite-
wing radiographs or panoramic imaging (if edentulous or if bite-wing 
x-rays are difficult due to limited teeth) will be obtained at screening 
and Weeks 26 and 52 or, if applicable, at discontinuation from the 
study.  Additional dental exams will be performed as clinically 
warranted based on predefined safety criteria (e.g., persistent severe dry 
mouth). 
• Oral exam by the Investigator at each study visit where a dental exam is 
not required. 
• Columbia Suicide Severity Rating Scale (C-SSRS) on Day 1 (before 
first injection of study drug) and each subsequent study visit or, if 
applicable, at discontinuation from the study. 
Effectiveness 
Assessments 
The following effectiveness assessments will be performed at each study 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
visit: 
• USFR (Assessor); 
• CGI-S and CGI-C (Assessor);  
• DFSS-I; 
• PGI-S and PGI-C (Subject); and 
• DIS (Subject). 
In addition, DFSS will be assessed daily via the subject’s diary the first 
2 weeks after each injection, then weekly for the remainder of each 
treatment session. 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
5 TABLE OF CONTENTS 
1 
PROTOCOL AMENDMENT SUMMARY ...................................................................2 
2 
SIGNATURE PAGE .......................................................................................................4 
3 
PROCEDURES IN CASE OF EMERGENCY ..............................................................5 
4 
SYNOPSIS ......................................................................................................................6 
5 
TABLE OF CONTENTS ..............................................................................................13 
6 
ABBREVIATIONS AND DEFINITION OF TERMS .................................................18 
7 
BACKGROUND AND SIGNIFICANCE ....................................................................19 
7.1 
Sialorrhea .................................................................................................................19 
7.2 
MYOBLOC ..............................................................................................................19 
7.3 
Safety of MYOBLOC in Sialorrhea .........................................................................20 
7.3.1 
Sponsor’s Dose-Escalation Study ........................................................................20 
7.3.2 
Adverse Event Reports in the Sponsor’s Postmarketing 
Pharmacovigilance Database ...............................................................................20 
7.3.3 
Adverse Events Reports in the Literature ............................................................21 
7.4 
Efficacy of MYOBLOC in Sialorrhea .....................................................................22 
7.4.1 
Sponsor’s Dose-Escalation Study ........................................................................22 
7.4.2 
Literature Reports ................................................................................................23 
7.4.2.1 
Double-Blind, Placebo-Controlled Studies in Adults .....................................23 
7.4.2.2 
Double-Blind, Active Comparator Study in Adults .......................................24 
7.4.2.3 
Open-Label Studies in Adults .........................................................................24 
7.4.2.4 
Open-Label Study in Children ........................................................................25 
7.5 
Study Rationale ........................................................................................................25 
7.5.1 
Route of Administration ......................................................................................25 
7.5.2 
Dose Selection and Dosage Regimen ..................................................................25 
7.5.3 
Treatment Period .................................................................................................26 
8 
STUDY OBJECTIVES .................................................................................................26 
8.1 
Primary Objective ....................................................................................................26 
8.2 
Secondary Objective ................................................................................................27 
9 
STUDY ENDPOINTS ..................................................................................................27 
9.1 
Safety Endpoints ......................................................................................................27 
9.2 
Effectiveness Endpoints ...........................................................................................27 
10 
STUDY DESIGN ..........................................................................................................27 
11 
SELECTION OF SUBJECTS .......................................................................................29 
11.1 
Population Base ........................................................................................................29 
11.1.1 
Inclusion Criteria .................................................................................................29 
11.1.2 
Exclusion Criteria ................................................................................................30 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
12 
ENROLLMENT PROCEDURES AND SUBJECT WITHDRAWAL ........................32 
12.1 
Screening Failures ....................................................................................................32 
12.2 
Randomization and Blinding ....................................................................................32 
12.3 
Subject Withdrawal Criteria .....................................................................................32 
13 
STUDY DRUG MATERIALS AND MANAGEMENT ..............................................34 
13.1 
Study Drug ...............................................................................................................34 
13.2 
Study Drug Administration and Compliance ...........................................................34 
13.3 
Study Drug Packaging and Labeling ........................................................................35 
13.4 
Study Drug Storage ..................................................................................................35 
13.5 
Study Drug Accountability .......................................................................................35 
13.6 
Study Drug Handling and Disposal ..........................................................................35 
14 
STUDY PROCEDURES ..............................................................................................35 
14.1 
Schedule of Assessments .........................................................................................35 
14.2 
Screening ..................................................................................................................40 
14.3 
Treatment Session 1 .................................................................................................40 
14.3.1 
Day 1 ...................................................................................................................40 
14.3.2 
Weeks 4, 8, and 13 ..............................................................................................41 
14.4 
Treatment Session 2 .................................................................................................42 
14.4.1 
Day 1 ...................................................................................................................42 
14.4.2 
Weeks 14, 17, 21, and 26 ....................................................................................42 
14.5 
Treatment Session 3 .................................................................................................43 
14.5.1 
Day 1 ...................................................................................................................43 
14.5.2 
Weeks 27, 30, 34, and 39 ....................................................................................43 
14.6 
Treatment Session 4 .................................................................................................44 
14.6.1 
Day 1 ...................................................................................................................44 
14.6.2 
Weeks 40, 43, 47, and 52 ....................................................................................44 
14.7 
Early Discontinuation ...............................................................................................45 
14.8 
Interim Telephone Follow-ups .................................................................................46 
14.9 
Post-Study Telephone Contact .................................................................................46 
15 
EFFECTIVENESS ASSESSMENTS ...........................................................................46 
15.1 
Unstimulated Salivary Flow Rate (USFR) ...............................................................47 
15.2 
Clinical Global Impression of Severity (CGI-S) and Change (CGI-C) ...................47 
15.3 
Patient Global Impression of Severity (PGI-S) and Change (PGI-C) ......................47 
15.4 
Drooling Frequency and Severity Scale (DFSS) ......................................................48 
15.5 
Drooling Impact Score (DIS) ...................................................................................48 
16 
SAFETY ASSESSMENTS ...........................................................................................48 
16.1 
Medical/Surgical/Medication History ......................................................................48 
16.2 
Adverse Events .........................................................................................................49 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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16.2.1 
Definition of Adverse Event ................................................................................49 
16.2.2 
Investigator Assessment of Adverse Events ........................................................50 
16.2.2.1 
Intensity of Adverse Event .............................................................................50 
16.2.2.2 
Relationship of Adverse Events to Study Drug ..............................................50 
16.2.2.3 
Action Taken with Regard to Study Continuation/Discontinuation ...............51 
16.2.2.4 
Outcome of Adverse Event .............................................................................51 
16.2.2.5 
Indication of Seriousness of Adverse Event ...................................................51 
16.2.3 
Dental Adverse Events ........................................................................................51 
16.2.4 
Adverse Events of Special Interest ......................................................................51 
16.2.4.1 
Aspiration and Aspiration Pneumonia ............................................................52 
16.2.4.2 
Choking...........................................................................................................54 
16.2.4.3 
Dysphagia .......................................................................................................55 
16.2.5 
Pregnancy ............................................................................................................55 
16.2.6 
Serious Adverse Events .......................................................................................56 
16.2.7 
Follow-up of All Adverse Events/Serious Adverse Events ................................56 
16.2.8 
Adverse Event Reporting ....................................................................................57 
16.2.8.1 
Adverse Events Requiring Expedited Reporting ............................................57 
16.2.8.2 
Timeframe for Collecting and Reporting Serious Adverse Events, 
Adverse Events of Special Interest, and Other Immediately Reportable 
Adverse Events ...............................................................................................57 
16.3 
Vital Signs ................................................................................................................58 
16.4 
Clinical Laboratory Evaluations ...............................................................................58 
16.4.1 
Standard Laboratory Tests ...................................................................................58 
16.4.2 
Pregnancy Test ....................................................................................................58 
16.5 
Neurologic Exam ......................................................................................................59 
16.6 
Dental Exam .............................................................................................................59 
16.7 
Oral Exam ................................................................................................................59 
16.8 
Physical Exam ..........................................................................................................59 
16.9 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................60 
16.10 
Concomitant Medications ........................................................................................60 
17 
STATISTICS ................................................................................................................61 
17.1 
General Statistical Considerations ...........................................................................61 
17.2 
Sample Size ..............................................................................................................61 
17.3 
Analysis Populations ................................................................................................61 
17.4 
Demographic and Baseline Characteristics ..............................................................61 
17.5 
Subject Disposition ..................................................................................................62 
17.6 
Safety Endpoints ......................................................................................................62 
17.7 
Statistical Methods for Safety ..................................................................................62 
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17.8 
Effectiveness Endpoints ...........................................................................................63 
17.9 
Statistical Methods for Effectiveness .......................................................................63 
18 
ETHICS .........................................................................................................................64 
18.1 
Ethics Review ...........................................................................................................64 
18.2 
Ethical Conduct of the Study ...................................................................................64 
18.3 
Study Conduct ..........................................................................................................65 
18.4 
Institutional Review Board Approval ......................................................................65 
18.5 
Informed Consent and HIPAA Authorization ..........................................................66 
19 
INVESTIGATOR OBLIGATIONS .............................................................................67 
19.1 
Protocol Adherence and Subject Welfare ................................................................67 
19.2 
Protocol Modification ..............................................................................................67 
19.3 
Compliance with Law, Audit, and Debarment .........................................................67 
19.3.1 
Statement of Investigator (Form FDA 1572) ......................................................67 
19.3.2 
Financial Disclosure ............................................................................................67 
19.3.3 
Inspections and Audits ........................................................................................68 
19.3.4 
Debarment ...........................................................................................................68 
19.4 
Adverse Event Reporting .........................................................................................68 
19.5 
Drug Accountability .................................................................................................68 
19.6 
Data Handling and Recordkeeping ..........................................................................68 
19.6.1 
Case Report Forms ..............................................................................................68 
19.6.2 
Subject Identification ...........................................................................................69 
19.6.3 
Administrative Documentation ...........................................................................69 
19.6.4 
Retention of Records ...........................................................................................70 
20 
STUDY MONITORING AND QUALITY CONTROL/ASSURANCE .....................71 
20.1 
Study Monitoring .....................................................................................................71 
20.2 
Inspections and Audits .............................................................................................72 
20.2.1 
Inspection of Records ..........................................................................................72 
20.2.2 
Audits ..................................................................................................................72 
21 
CONFIDENTIAL INFORMATION ............................................................................73 
21.1.1 
Confidentiality of Data ........................................................................................73 
21.1.2 
Confidentiality of Subject Records .....................................................................74 
22 
STUDY DISCONTINUATION CRITERIA ................................................................74 
23 
DISSEMINATION AND PUBLICATION OF STUDY RESULTS ...........................75 
24 
REFERENCES ..............................................................................................................75 
25 
PROTOCOL AMENDMENT DETAILS .....................................................................77 
 
 
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TABLES 
Table 1. Emergency Contact Information ................................................................................5 
Table 2. Schedule of Study Assessments ...............................................................................36 
Table 3. Hematology, Chemistry and Urinalysis Tests ..........................................................58 
Table 4. Changes for SN-SIAL-351 Protocol (February 12, 2015)   SN-SIAL-351, 
Amendment No. 01 (July 23, 2015) .........................................................................78 
 
APPENDICES 
Appendix A 
Ultrasound and Anatomically Guided Injection Procedures 
Appendix B 
Unstimulated Salivary Flow Rate (USFR) Collection 
Appendix C 
Clinical Global Impression of Severity (CGI-S) and Change (CGI-C) 
Appendix D 
Patient Global Impression of Severity (PGI-S) and Change (PGI-C) 
Appendix E 
Drooling Frequency and Severity Scale (DFSS) 
Appendix F 
Drooling Impact Score (DIS) 
Appendix G 
Neurologic Exam 
Appendix H 
Dental and Oral Exam 
Appendix I 
Columbia Suicide Severity Rating Scale (C-SSRS) Baseline Version 
Appendix J 
Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version 
 
 
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6 ABBREVIATIONS AND DEFINITION OF TERMS 
ADL 
Activities of Daily Living 
AESI 
Adverse Events of Special Interest 
ALS 
Amyotrophic Lateral Sclerosis 
BP 
Blood Pressure 
CAP 
College of American Pathologist 
CD 
Cervical Dystonia 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CIB 
Clinical Investigator’s Brochure 
CLIA 
Clinical Laboratory Improvement Act of 1988 
C-SSRS 
Columbia Suicide Severity Rate Scale 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
DFSS 
Drooling Frequency and Severity Score 
DIS 
Drooling Impact Score 
eCRF(s) 
Electronic Case Report Form(s) 
FDA 
Food and Drug Administration 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB(s) 
Institutional Review Board(s) 
LAR 
Legally Authorized Representative 
LD50 
Median Lethal Dose 
Max 
Maximum 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
n 
Number 
NG 
Nasogastric 
PD 
Parkinson’s Disease 
PEG 
Percutaneous Endoscopic Gastrostomy 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
RR 
Respiration Rate 
SAE(s) 
Serious Adverse Event(s) 
SD 
Standard Deviation 
SAP 
Statistical Analysis Plan 
TEAE(s) 
Treatment-Emergent Adverse Event(s) 
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Temp 
Temperature 
ULN 
Upper Limit of Normal 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US 
United States 
USFR 
Unstimulated Salivary Flow Rate 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
Wk 
Week 
 
7 BACKGROUND AND SIGNIFICANCE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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8 STUDY OBJECTIVES 
8.1 Primary Objective 
The primary objective of this study is: 
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• To determine the long-term safety and tolerability of MYOBLOC (administered 
intraglandularly as a single total dose of 3,500 Units) treatments every 13 weeks over 
a maximum possible duration of 1 year in adult subjects with troublesome sialorrhea. 
8.2 Secondary Objective 
The secondary objective of this study is: 
• To assess the magnitude of therapeutic responses of MYOBLOC (administered 
intraglandularly as a single total dose of 3,500 Units) using effectiveness assessments 
performed at intervals after treatments every 13 weeks over a maximum possible 
duration of 1 year. 
9 STUDY ENDPOINTS 
9.1 Safety Endpoints 
• Occurrence, seriousness, severity, and causality assessment of adverse events at each 
study visit; 
• Occurrence of adverse events of special interest (i.e., aspiration, aspiration 
pneumonia, choking, dysphagia) at each study visit as assessed by the Investigator; 
• Columbia Suicide Severity Scale (C-SSRS) at each study visit; and 
• Occurrence of dental adverse events. 
9.2 Effectiveness Endpoints 
• Unstimulated salivary flow rate (USFR) (Assessor) at each study visit; 
• Clinical Global Impression of Severity (CGI-S) and Change (CGI-C) (Assessor) at 
each study visit; 
• DFSS-I (Assessor) at each study visit;  
• DFSS as assessed via subject’s diary at each assessment time point; 
• Patient Global Impression of Severity (PGI-S) and Change (PGI-C) at each 
study visit; and 
• Drooling Impact Score (DIS) (Subject) at each study visit. 
10 STUDY DESIGN 
This is a Phase 3, multicenter, open-label, outpatient study of safety/tolerability and 
effectiveness of repeated doses (3,500 Units) of MYOBLOC in adult subjects with 
troublesome sialorrhea over a maximum 1-year duration.  The study population will be 
comprised of a mixture of patient populations including, but not limited to, subjects with 
PD-related sialorrhea, subjects with sialorrhea secondary to other non-PD conditions 
(e.g., cerebral palsy, ALS, stroke, traumatic brain injury), or sialorrhea secondary to oral 
cancer or medications (e.g., neuroleptics).  The study is planned to be conducted at 20 or 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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more study sites and include approximately 120 to 200 male and female subjects (or until 
enough subjects have completed to meet FDA safety database requirements; see further 
details in Section 11.1).  A diagnosis of PD fulfills the UK Parkinson’s Disease Society Brain 
Bank diagnostic criteria, and a diagnosis of ALS fulfills the El Escorial World Federation of 
Neurology criteria. 
The planned duration of participation for each subject is a minimum of 26 weeks and a 
maximum of 52 weeks, excluding the screening period, which can last up to 21 days, with 
study drug injected at approximately 13-week (±2 weeks) intervals for a maximum of 
4 treatments over this 1-year period. 
 
 
During the screening period, the following will be assessed to evaluate the subject’s 
eligibility to participate in the study:  inclusion and exclusion criteria; medical, surgical, and 
medication history; presence or prior history of aspiration, aspiration pneumonia, choking, 
and/or dysphagia; complete physical exam (including vital signs, height, and weight); 
neurologic exam; dental exam; clinical laboratory testing; urine pregnancy testing (females 
of childbearing potential only); and forced vital capacity (FVC) (if warranted, such as in ALS 
patients).  All subjects successfully completing screening will have the following procedures/ 
assessments conducted at baseline (Day 1) before the first injection of MYOBLOC:  brief 
physical exam (including vital signs); FVC (if warranted); neurologic exam; Columbia 
Suicide Severity Rate Scale (C-SSRS); oral exam; saliva production quantitatively 
determined via USFR; qualitative assessments by the Investigator including CGI-S and 
DFSS-I; subject assessments including PGI-S, DFSS, DIS; and urine pregnancy test (result 
must be negative to proceed with the injection).  Those subjects who satisfy all eligibility 
criteria may receive a dose of MYOBLOC (3,500 Units) via injections into the 
submandibular and parotid glands on Day 1.  Subjects will be contacted by telephone 
24 hours post-injection to inquire about their health status. 
Subsequent study visits will occur at Weeks 4 (±3 days), 8 (±3 days), 13 (±2 weeks), 17 
(±5 days), 26 (±2 weeks), 30 (±5 days), 39 (±2 weeks), 43 (±5 days), and 52 (±2 weeks), 
with safety and effectiveness assessments made as detailed in the Schedule of Assessments in 
Table 2 in Section 14.1; telephone follow up will be done at Weeks 14 (±1 day), 21 
(±5 days), 27 (±1 day), 34 (±5 days), 40 (±1 day), and 47 (±5 days)
 
 
 
 
 
 
Injections at each treatment session will be done when the subject returns to baseline status 
as determined by the Principal Investigator, with a minimum interval of 11 weeks from the 
prior injection but no later than 15 weeks from the prior injection.  If after the first treatment 
of 3,500 Units the subject develops intolerable side effects, but still wishes to remain in the 
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study, the Investigator has the discretion to decrease subsequent doses, but to no less than a 
total dose of 2,500 Units.   
11 SELECTION OF SUBJECTS 
11.1 Population Base 
Adult subjects with troublesome sialorrhea and a minimum USFR (as defined in 
Section 11.1.1) are eligible for the study.  Enrollment will continue until a minimum total of 
300 subjects (across this protocol and the prior MYOBLOC clinical trial in sialorrhea 
expected to meet FDA safety database requirements) have been treated with clinically 
relevant doses (≥2,500 Units) of MYOBLOC for a minimum of 6 months and 100 subjects 
treated with MYOBLOC at clinically relevant doses for a minimum of 1 year.  Sixty of the 
100 subjects must be treated with 3,500 Units for the minimum period of 6 months.  It is 
estimated that approximately 120 to 200 subjects will be enrolled in this open-label study in 
order to accrue a sufficiently large safety database for evaluation.  The study population 
should be comprised of a mixture of patient populations including, but not limited to, 
subjects with PD-related sialorrhea, subjects with sialorrhea secondary to other non-PD 
conditions (e.g., cerebral palsy, ALS, stroke, traumatic brain injury), or sialorrhea secondary 
to oral cancer or medications (e.g., neuroleptics).  Entry into the study is open to both men 
and women and to all racial and ethnic subgroups. 
 
