Conditions: Temporomandibular Disorders (TMD)
Keywords: Temporomandibular Disorders TMD Temporomandibular Joint TMJ
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 126
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the efficacy and safety of rimegepant versus placebo in the acute treatment of Temporomandibular Disorders (TMD), which are medical conditions involving the temporomandibular joint (the joint connecting the jawbone to the skull) and surrounding muscles and tissues.

Detailed description:

Arms:
arm 1: One dose of rimegepant 75 mg ODT arm 2: One dose of matching placebo

Interventions: intervention 1: Rimegepant intervention 2: Placebo
Intervention descriptions: intervention 1: 75 mg ODT intervention 2: matching placebo

Protocol document:
Prot_000.pdf: 
Study BHV3000-317 Clinical Protocol, Version 3.0 
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Page 1 of 79 
 
 
 
 
 
DRUG: 
BHV-3000 (rimegepant) 
 
 
STUDY NUMBER(S): 
BHV3000-317 
 
 
PROTOCOL TITLE: 
A Phase 2/3, Double-Blind, Randomized, Placebo- 
Controlled, Safety and Efficacy Trial of BHV-3000 
(rimegepant) Orally Disintegrating Tablet (ODT) for 
the Acute Treatment of Temporomandibular 
Disorders (TMD) 
 
 
IND NUMBER: 
158955 
 
 
SPONSOR: 
Biohaven Pharmaceuticals Holding Company Limited 
 
 
ORIGINAL PROTOCOL DATE: 
09 December 2021 
 
 
VERSION NUMBER: 
Amended Protocol Version 3 
 
 
VERSION DATE: 
31 March 2022 


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SUMMARY OF CHANGES 
 
Version Number 
Brief Description Summary of Changes 
Date 
Version 1.0 – Original 
Not Applicable 
09 December 2021 
Version 2.0 – Amendment 1 To further clarify how a subject should choose which rescue 
medication to take, the following sentence has been added to 
the Study Design section in the synopsis and to Sections 
4.1.2.1 and 5.5: Subjects may administer whichever 
protocol permitted standard of care rescue medication they 
choose to reduce symptoms and that they have available. 
The following sentence was added to the same sections to 
clarify how a subject should choose which medication to 
take when they have non-qualifying TMD pain: Subjects 
may administer whichever protocol permitted standard of 
care medication they choose to reduce symptoms and that 
they have available. 
To provide guidance to women of childbearing potential 
who will administer a home pregnancy test, Table 1 
Schedule of Activities and Section 6.3.4.2 have been 
updated to include the following statement: Subjects will be 
provided with the accompanying package insert that contains 
instructions for use and interpretation of results. 
To ensure safety to subjects and ensure that subjects do not 
experience opioid withdrawal, Section 5.4, Number 10 was 
updated from “Use of narcotic medication, such as opioids 
(e.g., morphine, codeine, oxycodone and hydrocodone) is 
prohibited for at least 2 days prior to randomization” to “Use 
of narcotic medication, such as opioids (e.g., morphine, 
codeine, oxycodone and hydrocodone) is prohibited for at 
least 30 days prior to the Screening Visit and throughout the 
study”. 
To clarify that the eDiary will be recording the date and time 
subjects take study therapy and the eDiary is set up to follow 
study-specific specifications developed by the eDiary 
Vendor and the Sponsor, Section 4.1.2.1 was updated from 
“Subjects will record the date and time study therapy was 
taken in their eDiary” to “Subjects will record the date and 
time study therapy was taken in their eDiary according to the 
eDiary vendor’s specifications.” 
In Section 5.5, Cyclobenzaprine was removed from the list 
of allowable daily medication because cyclobenzaprine is 
allowed as a rescue medication and as a permitted 
medication to treat a non-qualifying TMD-associated pain 
(i.e., pain < 6 on a NRS[0-10] in the jaw and/or temple area 
on either side). 
09 February 2022 


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Version 3.0 – Amendment 2 Synopsis and Section 2.1 Primary Objective(s): The primary 
objective was changed from To evaluate the efficacy of 
rimegepant compared with placebo in the acute treatment of 
Temporomandibular Disorders on change from baseline of 
pain on NRS (0-10) score at 2 hours post-dose. To To 
evaluate the efficacy of rimegepant compared with placebo 
in the acute treatment of Temporomandibular Disorders on 
the time-weighted sum of pain intensity difference from 
baseline scores for the first 2 hours post-dose (SPID-2). 
Synopsis and Section 2.2 Secondary Objective(s): The 
secondary objectives were changed from: 
1. To evaluate rimegepant compared to placebo on ≥ 30% 
reduction from baseline of pain NRS (0-10) score at 2 
hours post-dose. (this objective was deleted) 
2. To evaluate rimegepant compared to placebo on ≥ 50% 
reduction from baseline of pain NRS (0-10) score at 2 
hours post-dose. (this objective was deleted) 
3. To evaluate rimegepant compared to placebo on the 
proportion of subjects that are pain free at 2 hours post- 
dose. 
4. To evaluate rimegepant compared to placebo on the 
probability of requiring rescue medication within 24 
hours of initial treatment. 
To 
1. To evaluate rimegepant compared with placebo on the 
time-weighted sum of pain intensity difference from 
baseline scores for the first 24 hours post-dose (SPID- 
24). (this objective was added 
2. To evaluate rimegepant compared to placebo on 
change from baseline of pain on NRS (0-10) score at 2 
hours post-dose.(this was the old primary objective. It 
was moved and is now a secondary objective) 
3. To evaluate rimegepant compared to placebo on the 
proportion of subjects that are pain free at 2 hours post- 
dose. 
4. To evaluate rimegepant compared to placebo on time 
to onset of meaningful pain relief post-dose. (this is a 
new secondary objective) 
5. To evaluate rimegepant compared to placebo on time 
to onset of initial pain relief post-dose. (this is a new 
secondary objective) 
31 March 2022 