 
 
 
11.1.1 Inclusion Criteria 
To be eligible for participation, subjects with troublesome sialorrhea must meet all of the 
following criteria: 
1. Able to read and provide written informed consent before enrollment into the study, or 
the subject’s caregiver (Legally Authorized Representative) can provide written 
informed consent. 
2. Male or female, 18 to 85 years of age (inclusive). 
3. Seeking treatment for troublesome sialorrhea for at least 3 months that is occurring 
secondary to any disorder or related to any cause, including, but not limited to, PD, adult 
cerebral palsy, ALS, stroke, traumatic brain injury, oral cancer, and side effects of other 
medications.  Note:  A diagnosis of PD fulfills the UK Parkinson’s Disease Society 
Brain Bank diagnostic criteria.  A diagnosis of ALS fulfills the El Escorial World 
Federation of Neurology criteria. 
4. Minimum USFR of 0.2 g/min at screening (unstimulated normal rate is 0.3 g/min) 
[Wang 1998]. 
5. Minimum Investigator’s DFSS score of 4 (range 2-9, a score of 2 = “never drools”) at 
screening. 
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6. Ability and availability to participate in the study for up to 1 year (ALS subjects:  ability 
and availability to participate in the study for at least 6 months), based on overall health 
of the subject and disease prognosis, as applicable, in the opinion of the Investigator, and 
able to comply with all requirements of the protocol, including completion of study 
questionnaires.  A caregiver may be designated to assist with assessments. 
11.1.2 Exclusion Criteria 
Subjects who meet any of the following criteria will not be allowed to participate: 
1. A moderate to high risk of aspiration will exclude participation in this study. Moderate 
to high risk of aspiration is defined by any one of the following: 
• History of aspiration pneumonia in the last 6 months before screening  
• Speech pathologist and/or formal swallowing test (e.g., with barium, endoscopy, 
dynamic swallowing study, imaging study, fiber-optic endoscopic swallowing 
evaluation or other imaging scan) that concludes that a  moderate to severe risk of 
aspiration exists 
• Due to perceived risk of aspiration, a health care professional has recommended PEG 
or G-tube but subject declined 
• In the Investigator’s clinical judgment, the subject is at moderate to high risk of 
aspiration. 
Subjects whose risk of aspiration are judged by the Investigator to be satisfactorily 
controlled by placement of PEG tube or G-tube for nutritional support are eligible to 
participate. 
2. Respiratory FVC of <20% of predicted.  FVC will be tested in all ALS subjects, and also 
in other subjects at Investigator discretion if warranted. 
3. Prior botulinum toxin type A or B treatment in the salivary gland(s) identified for 
treatment in this study within 24 weeks before screening. Prior botulinum toxin type A 
or B treatment into other anatomical regions not selected for treatment in this study is 
not exclusionary, but must have occurred at least 12 weeks before screening. 
• In the Investigator’s assessment, prior toxin exposure must have been well tolerated 
and without any significant long-term side effects in the case of repeated prior 
exposure. Subjects should be excluded if, in the Investigator’s opinion, the subject 
failed to respond to previous treatment with botulinum toxin. Subjects should not 
receive nor have any plans for receiving any botulinum toxin treatment, other than 
the study drug (MYOBLOC), during the entire course of the study (from the point 
the informed consent is signed until subject’s participation is complete). 
4. Prior salivary gland surgery. 
5. Concomitant use, or exposure within 5 half lives of screening, of aminoglycoside 
antibiotics, curare-like agents, or other agents that interfere with neuromuscular function. 
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6. Current treatment or treatment at any time during the study with Coumadin® (warfarin) 
or similar anti-coagulant medications.  Anti-platelet medications are not specifically 
exclusionary. 
7. Anticipated or scheduled surgery during the study period. A PEG tube/G tube may be 
placed for nutritional support at any time during the study and will not exclude the 
subject from continued study participation. 
8. 
Major surgery (requiring general anesthesia, except PEG tube/G-tube placement) within 
the previous 6 months before screening.  If surgery occurred more recently than 
6 months before screening, Investigator must have sufficient documentation to 
demonstrate the subject has fully recovered and stabilized.  Prior movement disorder-
related surgery (e.g., pallidotomy, thalamic/subthalamic/pallidal deep brain stimulation) 
will not exclude the subject, provided the surgery was performed at least 6 months 
before screening. 
9. Anticholinergic and antihistamine medication eligibility restrictions (see also 
Section 16.10): 
• Oral/transdermal pharmacologic treatment (specifically antihistamines and those 
medications with anticholinergic properties) for troublesome sialorrhea must be 
discontinued during the 30-day period before screening and are not allowed in the 
entire duration of the study, except ALS subjects as allowed herein.  For ALS 
subjects only: such medications for the treatment of sialorrhea are allowed; however, 
conversion to, or continuation of, a short-acting medication (duration of action of 
approximately 8 hours or less) is required at a stable dose/regimen at least 2 weeks 
before the first injection of study drug (i.e., Day 1 of Treatment Session 1).  The 
short-acting anti-cholinergic medication for the treatment of sialorrhea may be 
continued throughout screening and study participation provided that the ALS subject 
agrees to hold the medication for at least 8 hours before the screening, baseline, and 
all subsequent study visits, so that the effectiveness and safety of the study drug can 
be properly evaluated. 
• Antihistamines and anticholinergic medications taken for a non-sialorrhea condition 
should be avoided as much as possible, but are not exclusionary.   
10. Evidence of any clinically significant neurologic disease (e.g., myasthenia gravis, 
Lambert-Eaton syndrome), cardiovascular, hematologic (including bleeding diathesis), 
hepatic, renal, gastrointestinal, endocrine, pulmonary, musculoskeletal, psychiatric 
disease or condition, or dental condition, which in the judgment of the Investigator or 
screening dentist would put the subject at risk while in the study, could influence the 
results of the study, or negatively impact the subject’s ability to participate in the study 
 
 
11. Pregnancy or lactation 
• As assessed by the Investigator, females of childbearing potential must agree to 
practice a medically acceptable method of contraception (e.g., intrauterine device, 
hormonal contraception started at least one full cycle before study enrollment or 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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barrier method in conjunction with spermicide) for the duration of the study 
(including 2 months after study completion).  For the purposes of this study, all 
females are considered to be of childbearing potential unless they are confirmed by 
the Investigator to be post-menopausal (at least 1 year since last menses), biologically 
sterile, or surgically sterile (e.g., s/p hysterectomy, bilateral oophorectomy, tubal 
ligation). 
12. History of drug or alcohol abuse currently or within the previous 6 months, as 
determined by the Investigator. 
13. Current infection at the sialorrhea treatment injection site(s). 
14. Participation in another clinical drug, device, or biological agent study within 30 days 
of screening or while participating in this study. 
15. Any other condition or clinical finding that, in the opinion of the Investigator and/or the 
Sponsor, is determined to be unsuitable for enrollment into this study. 
12 ENROLLMENT PROCEDURES AND SUBJECT WITHDRAWAL 
12.1 Screening Failures 
Screening failures are potential study subjects who provide written informed consent and 
HIPAA authorization, complete some screening procedures but are determined to be 
ineligible for treatment with study drug.  A screening log for all subjects who are screened 
will be maintained.  The screening log will uniquely identify each subject and report whether 
he/she passed or failed screening, and, if he/she did not pass, the reason(s) for the screening 
failure.  Subjects who fail screening may rescreen at a later time as long as at least 30 days 
have passed since screen fail per Investigator discretion. 
12.2 Randomization and Blinding 
This is an open-label study. 
12.3 Subject Withdrawal Criteria 
Once a subject starts study treatment, any subject not completing the study for any reason 
will be considered a premature termination and the Investigator must record the reason(s) for 
withdrawal in the subject’s source document and electronic case report form (eCRF).  Any 
subject that discontinues prematurely, regardless of the reason, will be requested to complete 
all early discontinuation assessments and procedures (see Section 14.7).  Once withdrawn, 
subjects may not re-enter the study, nor will they be replaced. 
Subjects are free to discontinue their participation in the study at any time and without 
prejudice to further treatment.  In such cases, the subject/caregiver will be queried as to the 
reason(s) for the decision to withdraw consent and the reasons(s) clearly documented in the 
subject’s source document and eCRF to ensure the decision was not due to an adverse event 
(if due to an adverse event, the adverse event should be indicated as the reason for 
discontinuation even if the Investigator would not have considered discontinuation of 
treatment because of the adverse event). 
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The Investigator or Sponsor may discontinue individual subjects from the study at any time if 
it is deemed clinically appropriate or for any reason, including the following: 
• An intolerable adverse event or serious adverse event (SAE); 
• Insufficient therapeutic response, including: 
 Lack of effectiveness – no improvement in USFR or CGI-C after the subject’s 
initial treatment when comparing scores at Week 4 versus respective scores at 
baseline (Day 1); 
 Loss of effectiveness – after demonstrating some improvement in USFR and 
CGI-C scores post-injection on the subject’s initial treatment, 1 or both of 
these assessments is not improved on subsequent injections at Week 4 versus 
the respective score at baseline (Day 1); 
• Requires a medication that was prohibited (see Sections 11.1.2 and 16.10) by the 
protocol; 
• Does not follow guidelines specified in the protocol; 
• Is lost to follow up; and 
• In the Investigator’s opinion, does not continue to meet entry criteria. 
The clinical course of each adverse 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 must be followed up to 
determine the final outcome (see Section 16.2.7). 
Subjects prematurely discontinuing due to lack of effectiveness or loss of effectiveness will 
be encouraged to return to the study site to complete early termination study procedures to 
evaluate safety and saliva production. 
In cases where a subject fails to return for required visits, repeated attempts will be made to 
reach the subject/caregiver 
 
  If repeated attempts are unsuccessful, lost to follow up will be recorded in the 
subject’s source document and eCRF as the reason for early termination. 
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13 STUDY DRUG MATERIALS AND MANAGEMENT 
13.1 Study Drug 
MYOBLOC® (rimabotulinumtoxinB) Injection is a clear and colorless to light-yellow sterile 
injection solution of a purified neurotoxin.  Each single-use vial of formulated MYOBLOC 
(supplied by the Sponsor, Solstice Neurosciences, LLC) contains 5,000 Units of botulinum 
toxin type B per 1.0 mL in 0.05% human serum albumin, 0.01 M sodium succinate, and 
0.1 M sodium chloride at approximately pH 5.6. 
13.2 Study Drug Administration and Compliance 
Subjects will receive single dose injections of MYOBLOC every 13 weeks (±2 weeks) for a 
maximum total of 4 treatments.  MYOBLOC will be injected first into the submandibular 
glands (right and then left) followed by the parotid glands (right and then left)
 
 
• Total dose of 3,500 Units (0.7 mL) of MYOBLOC with 1,500 Units (0.3 mL) injected 
into each parotid gland and 250 Units (0.05 mL) injected into each submandibular 
gland. 
Subsequent injections at each treatment session will be done when subjects return to baseline 
status as determined by the Investigator, with a minimum interval of 11 weeks from the prior 
injection. Study drug injections should not be administered if an adverse event of dysphagia 
or dry mouth of moderate to severe severity persists without prior consultation with the 
Medical Monitor. If the adverse event has not resolved or has not improved to a mild severity 
by the end of the per protocol window for injections to occur (every 13 ± 2 weeks), the 
Medical Monitor should be contacted to discuss whether or not the subject should be dosed, 
discontinued, etc.  
If after the first treatment of 3,500 Units the subject develops intolerable side effects, but still 
wishes to remain in the study, the Investigator has the discretion to decrease subsequent 
doses, but to no less than a total dose of 2,500 Units.  If this does occur, the total dose can 
therefore be 2,500 Units to 3,500 Units of MYOBLOC.  The Investigator must clearly 
indicate the adjusted dose given.  MYOBLOC will be injected first into the submandibular 
glands (right then left) followed by the parotid glands (right then left) as follows: 
• Total dose of 2,500 to 3,500 Units (0.5 mL to 0.7 mL) of MYOBLOC with 1,000 to 
1,500 Units (0.2 mL to 0.3 mL) injected equally into each parotid gland and 
250 Units (0.05 mL) injected into each submandibular gland. 
All MYOBLOC injections will be performed by Investigators who have prior experience or 
have been appropriately trained with injecting botulinum toxin and such experience/training 
will be documented in the study records.  Injections will be guided by external anatomical 
landmarks or by external anatomical landmarks with ultrasound-guided confirmation 
(Appendix A).  Sites designated as “ultrasound” sites will perform all their injections with 
ultrasound-guidance.  
 
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13.3 Study Drug Packaging and Labeling 
Study drug will be supplied in a 3.5-mL glass vial containing a volume of 1.0 mL 
(5,000 Units of MYOBLOC).  All study drug will be labeled as investigational drug for 
research purposes only, in compliance with federal regulations. 
 
 
13.4 Study Drug Storage 
Study drug must be stored in a secure refrigerator (2°C to 8°C) with access restricted to 
authorized personnel only. 
13.5 Study Drug Accountability 
Accurate recording of all investigational agent received, dispensed, administered, and 
returned will be maintained by study site personnel.  The investigational agent is to be used 
only as described by this study protocol by an appropriately licensed Investigator named in 
Form FDA 1572. 
Study staff should retain the original individual vial cartons, as well as all vials, including 
those empty, partially empty, or full.  All used and unused investigational agent must be 
inventoried.  If any investigational agent is lost or damaged, its disposition should be 
documented.  Used and unused investigational agents will be retained at the participating 
sites to enable a full investigational drug inventory by the sites’ respective monitors.  The 
Sponsor will provide instructions to return the unused study drug to the Sponsor or Sponsor’s 
designee for proper destruction in accordance with local and federal regulations. 
 
 
 
 
 
 
14 STUDY PROCEDURES 
14.1 Schedule of Assessments 
A schedule of assessments is shown in Table 2.  No protocol related procedures should be 
performed before subjects provide written informed consent and HIPAA authorization. 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
Table 2. 
Schedule of Study Assessments 
 
 
Treatment Session 1 
Treatment Session 2 
Activity 
Screening 
(Day -21 to -1) 
Day 1 (a) 
Wk 4 (c) 
(± 3 days) 
Wk 8 (c) 
(± 3 days) 
Wk 13 (d) 
(± 2 wks) 
Wk 14 (b) 
(± 1 day) 
Wk 17 (c) 
(± 5 days) 
Wk 21 (b) 
(± 5 days) 
Wk 26 (d) 
(± 2 wks) 
Written Informed Consent and HIPAA 
Authorization (e) 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Surgical/Medication History (f) 
X 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
X 
 
X 
 
 
 
X 
Brief Physical Examination 
 
X 
 
X 
 
 
X 
 
 
Weight 
X 
X 
X 
X 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Neurologic Examination 
X 
X 
As needed 
X 
 
As needed 
 
As needed 
Dental Questionnaire (Subject or Caregiver) 
X 
 
 
 
 
 
 
 
 
Dental Exam by Licensed Dentist (DDS, DMB) 
X (g) 
 
X 
As needed 
X 
 
As needed 
 
X (g) 
Oral Examination by Investigator 
 
X 
 
X 
 
 
X 
 
 
Clinical Laboratory Tests (hematology, full 
chemistry panel including glucose and  
alkaline phosphatase, urinalysis) (fasting) 
X 
 
As needed 
X 
 
As needed 
 
X 
Urine Pregnancy Test (h) 
X 
X 
As needed 
 
As needed 
 
As needed 
Vital Signs (sitting BP and pulse after 5 minutes 
rest, RR, Temp) 
X 
X 
X 
X 
X 
 
X 
 
X 
Forced Vital Capacity (i) 
X 
X 
X 
As needed 
X 
 
As needed 
 
As needed 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS Baseline Version 
 
X 
 
 
 
 
 
 
 
C-SSRS Since Last Visit Version 
 
 
X 
X 
X 
 
X 
 
X 
Concomitant Medications Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Training 
X 
 
 
 
 
 
 
 
 
Subject Diary Review 
 
 
X 
X 
X 
 
X 
 
X 
Salivary Flow Rate Collection (USFR) (j) 
X 
X 
X 
X 
X 
 
X 
 
X 
Clinical Global Impression-Severity (CGI-S) (j) (k) 
 
X 
X 
X 
X 
 
X 
 
X 
Clinical Global Impression-Change (CGI-C) (j) (k) 
 
 
X 
X 
X 
 
X 
 
X 
Patient Global Impression of Severity (PGI-S) (k) 
 
X 
X 
X 
X 
 
X 
 
X 
Patient Global Impression of Change (PGI-C) (k) 
 
 
X 
X 
X 
 
X 
 
X 
Drooling Impact Score (DIS) by Subject 
 
X 
X 
X 
X 
 
X 
 
X 
DFSS-I (j) 
X 
X 
X 
X 
X 
 
X 
 
X 
DFSS by Subject (DFSS-S) (l) 
 
X 
X 
X 
X 
 
X 
 
X 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
Table 2. 
Schedule of Study Assessments 
 
 
Treatment Session 1 
Treatment Session 2 
Activity 
Screening 
(Day -21 to -1) 
Day 1 (a) 
Wk 4 (c) 
(± 3 days) 
Wk 8 (c) 
(± 3 days) 
Wk 13 (d) 
(± 2 wks) 
Wk 14 (b) 
(± 1 day) 
Wk 17 (c) 
(± 5 days) 
Wk 21 (b) 
(± 5 days) 
Wk 26 (d) 
(± 2 wks) 
Review of Common Classes of Anticholinergic & 
Antihistamine Medications 
X 
 
 
 
 
 
 
 
 
Study Drug Injection (m) 
 
X (1st) (n) 
 
 
X (2nd) 
 
 
 
X (3rd) 
Telephone Follow-up  
 
 
 
 
 
X (o) 
 
X 
 
Abbreviations:  AE = adverse event, BP = blood pressure, C-SSRS = Columbia Suicide Severity Rating Scale, DFSS = Drooling Frequency and Severity Scale, HIPAA = Health 
Insurance Portability and Accountability Act, RR = respiration rate, Temp = temperature, USFR = unstimulated salivary flow rate, VAS = visual analog scale, wks = weeks 
(a) All screening and baseline assessments and results must be available before injection of MYOBLOC. 
(b) Telephone follow-up. 
(c) Office visit. 
(d) Office visit.  Serves as last visit of current treatment session and first visit of subsequent treatment session.  Study drug injection will occur after the 13-week assessments have been 
completed for the prior treatment session. 
(e) Must be obtained before conducting any study procedure. 
(f) Includes baseline history of aspiration, aspiration pneumonia, choking, and dysphagia. 
(g) Includes 4 bite-wing radiographs or panoramic imaging (if edentulous or if bite-wing x-rays are difficult due to limited teeth).  If the subject has no teeth, then the dentist will 
determine if panoramic imaging is required at any visit after screening. 
(h) Females of childbearing potential only. 
(i) Forced vital capacity will be measured in all subjects with amyotrophic lateral sclerosis and in other subjects if warranted at the discretion of the Investigator. 
(j) When possible, assessments should be done by the same person in a given subject to ensure consistency throughout the study. 
(k) Global measure of effectiveness must be completed before USFR. 
(l) Subject-rated via entry in diary (not during study visit), daily for first 2 weeks after study drug injection and then weekly for remainder of treatment session. 
(m) Subjects will receive injections guided by external anatomical landmarks or by external anatomical landmarks with ultrasound-guided confirmation.  Sites designated as “ultrasound” 
sites will perform all their injections with ultrasound-guidance. 
(n) Subjects will be injected after completion of all assessments and then will be contacted by telephone 24 hours (±1 day) post-injection to inquire about their health status and remind 
the subject to complete their diary. 
(o) Telephone follow-up by the study staff will be conducted 1 week (±1 day) after study drug injection to assess how the subject feels, document adverse events as appropriate, document 
any new medications the subject may be taking, and remind the subject to complete their diary. 
 
 
 
 
 
 
 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
Table 2. 
Schedule of Study Assessments 
 
Treatment Session 3 (Optional)* 
Treatment Session 4 (Optional)* 
 
Activity 
Wk 27 
(± 1 day) 
Wk 30 (a) 
(± 5 days) 
Wk 34 (b) 
(± 5 days) 
Wk 39 (c) 
(± 2 wks) 
Wk 40 
(± 1 day) 
Wk 43 (a) 
(± 5 days) 
Wk 47 (b) 
(± 5 days) 
Wk 52 (a) 
(± 2 wks) 
Early  
Discontinuation 
Complete Physical Examination 
 
 
 
X 
 
 
 
X 
X 
Brief Physical Examination 
 
X 
 
 
 
X 
 
 
 
Weight 
 
X 
 
X 
 
X 
 
X 
X 
Neurologic Examination 
 
As needed 
 
As needed 
 
As needed 
 
X 
X 
Dental Exam by Licensed Dentist (DDS, DMB) 
 
As needed 
 
As needed 
 
As needed 
 
X (d) 
X (d) 
Oral Examination by Investigator 
 
X 
 
X 
 
X 
 
 
 
Clinical Laboratory Tests (hematology, full 
chemistry panel including glucose and alkaline 
phosphatase, urinalysis) (fasting) 
 
As needed 
 
As needed 
 
As needed 
 
X 
X 
Urine Pregnancy Test (e) 
 
As needed 
 
As needed 
 
As needed 
 
X 
X 
Vital Signs (sitting BP and pulse after 5 minutes 
rest, RR, Temp) 
 
X 
 
X 
 
X 
 
X 
X 
Forced Vital Capacity 
 
As needed 
 
As needed 
 
As needed 
 
As needed 
As needed 
Adverse Events Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X (f) 
C-SSRS Since Last Visit Version 
 
X 
 
X 
 
X 
 
X 
X 
Concomitant Medications Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Review 
 
X 
 
X 
 
X 
 
X 
X 
Salivary Flow Rate Collection (USFR) (g) 
 
X 
 
X 
 
X 
 
X 
X 
Clinical Global Impression-Severity (CGI-S) (g) 
(h) 
 
X 
 
X 
 
X 
 
X 
X 
Clinical Global Impression-Change (CGI-C) (g) (h) 
 
X 
 
X 
 
X 
 
X 
X 
Patient Global Impression of Severity (PGI-S) (h) 
 
X 
 
X 
 
X 
 
X 
X 
Patient Global Impression of Change (PGI-C) (h) 
 
X 
 
X 
 
X 
 
X 
X 
Drooling Impact Score by (DIS) Subject 
 
X 
 
X 
 
X 
 
X 
X 
DFSS-I (g) 
 
X 
 
X 
 
X 
 
X 
X 
DFSS by Subject (DFSS-S) (i) 
 
X 
 
X 
 
X 
 
X 
X 
Study Drug Injection (j) 
 
 
 
X (4th) 
 
 
 
 
 
Telephone Follow-up 
X (k) 
 
X 
 
X (k) 
 
X 
 
 
Abbreviations:  AE = adverse event, BP = blood pressure, C-SSRS = Columbia Suicide Severity Rating Scale, DFSS = Drooling Frequency and Severity Scale, RR = respiration rate, 
Temp = temperature, USFR = unstimulated salivary flow rate, wks = weeks 
* Treatment Sessions 3 and 4 are designated as likely, but may not be necessary as the study progresses because the study may be stopped early once enough subjects have completed the 
study to meet FDA safety database requirements.  Any subject that enters the study, however, is required to participate through at least 6 months (i.e., complete Treatment Sessions 1 
and 2). 
(a) Office visit. 
(b) Telephone follow-up. 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
 
Table 2. 
Schedule of Study Assessments 
 
Treatment Session 3 (Optional)* 
Treatment Session 4 (Optional)* 
 
Activity 
Wk 27 
(± 1 day) 
Wk 30 (a) 
(± 5 days) 
Wk 34 (b) 
(± 5 days) 
Wk 39 (c) 
(± 2 wks) 
Wk 40 
(± 1 day) 
Wk 43 (a) 
(± 5 days) 
Wk 47 (b) 
(± 5 days) 
Wk 52 (a) 
(± 2 wks) 
Early  
Discontinuation 
(c) Office visit.  Serves as last visit of current treatment session and first visit of subsequent treatment session.  Study drug injection will occur after the 13-week assessments have been 
completed for the prior treatment session. 
(d) Includes 4 bite-wing radiographs or panoramic imaging (if edentulous or if bite-wing x-rays are difficult due to limited teeth).  If the subject has no teeth, then the dentist will 
determine if panoramic imaging is required at any visit after screening. 
(e) Females of childbearing potential only. 
(f) Subjects who discontinue because of an AE before completion of the study will be called 13 weeks ± 3 days after his/her last injection to determine if the AE has resolved. 
 