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6. To evaluate rimegepant compared to placebo on the 
probability of requiring rescue medication within 24 
hours of initial treatment. 
Synopsis and Section 2.3 CCI 
: Two 
secondary objectives were moved to CCI 
 
 
The two are: 
CCI 
The remainder of theCCI 
 remained 
unchanged. 
Section 3.1 Primary Endpoint(s) was changed from: 
Change from baseline of pain will be assessed using the 
number of evaluable subjects that report TMD-associated 
pain level of ≥ 6 on NRS (0-10) at baseline and report pain 
level at 2 hours post-dose recorded in the eDiary. 
To: Difference in SPID-2 scores between treatment groups 
will be assessed across the first 2 hours post-dose using the 
number of randomized and treated subjects. 
Section 3.2 Secondary Endpoints was changed from: 
1. Greater than 30% reduction from baseline of pain will 
be assessed using the number of subjects that 
experience at least a 30% reduction from baseline of 
pain on NRS (0-10) at 2 hours post-dose recorded in 
the eDiary (this was removed). 
2. Greater than 50% reduction from baseline of pain will 
be assessed using the number of subjects that 
experience at least a 50% reduction from baseline of 
pain on NRS (0-10) at 2 hours post-dose recorded in 
the eDiary. (this was removed) 
3. Pain freedom will be assessed using the number of 
evaluable subjects that report no pain at 2 hours post- 
dose. Pain will be measured on NRS (0-10). 
4. The probability of requiring rescue medication will 
be assessed using the number of subjects that take 
rescue medication within 24 after administration of 
study medication (rimegepant or placebo). 


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To: 
1. Difference in SPID-24 scores between treatment 
groups will be assessed across the first 24 hours post- 
dose using the number of randomized and treated 
subjects on NRS (0-10). (this was added) 
2. Change from baseline will be assessed at 2 hours post- 
dose using the number of randomized and treated 
subjects. (this was added) 
3. Pain freedom will be assessed using the number of 
evaluable subjects that report no pain at 2 hours post- 
dose. Pain will be measured on NRS (0-10). 
4. Onset of meaningful pain relief will be assessed by the 
first nominal timepoint at which the pain on NRS (0- 
10) decreases by 30% from baseline. (this was added) 
5. Onset of initial pain relief will be assessed by the first 
nominal timepoint at which the pain on NRS (0-10) 
decreases by 1 point from baseline. (this was added) 
6. The probability of requiring rescue medication will 
be assessed using the number of subjects that take 
rescue medication within 24 hours after administration 
of study medication (rimegepant or placebo). 
5.2 Inclusion Criteria #2.e: The following text was removed 
The following is not exclusionary but does not qualify as 
primary diagnosis for inclusion: 
 
Disc disorders (I.2.A.1-4), when not associated with 
mechanically induced arthralgia 
 
Degenerative joint diseases (I.3.A.1-2) 
 
Tendonitis (II.1.B) 
 
Contracture (II.2) 
 
Hypertrophy (II.3) 
 
Headache attributed to TMD (III.1) 
Section 5.3 Exclusion Criteria Number 1.c.ii. Joint Disorders 
was clarified. Previous text: 
i. 
Joint Disorders: 
(1) Disc disorders (I.2.A.1-4), when 


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associated with mechanically induced 
arthralgia 
(2) Hypomobility disorders other than disc 
disorders (I.2.B) 
(3) Hypermobility disorders (I.2.C.) 
New text: 
i. 
Joint Disorders: 
(1) Disc disorders (I.2.A.1-4) only when 
associated with mechanically induced 
arthralgia 
(2) Other hypomobility disorders (I.2.B), such 
as adhesions/adherence, ankylosis 
(3) Hypermobility disorders (I.2.C.), such as 
subluxation, luxation 
In addition, Contracture (II.2) was added as vii, which also 
caused the remainder of the list under section 2.C to be 
renumbered viii through xi. 
Section 5.3, 1.d was clarified as follows: 
From: 
d. 
Subject has a history of neuropathic/idiopathic 
pain disorder. 
To: 
d. Subject has a history of neuropathic (e.g., 
trigeminal neuralgia, postherpetic neuralgia) 
or idiopathic pain disorder. 
Section 5.3 Exclusion Criteria, 5.g.: Severe hepatic 
impairment (Child-Pugh C) is exclusionary in all cases was 
added. 
Section 9.2 Sample Size was updated from If 80% of the 200 
randomized (100 per treatment arm) have a TMD associated 
pain reaching intensity of ≥ 6 on the NRS prior to 
treatment, and provide at least one post baseline efficacy 
data point, we expect roughly 160 total or 80 per treatment 
group in the Modified Intent to Treat (mITT) population for 
analysis. To If 80% of the 200 randomized (100 per 
treatment arm) treat with study drug, we expect roughly 160 
total or 80 per treatment group in the randomized and 
treated population for analysis. 


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The third paragraph in Section 9.3 Population for Analysis 
was updated from The set of treated subjects consists of all 
subjects who take study therapy (rimegepant or placebo) to 
The set of treated subjects consists of all randomized 
subjects who take study therapy (rimegepant or placebo). 
In addition the following paragraph was deleted from 
Section 9.3: The mITT set consists of randomized subjects 
that take study therapy, have a TMD associated pain in the 
jaw and/or temple area which reaches pain intensity of ≥ 6 
on the NRS (0-10) prior to treatment, and provide at least 
one post baseline efficacy data point, 
Section 9.4.2 Primary Endpoint(s) was updated from The 
change from baseline efficacy endpoint is analyzed on the 
mITT population using a generalized linear mixed effect 
model that includes subject as a random effect, the baseline 
NRS (0-10) value as a covariate, and fixed effects for 
treatment group, stratification factor (use of daily 
medications / oral devices to reduce the intensity of TMD 
symptoms), scheduled time point, and time point by 
treatment group interaction. Time points included in the 
model are nominally at 15, 30, 45, 60, 90 and 120 minutes 
post-dose. Repeated measurements within-subject will be 
modeled using an unstructured covariance structure for 
within-subject error. In the case that the model fails to 
converge, a Huynh-Feldt error structure will be attempted, 
followed by an AR(1) structure. Error degrees of freedom 
will be calculated using a Kenward-Roger approximation. 
The difference estimate (rimegepant - placebo), standard 
error, 95% confidence interval, and p-value will be reported 
for 2 hours post-dose. 
In the event a subject uses a non-study rescue medication on 
or before 2 hours post-dose, all data points after rescue 
medication was administered will be set to missing (RM = 
M: Rescue medication use = Missing). Likewise, if a subject 
fails to log their pain score after study drug is administered, 
through 2 hours post-dose, this data will be considered 
missing (NC = M: Non-completers = Missing). 
Sensitivity analyses will be described in the SAP. 
To The SPID-2 will be calculated by multiplying the PID 
score (difference between NRS at each time point and 
baseline NRS) at each post-dose timepoint by the duration 
(in hours) since the preceding timepoint, then summing the 
values over the 2 hours. This is analyzed on the treated 
population using an analysis of covariance (ANCOVA) 
model that includes the baseline NRS (0-10) value as a 
covariate, and main effects for treatment group and 
stratification factor (use of daily medications / oral devices 


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to reduce the intensity of TMD symptoms). 
The least squares mean (LS mean), standard error (SE), 
and 95% confidence interval (CI) for each treatment group 
will be reported, as well as the difference estimate 
(rimegepant - placebo), SE, 95% CI, and p-value. 
Intercurrent events will be treated as failures, with the 
assumption that the subject does not improve once the 
intercurrent event occurs. In the event a subject uses a non- 
study rescue medication on or before 2 hours post-dose, all 
data points after rescue medication was administered will be 
set to the last available observation prior to rescue 
medication usage (RM = Rescue medication use, F = 
Failure). Likewise, if a subject fails to log their pain score at 
any time after study drug is administered, through 2 hours 
post-dose, this data will be imputed to the last available 
observation (NC = Non-completers, F= Failure). 
Sensitivity analyses will be described in the SAP. 
The first paragraph in Section 9.4.3 Secondary Endpoint(s) 
was updated from If the primary endpoint test is significant, 
then the secondary endpoints are evaluated using a 
hierarchical gate-keeping procedure, with each test in the 
hierarchy conducted at p=0.05. These secondary endpoints 
will be tested in the order shown in the Study Objectives 
section of this protocol. Secondary endpoints will be 
analyzed on the mITT population. to If the primary 
endpoint test is significant at alpha  0.05, then the 
secondary endpoints will be analyzed at an alpha level of  
0.05 using Hochberg’s procedure. Secondary endpoints will 
be analyzed on the treated population. 
Section 9.4.3.1 SPID-24; Section 9.4.3.2 Change from 
Baseline of Pain on NRS; Section 9.4.3.4 Time to Onset of 
Meaningful Pain Relief; section 9.4.3.5 Time to Onset of 
Initial Pain Relief were all added. Sections 9.4.3.3 Pain 
Freedom at 2 Hours, and 9.4.3.6 Rescue Medication Use 
through 24 Hours are new sections that were edited from 
previous Section 9.4.3 text. 
Section 9.4.4 Adjustment for Multiplicity was updated from 
Type 1 error is controlled through the use of hierarchical 
testing. The significance of the primary endpoint is 
evaluated at the two-sided alpha level of 0.05. If the primary 
endpoint is significant, then the following secondary 
endpoints will be tested hierarchically in the following 
order, each at the 0.05 level: 
1. 
Proportion of subjects with a ≥ 30% reduction from 
baseline of pain NRS (0-10) score at 2 hours post-dose. 


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2. Proportion of subjects with a ≥ 50% reduction from 
baseline of pain NRS (0-10) score at 2 hours post-dose. 
3. Proportion of subjects that are pain free at 2 hours 
post-dose. 
4. Proportion of subjects requiring rescue medication 
within 24 hours of initial treatment. 
Thus, a secondary endpoint will be tested only if the 
preceding secondary endpoint in the hierarchy is 
determined to be significant. Descriptive p-values will be 
provided for any non-significant secondary endpoints and 
comparative CCI 
 
The
significance of the primary endpoint is evaluated at the two- 
sided alpha level of 0.05. If the primary endpoint is 
significant, then the secondary endpoints are tested using 
Hochberg’s procedure. 
No attempt will be made to adjust for multiplicity when 
testing the CCI 
Section 9.4.5 Missing Data was updated from For the 
primary endpoint of change in NRS from baseline, subjects 
who fail to record their pain at 2 hours post-dose will be 
considered missing (NC = M); the MMRM analysis model 
will be used, which assumes missing data are missing at 
random (MAR). 
For the secondary endpoints of proportion of subjects with 
30% reduction from baseline of pain at 2 hours post-dose, 
50% reduction from baseline of pain at 2 hours post-dose, 
and pain freedom at 2 hours post-dose, missing data at 2 
hours post-dose will be imputed as a failure (NC = F). 
For the secondary endpoint of proportion of subjects who 
use rescue medication through 24 hours-post dose, there will 
be no imputation for missing data, the analysis will be based 
on non-missing, observed data. 
Additional methods for handling of missing data, including 
sensitivity analyses, will be described in detail in the SAP. to 
For the primary and secondary endpoints of SPID-2, SPID- 
24, change in NRS from baseline, time to onset of 