(g) When possible, assessments should be done by the same person in a given subject to ensure consistency throughout the study. 
(h) Global measure of effectiveness must be completed before USFR. 
(i) Subject-rated via entry in diary (not during study visit), daily for first 2 weeks after study drug injection and then weekly for remainder of treatment session. 
(j) Subjects will receive injections guided by external anatomical landmarks or by external anatomical landmarks with ultrasound-guided confirmation.  Sites designated as “ultrasound” 
sites will perform all their injections with ultrasound-guidance.   
(k) Telephone follow-up by the study staff will be conducted 1 week (±1 day) after study drug injection to assess how the subject feels, document adverse events as appropriate, document 
any new medications the subject may be taking, and remind the subject to complete their diary. 
 
 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
14.2 Screening 
Subjects who provide written consent to participate and HIPAA authorization to use their 
personal health information will be screened for inclusion in the study.  A screening window 
of up to 21 days is provided to ensure the Investigator has adequate time to evaluate the 
subject’s medical/surgical history, screening laboratory tests, and other eligibility criteria. 
The following activities will be completed: 
• Review of inclusion and exclusion criteria; 
• Demographics; medical/surgical/medication history; and baseline history of 
aspiration, aspiration pneumonia, choking, and dysphagia; 
• Salivary flow rate collection (USFR); 
• DFSS-I; 
• Complete physical examination (including vital signs, height, and weight); 
• Neurologic exam; 
• Dental exam by a licensed dentist (DDS or DMD), including 4 bite-wing radiographs 
or panoramic imaging (if edentulous or if bite-wing x-rays are difficult due to limited 
teeth); 
• Dental questionnaire by subject or caregiver; 
• Screening laboratory tests (full chemistry panel including glucose and alkaline 
phosphatase; hematology; urinalysis) in fasting state; 
• Urine pregnancy test (females of childbearing potential only); and 
• Respiratory function including FVC in all subjects with ALS, and in other subjects if 
warranted at the discretion of the Investigator. 
 
 
  Subjects will be advised to contact study staff if they require 
ANY new medication so the Investigator can be consulted on the potential impact to the 
subject’s eligibility in the study (see Section 16.10). 
14.3 Treatment Session 1 
14.3.1 Day 1 
Subjects who are deemed eligible for treatment based on screening assessments/procedures 
will have the assessments listed below completed on Day 1 (baseline) before injection of 
MYOBLOC. 
• Evaluation of adverse events; 
• Brief physical exam (including vital signs and weight); 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
• FVC in all subjects with ALS, and other subjects if done at screening; 
• Neurologic exam; 
• Oral exam by the Investigator; 
• Columbia Suicide Severity Rating Scale (C-SSRS) Baseline version; 
• Urine pregnancy test (females of childbearing potential only, performed just before 
injection of study drug).  Result must be negative to proceed with the injection; 
• CGI-S (Assessor) before USFR; 
• Saliva production quantitatively determined via USFR collection; 
• DFSS-I;  
• PGI-S (Subject); 
• DIS (Subject); and 
• DFSS-S – site personnel will teach the subject how to use the subject diary to 
complete the DFSS and the subject will perform a practice entry at this visit, with the 
first real entry to occur that evening. 
 
 
 
Once all assessments have been completed, evaluated, and eligibility confirmed, the subject 
will receive a dose of MYOBLOC via injections into the submandibular and parotid glands 
as detailed in Section 13.2.  Subjects will be contacted by telephone 24 hours (±1 day) post-
injection to inquire about their health status and to remind the subject to complete their diary. 
14.3.2 Weeks 4, 8, and 13 
Subjects will return to the clinic for follow-up assessments/procedures at Weeks 4, 8, and 13.  
Visit windows are provided to allow flexibility in scheduling subjects for appointments: 
Weeks 4 and 8 have a ±3 day window and Week 13 has a ±2 week window.  The following 
assessments will be completed at each study visit unless otherwise specified: 
• Complete (Weeks 4 and 13) and brief (Week 8) physical exam (including vital signs 
and weight); 
• FVC in all subjects with ALS, and other subjects if done at screening, at Weeks 4 and 
13 and as needed, per Investigator discretion, at Week 8; 
• Clinical laboratory tests (fasting), including full chemistry panel (including glucose 
and alkaline phosphatase), hematology, and urinalysis at Week 13 and as needed, per 
Investigator discretion, at Weeks 4 and 8; 
• Urine pregnancy test (as clinically warranted); 
• Neurologic exam at Week 13 and as clinically warranted at Weeks 4 and 8; 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
• Dental exam by a licensed dentist at Weeks 4 and 13, and as clinically warranted 
based on predefined safety criteria; 
• Oral exam by Investigator (Week 8); 
• Evaluation of adverse events; 
• C-SSRS Since Last Visit version; 
• Review of concomitant medications; 
• Review of subject diary; 
• CGI-S and CGI-C (Assessor) before USFR; 
• USFR collection; 
• DFSS-I;  
• PGI-S and PGI-C (Subject); 
• DIS (Subject); and 
• DFSS-S via entry in the subject’s diary, not during study visit, daily for first 2 weeks 
after injection of MYOBLOC and then weekly for remainder of treatment session. 
14.4 Treatment Session 2 
14.4.1 Day 1 
On Day 1 of treatment session 2 (same day as Week 13 visit), subjects may receive 
MYOBLOC (as detailed in Section 13.2) after all 13-week assessments have been completed 
for the prior treatment session. 
14.4.2 Weeks 14, 17, 21, and 26 
A telephone follow up will be made 1 week (±1 day) after injection of MYOBLOC 
(Week 14) and at Week 21 (±5 days) to inquire about subjects’ health status and to assess 
adverse events and review concomitant medications (see Section 16.10).  Subjects will return 
to the clinic at Week 17 (±5 days) and Week 26 (±2 weeks) and the assessments listed below 
will be completed at each visit, unless otherwise specified.  Note that the Week 26 visit will 
serve as the Day 1 visit for the subsequent injection of MYOBLOC (see Section 14.5.1). 
• Evaluation of adverse events; 
• Brief (Week 17) and complete (Week 26) physical exam (including vital signs and 
weight); 
• FVC (as clinically warranted); 
• Clinical laboratory tests (fasting), including full chemistry panel (including glucose 
and alkaline phosphatase), hematology, and urinalysis at Week 26 and as needed, per 
Investigator discretion, at Week 17; 
• Urine pregnancy test (as clinically warranted); 
• Neurologic exam (as clinically warranted); 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
• Dental exam by a licensed dentist at Week 26 (including 4 bite-wing radiographs or 
panoramic imaging [if edentulous or if bite-wing x-rays are difficult due to limited 
teeth]), and as clinically warranted based on predefined safety criteria; 
• Oral exam by Investigator (Week 17); 
• C-SSRS Since Last Visit version; 
• Review of concomitant medications; 
• Review of subject diary; 
• CGI-S and CGI-C (Assessor) before USFR; 
• USFR collection; 
• DFSS-I;  
• PGI-S and PGI-C (Subject); 
• DIS (Subject); and 
• DFSS-S via entry in the subject’s diary, not during study visit, daily for first 2 weeks 
after injection of MYOBLOC and then weekly for remainder of treatment session. 
14.5 Treatment Session 3 
14.5.1 Day 1 
On Day 1 of treatment session 3 (same day as Week 26 visit), subjects may receive 
MYOBLOC (as detailed in Section 13.2) after all 13-week assessments have been completed 
for the prior treatment session. 
14.5.2 Weeks 27, 30, 34, and 39 
A telephone follow up will be made 1 week (±1 day) after injection of MYOBLOC 
(Week 27) and at Week 34 (±5 days) to inquire about subjects’ health status and to assess 
adverse events and review concomitant medications (see Section 16.10).  Subjects will return 
to the clinic at Week 30 (±5 days) and Week 39 (±2 weeks) and the assessments listed below 
will be completed at each visit, unless otherwise specified.  Note that the Week 39 visit will 
serve as the Day 1 visit for the subsequent injection of MYOBLOC (see Section 14.6.1). 
• Evaluation of adverse events; 
• Brief (Week 30) and complete (Week 39) physical exam (including vital signs and 
weight); 
• FVC (as clinically warranted); 
• Clinical laboratory tests (as clinically warranted); 
• Urine pregnancy test (as clinically warranted); 
• Neurologic exam (as clinically warranted); 
• Dental exam by a licensed dentist (as clinically warranted based on predefined safety 
criteria); 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
• Oral exam by Investigator; 
• C-SSRS Since Last Visit version; 
• Review of concomitant medications; 
• Review of subject diary; 
• CGI-S and CGI-C (Assessor) before USFR; 
• USFR collection; 
• DFSS-I;  
• PGI-S and PGI-C (Subject);  
• DIS (Subject); and 
• DFSS-S via entry in the subject’s diary, not during study visit, daily for first 2 weeks 
after injection of MYOBLOC and then weekly for remainder of treatment session. 
14.6 Treatment Session 4 
14.6.1 Day 1 
On Day 1 of treatment session 4 (same day as Week 39 visit), subjects may receive 
MYOBLOC (as detailed in Section 13.2) after all 13-week assessments have been completed 
for the prior treatment session. 
14.6.2 Weeks 40, 43, 47, and 52 
A telephone follow up will be made 1 week (±1 day) after injection of MYOBLOC 
(Week 40) and at Week 47 (±5 days) to inquire about subjects’ health status and to assess 
adverse events and review concomitant medications (see Section 16.10).  Subjects will return 
to the clinic at Week 43 (±5 days) and Week 52 (±2 weeks) and the assessments listed below 
will be completed at each visit, unless otherwise specified. 
• Evaluation of adverse events; 
• Brief (Week 43) and complete (Week 52) physical exam (including vital signs and 
weight); 
• FVC (as clinically warranted); 
• Clinical laboratory tests (fasting), including full chemistry panel (including glucose 
and alkaline phosphatase), hematology, and urinalysis at Week 52 and as clinically 
warranted at Week 43; 
• Urine pregnancy test at Week 52 and as clinically warranted at Week 43; 
• Neurologic exam at Week 52 and as clinically warranted at Week 43; 
• Dental exam by a licensed dentist at Week 52 (including 4 bite-wing radiographs or 
panoramic imaging [if edentulous or if bite-wing x-rays are difficult due to limited 
teeth]) and as clinically warranted based on predefined safety criteria at Week 43; 
• Oral exam by Investigator at Week 43; 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
• C-SSRS Since Last Visit version; 
• Review of concomitant medications; 
• Review of subject diary; 
• CGI-S and CGI-C (Assessor) before USFR; 
• USFR collection; 
• DFSS-I;  
• PGI-S and PGI-C (Subject); 
• DIS (Subject); and 
• DFSS-S via entry in the subject’s diary, not during study visit, daily for first 2 weeks 
after injection of MYOBLOC and then weekly for remainder of treatment session. 
14.7 Early Discontinuation 
If the subject is withdrawn from the study before completion of the study, the reason for 
withdrawal from the study must be documented in the subject’s source document and eCRF.  
Whenever a subject withdraws, the procedures/assessments listed below should be 
conducted. 
• Evaluation of adverse events; 
• Complete physical exam (including vital signs and weight); 
• FVC (as clinically warranted); 
• Clinical laboratory tests (fasting), including full chemistry panel (including glucose 
and alkaline phosphatase), hematology, and urinalysis; 
• Urine pregnancy test; 
• Neurologic exam; 
• Dental exam by a licensed dentist (including 4 bite-wing radiographs or panoramic 
imaging [if edentulous or if bite-wing x-rays are difficult due to limited teeth]); 
• C-SSRS Since Last Visit version; 
• Review of concomitant medications; 
• Review of subject diary; 
• CGI-S and CGI-C (Assessor) before USFR; 
• USFR collection; 
• DFSS-I; 
• PGI-S and PGI-C (Subject); 
• DIS (Subject); and 
• DFSS-S via entry in subject’s diary, not during study visit. 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
14.8 Interim Telephone Follow-ups 
Study staff will perform an Interim Telephone Follow-Up 24 hours (±1 day) after the first 
injection of MYOBLOC, 1 week (±1 day) after each subsequent injection of MYOBLOC, 
and at Weeks 21, 34, and 47 (±5 days) to assess how the subject feels, document adverse 
events as appropriate, review concomitant medications, and to remind the subject to complete 
their diary. 
14.9 Post-Study Telephone Contact 
If a subject discontinues study participation because of an adverse event, the subject will be 
evaluated in the office as soon as possible, and also contacted 13 weeks (±3 days) after the 
last injection of study drug to determine if the adverse event has resolved, continues 
unabated, or has reached a new baseline.  
 
 
15 EFFECTIVENESS ASSESSMENTS 
Global Measures of Effectiveness 
The global measures of effectiveness by the clinician (CGI-S and CGI-C) should be 
completed before the quantitative measure of saliva. 
Assessors 
In order to maintain consistency of rating assessments, an assessor will be trained 
(i.e., Investigator or other clinician named on Form FDA 1572) and this same assessor should 
perform a given assessment for a subject throughout the study.  Another assessor (clinician 
named on Form FDA 1572) will also undergo training to ensure consistency in scale ratings 
should a back-up assessor be necessary to perform assessment(s). 
Caregiver Assistance 
If a subject elects to have a caregiver assist with completing rating scale activities, that same 
caregiver should then consistently assist with the ratings throughout the study.  Note that the 
caregiver may assist in the physical completion of scales, but all responses recorded on the 
scales must be provided from the subject either verbally or by gesture. 
Study Participants with Parkinson’s Disease 
 
 
 
 Therefore, PD subjects should complete the rating scales at least 1 hour after their 
first dose of PD medication and at least 1 hour postprandial.  
 
Study Participants with ALS 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
For ALS subjects on short-acting anticholinergics or antihistamines (duration of action of 
8 hours or less), for the treatment of troublesome sialorrhea, these medications must be held 
at least 8 hours before the screening, baseline, and all subsequent study visits, so that the 
effectiveness of the study drug can be properly evaluated.  All subjects must be converted to 
a short-acting medication (duration of action of approximately 8 hours or less) at least 
2 weeks before the first injection of study drug (i.e., Day 1 of Treatment Session 1). 
15.1 Unstimulated Salivary Flow Rate (USFR) 
Salivary flow rate, as described by Proulx and colleagues [2005] and Vivino and 
colleagues [1999] will be determined in an unstimulated state (i.e., at least 1 hour 
postprandial) at screening, just before the first injection of study drug (Day 1) to establish a 
baseline salivary flow rate, and at each subsequent study visit according to instructions 
detailed in Appendix B.  Briefly, saliva will be collected over a 5-minute collection period 
using weighing cups
 
 
  They will be asked 
to expectorate, as needed, any saliva that accumulates in their mouth into the pre-weighed 
cup during the 5-minute collection period. 
 
 
  
Although not a rating scale, the same person should conduct this assessment throughout the 
study to minimize collection technique bias. 
15.2 Clinical Global Impression of Severity (CGI-S) and Change (CGI-C) 
The CGI-S scale will be used to record the severity of illness (sialorrhea) on Day 1 
(i.e., study baseline) before the first injection of study drug, at each subsequent study visit or, 
if applicable, at discontinuation from the study.  CGI-S will be assessed by a trained assessor 
on a 7-point scale ranging from “normal” to “among the most extremely ill patients” 
(Appendix C).  The CGI-C, used to record change or improvement in illness from baseline 
(i.e., pre-injection) of each treatment session, will be assessed at each study visit after Day 1 
by the assessor on a 7-point scale ranging from “very much improved” to “very much worse” 
(Appendix C).  Both CGI scales will be completed independent of the subject’s self-
assessment (PGI-S and PGI-C) so neither party knows how the other has rated the scales.  
 
15.3 Patient Global Impression of Severity (PGI-S) and Change (PGI-C) 
The PGI-S scale will be used by the subject to rate the severity of his/her illness (sialorrhea) 
on Day 1 (i.e., study baseline) before the first injection of study drug, at each subsequent 
study visit, or, if applicable, at discontinuation from the study.  PGI-S will be assessed on a 
8-point scale ranging from “normal” to “among the most extremely ill” (Appendix D).  The 
PGI-C will be used by the subject to rate his/her impression of change in symptoms (drooling 
or sialorrhea) from Day 1 (i.e., study baseline) or just before subject’s most recent injection 
of study drug to the time of assessment at each study visit.  The PGI-C is assessed on a 
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7-point scale ranging from “very much improved” to “very much worse” (Appendix D).  
Both PGI scales need to be completed independent of the assessor who completes the CGI 
scales so neither party knows how the other has rated the scales. 
 
 
15.4 Drooling Frequency and Severity Scale (DFSS) 
The DFSS will be used to assess the frequency and severity of drooling.  The DFSS-I will be 
performed by a trained assessor independent of the DFSS performed by the subject (DFSS-S) 
(Appendix E).  The DFSS-I will be completed at screening, on Day 1 (i.e., study baseline) 
before the first injection of study drug, at each subsequent study visit, or, if applicable, at 
discontinuation from the study.  Severity is assessed on a 5-point scale ranging from 1 (dry, 
never drools) to 5 (profuse, clothing, hands, tray, objects become wet).  Frequency is 
assessed on a 4-point scale ranging from 1 (never drools) to 4 (constantly drools).  The DFSS 
total score ranges from 2 to 9.  The assessor’s initial assessment at screening should be based 
on the prior 4 weeks, with subsequent assessments based on the timeframe since the prior 
study visit.  The assessor should not review the subject-rated scales before performing his/her 
own assessment.  The subject will complete this assessment in the diary on a daily basis for 
the first 2 weeks of each treatment session and then weekly for the remainder of the treatment 
session. 
15.5 Drooling Impact Score (DIS) 
The DIS is a 10-item questionnaire with each item rated by the subject to evaluate the impact 
of sialorrhea on daily activities (e.g., speech, social activities) (Appendix F).  The DIS will be 
completed on Day 1 (i.e., study baseline) before the first injection of study drug, at each 
subsequent study visit, or, if applicable, at discontinuation from the study.  For each question 
the subject is requested to compare their current status to their last study visit using a 4-point 
scale ranging from 1 (not at all) to 4 (very much).  The DIS total score ranges from 10 to 40.  
On Day 1 before the first injection of study drug, the subject will be asked to reference the 
prior 4 weeks, with subsequent assessments based on the timeframe since the prior study 
visit. 
 
16 SAFETY ASSESSMENTS 
16.1 Medical/Surgical/Medication History 
The medical history (with demographic information, sialorrhea history with date of onset), 
should also include current co-morbidities, relevant past illnesses, all current medications 
(including those taken within 30 days before screening), surgical procedures performed 
within the prior 6 months, and past treatment(s) for sialorrhea. 
As part of the screening medical history assessment and exclusion criteria review, subjects 
will be evaluated for presence or prior history of aspiration, aspiration pneumonia, choking, 
and/or dysphagia.  
 