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meaningful pain relief, and time to onset of initial pain 
relief, subjects who fail to record their pain during the 
timeframe of interest for each endpoint will be considered 
failures (NC = F) and this data will be imputed to the last 
available observation prior to the missing data occurrence. 
For the secondary endpoint of proportion of subjects that are 
pain free at 2 hours post-dose, missing data at 2 hours post- 
dose will be imputed as a failure (NC = F), and these 
subjects will not be considered as having achieved pain 
freedom. 
For the secondary endpoint of proportion of subjects who 
use rescue medication through 24 hours-post dose, there will 
be no imputation for missing data, the analysis will be based 
on non-missing, observed data. 
Additional methods for handling of missing data, including 
sensitivity analyses, will be described in detail in the SAP. 
Section 9.4.6 Rescue Medication was updated from For the 
primary endpoint of change from baseline in NRS, the 
intercurrent event of use of non-study rescue medications 
on or before the time point of interest (2 hours post-dose) 
will be handled with a hypothetical strategy. Specifically, 
the assumption will be that had the subject not used a 
rescue medication, their efficacy would have been similar 
to the efficacy of subjects from the same treatment group 
who did not use rescue medication. These data points after 
rescue medication was administered will be set to missing 
(RM = M). 
For the secondary endpoints of proportion of subjects with 
30% reduction from baseline of pain at 2 hours post-dose, 
50% reduction from baseline of pain at 2 hours post-dose, 
and pain freedom at 2 hours post-dose, subjects that take 
rescue medication on or before the time point of interest (2 
hours post-dose) will be considered as failures (RM = F). 
Rescue medications are described in more detail in Section 
5.5 to For the primary and secondary endpoints of SPID-2, 
SPID-24, change in NRS from baseline, time to onset of 
meaningful pain relief, and time to onset of initial pain 
relief, use of non-study rescue medications on or before the 
time point of interest (2 hours post-dose or 24 hours post- 
dose) will be handled as failures (RM = F). Specifically, the 
assumption will be that once the subject has used a rescue 
medication, their pain will not improve any further and 
these data points will be set to the last value recorded prior 
to the use of the rescue medication. 


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For the secondary endpoint of pain freedom at 2 hours 
post-dose, subjects that take rescue medication on or before 
the time point of interest (2 hours post-dose) will be 
considered as failures (RM = F). 
Rescue medications are described in more detail in Section 
5.5 


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BHV3000-317 
A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Safety 
and Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating 
Tablet (ODT) for the Acute Treatment of Temporomandibular 
Disorders (TMD) 
Protocol v3.0 Amendment 2: 31Mar2022 
 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BHV-3000 
(rimegepant) are the confidential and proprietary information of Biohaven Pharmaceutical 
Holding Company Limited. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Conference on Harmonization guidelines and will 
make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Biohaven Pharmaceutical Holding 
Company Limited or specified designees. I will discuss the material with them to ensure that 
they are fully informed about BHV-3000 (rimegepant) and the study. 
 
 
 
 
 
 
 
 
Principal Investigator Name (printed) 
Signature 
Date 


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STUDY SUMMARY (SYNOPSIS) 
 
 
Title: 
A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating Tablet 
(ODT) for the Acute Treatment of Temporomandibular Disorders (TMD) 
Rationale: 
Temporomandibular Disorders (TMD) is a heterogenous group of 30+ 
conditions involving the temporomandibular joint and surrounding muscles 
and tissues. It is characterized by pain, functional limitations of the 
mandible, and/or clicking in the TMJ during motion. TMD is considered 
the most common cause of non-dental facial pain, with reported prevalence 
ranging from 4.6-25% of the US population.1 
Despite high prevalence and disability associated with TMD, there are no 
clear guidelines for treatment or evidence to support a single agent. 
Treatment can be invasive or non-invasive and first-line approach is 
usually a combination of self-care techniques and NSAIDs.2 
The proposed study is based on the evolving preclinical and clinical 
evidence suggesting a role for calcitonin gene related peptide (CGRP) in 
the development of TMD. BHV-3000 (rimegepant) is a small molecule 
CGRP receptor antagonist that is being developed for the potential 
treatment of TMD. The data from this study will allow characterization of 
the safety and efficacy of orally disintegrating tablet (ODT) of rimegepant 
versus placebo in the treatment of Temporomandibular Disorders. 
Target 
Population: 
The study will recruit male and female subjects 18 years of age and older 
with a history of TMD diagnosed by healthcare provider that meets the 
criteria consistent with a diagnosis according to the DC/TMD (Diagnostic 
Criteria for Temporomandibular Disorders) and includes at least one of the 
following: Myalgia (II.1.A.1-3) and/or Arthralgia (I.1.A.).3 Subjects will 
have had a minimum 3-month to a maximum 5-year history of TMD prior 
to the Screening Visit. 
Subjects must have had at least one instance of TMD-associated pain in the 
jaw and/or temple area on either side that reached intensity of  6 on a 11- 
point Numerical Rating Scale (NRS, 0-10) in the past 30 days prior to the 
Screening Visit. 
Number of 
Subjects: 
Approximately 200 subjects will be randomized to result in 160 (80 per 
arm) evaluable subjects. The subjects will be randomized in a 1:1 ratio to 
the rimegepant or placebo treatment groups. The randomization will be 
stratified by the use of daily medications and/or oral devices to reduce the 