  To ensure that these events are consistently rated across investigator sites, the 
definitions for the diagnosis and intensity provided in Section 16.2.4 should be used for 
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baseline evaluation and all subsequent assessments.  The Investigator must determine, based 
on clinical evaluation, whether subsequent occurrences of aspiration, aspiration pneumonia, 
choking, and/or dysphagia during the study qualify as adverse events, as defined in 
Section 16.2.1. 
16.2 Adverse Events 
All adverse events and details for the events will be recorded on the subject’s source 
document and on the Adverse Event eCRF.  An adverse event should be documented in 
terms of a medical diagnosis.  When this is not possible, the adverse event should be 
documented in terms of signs and/or symptoms observed or reported. 
Adverse events can be collected by either the Investigator or the Study Coordinator; 
however, the Investigator must determine the intensity of the adverse event (Section 
16.2.2.1), assess whether or not the study drug caused the adverse event (Section 16.2.2.2), 
record whether the adverse event led to discontinuation of the subject from the study 
(Section 16.2.2.3), record the outcome of the adverse event (Section 16.2.2.4), and determine 
if the adverse event is serious (Sections 16.2.2.5 and 16.2.6). 
For this study, adverse events will be collected beginning with the start of dosing on Day 1 
and will end at study completion (52 weeks ±1 week).  Subjects who discontinue because of 
an adverse event before study completion will be contacted 13 weeks (±3 days) after their 
last injection of study drug (see Section 16.2.7).  Serious adverse events will be collected 
after signing informed consent until 30 days after study completion if the study site becomes 
aware of the event. 
16.2.1 Definition of Adverse Event 
An adverse event is defined as any untoward medical occurrence in a patient administered a 
medicinal product.  An adverse event includes any noxious, pathologic, or unintended change 
in anatomic, physiologic, or metabolic functions as indicated by physical signs, symptoms 
and/or laboratory changes occurring in any phase of the clinical study whether associated 
with study drug, active comparator, or placebo, and whether or not considered to be drug 
related. 
Examples include an exacerbation of pre-existing conditions or events, intercurrent illnesses, 
drug interaction, or the significant worsening of the disease under investigation that is not 
recorded elsewhere in the eCRF under specific effectiveness assessments.  Anticipated 
fluctuations of pre-existing conditions that do not represent a clinically significant 
exacerbation or worsening need not be considered adverse events. 
In clinical studies, an adverse event can include an undesirable medical condition occurring 
at any time during study participation, including run-in or wash-out periods, even if no study 
treatment has been administered. 
Intercurrent illness and/or sequelae from intercurrent illness occurring between study 
screening/enrollment and dosing with study drug will be captured on the Adverse Event 
eCRF. 
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16.2.2 Investigator Assessment of Adverse Events 
16.2.2.1 Intensity of Adverse Event 
The Investigator must assess the intensity of each adverse event as mild, moderate, or severe 
as defined below. 
• Mild:  an awareness of symptoms but easily tolerated 
• Moderate:  symptoms interfering with daily activities 
• Severe:  incapacitating, with inability to perform normal daily activities 
16.2.2.2 Relationship of Adverse Events to Study Drug 
For each adverse event, the Investigator must assess the attribution of the study drug to the 
adverse event and determine whether the adverse event is or is not related to the study or test 
drug as defined below.  The Investigator must also assess if the adverse event is related to the 
primary underlying condition/disease (e.g., PD, ALS).  When in doubt, the adverse event 
should be considered at least “possibly related” to the study drug until further evidence 
becomes available to refute this assessment.  Generally, an adverse event would not be 
considered related to both study drug and the underlying condition/disease. 
Definitely Not Related 
• Subject did not receive the test drug, the temporal sequence of the adverse event onset 
relative to administration of the test drug is not reasonable, or there is another obvious 
cause of the adverse event. 
Possibly Related 
• There is evidence of exposure to the test drug, the temporal sequence of the adverse 
event onset relative to administration of the test drug is reasonable, but the adverse 
event could have been due to another equally likely cause. 
Probably Related 
• There is evidence of exposure to the test drug, the temporal sequence of the adverse 
event onset relative to administration of the test drug is reasonable, and the adverse 
event is more likely explained by the test drug than by any other cause. 
Definitely Related 
• There is evidence of exposure to the test drug, the temporal sequence of the adverse 
event onset relative to administration of the test drug is reasonable, and the adverse 
event is more likely explained by the test drug than by any other cause, and the 
adverse event shows a pattern consistent with previous knowledge of the test drug or 
test drug class. 
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16.2.2.3 Action Taken with Regard to Study Continuation/Discontinuation 
For each adverse event, the Investigator must indicate whether or not the adverse event 
caused the subject to discontinue from the study (more than one adverse event may be 
associated with the decision to discontinue a subject). 
16.2.2.4 Outcome of Adverse Event 
The Investigator must assess the outcome of each adverse event as:  unresolved, resolved, 
resolved with sequelae, unknown, or death. 
16.2.2.5 Indication of Seriousness of Adverse Event 
For each adverse event, the Investigator must determine if the adverse event meets the 
criteria for a Serious Adverse Event (SAE) as defined in Section 16.2.6. 
16.2.3 Dental Adverse Events 
Dental and oral health will be followed closely throughout the course of the study, with 
exams performed by either a licensed dentist (DDS or DMD) at each site, or oral examination 
by the Investigator.  Dental adverse events (i.e., anything related to oral and dental health) 
will be reported as such if: 
•
Any finding from the dental or oral exam is determined to be clinically significant or
require treatment/follow-up with a dentist, in the opinion of the Investigator or study
dentist.
•
An issue related to tooth or mouth discomfort is mentioned by the subject in response 
to a traditional non-leading question (e.g., “how have you been feeling since the last 
time I saw you?”).
All adverse events meeting the classification of “dental adverse events” will be included in 
the all adverse events analysis, as well as designated as a dental adverse event in the adverse 
event eCRF to enable appropriate safety sub-analyses. 
16.2.4 Adverse Events of Special Interest 
Adverse events indicative of compromised airway protection as manifested by aspiration, 
aspiration pneumonia, choking, and dysphagia will be closely evaluated as adverse events of 
special interest (AESI).  In order to properly evaluate the events pre-identified for 
compromised airway protection, a detailed baseline evaluation of the subject’s presence or 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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prior history of aspiration, aspiration pneumonia, choking, and dysphagia must be taken at 
screening and captured in the subject’s source documents and eCRF. 
To ensure that these events are consistently rated on the same criterion throughout the study, 
the definitions for diagnosis and intensity identified below should be used for baseline 
evaluations.  This thorough baseline evaluation will assist the Investigator in determining, 
based on a clinical evaluation, whether or not occurrences of aspiration, aspiration 
pneumonia, choking, and dysphagia during the study qualify as adverse events, as defined in 
Section 16.2.1. 
16.2.4.1 Aspiration and Aspiration Pneumonia 
Definition 
The presence of oral secretions, food substances, fluids, and/or gastric contents in the airways 
and/or the lungs may be the result of choking and/or dysphagia.  Aspiration of small 
fragments of material can produce airway obstruction as well as lung abscesses.  Aspiration 
of gastric contents with a low pH due to the presence of hydrochloric acid may injure the 
alveolar epithelium producing diffuse interstitial and alveolar edema.  Anaerobic organisms 
may also be present in the lung and peripheral blood cultures. 
ASPIRATION 
Diagnosis 
The diagnosis of aspiration should include: 
• New onset of respiratory symptoms and one of the following without an 
alternative medical cause: 
o Abnormal chest examination (rales, wheezing) 
o Abnormal gas exchange 
o Abnormal chest x-ray 
Supportive information – 
• Recent diagnosis of aspiration pneumonia 
• Recent diagnosis of dysphagia 
Intensity 
• Mild 
o Asymptomatic or associated with a cough 
• Moderate (any one of the following) 
o Abnormal chest x-ray 
o Productive cough 
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o Abnormal lung examination (wheezing, rales) 
o Hypoxia 
• Severe (any one of the following) 
o Respiration compromise 
o Pneumonia 
o Pneumonitis 
ASPIRATION PNEUMONIA 
Diagnosis 
One or more serial chest x-rays with one of the following: 
• New or progressive and persistent infiltrate 
• Consolidation 
• Cavitation 
And at least one of the following 
• Fever (>38°C) with no other cause 
• Leukopenia (<4,000 white blood cells (WBC)/mm3) or leukocytosis 
(>12,000 WBC/mm3) 
And at least one of the following 
• New onset purulent* sputum or change in character of sputum 
• New onset or worsening cough, or dyspnea, or tachypnea 
• Rales or bronchial breath sounds 
• Worsening gas exchange 
• Cultures positive for anaerobes or mixed oral flora 
* Purulent sputum includes secretions from the lungs, bronchi, or trachea that contain  
>25 neutrophils and <10 squamous epithelial cells per low power field (10X). 
Supportive Information – 
• Documentation of a temporal relationship between the onset of symptoms and 
the aspiration of fluids (e.g., gastric contents, inert liquids) or particulate matter 
(e.g., food) 
• Positive peripheral blood and/or sputum culture 
Intensity 
• Mild (all of the following) 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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o Defervescence on oral antibiotics 
o Satisfactory response to outpatient treatment 
o No need for supplemental oxygen 
• Moderate (any one of the following) 
o Hospitalized 
o Treated with intravenous antibiotics 
• Severe (any one of the following) 
o Supplemental oxygen needed 
o Positive blood culture(s) 
o Invasive procedure required (intubation, lung biopsy, chest tube, surgery) 
o Presence of empyema, cavitation 
16.2.4.2 Choking 
Definition 
Obstruction of the larynx, trachea, or esophagus by a partially swallowed foreign body, food, 
or liquid or laryngospasm may be described as choking. 
Diagnosis 
The diagnosis of choking should include: 
• An observed episode with description of the circumstances and any inciting factor(s) 
• Coughing with self clearance of obstruction or penetration of airway 
Supportive Information – 
• Recent diagnosis of aspiration pneumonia 
• Recent diagnosis of dysphagia 
• Imaging study such as a barium swallow 
Intensity 
• Mild 
o Occasional episode while eating or drinking (<once/day) 
• Moderate 
o Frequent episodes while eating or drinking (≥once/day) 
• Severe 
o Episode that requires intervention with or without loss of consciousness, may be 
associated with hypoxia 
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16.2.4.3 Dysphagia 
Definition 
Dysphagia is defined as difficulty swallowing (dys meaning difficulty/disordered and phagia 
meaning to eat).  Depending on the severity and the neuromuscular component compromised, 
dysphagia can impair the subject’s ability to swallow liquids (including saliva), solids or 
both.  The normal swallow occurs in 3 phases:  oral, pharyngeal, and esophageal with each 
phase lasting approximately one second.  The oral phase is under voluntary neuromuscular 
control, whereas the pharyngeal and esophageal phases are involuntary requiring an intact 
swallowing reflex.  Damage, compression, paralysis, and/or fatigue of the neuromuscular 
components may lead to dysphagia. 
Diagnosis 
The diagnosis of dysphagia should include: 
• New onset of difficulty swallowing for solids, liquids or both 
• Assessment of symptoms to identify other causes, such as dry mouth 
• Clinical or radiographic observation and/or documentation of the subject’s ability to 
swallow solids and liquids 
Supportive Information – 
• Recent episode of choking requiring intervention and/or treatment 
• Repeated episodes of coughing while eating or drinking 
• Recent diagnosis of aspiration pneumonia 
• Imaging study such as a barium swallow 
Intensity 
• Mild 
o Occasional difficulty swallowing but no choking 
• Moderate 
o Frequent difficulty swallowing with choking but able to eat and drink 
without assistance 
• Severe 
o Inability to swallow liquids, solids or both without choking or medical 
intervention 
16.2.5 Pregnancy 
Although pregnancy is not considered an adverse event, it is the responsibility of the 
Investigator to report any pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs during the study or within 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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13 weeks after the last injection of study drug.  All subjects who become pregnant must be 
withdrawn from the study and must be followed to the completion/termination of the 
pregnancy.  If the pregnancy continues to term, the outcome (health of infant) and status of 
mother and child must also be reported to the Sponsor. 
16.2.6 Serious Adverse Events 
An SAE or serious adverse drug experience is any untoward medical occurrence at any 
dose that: 
• Results in death during the period of protocol-defined surveillance; 
• Is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" 
refers to an event in which the subject, in the view of the Investigator, was at 
immediate risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe); 
• Requires inpatient hospitalization or prolongation of existing hospitalization*; 
• Results in persistent or significant disability or incapacity; and 
• Results in a congenital anomaly/birth defect. 
* Hospitalization:  Out-patient treatment in an emergency room is not in itself an SAE, although the 
reasons for it might be (e.g., bronchospasms, laryngeal edema).  Hospital admission and/or surgical 
operations planned before or during a study are not considered SAEs if the illness or disease existed 
before the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.  It should be noted that for this study, subjects with planned or anticipated surgery 
should not be enrolled into the study. 
Important Medical Events:  Medical and scientific judgment should be exercised in deciding 
whether a case is serious in situations where important medical events may not be 
immediately life-threatening or result in death, hospitalization, disability, or incapacity but 
may jeopardize the subject or may require medical or surgical intervention to prevent one or 
more outcomes listed in the definition of serious.  These should usually be considered as 
serious, and examples of such events are: 
• Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment; 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine; 
• Intensive treatment in an emergency room or at home for allergic bronchospasms; and 
• Development of drug dependency or drug abuse. 
All SAEs will be assessed by the Investigator as detailed in Section 16.2.2. 
16.2.7 Follow-up of All Adverse Events/Serious Adverse Events 
The clinical course of each adverse 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 must be followed to 
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Protocol No. SN-SIAL-351, Amendment No. 01 
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determine the final outcome.  The Investigator must provide the Sponsor with all relevant 
follow-up information necessary to facilitate a thorough understanding of the event and 
judgment regarding the relationship to the study drug or placebo.  Subjects who discontinue 
because of an adverse event before completing the study (Week 52) will be evaluated 
immediately and contacted 13 weeks (±3 days) after their last injection of study drug to 
determine if the adverse event has resolved, continues unabated, or has reached a new 
baseline.  
 
 
16.2.8 Adverse Event Reporting 
16.2.8.1 Adverse Events Requiring Expedited Reporting 
The following events should be forwarded to the Sponsor within 24 hours of becoming aware 
of the event: 
• All SAEs, regardless of causality; 
• Overdose (with or without an adverse event); 
• Inadvertent or accidental exposure; 
• All adverse events of special interest (see Section 16.2.4); 
• Pregnancy (see Section 16.2.5); and 
• Unexpected therapeutic benefit. 
16.2.8.2 
Timeframe for Collecting and Reporting Serious Adverse Events, Adverse Events 
of Special Interest, and Other Immediately Reportable Adverse Events 
Serious adverse events, adverse events of special interest, and other immediately reportable 
adverse events occurring during the study period (or within 13 weeks ±3 days of last study 
drug injection for subjects discontinuing participation prematurely) must be reported via 
telephone to the Medical Monitor or designee and then followed up using the appropriate 
Adverse Event Form, within 24 hours of the time any study staff member is made aware of 
the event.  Additional eCRF and/or paper documentation may need to be supplied to the 
Sponsor (or designee). 
You must also report any SAE of which you become aware that occurred within 13 weeks 
after the last dose of study drug (regardless of relationship to study drug).  Any SAEs (at 
least possibly related to study drug) that you become aware of after 13 weeks after the last 
dose of study drug should also be reported to the Sponsor (or designee)  These post-study 
events should be reported to the Sponsor using MedWatch Forms 
 
 
When reporting adverse events of special interest, study staff should provide copies of 
supporting documentation described in Section 16.2.4.  Please note that the supporting 
documentation provided must be redacted to remove any subject identifiers other than the 
study subject identification number and subject’s initials. 
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16.3 Vital Signs 
Resting vital signs (blood pressure, pulse, respiratory rate, and temperature) will be measured 
after sitting quietly for at least 5 minutes at screening and each study visit or, if applicable, at 
discontinuation from the study. 
16.4 Clinical Laboratory Evaluations 
16.4.1 Standard Laboratory Tests 
Safety blood and urine specimens (fasting) (see Table 3) will be will be collected from all 
subjects at screening and Weeks 13, 26, and 52 or, if applicable, at discontinuation from the 
study.  Clinical laboratory testing will also be performed as needed at the Investigator’s 
discretion throughout the study.  For this multicenter study, a central laboratory (TBD) will 
be used that is directly accredited by the College of American Pathologists (CAP) and 
licensed by the Clinical Laboratory Improvement Act of 1988 (CLIA); both certification and 
accreditation must be renewed every 2 years.  The laboratory will need to provide a copy of 
current certification and provide the Laboratory Normals for their laboratory values to 
determine the upper limit of normal (ULN). 
Table 3. Hematology, Chemistry and Urinalysis Tests 
Hematology 
Chemistry 
Urinalysis 
Hemoglobin 
Cholesterol 
Specific gravity 
Hematocrit 
Phosphorus 
pH 
Platelet count 
Sodium 
Glucose 
Red blood cell count 
Potassium 
Blood 
MCV 
Calcium 
Protein 
MCH 
Urea nitrogen 
Color 
MCHC 
Creatinine 
Nitrites 
WBC count 
Albumin 
Ketones 
WBC differential (%) 
Total protein 
Bilirubin 
bands 
Aspartate aminotransferase 
Urobilinogen 
neutrophils 
Alanine aminotransferase 
Leukocyte esterase 
lymphocytes 
Alkaline phosphatase 
 
monocytes 
Gamma-glutamyl transferase 
 
eosinophils 
Uric acid 
 
basophils 
Total bilirubin 
 
 
Glucose 
 
 
Lactate dehydrogenase 
 
Abbreviations:  MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin 
concentration, MCV = mean corpuscular volume, WBC = white blood cell 
 
16.4.2 Pregnancy Test 
A “dip-stick” urine pregnancy test will be performed for all female subjects of childbearing 
potential at screening, on Day 1 (before the first injection of study drug), as needed at the 
Investigator’s discretion throughout the study, and at Week 52 or, if applicable, at 
discontinuation from the study.  Sites are encouraged to use any FDA-approved urine 
pregnancy test. 
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16.5 Neurologic Exam 
A neurologic exam will be performed at screening, on Day 1 (before the first injection of 
study drug), and at Weeks 13 and 52.  A neurologic exam will also be performed as needed at 
the Investigator’s discretion throughout the study and, if applicable, at discontinuation from 
the study.  The neurologic exam will consist of 9 sections to evaluate:  1) level of 
consciousness; 2) speech; 3) cranial nerves; 4) motor; 5) sensory; 6) coordination; 7) gait; 
8) reflexes; and 9) Romberg test (Appendix H). 
16.6 Dental Exam 
An oral dental exam (Appendix I) will be performed by a licensed dentist (DDS or DMD) at 
screening and Weeks 4, 13, 26, and 52 or, if applicable, at discontinuation from the study.  
Four bite-wing radiographs or panoramic imaging 
 
 will be obtained at screening and Weeks 26 and 52 or at 
discontinuation from the study. 
 
  A dental exam will 
also be performed as clinically warranted based on predefined safety criteria (e.g., persistent 
dry mouth).  See Section 16.2.3 for findings to be reported as dental adverse events.  Subjects 
will be advised to continue their dental care visits with their regular dentist throughout the 
course of the study. 
Subjects or their caregiver will also complete a dental questionnaire at screening 
(Appendix I). 
16.7 Oral Exam 
An oral exam (Appendix I) will be performed by the Investigator at each study visit where a 
dental exam is not required.  This will include a visual inspection for detection of any major 
dental issues and, if clinically warranted, the subject will undergo a dental exam (see 
Section 16.6).  See Section 16.2.3 for findings to be reported as dental adverse events. 
16.8 Physical Exam 
A complete physical exam will be performed at screening and Weeks 4, 13, 26, 39, and 52, 
or, if applicable, at discontinuation from the study.  The complete exam will involve gross 
examination of general appearance; head, ears, eyes, nose and throat; skin; extremities; chest; 
abdomen; and lymph nodes.  Cardiac and pulmonary auscultation and measurement of vital 
signs (see Section 16.3) and weight will also be conducted as part of the complete physical 
exam. 
A brief physical exam, consisting of cardiac and pulmonary auscultation and measurement of 
vital signs (see Section 16.3) will be performed on Day 1 (before the first injection of study 
drug) and at Weeks 8, 17, 30, and 43.  Height will be recorded at screening only. 
FVC will be measured in all subjects with ALS, and in other subjects if warranted, at the 
discretion of the Investigator at screening, before the first injection of study drug on Day 1, at 
Weeks 4, 8 (as clinically warranted), and 13.  Thereafter, FVC will be checked if warranted 
at Investigators’ discretion (such as if the subject has ALS). 
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16.9 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS measures both suicidal ideation and suicidal behavior and will be completed on 
Day 1 (before the first injection of study drug), at each subsequent study visit, or, if 
applicable, at discontinuation from the study.  The Baseline version of the C-SSRS 
(Appendix J) will be used to assess lifetime suicidality on Day 1.  At all other protocol-
specified time points, the C-SSRS – Since Last Visit version (Appendix K) will be used to 
assess the subject’s suicidality since the last assessment. 
The C-SSRS has three subscales: suicidal ideation, suicidal behavior, and intensity of 
suicidal ideation.  Both suicidal ideation subscale and suicidal behavior subscale have 5 yes-
no items each, with a sum score ranging from 0 to 5 and higher score indicating greater 
severity. The intensity of suicidal ideation has 5 items, with a sum score ranging from 2 to 25 
and higher score indicating greater risk. 
16.10 Concomitant Medications 
In general, concomitant medications that interfere with neuromuscular function or have the 
potential to confound effectiveness/safety results with regard to sialorrhea will not be 
allowed during the study, including: 
• Aminoglycoside antibiotics (not allowed for entire study); 
• Curare-like agents (not allowed for entire study); 
• Anticholinergics and Antihistamines 
o Strictly prohibited if used for the treatment of sialorrhea, with the exception of 
ALS subjects as noted in exclusion criterion #9, which allows for ALS subjects to 
continue anticholinergic/antihistamine treatment for sialorrhea provided that they 
continue or convert to a short-acting medication (duration of action approximately 
8 hours or less) at a stable dose/regimen for at least 2 weeks before the first 
injection of study drug (Day 1 of Treatment Session 1).  The ALS subject must 
continue to meet all other eligibility criteria following such conversion/dose 
stabilization.  The ALS subject must hold the medication 8 hours before any clinic 
visit. 
o Antihistamines and anticholinergic medications taken for a non-sialorrhea 
condition should be avoided as much as possible, but are not exclusionary. 
• Botulinum toxin type A (not allowed for entire study); and 
• Botulinum toxin type B, except that provided as study drug. 
Additionally, Coumadin (warfarin) and similar anti-coagulant medications will not be 
allowed during the study. 
Other medications not listed above, either specifically or by category, that do not interfere 
with neuromuscular function or do not have a potential to confound safety/effectiveness 
results with regard to sialorrhea, may be used by subjects in this study, at the discretion of the 
Principal Investigator.  
 