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Objectives 
(Primary): 
 
 
Objectives 
(Secondary): 
intensity of TMD symptoms (yes or no). 
To evaluate the efficacy of rimegepant compared with placebo in the acute 
treatment of Temporomandibular Disorders on the time-weighted sum of 
pain intensity difference from baseline scores for the first 2 hours post- 
dose (SPID-2). 
1. To evaluate rimegepant compared with placebo on the time-weighted 
sum of pain intensity difference from baseline scores for the first 24 
hours post-dose (SPID-24). 
2. To evaluate rimegepant compared to placebo on change from baseline 
of pain on NRS (0-10) score at 2 hours post-dose. 
3. To evaluate rimegepant compared to placebo on the proportion of 
subjects that are pain free at 2 hours post-dose. 
4. To evaluate rimegepant compared to placebo on time to onset of 
meaningful pain relief post-dose. 
5. To evaluate rimegepant compared to placebo on time to onset of initial 
pain relief post-dose. 
6. To evaluate rimegepant compared to placebo on the probability of 
requiring rescue medication within 24 hours of initial treatment. 
CCI 
 


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CCI 
Study 
Design: 
This is a double-blind, randomized, multicenter, outpatient evaluation of 
the safety and efficacy of rimegepant as compared to placebo for the acute 
treatment of Temporomandibular Disorders (TMD). The study drug will be 
rimegepant presented in a 75 mg ODT or matching placebo. 
A subject whose TMD-associated pain of  6 on a NRS (0-10) and who is 
otherwise found acceptable for entry into this trial based on inclusion and 
exclusion criteria will first participate in the screening phase (3 to 14 day 
period). Subjects must remain on the same dose of daily medications used 
to reduce the intensity of TMD symptoms from screening through the 
duration of the study and may not start new daily medication. Subjects 
must remain on the consistent use of oral devices used to reduce the 
intensity of TMD symptoms from screening through the duration of the 
study and may not start use of new oral devices. 
After randomization, the subject will be dispensed a single dose of the 
double-blind study medication. The subject will be instructed to take their 
study medication, as an outpatient, when (if) they have an TMD-associated 
pain in the jaw and/or temple area on either side which reaches pain 
intensity of  6 on the NRS (0-10). The subject will record efficacy data in 
an eDiary for 24 hours after taking study medication. CCI 
Pain severity will be recorded 
using a NRS (0-10) at time of taking study medication and after dosing at 
time points of 15, 30, 45, 60, and 90 minutes and 2, 4, 8 and 24 hours. 
CCI 
The subject will be instructed to 


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telephone the study center immediately if a severe or serious adverse event 
occurs. 
At the end of 2 hours after dosing with study medication (and after the 2- 
hour assessments have been completed on the eDiary), subjects will be 
permitted to use the following rescue medication: acetaminophen (up to 
1000 mg/day); or aspirin, ibuprofen, naproxen (or any other type of non- 
steroidal anti-inflammatory [NSAID]), or cyclobenzaprine (all up to the 
daily recommended dose indicated on the drug packaging). Subjects may 
administer whichever protocol permitted standard of care rescue 
medication they choose to reduce symptoms and that they have available. 
These are the only medications allowed for rescue treatment after 2 hours 
post dose of study medication. If at the end of 24 hours after dosing with 
study medication (but before the End of Treatment Visit) subjects are in 
need of pain relief, they may take their prescribed standard of care 
medications, including muscle relaxants if not contraindicated, provided all 
of the assessments have been completed on the eDiary. Exclusionary 
rescue medication such as opioids and butalbital compounds are not 
allowed on this study. 
Similarly, if the TMD-associated pain is relieved by study medication at 2 
hours after dosing but then recurs to a pain intensity of  6 on the NRS (0- 
10) between 2 and 24 hours, the subject will be permitted to take the same 
rescue therapy as outlined above. In all circumstances, the subject will 
always continue to complete his or her eDiary for up to 24-four hours after 
consuming the study medication. During the [up to] 66 days the subject is 
participating in the study, if the subject has a non-qualifying TMD- 
associated pain (i.e., pain < 6 on a NRS[(0-10]) in the jaw and/or temple 
area on either side), the subject is permitted to use only the following 
medications: acetaminophen (up to 1000 mg/day); or aspirin, ibuprofen, 
naproxen (or any other type of non- steroidal anti-inflammatory [NSAID]), 
or cyclobenzaprine (all up to the daily recommended dose indicated on the 
drug packaging). Subjects may administer whichever protocol permitted 
standard of care medication they choose to reduce symptoms and that they 
have available. 
Subjects will return to the study site within 7 days (+2) of study treatment 
for review of the eDiary, assessment of medication compliance, and 
monitoring of tolerability and safety (including vital signs, laboratory tests, 
and electrocardiography). If a subject has NOT experienced a TMD- 
associated pain of sufficient severity within 45 days after randomization, 
they still are required to complete all EOT visit procedures. All subjects 
must return used/unused study medication and eDiary to the study center. 


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STUDY SCHEMATIC 
BHV3000-317 Acute Treatment of Temporomandibular Disorders Study 
 
 
 
 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .............................................. 12 
STUDY SUMMARY (SYNOPSIS) ............................................................................................. 13 
CCI 
 
STUDY SCHEMATIC ................................................................................................................. 17 
TABLE OF CONTENTS ............................................................................................................. 18 
LIST OF TABLES ....................................................................................................................... 20 
LIST OF ABBREVIATIONS ...................................................................................................... 21 
1 
INTRODUCTION AND RATIONALE .............................................................................. 22 
1.1 
Background ....................................................................................................................... 22 
1.2 
Product Development Background ................................................................................. 23 
1.2.1 
Clinical Adverse Event Profile .................................................................................. 23 
1.3 
Study Rationale ................................................................................................................ 23 
1.3.1 
Study Design Rationale .............................................................................................. 24 
1.3.2 
Dose Selection Rationale ............................................................................................ 25 
1.3.3 
Research Hypothesis .................................................................................................. 25 
1.3.4 
Benefit/Risk ................................................................................................................. 25 
1.3.4.1 
Benefit/Risk Assessment ...................................................................................... 25 
2 
STUDY OBJECTIVES ......................................................................................................... 26 
2.1 
Primary Objective(s) ........................................................................................................ 26 
2.2 
Secondary Objective(s) .................................................................................................... 26 
3 
STUDY ENDPOINTS ........................................................................................................... 28 
3.1 
Primary Endpoint(s) ........................................................................................................ 28 
3.2 
Secondary Endpoint(s) ..................................................................................................... 28 
3.3 
Measures of interest ......................................................................................................... 28 
4 
STUDY PLAN ....................................................................................................................... 29 
4.1 
Study Design and Duration ............................................................................................. 29 
4.1.1 
Screening Phase (3-14 days) ...................................................................................... 35 
4.1.2 
Acute Treatment (Randomization) Phase ................................................................ 35 
4.1.2.1 
eDiary Data Collection ......................................................................................... 35 
4.1.3 
Extension Phase .......................................................................................................... 36 
4.1.4 
Washout Phase ........................................................................................................... 36 
4.1.5 
End of Treatment ....................................................................................................... 36 
4.2 
Post Study Access to Therapy ......................................................................................... 37 
5 
POPULATION ...................................................................................................................... 37 
5.1 
Number of Subjects .......................................................................................................... 37 
5.2 
Inclusion Criteria ............................................................................................................. 37 
5.3 
Exclusion Criteria............................................................................................................. 38 
5.4 
Prohibited and Restricted Concomitant Medications ................................................... 43 
5.5 
Daily and Rescue Medications and Oral Devices ........................................................... 44 
5.6 
Women of Childbearing Potential .................................................................................. 46 


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5.7 
Other Restrictions and Precautions ................................................................................ 47 
5.8 
Protocol Deviations ........................................................................................................... 47 
6 
STUDY CONDUCT AND DESCRIPTION OF STUDY PROCEDURES ...................... 48 
6.1 
Study Materials ................................................................................................................ 48 
6.2 
Eligibility Assessments ..................................................................................................... 49 
6.2.1 
Symptom Questionnaire – DC/TMD ........................................................................ 49 
6.2.2 
Clinical Exam Form (NA) – DC/TMD ..................................................................... 49 
6.3 
Safety Assessments ........................................................................................................... 49 
6.3.1 
Vital Signs and Physical Measurements (Height and Weight) ............................... 49 
6.3.2 
Electrocardiogram (ECG) ......................................................................................... 49 
6.3.3 
Physical Exam ............................................................................................................. 49 
6.3.4 
Laboratory Assessments ............................................................................................ 49 
6.3.4.1 
Safety Laboratory Testing ................................................................................... 49 
6.3.4.2 
Pregnancy Testing ................................................................................................ 50 
6.3.5 
Columbia Suicidality Severity Rating Scale (CSSRS)............................................. 50 
6.4 
Efficacy Assessments ........................................................................................................ 51 
6.4.1 
Pain .............................................................................................................................. 51 
6.4.2 
Rescue Medication ...................................................................................................... 51 
6.5 
Early Discontinuation from the Study ........................................................................... 51 
6.5.1 
Lost to Follow Up ....................................................................................................... 52 
7 
STUDY DRUG MANAGEMENT ....................................................................................... 53 
7.1 
Description of Study Drug ............................................................................................... 53 
7.1.1 
Investigational Product .............................................................................................. 53 
7.1.2 
Non-Investigational Product ..................................................................................... 53 
7.1.3 
Packaging, Shipment and Storage ............................................................................ 53 
7.2 
Dose and Administration ................................................................................................. 53 
7.2.1 
Method of Assigning Subject Identification ............................................................. 54 
7.2.2 
Selection and Timing of Dose and Administration .................................................. 54 
7.2.3 
Dose Modifications. .................................................................................................... 54 
7.3 
Blinding and Unblinding ................................................................................................. 54 
7.4 
Treatment Compliance .................................................................................................... 55 
7.5 
Destruction and Return of Study Drug .......................................................................... 55 
8 
ADVERSE EVENTS ............................................................................................................. 56 
8.1 
Serious Adverse Events .................................................................................................... 57 
8.1.1 
Definition of Serious Adverse Event (SAE) ............................................................. 57 
8.1.2 
Collection and Reporting Serious Adverse Events .................................................. 58 
8.2 
Non-serious Adverse Events ............................................................................................ 59 
8.2.1 
Collection and Reporting of Non-Serious Adverse Events ..................................... 60 
8.2.2 
Laboratory Test Abnormalities ................................................................................. 60 
8.3 
Overdose ............................................................................................................................ 60 
8.4 
Pregnancy .......................................................................................................................... 60 
8.5 
Potential Drug Induced Liver Injury (DILI) ................................................................. 61 
8.6 
Adverse Events of Special Interest .................................................................................. 61 