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17 STATISTICS 
Detailed methodology for the summary and statistical analysis of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be prepared and 
finalized before database lock. 
17.1 General Statistical Considerations 
Categorical variables will be summarized in general using frequencies and percentages, 
whereas continuous variables will be summarized in general using descriptive statistics of 
number of observations (n), mean, standard deviation (SD), minimum (Min), median, and 
maximum (Max). 
17.2 Sample Size 
Approximately 120 to 200 subjects will be enrolled in this study.  The sample size is based 
on the requirements of the final safety database for approval. 
17.3 Analysis Populations 
All subjects who return to the clinic on Day 1 (i.e., study baseline) and have all required 
baseline (before injection of study drug) assessments/procedures completed will be 
considered study participants.  Study populations, identified and finalized before the database 
lock, are as follows: 
Safety Population 
This population is defined as all subjects who are injected with at least 1 dose of study drug.  
Where applicable, subject grouping will be based on the actual doses the subject received at 
each session and grouped into 3 groups: low dose (2,500 to 2,999 Units), medium dose 
(3,000 to 3,499 Units), and high dose (3,500 Units). 
Intention-to-Treat (ITT) Population 
This population is defined as all subjects who are injected with study drug and have at least 
1 post-baseline measurement recorded in the eCRF for both USFR and CGI-C.  The ITT 
population will be used for effectiveness analyses. 
17.4 Demographic and Baseline Characteristics 
Descriptive summaries of subject demographic and baseline characteristics will be presented 
for the safety population and ITT population.  Subject characteristics will include a summary 
of demography, baseline disease characteristics, pre-existing medical conditions, prior 
therapies for the treatment of sialorrhea, as well as baseline effectiveness measures of USFR, 
CGI-S, PGI-S, DFSS-I, and DFSS-S. 
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17.5 Subject Disposition 
Descriptive summaries of subject disposition will be presented for the safety population and 
ITT population.  A detailed description of individual subject disposition will be provided in a 
data listing. 
17.6 Safety Endpoints 
Safety endpoints include adverse events and AESI, vital signs and weight, neurological 
exam, physical examination, dental exam, C-SSRS, and clinical laboratory tests.  Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
adverse event dictionary. 
For safety endpoints, records with valid data within each visit or assessment time point will 
be identified for initial and repeat, where applicable.  The initial record will be used in 
statistical analysis, whereas all records will be presented in data listings.  Missing or invalid 
data will be treated as missing for the corresponding visit or time point. 
The baseline of each treatment session consists of the corresponding measurement value 
obtained at pre-injection of each treatment session (i.e., Day 1, Weeks 13, 26, and 39). 
17.7 Statistical Methods for Safety 
Frequency of treatment-emergent adverse events (TEAEs) will be calculated for each body 
system, by preferred term, and by treatment session, for number of subjects and proportion 
reporting the event and AESI.  The incidence of subjects reporting TEAEs will also be 
reported without those TEAEs categorized as related to the primary underlying disease 
conditions by the Investigator.  The severity of the adverse events and the relationship to 
study drug will be summarized for each body system and preferred term.  Withdrawals due to 
adverse events will be summarized for each body system and preferred term.  Narratives will 
be presented for all deaths, subjects reporting SAEs, and subjects withdrawn due to adverse 
events. 
Vital signs and weight will be summarized descriptively for continuous variable at each 
pre-injection visit (i.e., Day 1, Weeks 13, 26, and 39) and at each post-injection time point of 
4 weeks post-injection (i.e., Weeks 4, 17, 30, and 43), 8 weeks post-injection (i.e., Week 8, 
first Treatment Session only), and 13 weeks post-injection (i.e., Weeks 13, 26, 39, and 52).  
The change scores in weight, vital signs, and neurologic exam average score from 
pre-injection (i.e., Day 1, Weeks 13, 26, and 39) at 4 weeks post-injection (i.e., Weeks 4, 17, 
30, and 43), 8 weeks post-injection (i.e., Week 8, first Treatment Session only), and 13 weeks 
post-injection (i.e., Weeks 13, 26, 39, and 52) will be analyzed, using a paired t-test where 
applicable, by treatment dose group defined in Section 17.3 for the safety population 
(i.e., low dose, medium dose, and high dose). 
Neurologic exam average score will be summarized descriptively for continuous variable at 
baseline (Day 1, before first injection of study drug), and post-baseline Weeks 13 and 52.  
The change scores in neurologic exam average score from baseline at post-baseline time 
points will be analyzed, using a paired t-test where applicable, by treatment dose group 
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defined in Section 17.3 for the safety population (i.e., low dose, medium dose, and high 
dose). 
Physical examination will be summarized for abnormal findings at pre-injection of each 
session and will be reported at post-injection Week 13 (i.e., Weeks 13, 26, 39, and 52), using 
shift tables.  
Each of the three C-SSRS subscales (suicidal ideation, suicidal behavior, and intensity of 
suicidal ideation) will be summarized descriptively for continuous variable at each 
pre-injection visit (i.e., Day 1, Weeks 13, 26, and 39) and at each post-injection time point of 
4 weeks post-injection (i.e., Weeks 4, 17, 30, and 43), 8 weeks post-injection (i.e., Week 8, 
first Treatment Session only), and 13 weeks post-injection (i.e., Weeks 13, 26, 39, and 52). 
The change scores in C-SSRS subscales from pre-injection at 4 weeks, 8 weeks (first 
Treatment Session only), and 13 weeks post-injection will be analyzed, using a paired t-test 
where applicable, by treatment dose group defined in Section 17.3 for the safety population 
(i.e., low dose, medium dose, and high dose). 
Clinical laboratory tests of hematology, chemistry, and urinalysis (specific gravity and pH) 
will be summarized descriptively at available visits.  Qualitative analysis of laboratory tests 
in terms of abnormality will be performed, using the shift-table method, for individual post-
screening visits.  Abnormal findings of clinical laboratory tests for individual subjects will be 
provided by data listing. 
Abnormal findings of dental exam for individual subjects will be provided by data listing. 
17.8 Effectiveness Endpoints 
Effectiveness endpoints include USFR, CGI-C, CGI-S, DFSS-I, PGI-C, PGI-S, DIS, and 
DFSS-S. 
17.9 Statistical Methods for Effectiveness 
As subjects will receive multiple single-dose injections, each single-dose injection plus its 
follow-up period will be considered as a treatment session.  Post-injection effectiveness 
endpoints over each of the treatment sessions include USFR, CGI-C, CGI-S, DFSS-I, PGI-C, 
PGI-S, DIS, and DFSS-S at the injection visit (i.e., Day 1, Weeks 13, 26, and 39), 4 weeks 
post-injection (i.e., Weeks 4, 17, 30, and 43), 8 weeks post-injection (i.e., Week 8, first 
Treatment Session only), and 13 weeks post-injection (i.e., Weeks 13, 26, 39, and 52).  The 
pre-injection time points are Day 1 and Weeks 13, 26, and 39 for each of the consecutive 
treatment sessions.  Missing post-injection measurements will not be imputed, whereas 
missing measurements at the pre-injection of each treatment session will be imputed by the 
site-specific average of those subjects who receive the treatment at the corresponding 
treatment session. 
For each treatment session, effectiveness analysis of the treatment response will be 
performed on USFR change from pre-injection, CGI-C, CGI-S, PGI-C, PGI-S, and DIS 
change from pre-injection, DFSS-I change from pre-injection, and DFSS-S change from 
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pre-injection at each of the post-injection time points for the ITT population, using a paired 
t-test.  The ITT population will be grouped into three groups by the actual doses the subject 
received at each session as the following: low dose (2,500 to 2,999 Units), medium dose 
(3,000 to 3,499 Units), and high dose (3,500 Units). 
In addition, the proportion of treatment responders will be reported for the CGI-C and PGI-C 
at both pre-injection and post-injection time points over each treatment session.  Before the 
analysis, the CGI-C and PGI-C variables will be dichotomized into 2 categories, with “very 
much improved” and “much improved” into 1 category and the remaining levels in the other 
category. 
18 ETHICS 
This study will be conducted according to Good Clinical Practice (GCP) guidelines; US 
Code of Federal Regulations (CFRs) dealing with Protection of Human Subjects (US 21 CFR 
Part 50) and Institutional Review Boards (US 21 CFR Part 56); the Nuremberg Code; and the 
Declaration of Helsinki, revised version of Seoul, October 2008 (in compliance with the 
FDA’s guidance). 
18.1 Ethics Review 
The US FDA regulates studies of drugs, biologics, and medical devices.  Consequently, these 
studies are subject to regulations and guidance issued by the FDA and are included in the 
following parts of the US CFR and guideline document: 
• 21 CFR Part 11 - Electronic Records; Electronic Signatures; 
• 21 CFR Part 50 - Protection of Human Subjects; 
• 21 CFR Part 56 - Institutional Review Boards (IRBs); 
• 21 CFR Part 312 - Investigational New Drug (IND) Application; and 
• ICH E6:  Good Clinical Practice. 
Copies of these materials can be downloaded from the FDA’s website at www.fda/gov. 
The purpose of these regulations, legal obligations, and guidelines is to define the standards 
and principles for the proper conduct of clinical trials that have been developed by the 
medical, scientific, and regulatory communities.  They are not intended to impede or restrict 
clinical research. 
18.2 Ethical Conduct of the Study 
As a Principal Investigator, you agree to conduct this study in accordance with the ethical 
standards defined within GCP in order to ensure that: 
• Human subjects are provided with an adequate understanding of the possible risks of 
their participation in the study, and that they have a free choice to participate or not; 
• The study is conducted with diligence and in conformance with the protocol in such a 
way as to ensure the integrity of the findings; and 
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• The potential benefits of the research justify the risks. 
Solstice Neurosciences is the Sponsor of the IND.  The Sponsor is responsible for the 
following: 
• Selecting qualified Investigators; 
• Providing Investigators with the information they need to properly conduct an 
investigation (i.e., protocol training); 
• Ensuring proper monitoring of the investigation; 
• Ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND; 
• Maintaining the IND; and 
• Ensuring that FDA and all participating Investigators are properly informed of 
significant new information regarding adverse effects or risks associated with the 
drug being studied. 
18.3 Study Conduct 
This study will be conducted in accordance with the Sponsor’s standards that meet GCP 
regulations.  These standards reflect the following guidelines: 
• GCP:  Consolidated Guideline (International Conference on Harmonization [ICH] 
Technical Requirements for the Registration of Pharmaceuticals for Human Use, 
May 1996); 
• US CFR dealing with clinical studies (21 CFR Parts 50, 54, 56, 312, and 314); 
• HIPAA of 1996 (45 CFR Part 164); and 
• Declaration of Helsinki, revised version of Seoul, October 2008. 
18.4 Institutional Review Board Approval 
Before initiating the study, the Principal Investigator will obtain written approval from a 
central IRB or the Principal Investigator’s IRB (if such site is not eligible to use a central 
IRB) that complies with the requirements specified in GCP Title 21 Part 56 of the US CFR 
relating to IRBs and the ICH Guideline for GCP (E6).  Study drug will not be shipped until 
IRB approval is obtained.  Should changes to the study protocol become necessary, protocol 
amendments (provided by the Sponsor) will be submitted in writing to the central IRB (and 
the Principal Investigator’s IRB) for IRB approval before implementation.  In addition, the 
Principal Investigator’s IRB must approve all site-specific advertising used to recruit subjects 
for the study.  If the duration of the study is greater than 1 year, re-approval by the IRB must 
be obtained annually (or at more frequent intervals if required by the IRB). 
Progress reports will be submitted to the central IRB annually or at a frequency requested by 
the IRB.  You must also provide progress reports to your IRB, as well as any SAE reports 
from your study site.  You are also responsible for providing the IRB with reports of any 
SAEs from any other study conducted with the study drug.  The latter will be provided by the 
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Sponsor.  If you are using the central IRB selected by the Sponsor, safety updates (except 
SAEs occurring at your site) will be reported directly to the central IRB on your behalf. 
18.5 Informed Consent and HIPAA Authorization 
Properly executed written informed consent, in compliance with 21 CFR 50 and ICH 
guidelines, shall be obtained from each subject before entering the subject into the study.  
Attention is directed to the basic elements that are required in the informed consent under 
US CFR for Protection of Human Subjects (21 CFR 50.25) and/or ICH E6 4.8.10.  Where 
applicable, the consent form or appended document must also include required elements to 
maintain compliance with 45 CFR Part 164 (HIPAA) and/or 21 CFR Part 50.27/ICH E6 
4.8.8.  For this study, a standard Informed Consent Form (ICF) will be approved by a central 
IRB.  Any study site that requires a site-specific ICF must have the document approved by 
the Sponsor before submission to the site’s IRB.  The final IRB-approved ICF must be 
provided to the Sponsor for regulatory purposes. 
Informed consent is a process of interaction between the Investigator and a potential 
subject/Legally Authorized Representative (LAR) in which the Investigator (or appropriate 
designee) explains the aims, methods, anticipated benefits (or lack thereof), and potential 
risks of participating in a study, and informs the potential subject of their rights.  The 
subject/LAR will be given ample time and opportunity to inquire about details of the study so 
the subject can voluntarily make an informed decision about whether or not to participate in 
the study.  All potential subjects will be given a current IRB- and Sponsor-approved copy of 
the ICF to read2 to ensure they are given accurate information, and to assist in verifying that 
consent was obtained.  Information provided verbally, as supplemental explanation and/or 
answers to questions, must be accurate and consistent with the ICF, and must not be coercive 
or misleading.  No subject will undergo any study procedures before the subject/LAR signs 
and dates the ICF, which should be signed before screening.  A completed, signed copy will 
be given to the subject/LAR and a signed original shall be maintained in the subject’s clinical 
file.  Subjects who refuse to participate or who withdraw from the study will be treated 
without prejudice. 
Each subject/LAR must also sign a HIPAA authorization form before his/her participation in 
the study.  A signed copy must be provided to the subject and a signed original shall be 
maintained in the subject’s clinical file. 
2 Potential subject/LAR is to be consented using an ICF that is written in a language they understand.  It is not acceptable to 
verbally translate an ICF from the language in which it is written and have the subject/LAR sign the written ICF.  
Additionally, if the person obtaining consent is not fluent in the language in which the consent is written (able to explain 
the consent/answer questions to the subject/LAR), the subject/LAR’s consent must be witnessed by someone who is 
fluent in the language in which the consent is written, and will be able translate any questions/explanations during the 
consent process. 
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19 INVESTIGATOR OBLIGATIONS 
19.1 Protocol Adherence and Subject Welfare 
As a Principal Investigator, you are responsible for ensuring that the study is conducted 
according to the protocol as written, and for protecting the rights, safety, and welfare of 
subjects under your care. 
19.2 Protocol Modification 
Only the Sponsor may modify the protocol.  You will be immediately notified of protocol 
changes and provided with a copy of the protocol amendment.  A protocol amendment that 
has an impact on subject risk or has changes to the study objectives, study design, subject 
population, study procedures, or study drug must be submitted to the IRB for review and 
approval, in writing, before implementation.  If the protocol amendment requires a change to 
the ICF, then the revised ICF must be IRB-approved in advance of use. 
19.3 Compliance with Law, Audit, and Debarment 
19.3.1 Statement of Investigator (Form FDA 1572) 
As a Principal Investigator, you must sign a Statement of Investigator (Form FDA 1572) 
before initiating the study.  The names of all Sub-investigators and other clinical experts 
(e.g., study dentist) directly involved in the treatment or evaluation of study subjects must 
appear on this form. 
19.3.2 Financial Disclosure 
You as a Principal Investigator, Sub-investigators, and other clinical experts (e.g., study 
dentist) directly involved in the treatment or evaluation of study subjects must sign financial 
disclosure forms before initiating this study.  Financial disclosure also pertains to the spouse 
and dependent children of the Investigator(s) and other clinical experts.  In general, the FDA 
is concerned with certain types of financial interests including: 
• Compensation affected by the outcome of the study; 
• Significant equity interests in the Sponsor exceeding $50,000 including ownership, 
stick or stock options; 
• A proprietary interest in the tested product such as trademark, patent, copyright, or 
licensing agreement; and 
• Significant payments of other types made to the Investigator or institution to support 
investigator activities (i.e., honoraria, consulting fees) that exceed $25,000 
cumulatively.  These payments exclude the costs of this clinical trial. 
Investigators are required to promptly update the information if any relevant changes occur 
during the course of the study or for 1 year following completion of the study (defined as 
1 year after the last study visit by the last study subject at the Investigator’s study site). 
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19.3.3 Inspections and Audits 
As a Principal Investigator, you are required to maintain complete and accurate study 
documentation in compliance with current GCP standards and all applicable federal, state 
and local laws, rules, and regulations related to the conduct of a clinical study. 
 
 
 
 
You are required to make all study documentation promptly available for inspection, review, 
or audit at your study site upon request by either the Sponsor, its representatives, or any 
appropriate regulatory agencies.  
 
 
  Additionally, you should inform subjects, in writing, about the possibility of 
audits by authorized representatives of the Sponsor and/or regulatory authorities and that 
confidentiality of their data will be maintained in accordance with local laws.  See 
Section 20.2 for further details regarding study audits. 
19.3.4 Debarment 
Individuals ineligible from conducting or working on clinical studies, including those 
ineligible as a result of debarment under the Generic Drug Enforcement Act of 1992, will not 
be allowed to conduct or work on studies sponsored by Solstice Neurosciences, LLC.  You 
are required to immediately disclose to the Sponsor, in writing, if any person involved in the 
conduct of the study is debarred pursuant to a hearing by FDA under this anti-fraud law, or if 
any proceeding for debarment is pending, or is (to the best of your knowledge) threatened. 
19.4 Adverse Event Reporting 
In accordance with FDA reporting requirements, you are required to collect, document, and 
report all adverse events/SAEs as outlined in Section 16.2.8 of this protocol.  You must also 
report any SAE of which you become aware that occurred within 13 weeks after the last dose 
of study drug (regardless of relationship to study drug) and any SAEs (at least possibly 
related to study drug) that you become aware of after 13 weeks after the last dose. 
19.5 Drug Accountability 
All investigational agents required for completion of this study will be provided by the 
Sponsor.  The investigational agents are to be used only as described by this study protocol 
by an appropriately licensed Investigator named in Form FDA 1572.  Please refer to 
Section 13.5 for specific requirements for recording all investigational agents received, 
dispensed, administered, and returned. 
19.6 Data Handling and Recordkeeping 
19.6.1 Case Report Forms 
You will be provided with secure access to 21 CFR Part 11 compliant eCRFs for collecting 
subject data.  All information recorded in the eCRFs must be supported by source 
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documentation in the subject’s file.  The subject’s file must include (but is not limited to) the 
following: 
• An entry stating that the subject signed an ICF and HIPAA authorization form before 
entry into the study and is participating in the study; 
• Subject identification number and protocol number; 
• Diagnosis; 
• Entries for all therapy/medications; 
• Entries summarizing all clinic visits, including those for study purposes; and 
• Entries for all adverse events. 
All data entered into the eCRF must be source documented in the subject’s medical record.  
In some instances the source may serve as the eCRF. 
 
 
 
19.6.2 Subject Identification 
You must maintain a log sheet that lists each subject who is screened for possible 
participation in this study. 
The following information must be entered onto the log sheet: 
• Subject identification number and protocol number; 
• Subject initials; 
• Date (and time, where applicable) subject/caregiver signed the ICF and HIPAA 
authorization form; 
• Date of screening visit; 
• Whether or not the subject was treated with study drug; and 
• For subjects who do not receive treatment, the reason for exclusion. 
19.6.3 Administrative Documentation 
You must provide the Sponsor’s Study Monitor with the following documents before study 
initiation and retain a copy in your study files: 
• A current and complete curriculum vitae for the Principal Investigator and 
each Sub-investigator; 
• An original completed Form FDA 1572 signed and dated by the Principal 
Investigator; 
• Completed Financial Disclosure Form (copy is acceptable) for Principal Investigator, 
any Sub-investigators, and other clinical experts directly involved in the treatment or 
evaluation of study subjects; 
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• Approved Sponsor protocol (and any protocol amendments) signed and dated by 
the Principal Investigator (copy is acceptable); 
• IRB membership list or assurance number (copy is acceptable); 
• ICF and HIPAA authorization form approved by the IRB and accepted by the 
Sponsor (copy is acceptable); 
• Written IRB approval of the protocol (copy is acceptable);  
• Certifications and laboratory reference ranges for laboratories, where applicable 
(copy is acceptable).  (Documentation for approved central laboratories will be 
provided by the Sponsor.  The Investigator must provide certifications and current 
laboratory reference ranges for all local laboratories used for this study.); and 
• Acknowledgement of Clinical Investigator Brochure (CIB) receipt (copy is 
acceptable). 
In addition to the documents listed above, you should also retain the following items: 
• All original ICFs/HIPAA authorizations with required signatures; 
• All IRB approvals and correspondence (e.g., informed consent [including any 
approved revisions], protocol, adverse events, advertisements, newsletters); 
• Site copy of the Study Monitoring Log Sheet; 
• Clinical and nonclinical supply shipment forms; 
• Copies of all correspondence (emails, faxes, mail) pertaining to the study (except 
budget issues) between the Sponsor (or Clinical Research Organization [CRO]) and 
the site; 
• Copies of all SAE reports submitted to the Sponsor; 
• Copies of the CIB and/or approved package labeling; 
• Study personnel signature & delegation of authority log; and 
• Copies of all IND safety reports. 
The Clinical Study Agreement should be kept in a file separate from any study documents 
because this is a confidential agreement between you and the Sponsor. 
19.6.4 Retention of Records 
Essential documents must be retained at least 2 years after the last approval of a marketing 
application in an ICH region (with no pending marketing application) OR at least 2 years 
after formal discontinuation of clinical development of the product. 
The Investigator/study site must retain copies of all pertinent study information and records 
(e.g., eCRFs, original data, subject identification lists, ICFs, IRB approvals/approved 
documents) until notified, in writing, by the Sponsor that these copies are no longer required. 
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The Investigator is responsible to notify the Sponsor if the site or records are relocated and 
must provide the address of the new location. 
20 STUDY MONITORING AND QUALITY CONTROL/ASSURANCE 
20.1 Study Monitoring 
A Sponsor or CRO Clinical Research Associate (CRA) will be the Study Monitor for your 
study.  The Study Monitor is your primary contact for all study-related issues. 
 
 
 
The Study Monitor will visit your site at periodic intervals throughout the trial as defined in 
the monitoring plan, after which a report on all monitoring activities will be submitted to the 
Sponsor.  The first visit (“initiation” visit) is before subjects are enrolled into the clinical 
trial.  During this visit, the Study Monitor will review the study protocol with you and your 
staff, confirm receipt of study supplies, and verify that you are ready to enroll subjects.  
Subsequent visits will be scheduled at periodic intervals to verify that the clinical trial is 
being conducted and data are generated, recorded, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.  For this study, the Sponsor will be 
the Data Coordinating Center and will implement quality control procedures beginning with 
the data entry system (eCRF) and generate data quality control checks that will be run on the 
database.  Any missing data or data anomalies will be communicated to the site for 
clarification and resolution. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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After the close-out visit, you may be asked to provide additional information to support the 
clarification and/or correction of clinical data entries. 
20.2 Inspections and Audits 
The Sponsor will secure agreement from all involved parties to ensure direct access to all 
trial-related sites, source data/documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by local and regulatory authorities. 
20.2.1 Inspection of Records 
The Sponsor, its agents, the IRB, and any applicable regulatory agency will be provided with 
direct access to all information in original source documents and/or certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
 
 
 
 
 
 
20.2.2 Audits 
It may be necessary for the Sponsor, its agents, and/or a regulatory agency to audit your site.  
The purpose of an audit is to assess the accuracy, adequacy, and consistency of the study 
records and subject data, as well as to assess your adherence to the procedures described in 
this protocol.  Direct access must be provided to all information in original source documents 
and/or certified copies of original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. 
 
 
 
 
 
 
 
 
 
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21 CONFIDENTIAL INFORMATION 
21.1.1 Confidentiality of Data 
Confidential information refers to any information provided to you by the Sponsor or its 
agents that has not been previously published.  This includes, but is not limited to, the 
clinical protocol (and protocol amendments, if any), eCRFs, assay methods, CIB, and basic 
scientific data.  Any data that you collect during the study are also considered confidential.  
All confidential information remains the sole property of the Sponsor, may not be disclosed 
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to others without prior written consent from the Sponsor, and may not be used except in the 
performance of this study.  You are required to provide the Sponsor with complete test 
results and all data obtained during this study.  At the discretion of the Sponsor, the 
information from this study may be made available to any applicable regulatory agency 
and/or other physicians who are conducting similar studies. 
21.1.2 Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports, and other 
records will be coded using subject identification numbers and/or subject initials.  Only 
research staff and Sponsor officials will have access to the records.  Subject information will 
not be released without written permission, except as necessary for monitoring by the 
Sponsor or a regulatory agency. 
By participating in this protocol, you agree that within local regulatory restrictions and 
ethical considerations, the Sponsor or any regulatory agency may consult and/or copy study 
documents in order to verify eCRF data. 
Subject confidentiality will be maintained in any publications or presentations that result 
from this study. 
22 STUDY DISCONTINUATION CRITERIA 
The Sponsor has the right to terminate this study at any time.  You will be notified by 
telephone and in writing if the Sponsor decides to suspend or discontinue the study for any 
reasons.  The written notice will provide you with the reason that the study was suspended or 
discontinued along with instructions on how you should proceed. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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23 DISSEMINATION AND PUBLICATION OF STUDY RESULTS 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages publication of such data in reputable scientific journals and at seminars or 
conferences.  The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study is described in the Clinical Trial 
Agreement between the Sponsor and the institution of the Investigator. 
24 REFERENCES 
Benson J, Daugherty KK.  Botulinum toxin A in the treatment of sialorrhea.  Ann 
Pharmacother. 2007;41:79-85. 
Basciani M, Di Rienzo F, Fontana A, Copetti M, Pellegrini F, Intiso D.  Botulinum toxin 
type B for sialorrhoea in children with cerebral palsy: a randomized trial comparing three 
doses.  Dev Med Child Neurol. Jun 2011;53(6):559-564. 
Chinnapongse R, Gullo K, Nemeth P, Zhang Y, Griggs L. Safety and efficacy of botulinum 
toxin type B for treatment of sialorrhea in Parkinson's disease: a prospective double-blind 
trial.  Mov Disord. Feb 2012;27(2):219-226. 
Comella CL, Jankovic J, Shannon KM, Tsui J, Swenson M, Leurgans S, et al.  Comparison 
of botulinum toxin serotypes A and B for the treatment of cervical dystonia.  Neurology. 
2005;65:1423-1429. 
Contarino MF, Pompili M, Tittoto P, Vanacore N, Sabatelli M, Cedrone A, et al.  Botulinum 
toxin B ultrasound-guided injections for sialorrhea in amyotrophic lateral sclerosis and 
Parkinson's disease.  Parkinsonism Relat Disord. 2007;13:299-303. 
Costa J, Rocha ML, Ferreira J, Evangelista T, Coelho M, de Carvalho M.  Botulinum toxin 
type-B improves sialorrhea and quality of life in bulbar onset amyotrophic lateral sclerosis.  
J Neurol. 2008;255:545-550. 
Fairhurst CB, Cockerill H.  Management of drooling in children.  Arch Dis Child Educ Pract 
Ed.  2011;96:25-30. 
Fuster Torres MA, Berini Aytés L, Gay Escoda C.  Salivary gland application of botulinum 
toxin for the treatment of sialorrhea.  Med Oral Patol Oral Cir Bucal. 2007;12:E511-E517. 
Glickman S, Deaney CN.  Treatment of relative sialorrhea with botulinum toxin type A: 
description and rationale for an injection procedure with case report.  Eur J Neurol. 
2001;8:567-571. 
Guidubaldi A, Fasano A, Ialongo T, Piano C, Pompili M, Mascianà R, et al.  Botulinum toxin 
A versus B in sialorrhea: a prospective, randomized, double-blind, crossover pilot study in 
patients with amyotrophic lateral sclerosis or Parkinson's disease.  Mov Disord. 
Feb 2011;26(2):313-319. 
Confidential Information 
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Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
Hockstein NG, Samadi DS, Gendron K, Handler SD.  Sialorrhea: a management challenge.  
Am Fam Physician. 2004;69:2628-2634. 
Jackson CE, Gronseth G, Rosenfeld J, Barohn RJ, Dubinsky R, Simpson CB, et al.  
Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients.  
Muscle Nerve. 2009:39:137-143. 
Lagalla G, Millevolte M, Capecci M, Provinciali L, Ceravolo MG.  Long-lasting benefits of 
botulinum toxin type B in Parkinson’s disease-related drooling.  J Neurol. 2009;256:563-567. 
Myobloc® (rimabotulinumtoxinB) Injection [package insert].  South San Francisco, CA: 
Solstice Neurosciences, Inc.; 2010. 
Ondo WG, Hunter C, Moore W.  A double-blind placebo-controlled trial of botulinum 
toxin B for sialorrhea in Parkinson’s disease.  Neurology. 2004;62:37-40. 
Pappert EJ, Germanson T.  Botulinum toxin type B vs. type A in toxin-naïve patients with 
cervical dystonia:  Randomized, double-blind, noninferiority trial.  Mov Disord. 
2008;23:510-517. 
Postma AG, Heesters M, van Laar T.  Radiotherapy to the salivary glands as treatment of 
sialorrhea in patients with parkinsonism. Mov Disord. 2007;22:2430-2435. 
Potulska A, Friedman A.  Controlling sialorrhea: a review of available treatment options.  
Expert Opin Pharmacother. 2005;6:1551-1554. 
Proulx M, de Courval FP, Wiseman MA, Panisset M.  Salivary production in Parkinson’s 
Disease.  Mov Disord. 2005;20:204-207. 
Racette BA, Good L, Sagitto S, Perlmutter JS.  Botulinum toxin B reduces sialorrhea in 
parkinsonism.  Mov Disord. 2003;18:1059-1061. 
Steinlechner S, Klein C, Moser A, Lencer R, Hagenah J.  Botulinum toxin B as an effective 
and safe treatment for neuroleptic-induced sialorrhea.  Psychopharmacology (Berl). 
Jan 2010;207(4):593-597. 
Tan EK.  Botulinum toxin treatment of sialorrhea:  comparing different therapeutic 
preparations.  Eur J Neurol. 2006;13(Suppl 1):60-64. 
Tintner R, Gross R, Winzer UF, Smalky KA, Jankovic J.  Autonomic function after 
botulinum toxin type A or B: a double-blind, randomized trial.  Neurology. 2005;65:765-767. 
Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL 3rd, Tran-Johnson TK, et al.  
Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with 
Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial.  P92-01 
Study Group.  Arch Intern Med. 1999;159(2):174-181. 
Confidential Information 
Page 76 of 112 


Protocol No. SN-SIAL-351, Amendment No. 01 
July 23, 2015 
Wang SI, Zhao ZT, Li J, Zhu XZ, Dong H, Zhang YG.  Investigation of the clinical value of 
total saliva flow rates.  Arch Oral Biol. 1998;43:39-43. 
 
 
Confidential Information 
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SAP_001.pdf: 
PRODUCT: MYOBLOC® (rimabotulinumtoxinB) Injection 
STATISTICAL ANALYSIS PLAN PROTOCOL NUMBER: SN-SIAL-351 
SPONSOR: 
Solstice Neurosciences, LLC,  
a subsidiary of US WorldMeds, LLC 
4441 Springdale Rd, Louisville, KY 40241, USA 
TITLE: 
A Phase 3, Long-Term, Open-Label and Single-Arm Study of MYOBLOC® 
in the Treatment of Troublesome Sialorrhea in Adult Subjects 
DOCUMENT DATE: July 22, 2018 
IND NUMBER: 100,454 
NCT NUMBER: NCT02610868  


Solstice Neurosciences, LLC 
CONFIDENTIAL 
22Jul2018 
SAP SN-SIAL-351 
 
Page 1 of 36 
 
Version: Final (1.0) 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
Protocol No.: 
 
SN-SIAL-351 
Protocol Title: 
 
 
 
A Phase 3, Long-Term, Open-Label and Single-Arm 
Study of MYOBLOC® in the Treatment of Troublesome 
Sialorrhea in Adult Subjects 
 
Drug Name: 
 
MYOBLOC® (rimabotulinumtoxinB) injection 
Indication: 
Troublesome Sialorrhea 
 
Sponsor: 
Solstice Neurosciences, LLC 
a Subsidiary of US WorldMeds, LLC 
4010 Dupont Circle, Suite L-07 
Louisville, KY 40207 
 
Version: 
Final (1.0) 
 
Amendment(s): 
None 
 
Date: 
July 22, 2018 
 
Statistician 
 
 
 
 
 
Approved by: 
Name 
Title 
Signature: 
Date: 
 
 
Name 
 
Title 
Signature: 
Date: 
 
CONFIDENTIAL MATERIAL 
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This material is the property of Solstice Neurosciences, LLC and it must not be disclosed or used without written 
authorization from Solstice Neurosciences, LLC.
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SAP SN-SIAL-351 
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Version: Final (1.0) 
STATISTICAL ANALYSIS PLAN 
ABBREVIATIONS AND DEFINITIONS ................................................................................. 5 
1 
INTRODUCTION .......................................................................................................... 6 
1.1 
Trial Objectives ....................................................................................................... 6 
1.2 
Background Information .......................................................................................... 6 
2 
STUDY DESIGN ........................................................................................................... 7 
2.1 
Rationale................................................................................................................. 7 
2.2 
Description of Trial Design ...................................................................................... 7 
2.3 
Schedule of Assessments ....................................................................................... 8 
2.4 
Randomization .......................................................................................................13 
2.4.1 
Treatment randomization .......................................................................................13 
2.4.2 
Random allocation of landmarks-confirmation type ............................................... 13 
2.5 
Sample Size Estimation .........................................................................................13 
2.6 
Efficacy and Safety Measurements ........................................................................13 
2.6.1 
Effectiveness measures .........................................................................................13 
2.6.2 
Safety measures ....................................................................................................15 
2.6.3 
Other measures .....................................................................................................17 
2.7 
Drug Concentration and PK Measurements ...........................................................17 
2.8 
Handling of Missing, Incomplete, and Repeat Data ................................................18 
2.9 
Statistical Methods .................................................................................................18 
2.9.1 
Effectiveness analysis ............................................................................................19 
2.9.2 
Safety analysis .......................................................................................................19 
2.9.3 
Other analysis ........................................................................................................21 
2.10 
Interim Analysis......................................................................................................22 
3 
STUDY POPULATION ................................................................................................22 
3.1 
Definition of Subject Populations ............................................................................22 
3.2 
Screening and Enrollment ......................................................................................22 
3.3 
Population Demography .........................................................................................22 
3.4 
Disease Diagnosis and Prior Therapy ....................................................................22 
3.5 
Medical History ......................................................................................................23 
3.6 
Disposition of Study Participants ............................................................................23 
3.7 
Protocol Deviations and Violations .........................................................................23 
4 
EFFICACY EVALUATION ...........................................................................................23 
4.1 
Datasets Analyzed .................................................................................................23 
4.2 
Treatment Compliance ...........................................................................................23 
4.3 
Baseline Measures ................................................................................................23 
4.4 
Efficacy Results and Tabulations ...........................................................................23 
5 
SAFETY EVALUATION ..............................................................................................24 
5.1 
Extent of Drug Exposure ........................................................................................25 
5.2 
Early Termination ...................................................................................................25 
5.3 
Adverse Events ......................................................................................................25 
5.4 
Adverse Events of Special Interest (AESI) .............................................................25 
5.5 
Adverse Events Associated with Dental Disease ...................................................25 
5.6 
Adverse Events Associated to Distant Spread of Toxin Effect ................................26 
5.7 
Vital Signs and Weight ...........................................................................................26 
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5.8 
Neurologic Exam ....................................................................................................27 
5.9 
Lung Functioning Test............................................................................................27 
5.10 
Physical Examination .............................................................................................27 
5.11 
Clinical Laboratory Evaluation ................................................................................27 
5.12 
Suicidality Assessment ..........................................................................................27 
5.13 
Dental and Oral Examinations ................................................................................27 
5.14 
Concomitant Medication .........................................................................................27 
6 
REFERENCE ..............................................................................................................28 
7 
LIST OF STATISTICAL TABLE SHELLS ...................................................................29 
8 
LIST OF LISTING SHELLS .........................................................................................35 
9 
LIST OF FIGURES ......................................................................................................36 
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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALS 
Amyotrophic Lateral Sclerosis 
AUC 
Area Under the Curve 
CGI-C 
Clinical Global Impression - Change 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence Interval 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicidal Severity Rating Scale 
eCRF 
Electronic Case Report Form 
DAE 
Dental Adverse Event 
DFSS-I 
Drooling Frequency and Severity Scale - Assessor 
DFSS-S 
Drooling Frequency and Severity Scale - Subject 
DIS 
Drooling Impact Scale 
FVC 
Forced Vital Capacity 
ITT 
Intent-to-Treat Population 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCE 
New Chemical Entity 
NDA 
New Drug Application 
OL 
Open-Label Population 
OTC 
Over the Counter 
PD 
Parkinson’s Disease 
PGI-C 
Patient Global Impression - Change 
PGI-S 
Patient Global Impression - Severity 
SAE 
Serious Adverse Event 
SE 
Standard Error 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
USFR 
Unstimulated Salivary Flow Rate 
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1 
INTRODUCTION 
1.1 
Trial Objectives 
The primary objective of this study is: 
 
 
To determine the long-term safety and tolerability of MYOBLOC® (administered 
intraglandularly as a single total dose of 3,500 Units) treatments every 13 weeks over 
a maximum possible duration of 1 year in adult subjects with troublesome sialorrhea. 
The secondary objective of this study is: 
 
 
To assess the magnitude of therapeutic response of MYOBLOC (administered 
intraglandularly as a single total dose of 3,500 Units) using effectiveness assessments 
performed at intervals after treatments every 13 weeks over a maximum possible 
duration of 1 year. 
2 
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SAP SN-SIAL-351 
 
 
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2 
STUDY DESIGN 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
2.2 
Description of Trial Design 
This is a multi-center study with a single arm to evaluate the long-term safety and effectiveness 
of repeated doses (MYOBLOC 3,500 Units single-injection treatment) at intervals of every 13 
weeks over a maximum possible duration of 1 year in subjects with troublesome sialorrhea.  
The study population will be comprised of a mixture of patient populations, including subjects 
with PD-related sialorrhea, subjects with sialorrhea secondary to other non-PD conditions 
(e.g., cerebral palsy, ALS, stroke, traumatic brain injury) or secondary to oral cancer or 
medications (e.g., neuroleptics).   
 
After a screening period (up to 21 days), those subjects who satisfy all eligibility criteria will 
receive single dose injections of 3,500 Units of MYOBLOC at Day 1 and at subsequent 
intervals of every 13 weeks (+/-2 weeks) for a total of 4 treatments via injections into the 
submandibular and parotid glands.  Repeat injections at each treatment session will be done 
when subjects return to baseline status as determined by the Investigator, with a minimum of 
11 weeks from the prior injection. After the 1st treatment session for which subjects are injected 
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with 3,500 Units, the Investigator has the discretion to decrease subsequent injection doses, 
as a result of poor tolerability, but to no less than a total dose of 2,500 Units.  
 
Subjects will undergo safety and effectiveness assessments at Day 1 (1st injection), and Weeks 
4, 8, 13 (2nd injection), 17, 26 (3rd injection), 30, 39 (4th injection), 43, and 52. Telephone follow-
up will occur at Weeks 14, 21, 27, 34, 40 and 47 to assess how the subject feels after 1 week 
(±1 day) of study drug injection, document adverse events as appropriate, document any new 
medications the subject may be taking and remind the subject to complete their diary. 
 
At each visit, the following efficacy assessments will be collected, when possible by the same 
assessor for a given subject: 
 
 
Unstimulated salivary flow rate (USFR) 
 
Clinical Global Impression of Severity (CGI-S) 
 
Clinical Global Impression of Change (CGI-C), except for Day 1 
 
Drooling Frequency and Severity Scale (DFSS-I) by Investigator 
 
Drooling Frequency and Severity Scale (DFSS-S) by subject 
 
Patient Global Impression of Severity (PGI-S)   
 
Patient Global Impression of Change (PGI-C), except for Day 1 
 
Drooling Impact Score (DIS) by Subject 
 
Efficacy and safety assessments will be made throughout the study as detailed in the following 
section. 
2.3 
Schedule of Assessments 
The complete schedule of assessments for this study is shown in table below.   
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SAP SN-SIAL-351 
 
 
 
 
 
 
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Table A 
Schedule of Study Assessments 
 
 
Treatment Session 1 
Treatment Session 2 
Activity 
Screening 
(Day -21 to -
1) 
Day 1 (a) 
Wk 4 (c) 
(± 3 days) 
Wk 8 (c) 
(± 3 days) 
Wk 13 (d) 
(± 2 wks) 
Wk 14 (b) 
(± 1 day) 
Wk 17 
(c) 
(± 5 
days) 
Wk 21 
(b) 
(± 5 
days) 
Wk 26 
(d) 
(± 2 wks) 
Written Informed Consent and HIPAA 
Authorization (e) 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Surgical/Medication History (f) 
X 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
X 
 
X 
 
 
 
X 
Brief Physical Examination 
 
X 
 
X 
 
 
X 
 
 
Weight 
X 
X 
X 
X 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Neurologic Examination 
X 
X 
As needed 
X 
 
As 
needed 
 
As 
needed 
Dental Questionnaire (Subject or Caregiver) 
X 
 
 
 
 
 
 
 
 
Dental Exam by Licensed Dentist (DDS, DMB) 
X (g) 
 
X 
As needed 
X 
 
As 
needed 
 
X (g) 
Oral Examination by Investigator 
 
X 
 
X 
 
 
X 
 
 
Clinical Laboratory Tests (hematology, full 
chemistry 
panel 
including 
glucose 
and  
alkaline phosphatase, urinalysis) (fasting) 
X 
 
As needed 
X 
 
As 
needed 
 
X 
Urine Pregnancy Test (h) 
X 
X 
As needed 
 
As 
needed 
 
As 
needed 
Vital Signs (sitting BP and pulse after 5 minutes 
rest, RR, Temp) 
X 
X 
X 
X 
X 
 
X 
 
X 
Forced Vital Capacity (i) 
X 
X 
X 
As needed 
X 
 
As 
needed 
 
As 
needed 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS Baseline Version 
 
X 
 
 
 
 
 
 
 
C-SSRS Since Last Visit Version 
 
 
X 
X 
X 
 
X 
 
X 
Concomitant Medications Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Training 
X 
 
 
 
 
 
 
 
 
Subject Diary Review 
 
 
X 
X 
X 
 
X 
 
X 
Salivary Flow Rate Collection (USFR) (j) 
X 
X 
X 
X 
X 
 
X 
 
X 
Clinical Global Impression-Severity (CGI-S) (j) 
(k) 
 
X 
X 
X 
X 
 
X 
 
X 
Clinical Global Impression-Change (CGI-C) (j) 
(k) 
 
 
X 
X 
X 
 
X 
 
X 
Patient Global Impression of Severity (PGI-S) 
(k) 
 
X 
X 
X 
X 
 
X 
 
X 
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Table A 
Schedule of Study Assessments 
 