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9 
STATISTICS ........................................................................................................................ 62 
9.1 
General Procedures ..........................................................................................................62 
9.2 
Sample Size ...................................................................................................................... 62 
9.3 
Populations for Analysis ................................................................................................. 62 
9.4 
Statistical Methods .......................................................................................................... 62 
9.4.1 
Demographic and Baseline Characteristics ............................................................. 62 
9.4.2 
Primary Endpoint(s) ................................................................................................. 63 
9.4.3 
Secondary Endpoint(s) .............................................................................................. 63 
9.4.3.1 
SPID-24 ................................................................................................................ 63 
9.4.3.2 
Change from Baseline of Pain on NRS .............................................................. 63 
9.4.3.3 
Pain Freedom at 2 Hours .................................................................................... 64 
9.4.3.4 
Time to Onset of Meaningful Pain Relief .......................................................... 64 
9.4.3.5 
Time to Onset of Initial Pain Relief ................................................................... 64 
9.4.3.6 
Rescue Medication Use through 24 Hours ........................................................ 64 
9.4.4 
Adjustment for Multiplicity ..................................................................................... 64 
9.4.5 
Missing Data .............................................................................................................. 64 
9.4.6 
Rescue Medication ..................................................................................................... 65 
9.4.7 
Analysis of Safety ...................................................................................................... 65 
9.5 
Schedule of Analyses. ....................................................................................................... 66 
10 ETHICS AND RESPONSIBILITIES ................................................................................. 67 
10.1 
Good Clinical Practice .....................................................................................................67 
10.2 
Institutional Review Board/Independent Ethics Committee ....................................... 68 
10.3 
Informed Consent ............................................................................................................ 68 
10.4 
Case Report Forms .......................................................................................................... 69 
11 RECORDS MANAGEMENT ............................................................................................. 70 
11.1 
Source Documentation .....................................................................................................70 
11.2 
Study Files and Record Retention. ................................................................................ 71 
12 AMENDMENTS .................................................................................................................. 72 
13 STUDY REPORT AND PUBLICATIONS ........................................................................ 73 
14 STUDY DISCONTINUATION ........................................................................................... 74 
15 CONFIDENTIALITY .......................................................................................................... 75 
16 CLINICAL PROTOCOL APPROVAL FORM ................................................................ 76 
17 APPENDICES ...................................................................................................................... 77 
17.1 
APPENDIX I – Strong Inhibitors and inducers of CYP3A4 protein (Not all- 
inclusive) ........................................................................................................................... 77 
18 REFERENCES ..................................................................................................................... 78 
LIST OF TABLES 
Table 1 
BHV3000-317 Schedule of Assessments ............................................................. 30 


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AE 
Adverse Event 
LIST OF ABBREVIATIONS 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CGRP 
 Calcitonin Gene Related Peptide 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicidality Severity Rating Scale 
ECG 
 Electrocardiogram 
EOD 
Every other day 
ePRO 
Electronic Patient Reported Outcome 
GCP 
 Good Clinical Practice 
HRT 
Hormone Replacement Therapy 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
CCI  
mg 
Milligram 
mm 
Millimeter 
min 
Minute 
NRS 
Numerical Rating Scale 
ODT 
Oral disintegrating tablet 
PK 
Pharmacokinetic 
PRN 
As needed pro re nata 
SAE 
TMD 
TMJ 
Serious Adverse Event 
Temporomandibular Disorder 
Temporomandibular Joint 
ULN 
Upper Limit of Normal 


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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
Temporomandibular disorders are a large group of conditions associated with the 
temporomandibular joint, masticatory muscles, and surrounding musculoskeletal tissues. 
Most common symptoms are pain in the jaw and/or temple area, masticatory muscle soreness, 
functional limitations of the jaw and “clicking” sounds in the temporomandibular joint (TMJ).4,5 
Other associated symptoms may include ear pain, headache, neck pain, and teeth grinding 
(bruxism).2,6 Symptoms can range from mild and intermittent to severe and continuous causing 
significant disability, and a reduction in quality of life and work productivity.4,6 In the 
epidemiological studies, the prevalence ranged between 4.6 - 25% of the US population.1,6 
The etiology of TMD is multifactorial, encompassing biologic, environmental, social, 
behavioral, and multiple co-morbid factors in the development. In addition, multiple medical 
conditions co-occur with TMD, such as headaches, fibromyalgia, back pain, and irritable bowel 
syndrome.7 
Diagnosis is primarily based on patient history and physical exam, while imaging modalities are 
typically reserved for those with severe and persistent symptoms. 
Noninvasive therapies, such as self-care and pharmacological agents, should be attempted first 
and those typically include NSAIDs and acetaminophen as first line agents.5 In addition, muscle 
relaxants and benzodiazepines may be useful for muscle spasm and chronic bruxism while 
antidepressants are used for management of chronic pain. However, none of these agents have 
consistent efficacy demonstrated in clinical trials.1 
BHV-3000 (rimegepant) is a calcitonin gene-related peptide (CGRP) receptor antagonist in 
development for the acute treatment of TMD. The CGRP receptor is located within pain- 
signaling pathways, intracranial arteries, and the trigeminal ganglion. Its activation is thought to 
play a causal role in TMD pathophysiology. 
Treatment with a CGRP receptor antagonist is believed to exert multiple downstream effects that 
may provide benefits in treatment of TMD through the following possible mechanisms: 
 
Blocking Neurogenic Inflammation: Binding of CGRP receptor antagonists to CGRP 
receptors located on satellite glial cells would inhibit inflammation caused by trigeminal 
nerve release of CGRP onto satellite glial cells and cell bodies of a-delta fibers in the 
trigeminal ganglion. 
 