 
Treatment Session 1 
Treatment Session 2 
Activity 
Screening 
(Day -21 to -
1) 
Day 1 (a) 
Wk 4 (c) 
(± 3 days) 
Wk 8 (c) 
(± 3 days) 
Wk 13 (d) 
(± 2 wks) 
Wk 14 (b) 
(± 1 day) 
Wk 17 
(c) 
(± 5 
days) 
Wk 21 
(b) 
(± 5 
days) 
Wk 26 
(d) 
(± 2 wks) 
Patient Global Impression of Change (PGI-C) 
(k) 
 
 
X 
X 
X 
 
X 
 
X 
Drooling Impact Score (DIS) by Subject 
 
X 
X 
X 
X 
 
X 
 
X 
DFSS-I (j) 
X 
X 
X 
X 
X 
 
X 
 
X 
DFSS by Subject (DFSS-S) (l) 
 
X 
X 
X 
X 
 
X 
 
X 
Review of Common Classes of Anticholinergic& 
Antihistamine Medications 
X 
 
 
 
 
 
 
 
 
Study Drug Injection (m) 
 
X (1st) (n) 
 
 
X (2nd) 
 
 
 
X (3rd) 
Telephone Follow-up  
 
 
 
 
 
X (o) 
 
X 
 
Abbreviations:AE = adverse event, BP = blood pressure, C-SSRS = Columbia Suicide Severity Rating Scale, DFSS = Drooling Frequency and Severity Scale, HIPAA 
=Health Insurance Portability and Accountability Act,RR = respiration rate, Temp = temperature, USFR = unstimulated salivary flow rate, VAS = visual analog scale, wks = 
weeks 
(a) All screening and baseline assessments and results must be available before injection of MYOBLOC. 
(b) Telephone follow-up. 
(c) Office visit. 
(d) Office visit.  Serves as last visit of current treatment session and first visit of subsequent treatment session.  Study drug injection will occur after the 13-week assessments 
have been completed for the prior treatment session. 
(e) Must be obtained before conducting any study procedure. 
(f) Includes baseline history of aspiration, aspiration pneumonia, choking, and dysphagia. 
(g) Includes 4 bite-wing radiographs or panoramic imaging (if edentulous or if bite-wing x-rays are difficult due to limited teeth).If the subject has no teeth, then the dentist 
will determine if panoramic imaging is required at any visit after screening. 
(h) Females of childbearing potential only. 
(i) Forced vital capacity will be measured in all subjects with amyotrophic lateral sclerosis and in other subjects if warranted at the discretion of the Investigator. 
(j) When possible, assessments should be done by the same person in a given subject to ensure consistency throughout the study. 
(k) Global measure of effectiveness must be completed before USFR. 
(l) Subject-rated via entry in diary (not during study visit), daily for first 2 weeks after study drug injection and then weekly for remainder of treatment session. 
(m) Subjects will receive injections guided by external anatomical landmarks or by external anatomical landmarks with ultrasound-guided confirmation.  Sites designated 
as “ultrasound” sites will perform all their injections with ultrasound-guidance. 
(n) Subjects will be injected after completion of all assessments and then will be contacted by telephone 24 hours (±1 day) post-injection to inquire about their health status 
and remind the subject to complete their diary. 
(o) Telephone follow-up by the study staff will be conducted 1 week (±1 day) after study drug injection to assess how the subject feels, document adverse events as 
appropriate, document any new medications the subject may be taking, and remind the subject to complete their diary. 
 
 
 
 
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Table B 
Schedule of Study Assessments 
Treatment Session 3 (Optional)* 
Treatment Session 4 (Optional)* 
Activity 
Wk 
27 
(± 1 day) 
Wk 30 (a) 
(± 5 days) 
Wk 34 (b) 
(± 5 days) 
Wk 39 (c) 
(± 2 wks) 
Wk 
40 
(± 1 day) 
Wk 43 (a) 
(± 
5 
days) 
Wk 47 (b) 
(± 5 days) 
Wk 52 (a) 
(± 2 wks) 
Early 
Discontinuati
on 
Complete Physical Examination 
X 
X 
X 
Brief Physical Examination 
X 
X 
Weight 
X 
X 
X 
X 
X 
Neurologic Examination 
As 
needed 
As 
needed 
As 
needed 
X 
X 
Dental Exam by Licensed Dentist (DDS, DMB) 
As 
needed 
As 
needed 
As 
needed 
X (d) 
X (d) 
Oral Examination by Investigator 
X 
X 
X 
Clinical Laboratory Tests (hematology, full 
chemistry panel including glucose and alkaline 
phosphatase, urinalysis) (fasting) 
As 
needed 
As 
needed 
As 
needed 
X 
X 
Urine Pregnancy Test (e) 
As 
needed 
As 
needed 
As 
needed 
X 
X 
Vital Signs (sitting BP and pulse after 5 minutes 
rest, RR, Temp) 
X 
X 
X 
X 
X 
Forced Vital Capacity 
As 
needed 
As 
needed 
As 
needed 
As needed 
As needed 
Adverse Events Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X (f) 
C-SSRS Since Last Visit Version 
X 
X 
X 
X 
X 
Concomitant Medications Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Review 
X 
X 
X 
X 
X 
Salivary Flow Rate Collection (USFR) (g) 
X 
X 
X 
X 
X 
Clinical Global Impression-Severity (CGI-S) (g) 
(h) 
X 
X 
X 
X 
X 
Clinical Global Impression-Change (CGI-C) (g) 
(h) 
X 
X 
X 
X 
X 
Patient Global Impression of Severity (PGI-S) 
(h) 
X 
X 
X 
X 
X 
Patient Global Impression of Change (PGI-C) 
(h) 
X 
X 
X 
X 
X 
Drooling Impact Score by (DIS) Subject 
X 
X 
X 
X 
X 
DFSS-I (g) 
X 
X 
X 
X 
X 
DFSS by Subject (DFSS-S) (i) 
X 
X 
X 
X 
X 
Study Drug Injection (j) 
X (4th) 
Telephone Follow-up 
X (k) 
X 
X (k) 
X 
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Table 2. 
Schedule of Study Assessments 
 
Treatment Session 3 (Optional)* 
Treatment Session 4 (Optional)* 
 
Activity 
Wk 
27 
(± 1 day) 
Wk 30 (a) 
(± 5 days) 
Wk 34 (b) 
(± 5 days) 
Wk 39 (c) 
(± 2 wks) 
Wk 
40 
(± 1 day) 
Wk 43 (a) 
(± 
5 
days) 
Wk 47 (b) 
(± 5 days) 
Wk 52 (a) 
(± 2 wks) 
Early  
Discontinuati
on 
Abbreviations:AE = adverse event, BP = blood pressure,C-SSRS = Columbia Suicide Severity Rating Scale, DFSS = Drooling Frequency and Severity Scale, 
RR = respiration rate, Temp = temperature, USFR = unstimulated salivary flow rate, wks = weeks 
* Treatment Sessions 3 and 4 are designated as likely, but may not be necessary as the study progresses because the study may be stopped early once enough subjects 
have completed the study to meet FDA safety database requirements.  Any subject that enters the study, however, is required to participate through at least 6 months 
(i.e., complete Treatment Sessions 1 and 2). 
(a) Office visit. 
(b) Telephone follow-up. 
(c) Office visit.  Serves as last visit of current treatment session and first visit of subsequent treatment session.  Study drug injection will occur after the 13-week assessments 
have been completed for the prior treatment session. 
(d) Includes 4 bite-wing radiographs or panoramic imaging (if edentulous or if bite-wing x-rays are difficult due to limited teeth).If the subject has no teeth, then the dentist 
will determine if panoramic imaging is required at any visit after screening. 
(e) Females of childbearing potential only. 
(f) Subjects who discontinue because of an AE before completion of the study will be called 13 weeks ± 3 days after his/her last injection to determine if the AE has 
resolved. 
 
(g) When possible, assessments should be done by the same person in a given subject to ensure consistency throughout the study. 
(h) Global measure of effectiveness must be completed before USFR. 
(i) Subject-rated via entry in diary (not during study visit), daily for first 2 weeks after study drug injection and then weekly for remainder of treatment session. 
(j) Subjects will receive injections guided by external anatomical landmarks or by external anatomical landmarks with ultrasound-guided confirmation. Sites designated as 
“ultrasound” sites will perform all their injections with ultrasound-guidance.   
(k) Telephone follow-up by the study staff will be conducted 1 week (±1 day) after study drug injection to assess how the subject feels, document adverse events as 
appropriate, document any new medications the subject may be taking, and remind the subject to complete their diary. 
 
 
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2.4 
Randomization 
2.4.1 Treatment randomization 
This is an open-label study with a single arm, and all eligible subjects will receive the same 
dose of 3,500 Units of MYOBLOC.  No treatment randomization is necessary.   
2.4.2   Injection Technique Assignment  
Injections will be guided by external anatomical landmarks or by external anatomical 
landmarks with ultrasound-guided confirmation.  Sites designated as “ultrasound” sites will 
perform all their injections using external anatomical landmarks with ultrasound-guided 
confirmation.   
2.5 
Sample Size Estimation 
No sample size estimation is performed for this open-label study.  The study plans to enroll 
a total of 120 to 200 subjects. The sample size, 187 subjects is based on the requirements 
of the final safety database for approval. 
2.6 
Efficacy and Safety Measurements 
In this study, efficacy will be assessed, using USFR, CGI (severity and change), DIS, 
DFSS-I, DFSS-S, PGI (severity and change).  DFSS-S will be collected through subject’s 
diaries. 
 
Safety will be assessed through subject early terminations, adverse events, adverse 
events of special interest (including aspiration, aspiration pneumonia, and choking, 
dysphagia), dental and  oral examination (dental adverse events), physical examination, 
neurological examination, vital signs, lung functioning assessment, pregnancy test, clinical 
laboratory evaluations (hematology, chemistry, urinalysis), and concomitant medications 
as well as Columbia Suicide Severity Rating Scale (C-SSRS).   
2.6.1 Effectiveness measures 
Several effectiveness measures are assessed over each of the treatment Sessions 1 
through 4 at the injection visit (i.e., Day 1, and Weeks 13, 26, and 39), 4 weeks post-
injection (i.e., Weeks 4, 17, 30, and 43), 8 weeks post-injection (i.e., Week 8, first 
treatment session only), and 13 weeks post-injection (i.e., Weeks 13, 26, 39, and 52).   
Where applicable, the measurement value obtained at pre-injection of each treatment 
session (i.e., Day 1 and Weeks 13, 26, and 39 for each of the 4 treatment sessions, 
respectively) is defined as the baseline of the corresponding measures.  For the CGI-C 
and PGI-C, the corresponding severity score observed at pre-injection of each treatment 
session will be used as the baseline measurement of the corresponding session in 
analysis. 
 
Unstimulated Salivary Flow Rate (USFR) 
 
The USFR (g/minute) is the salivary flow rate assessed by the independent assessor in 
an unstimulated state (i.e., at least 1 hour postprandial) at screening, just before the first 
injection of study drug (Day 1) to establish a baseline salivary flow rate, and at each 
subsequent study visit (Appendix B of the protocol).  To determine USFR at each study 
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visit, saliva will be collected over a 5-minute collection period using weighing cups 
hey will be asked to expectorate, as 
needed, any saliva that accumulates in their mouth into the pre-weighed cup during the 
5-minute collection period.
  Although not a 
rating scale, the same person should conduct this assessment throughout the study to 
minimize collection technique bias.  
Clinical Global Impression of Severity (CGI-S) and Change (CGI-C) 
The CGI-S scale is used to record the severity of illness (sialorrhea) on Day 1 (i.e., study 
baseline) before the first injection of study drug, at each subsequent study visit or, if 
applicable, at discontinuation from the study. CGI-S will be assessed by a trained assessor 
on a 7-point scale ranging from “normal” to “among the most extremely ill patients” 
(Appendix C of the protocol). The CGI-C, used to record change or improvement in illness 
from baseline (i.e., pre-injection) of each treatment session, will be assessed at each study 
visit after Day 1 by the assessor on a 7-point scale ranging from “very much improved” to 
“very much worse” (Appendix C of the protocol). Both CGI scales will be completed 
independent of the subject’s self-assessment (PGI-S and PGI-C) so neither party knows 
how the other has rated the scales. 
Patient Global Impression of Severity (PGI-S) and Change (PGI-C) 
The PGI-S scale will be used by the subject to rate the severity of his/her illness 
(sialorrhea) on Day 1 (i.e., study baseline) before the first injection of study drug, at each 
subsequent study visit, or, if applicable, at discontinuation from the study. PGI-S will be 
assessed on a 8-point scale ranging from “normal” to “among the most extremely ill” 
(Appendix D of the protocol). The PGI-C will be used by the subject to rate his/her 
impression of change in symptoms (drooling or sialorrhea) from Day 1 (i.e., study baseline) 
or just before subject’s most recent injection of study drug to the time of assessment at 
each study visit. The PGI-C is assessed on a 7-point scale ranging from “very much 
improved” to “very much worse” (Appendix D of the protocol). Both PGI scales need to be 
completed independent of the assessor who completes the CGI scales so neither party 
knows how the other has rated the scales. 
Drooling Frequency and Severity Scale (DFSS) 
The DFSS is a 2-item scale used to assess the frequency and severity of drooling.  The 
DFSS will have two forms in this study, with one being performed by an independent 
assessor (DFSS-I) and the other by the subject (DFSS-S).  In both forms, drooling severity 
is assessed on a 5-point scale ranging from 1 (dry, never drools) to 5 (profuse, clothing, 
hands, tray, objects become wet), whereas drooling frequency is assessed on a 4-point 
scale ranging from 1 (never drools) to 4 (constantly drools) (Appendix E of the protocol).  
The total score ranges from 2 to 9 in each DFSS form.   The assessor’s initial assessment 
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of DFSS on Day 1 of Treatment Session 1 should be based on the prior 4 weeks, whereas 
the subsequent assessments of DFSS should be based on the timeframe since the prior 
study visit.  The independent assessor should not review the subject-rated scales before 
performing his/her own assessment. 
 
DFSS-S is collected via subject’s diary in this study on a daily basis for the first 2 weeks 
of each treatment session and then weekly for the remainder of the treatment session.  
 
Drooling Impact Score (DIS) 
 
The DIS is a 10-item questionnaire with each item rated by the subject to evaluate the 
impact of the disorder (sialorrhea) on daily activities (e.g., speech, social activities).  For 
each question, the subject is requested to compare their current status to their last study 
visit using a 4-point scale ranging from 1 (not at all) to 4 (very much) (Appendix F of the 
protocol).  The DIS total score ranges from 10 to 40.  The initial assessment of DIS on 
Day 1 of Treatment Session 1 before the first injection of study drug should be based on 
the prior 4 weeks, whereas the subsequent assessments should be based on the 
timeframe since the prior study visit.
 
 
2.6.2 Safety measures 
Adverse events are recorded at each study visit, starting from the first injection of 
MYOBLOC on Day 1 of Treatment Session 1 and ending at study completion (i.e., 52 ± 
1 week). Subjects who discontinue because of an adverse event before study completion 
will be contacted 13 weeks (±3 days) after their last injection of study drug to assess the 
adverse event.  Serious adverse events, adverse events of special interest, and other 
immediately reportable adverse events were collected during the study period (or within 
13 weeks ±3 days of last study drug injection for subjects discontinuing participation 
prematurely).  Dental and oral health are followed closely throughout the course of the 
study by monitoring dental adverse events (DAE), as defined in the study protocol.  
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) are measured after 
sitting quietly for at least 5 minutes at screening and each study visit, if applicable, at early 
termination from the study. 
 
Subjects’ suicidal ideation and behavior are measured at each study visit (including Day 
1 and Weeks 4, 8, 13, 17, 26, 30, 39, 43, and 52) or, if applicable, early termination from 
the study, using the Columbia Suicidal Severity Rating Scale (C-SSRS).  The C-SSRS 
baseline version (Appendix I of the protocol) will be used for Day 1, whereas the C-
SSRS since last visit version (Appendix J of the protocol) will be used for all of the other 
visits.  The C-SSRS has three subscales: suicidal ideation (Categories 1-5), suicidal 
behavior (Categories 6-10), and intensity of suicidal ideation.  Both suicidal ideation 
subscale and suicidal behavior subscale have 5 yes-no categories each, with a sum 
score ranging from 0 to 5 and higher score indicating greater severity. 
 
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
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Category 6 – Actual Attempt  
Category 7 – Interrupted Attempt  
Category 8 – Aborted Attempt 
Category 9 – Preparatory Acts or Behavior 
Category 10 – Suicidal Behavior 
 
The intensity of suicidal ideation has 5 items (2 are scored from 1 through 5 and the other 
three from 0 to 5), with a sum score ranging from 2 to 25 where higher score indicate 
greater risk. 
For the analysis, an intensity of suicidal ideation will be defined as the maximum suicidal 
ideation category (1-5 on the C-SSRS) present at the assessment. A score of 0 will be 
assigned if no ideation is present. 
 
Clinical laboratory tests are conducted at screening, Weeks 13, 26, as needed at the 
Investigator’s discretion throughout the study and at study completion (i.e., Week 52) or, 
if applicable, at early termination from the study. Laboratory tests are analyzed by a central 
laboratory and include the following parameters: 
 
Serum Chemistry: 
 
cholesterol, phosphorus, sodium (Na+), potassium (K+), calcium (Ca), urea nitrogen 
(BUN), creatinine, albumin, total protein, aspartate transaminase (AST), alanine 
transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), 
uric acid, total bilirubin, glucose, and lactate dehydrogenase (LDH). 
 
Hematology: 
 
hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, MCV, MCH, MCHC, 
white blood cell (WBC) count, WBC differentials (%), including bands, neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils   
 
Urinalysis: 
 
specific gravity, pH, glucose, blood, protein, color, nitrites, ketones, bilirubin, urobilinogen, 
and leukocyte esterase. 
 
 
A complete physical examination is performed at screening, Weeks 4, 13, 26, 39, and at 
study completion (i.e., Week 52) or, if applicable, at early termination from the study.  The 
complete examination will involve gross examination of general appearance; head, ears, 
eyes, nose and throat; skin; extremities; chest; abdomen; and lymph nodes. Cardiac and 
pulmonary auscultation and measurement of vital signs and weight will also be conducted 
as part of the complete physical exam.  A brief physical examination, consisting of cardiac 
and pulmonary auscultation is performed on Day 1 prior to injection of study drug and at 
Weeks 8, 17, 30, and 43.  Height will be recorded at screening only. Lung functioning is 
measured for subjects with ALS, using forced vital capacity (liter) (FVC), and in other 
subjects if warranted, at the discretion of the Investigator at screening, before the first 
injection of study drug on Day 1, at Weeks 4, 8 (as clinically warranted), and 13. 
Thereafter, FVC will be checked if warranted at Investigators’ discretion (such as if the 
subject has ALS). If any of the Physical Exam findings were abnormal and clinically 
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significant prior to treatment, the event was recorded as medical history, while if occurred 
after treatment they event was recorded as an Adverse Event. 
 
A neurologic exam is performed at screening, on Day 1 prior to injection of study drug, at 
Week 13, as needed at the Investigator’s discretion throughout the study, and at study 
completion (i.e., Week 52) or if applicable, at early termination from the study.  The 
neurologic exam consists of 9 sections to evaluate:  1) level of consciousness; 2) speech; 
3) cranial nerves; 4) motor; 5) sensory; 6) coordination; 7) gait; 8) reflexes; and 
9) Romberg test (Appendix G of the protocol). 
 
 
 
 
   
 
A dental exam is performed by a licensed dentist (DDS or DMD) at screening, at Weeks 
4, 13, 26, as needed at the Investigator’s discretion throughout the study and at study 
completion (i.e., Week 52) or, if applicable, at early termination from the study.  
 
 
 
 
 
  
Findings of dental exam that meet the DAE criteria as defined in the protocol will be 
reported as such.  Subjects or their caregiver will also complete a dental questionnaire at 
screening. 
 
An oral exam (Appendix H of protocol) is performed by the Investigator at each study visit 
where a dental exam is not planned by protocol.  
 
 
 
 
  Findings of the oral exam that meet the DAE criteria as defined in the protocol will 
be reported as such. 
 
A urine pregnancy test is performed on all females of child-bearing potential at screening, 
on Day 1 (before the first injection of the study drug), as needed at the Investigator’s 
discretion throughout the study, and at study completion (i.e., Week 52) or, if applicable, 
at early termination from the study.   
2.6.3 Other measures  
Prior treatment for sialorrhea and concomitant medications (including those taken within 
30 days before screening) taken over the course of the study will be recorded. 
 
The medical history with disease history, co-morbidities, relevant past illness, and surgical 
procedures performed within the prior 6 months are recorded at screening.  Subjects are 
also evaluated for presence or prior history of aspiration, aspiration pneumonia, choking, 
and/or dysphagia. 
2.7 
Drug Concentration and PK Measurements 
No drug concentration measures will be taken in this trial. 
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2.8 
Handling of Missing, Incomplete, and Repeat Data 
 
  
Missing Data of Effectiveness Measures 
 
Missing post-injection measurements will not be imputed, whereas missing 
measurements at the pre-injection of each treatment session will be imputed by the site-
specific average of those subjects who receive the treatment at the corresponding 
treatment session.  
 
Missing Data of Safety Parameters 
 
For safety parameters, missing or invalid data will be treated as missing for the 
corresponding assessment, except that for partial start dates of adverse events, missing 
day and month will be imputed to the date of first injection.  Completely unknown start 
dates will be imputed to date of first injection.  If day is missing and month and year are 
present then day is either set to the 1st of the month or the day of the month for the first 
injection. 
   
 
Handling of Repeated Data Records 
 
All data records with valid data of efficacy and safety measures are identified for initial and 
repeat within each study visit and/or assessment time point.  Should repeated data records 
exist within a study visit and/or assessment time point, the initial data record will be utilized 
for any statistical analyses of the corresponding study visit and/or assessment time point.  
All existing data records including the repeat data records in the study database will be 
presented in data listings and CRF data tabulations. 
 
Any resultant incomplete or missing data of either efficacy or safety parameters will be 
treated as missing in the statistical analyses involving these parameters. 
2.9 
Statistical Methods 
Unless specified otherwise, SAS Version 9.4 or higher will be utilized to perform the 
statistical analyses of efficacy and safety measures. 
 
Per the protocol, subjects who met all eligibility criteria were to receive single dose 
injections of 3,500 Units of MYOBLOC every 13 weeks (±2 weeks) over a maximum 
possible duration of 1 year,  for up to a total of 4 treatments via injections into the 
submandibular and parotid glands. Repeat injections at each treatment session were to 
be done when subjects returned to baseline status as determined by the Investigator, with 
a minimum interval of 11 weeks from the prior injection. If after the first treatment of 3,500 
Units the subject developed intolerable side effects, but still wished to remain in the study, 
the Investigator had the discretion to decrease subsequent doses, but 
to no less than a total dose of 2,500 Units. Since the majority of subjects received 3500 
Units, all statistical tables will present results under one treatment group labeled “Any 
Dose”. 
 
Additionally, 
listings 
will 
be 
categorized 
as 
L = low dose (1500-
2000 U); M = medium dose (2500-3000 U); H = high dose (3500 U). 
 
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Categorical variables will be summarized in general using frequencies and percentages, 
whereas continuous variables will be summarized in general using descriptive statistics of 
number of observations (n), mean, standard deviation (SD), minimum (Min), median, and 
maximum (Max).   
 
In both data listings and CRF domain data tabulations, subject ID will consist of site 
number plus the assigned subject number.  
 
Hypothesis testing, unless otherwise indicated, will be performed at the 5% significance 
level.  All p-values will be rounded to four decimal places; p-values less than 0.001 will be 
presented as '0.001' in all tables. All confidence intervals will be two-sided with 95% 
coverage.  
2.9.1 Effectiveness analysis 
As subjects receive multiple single-dose injections, each single-dose injection plus its 
follow-up period will be considered as a treatment session.   
 
Effectiveness measures obtained over each of the treatment sessions include USFR, 
CGI-S, CGI-C, DFSS-I, DFSS-S, PGI-S, PGI-C, and DIS at the injection visit (i.e., Day 1, 
except for CGI-C and PGI-C, and Weeks 13, 26, and 39), 4 weeks post-injection 
(i.e., Weeks 4, 17, 30, and 43), 8 weeks post-injection (i.e., Week 8, first treatment 
session only), and 13 weeks post-injection (i.e., Weeks 13, 26, 39, and 52).  The injection 
visit of Day 1 and Weeks 13, 26, and 39 is considered the baseline (or pre-injection), 
respectively, for each of the consecutive treatment sessions 1 through 4.  
  
For each treatment session, effectiveness analysis of the treatment response will be 
performed on USFR change from pre-injection, DFSS-I change from pre-injection, and 
DFSS-S change from pre-injection, CGI-S, CGI-C, PGI-S, PGI-C, and DIS change from 
pre-injection, at each of the post-injection time points using a t-test. 
 
In addition, the proportion of treatment responders will be reported for the CGI-C and PGI-
C at both pre-injection and post-injection time points over each treatment session.  Before 
the analysis, the CGI-C and PGI-C will be dichotomized into 2 categories, with “very much 
improved” and “much improved” into 1 category and the remaining levels in the other 
category. 
2.9.2 Safety analysis 
Safety measures include adverse events, adverse events of special interest (AESI), dental 
adverse events (DAE), adverse events associated with distant spread of toxin effect, vital 
signs and weight, physical exam, neurological exam, dental exam, oral exam, and clinical 
laboratory tests, as well as lung functioning test for ALS subjects.  Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) adverse event 
dictionary. 
 
Like for effectiveness analyses, the baseline for safety analysis includes the pre-injection 
visits of Day 1, and Weeks 13, 26, and 39, respectively, for each of the treatment sessions 
1 through 4. 
 
 
Drug Exposure 
 
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Frequency of drug exposure will be calculated based on the number of injections of study 
drug administrated.  Duration of drug exposure will be calculated for each subject for the 
average duration of individual treatment sessions and total duration of treatment sessions, 
with the former being the average of the durations of individual treatment sessions the 
subject has received and the latter being the sum of the durations of individual treatment 
sessions the subject has received.  Duration of drug exposure will be summarized for the 
safety population as defined in Section 3.1.     
 
Early Termination 
 
Subjects’ study disposition will be summarized.  A listing will be provided for all early 
terminations.  This listing will include a subject’s demographic variables, primary 
diagnosis, number of injections administrated, and the primary reason for early 
termination.     
 
Adverse Events, AESI, and DAE 
 
All of adverse events will be coded for preferred terminologies using MedDRA.    An AE 
that occurs on the 1st injection date or later will be defined as a TEAE.  An AE with start 
date missing and no valid stop date or stop date being after the first injection date will be 
considered as a TEAE.  TEAEs will be further separated by treatment session. 
 
TEAEs, AESIs, DAEs, and adverse events associated with distant spread of toxin effect 
will be analyzed by session.  Frequency of these types of adverse events will be calculated 
for each body system (or system organ class, SOC), by preferred term, for number of 
subjects and proportion reporting the event.  The severity of adverse events and the 
relationship to study medication will be summarized for each body system and preferred 
term.   
 
Withdrawals due to adverse events will be summarized for each body system and 
preferred term.  Serious adverse events (SAEs) (including deaths) will be listed for 
individual events.  
  
Narratives will be provided for all deaths, non-fatal serious adverse events, and subjects 
withdrawn due to adverse events. 
 
Vital Signs and Weight 
 
Vital signs and weight will be summarized descriptively by treatment session at pre-
injection (i.e., Day 1 and Weeks 13, 26, and 39) and at each post-injection time point of 
4 weeks post-injection (i.e., Weeks 4, 17, 30, and 43), 8 weeks post-injection (i.e., Week 8 
first treatment session only), and 13 weeks post-injection (i.e., Weeks 13, 26, 39, and 52).  
The change scores in vital signs and weight from baseline at 4 weeks, 8 weeks (first 
treatment session only), and 13 weeks post-injection will be summarized descriptively. 
 
Neurologic Exam 
 
Abnormal findings of neurological exam data will be listed, respectively, for individual 
subjects.     
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Lung Functioning Test 
 
Findings of forced vital capacity (FVC) data will be listed, respectively, for individual 
subjects.    
 
Physical Examination 
 
A complete Physical Examination was performed at Screening, Week 4, Week 13, Week 
26, Week 39, Week 52, and Early Discontinuation. A brief Physical Examination was 
performed at Day 1, Week 8, Week 17, Week 30, and Week 43 when body weight, height 
and body mass index (BMI) were recorded. If any of the Physical Examination findings 
were abnormal and clinically significant prior to treatment, the event was recorded as 
medical history, while if occurred after treatment the event was recorded as a TEAE.   
 
Suicidality Assessment 
 
For each treatment session, each of the three C-SSRS subscales (suicidal ideation, 
suicidal behavior, and intensity of suicidal ideation) will be summarized descriptively for 
continuous variable at each pre-injection visit (i.e., Day 1 and Weeks 13, 26, and 39) and 
at each post-injection time point of 4 weeks post-injection (i.e., Weeks 4, 17, 30, and 43), 
8 weeks post-injection (i.e., Week 8, first treatment session only), and 13 weeks post-
injection (i.e., Weeks 13, 26, 39, and 52).  The change scores in C-SSRS subscales from 
pre-injection at 4 weeks, 8 weeks (first treatment session only), and 13 weeks post-
injection will be summarized descriptively. 
 
Dental Examination and Oral Examination 
 
Abnormal findings of dental exam and oral exam will be listed, respectively, for individual 
subjects.  Dental adverse events will be included in the analysis of adverse events. 
 
Laboratory Assessments 
 
For each treatment session, clinical laboratory tests of hematology, chemistry, and 
urinalysis (specific gravity and pH) will be summarized descriptively at available visits.  
Qualitative analysis of laboratory tests in terms of abnormality will be performed, using the 
shift-table method, for individual post-screening visits. Abnormal findings of clinical 
laboratory tests for individual subjects will be provided by data listing.   
 
Pregnancy Test 
 
Any positive findings of the pregnancy test will be listed for individual subjects. 
2.9.3 Other analysis 
 
Concomitant medications were grouped into those taken pre-enrollment and those taken 
post-enrollment, based upon the starting date of both the concomitant medication and 
the enrollment date. Number and percent of subjects who take concomitant medications 
were reported for each Treatment Session.  Concomitant medications will be listed, 
respectively, for individual subjects.  
  
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2.10 Interim Analysis 
No interim analysis is planned. 
3 
STUDY POPULATION 
3.1 
Definition of Subject Populations 
All subjects who return to the clinic on Day 1 (i.e., study baseline) and have all required 
baseline (before injection of study medication) assessments/procedures completed will be 
considered study participants.  Study populations are defined in the following sections to 
assess the safety and effectiveness of MYOBLOC.  
 
Safety Population 
The safety population is defined as all subjects who are injected with at least one dose of 
study medication.  The safety population will be utilized for safety analyses. The safety 
population will be identified and finalized before database is locked. 
Intention-to-treat Population 
The intention-to-treat (ITT) population is defined as all subjects who are injected with study 
medication and have at least 1 post-baseline measurement recorded in the eCRF for both 
USFR and CGI-C. The ITT population will be used as the primary population for 
effectiveness analyses.  The treatment group identification of a subject in the ITT 
population will follow those of the safety population.  
3.2 
Screening and Enrollment 
 
 An enrollment summary including the 
number of subjects enrolled (i.e., study participants), treated (i.e., safety population), 
efficacy evaluable (i.e., ITT population), and completed the study will be presented by site.  
Study participants include all individuals who have all required baseline (before injection 
of study medication) assessments/procedures completed at Day 1 visit.  The number of 
subjects who received treatment doses will be summarized by session for safety 
population and for ITT population. 
3.3 
Population Demography 
For the safety and ITT populations, descriptive summaries of demography will be 
presented.   
 
Demography includes age in years (continuous and categorical 18 to 49, 50 to 64, 65 to 
74, and 75+), sex, race, ethnicity, weight, and height.  Demography will also be listed for 
all subjects enrolled. 
3.4 
Disease Diagnosis and Prior Therapy 
For the safety population, descriptive summaries will be presented for disease diagnosis 
and use of prior therapy and for severity of troublesome sialorrhea at baseline. The 
protocol indicated summarizing severity of troublesome sialorrhea at baseline. These were 
summarized using disease severity at baseline as measured by USFR, DFSS-I, DFSS-S, 
CGI-C, PGI-S and DIS. 
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Disease diagnosis, USFR, DFSS-I, DFSS-S, CGI-S, PGI-S, and DIS score at baseline 
(i.e., Day 1), and use of prior therapy will be listed for all subjects enrolled. 
 
The protocol indicated summarizing Disease Diagnosis and Prior Therapy, Medical 
History and Disposition for the safety and ITT populations, however since the difference 
between these two populations was only one subject, these were only summarized for the 
safety population. 
3.5 
Medical History 
Medical history will be listed for the safety population.  
3.6 
Disposition of Study Participants 
Subject disposition including completion and discontinuation along with CRF-based 
termination reason will be summarized for all enrolled subjects.)  Subjects’ early 
termination details will be listed for all subjects enrolled. 
  
Subjects’ treatment sequence and dose, and treatment date and time will be listed for all 
subjects treated. 
3.7 
Protocol Deviations and Violations 
A summary of protocol deviation and violations will be provided.  Subjects who are treated 
in the study, but not included in the ITT population will be listed. 
4 
EFFICACY EVALUATION 
4.1 
Datasets Analyzed 
The ITT population is defined as the population for effectiveness analysis.   
4.2 
Treatment Compliance 
For this study, the overall compliance rate will be summarized by demographic parameters 
for the safety population.  For a treatment session, the compliance rate, expressed as 
percent, is calculated by dividing the number of drug injections into the 4 locations of the 
submandibular and parotid glands by the total number of 4 injections that should have 
been given during a treatment session multiplied by 100. For a subject, the overall 
compliance rate is defined as the average of compliance rates for all treatment sessions. 
4.3 
Baseline Measures 
Descriptive statistics of the USFR, DFSS-I, DFSS-S, CGI-S, PGI-S, and DIS at baseline 
(or pre-injection) will be summarized within their corresponding tables indicated in the 
sections below.  
4.4 
Efficacy Results and Tabulations 
Descriptive and inferential statistics of USFR (g/minute) and changes from pre-injection at 
Day 1 to Weeks 4, 8 and 13, for Treatment Session 1 and from each subsequent pre-
injection at Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks 
following it respectively, will be presented for the ITT population.   
 
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Descriptive and inferential statistics of DFSS-I and changes from pre-injection at Day 1 to 
Weeks 4, 8, and 13, for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.  
  
Descriptive and inferential statistics of DFSS-S and changes from pre-injection at Day 1 
to Weeks 4, 8, and 13, for Treatment Session 1 and from each subsequent pre-injection 
at Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.   
 
Descriptive and inferential statistics of CGI-S and changes from pre-injection at Day 1 to 
Weeks 4, 8, and 13, for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.   
 
Descriptive and inferential statistics of CGI-C at pre-injection (except for Day 1), and at 
Weeks 4, 8, and 13 for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.   
 
Descriptive and inferential statistics of the proportion of the CGI-C treatment responders 
with much improved or better at pre-injection (except for Day 1) and at Week 4, 8, 13 
weeks post injection for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population. 
 
Descriptive and inferential statistics of PGI-S and changes from pre-injection at Day 1 to 
Weeks 4, 8, and 13, for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.   
 
Descriptive and inferential statistics of PGI-C at pre-injection (except for Day 1), and at 
Weeks 4, 8, and 13 for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.   
 
Descriptive and inferential statistics of the proportion of the PGI-C treatment responders 
with much improved or better at pre-injection (except for Day 1) and at Week 4, 8, 13 
weeks post injection for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population. 
 
Descriptive and inferential statistics of DIS and changes from pre-injection at Day 1 to 
Weeks 4, 8, and 13 for Treatment Session 1 and from each subsequent pre-injection at 
Weeks 13, 26 and 39 (Treatment Session 2, 3 and 4) to 4 and 13 weeks following it, 
respectively, will be presented for the ITT population.   
5 
SAFETY EVALUATION 
For safety evaluation, the safety population as defined in Section 3.1 will be utilized to 
conduct safety analyses.  
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5.1 
Extent of Drug Exposure 
Number of MYOBLOC dose injections will be tabulated as continuous variable as well as 
categorical variable, using the categories of 1 injection, 2 injections, 3 injections, and 4 
injections. 
  
Average duration and total duration of treatment sessions, following dose injection, will be 
also tabulated. 
 
Individual subjects’ number of treatment sessions and duration of treatment session will 
be listed for the safety population . 
5.2 
Early Termination 
Early termination from study will be categorically summarized  by subject population.  
Subjects’ study termination details will be listed.   
5.3 
Adverse Events 
An overall summary of AEs reported in this study will be provided for each treatment 
session. 
 
Incidences of subjects reporting treatment-emergent AEs will be reported for each 
treatment session.   
 
The severity of the treatment-emergent AEs will be summarized for each treatment 
session. 
 
The relationship to study drug of the treatment-emergent AEs will be summarized for each 
treatment session. 
 
Treatment-emergent AEs associated with early terminations will be summarized for each 
treatment session. 
 
Serious AEs (including death) will be summarized for each treatment session. 
 
Narratives will be presented for all deaths, non-fatal serious adverse events and subjects 
withdrawn due to adverse events. 
 
Details of all TEAEs will be listed for each subject of the safety population in listings  
Details of AEs associated with early terminations will be listed for individual  subject.  SAEs 
including deaths will be listed for each event.     
 
5.4 
Adverse Events of Special Interest (AESI) 
Analyses of AESI will include aspiration, aspiration pneumonia, choking, and dysphagia.    
Incidences of subjects reporting AESI will be reported for each treatment session.  Details 
of AESIs will be listed for individual subjects will be listed.   
 
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5.5 
Adverse Events Associated with Dental Disease 
Incidences of subjects reporting adverse events associated with dental disease, per 
sponsor-provided list, will be reported for each treatment session.   
 
Table B – Listing of Dental Disease Terms used for Analysis  
Term 
Angular cheilitis 
Breath odour  
Bruxisism 
Candida infection 
Chapped lips 
Dental caries 
Dental leakage 
Dental necrosis 
Device failure 
Gingival bleeding 
Gingivitis 
Glossitis 
Glossodynia 
Haemoptysis 
Lip swelling 
Mouth cyst 
Mouth swelling 
Mucosal inflammation 
Mucosal ulceration 
Oral candidiasis 
Oral discomfort 
Oral pain 
Periodontitis 
Pulpitis dental 
Sensitivity of teeth 
Stomatitis 
Swollen tongue 
Tongue coated 
Tongue discolouration 
Tongue dry 
Tooth abscess 
Tooth fracture 
Tooth infection 
Tooth injury 
Tooth loss 
Toothache 
 
Details of AEs associated with dental disease will be listed for each subject. 
5.6 
Adverse Events Associated to Distant Spread of Toxin Effect 
Incidences of subjects reporting adverse events associated with distant spread of toxin 
effect per the Agency-provided list will be reported for each treatment session.   
 
Table C – Listing of Distant Spread of Toxin Effect Terms used for Analysis 
Term 
Accommodation disorder 
Areflexia 
Aspiration 
Botulism 
Bradycardia 
Bulbar palsy 
Constipation 
Cranial nerve palsies 
multiple 
Cranial nerve paralysis 
Diaphragmatic paralysis 
Diplopia 
Dry mouth 
Dysarthria 
Dysphagia 
Dysphonia 
Dyspnoea 
Extraocular muscle paresis 
Eyelid function disorder 
Eyelid ptosis 
Facial palsy 
Facial paresis 
Hemiparesis 
Hypoglossal nerve paresis 
Hyporeflexia 
Hypotonia 
IIIrd nerve paresis 
Ileus paralytic 
IVth nerve paresis 
Monoparesis 
Muscular weakness 
Paralysis 
Paralysis flaccid 
Paraparesis 
Paresis 
Paresis cranial nerve 
Peripheral nerve palsy 
Peripheral paralysis 
Pelvic floor muscle 
weakness 
Pneumonia aspiration 
Pupillary reflex impaired  
Quadriparesis 
Respiratory arrest 
Respiratory depression  
Respiratory failure 
Speech disorder 
Trigeminal nerve paresis 
Urinary retention 
Vision blurred 
Vocal cord paralysis 
Vocal cord paresis 
 
 
Details of adverse events associated with distant spread of toxin effect will be listed for 
each subject. 
5.7 
Vital Signs and Weight 
For the safety population, descriptive statistics of vital signs and weight will be presented 
at pre-injection and post-injection time points for pulse, systolic BP, diastolic BP, 
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temperature, and respiratory rate as well as body weight for Treatment Session 1, 
Treatment Session 2, Treatment Session 3 and for Treatment Session 4. 
5.8 
Neurologic Exam 
For the safety population, abnormal findings of neurological exam data will be listed, 
respectively, for individual subjects.   
5.9 
Lung Functioning Test 
For the safety population, findings of forced vital capacity (FVC) data will be listed, 
respectively, for individual subjects.   
5.10 Physical Examination 
Clinically abnormal findings from the physical examinations are either reported with the 
medical history if they occurred prior to 1st injection or as adverse events if findings are 
after first injection.   
5.11 Clinical Laboratory Evaluation 
For the safety population, descriptive statistics of clinical laboratory tests will be presented 
at screening and end of treatment session respectively, for hematology, chemistry, and 
urinalysis (specific gravity and pH) for Treatment Session 1, Treatment Session 2, 
Treatment Session 4 as well as End of Study. Qualitative findings in terms of abnormal 
low, normal, and abnormal high at screening and end of treatment session will be 
tabulated for hematology, chemistry, and urinalysis, respectively, for Treatment Session 
1, Treatment Session 2, Treatment Session 4 as well as End of Study. 
 
Any clinically significant abnormalities (based upon laboratory ranges) observed during 
the study will be listed for hematology, chemistry, and urinalysis, as well as pregnancy 
test. 
5.12 Suicidality Assessment 
For the safety population, descriptive and inferential statistics of C-SSRS will be presented 
at pre-injection and post-injection time points, for each of the three C-SSRS subscales 
(suicidal ideation, suicidal behavior, and intensity of suicidal ideation) for Treatment 
Session 1,  Treatment Session 2, Treatment Session 3, and for Treatment Session 4.  The 
change scores in C-SSRS subscales from pre-injection at 4 weeks, 8 weeks (first 
Treatment Session only), and 13 weeks post-injection were summarized descriptively. 
5.13 Dental and Oral Examinations 
Abnormal findings of dental and oral examination will be listed, respectively, for individual 
subjects.   
5.14 Concomitant Medication 
Concomitant medications were grouped into those taken pre-enrollment and those taken 
post-enrollment, based upon the starting date of both the concomitant medication and the 
enrollment date. Number and percent of subjects who take concomitant medications are 
reported for each Treatment Session.  Concomitant medications will be listed, 
respectively, for individual subjects. 
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6 
REFERENCE 
 
Study Protocol No. SN-SIAL-351 
 
 
 
 
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