Decreasing Artery Dilation: By blocking the CGRP receptors located in smooth muscle 
cells within vessel walls, CGRP receptor antagonists would inhibit the pathologic dilation of 
arteries without the unwanted effect of active vasoconstriction. 


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 Inhibiting Pain Transmission: Binding of CGRP receptor antagonists to CGRP receptors 
would suppress the transmission of pain by inhibiting the central relay of pain signals from 
the trigeminal nerve to the caudal trigeminal nucleus. 
1.2 
Product Development Background 
Details of the clinical and preclinical studies are provided in the most current Investigator 
Brochure. A summary of data relevant to the study are presented below. 
1.2.1 
Clinical Adverse Event Profile 
Nurtec® ODT (rimegepant) is approved in the United States for the treatment of acute migraine 
and the preventive treatment of episodic migraine in adults. Nurtec® ODT (rimegepant) is 
generally safe and well tolerated in humans when given as single oral dose of 75 mg for the acute 
treatment of migraine as well as when given every other day for the preventive treatment of 
migraine. The BHV3000-201 study is a Phase 2/3, 52-week, open-label, safety study with 
rimegepant 75 mg, in which 1800 subjects received rimegepant up to once daily for up to one 
year. In the BHV3000-305 preventive treatment of migraine study, long-term safety was 
assessed in an open-label extension that included 603 patients who received rimegepant 75 mg at 
least every other day for up to one year. Please refer to the Investigators Brochure for a summary 
of the clinical safety profile. 
 
The primary identified AE of interest is potential change in liver function tests. Investigators 
must carefully monitor routine liver function tests (ALT, AST, total bilirubin, and ALP) and 
potentially liver related symptoms and signs. Clinicians should also monitor changes in 
hematology and other laboratory measures. Please refer to the current Investigators Brochure for 
further information regarding the clinical safety profile of rimegepant. 
1.3 
Study Rationale 
Temporomandibular Disorders (TMD) is a large group of 30+ conditions involving the 
temporomandibular joint and surrounding muscles and tissues. It typically manifests as 
intermittent or continuous pain in the jaw area, functional limitations of the jaw, and clicking 
sounds in the TMJ during motion.1 


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The joint and surrounding tissues receive sensory and nociceptive innervation from distal 
branches of mandibular nerve, the largest of the three divisions of the trigeminal nerve. Although 
the underlying mechanisms of TMD have not been fully elucidated, numerous studies have 
implicated trigeminal nerve and CGRP in the pathophysiology of the disease and suggested 
therapeutic benefits of CGRP antagonism. For example, a preclinical study showed that injection 
of CGRP into the TMJ capsule in rodents upregulated expression of proteins implicated in the 
development and maintenance of peripheral and central sensitization and nociception.8 
Furthermore, in the acute TMD model in mice, pretreatment with CGRP antagonist led to 
significant reduction in spontaneous orofacial pain behaviors.9 Moreover, induction of myogenic- 
TMD in mice triggered migraine-like hypersensitivity that could be attenuated by pretreatment 
with a CGRP antagonist and sumatriptan.10 Clinical studies have also shown that synovial CGRP 
levels are elevated in TMD patients and correlate with pain, impairment of mandibular mobility, 
and occlusal alterations.11,12 
BHV-3000 (rimegepant) is a calcitonin gene-related peptide (CGRP) receptor antagonist in 
development for the acute treatment of TMD. The CGRP receptor is located within pain- 
signaling pathways, intracranial arteries and the trigeminal ganglion, and its activation is thought 
to play a causal role in TMD pathophysiology. 
Currently, there are no TMD-specific therapies or clear guidelines on the treatment and most 
often TMD is treated with self-care techniques and NSAIDs. However, most patients have an 
inadequate relief of pain and recurrence of symptoms, prompting the need for novel 
pharmacologic interventions.1,2 
This study is being conducted to evaluate the efficacy, safety, and tolerability of rimegepant for 
the acute treatment of TMD. It will also further define the safety profile of rimegepant 
administration in this patient population, separately from the approved indication of acute and 
preventive treatment of migraine. 
1.3.1 
Study Design Rationale 
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and efficacy 
of rimegepant as compared to placebo in the acute treatment of TMD-associated pain. The study 
drug will be rimegepant formulated in a 75 mg ODT (administered sublingually) or a matching 
placebo. The subjects will be instructed to take their study medication, as an outpatient, when (if) 
they have a TMD-associated pain which reaches pain intensity of  6 on the NRS (0-10). 
The study will randomize approximately 200 subjects. The subjects will be randomized in a 1:1 
ratio to the rimegepant or placebo treatment groups. The randomization will be stratified by the 
use of daily medications / oral devices to reduce the intensity of TMD symptoms (yes or no). 
This study design is being utilized to assess the safety and efficacy in the acute treatment of 
Temporomandibular Disorders. 


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1.3.2 
Dose Selection Rationale 
The Phase 2b dose-ranging study CN170003 established that rimegepant 75 mg is the minimum 
effective dose for the acute treatment of migraine. The three Phase 3 studies BHV3000-301, 
BHV3000-302, and BHV3000-303 confirmed this efficacy using the current registrational 
endpoints for acute treatment of migraine. This observation and the flat dose-response with 
rimegepant and other CGRP receptor antagonists suggest that rimegepant 75 mg may be an 
effective dose for the acute treatment of Temporomandibular Disorders. The pharmacokinetic 
profile of rimegepant supports the dosing schedule of this protocol with up to daily dosing. 
Please refer to the current version of Investigators Brochure for a summary of the clinical safety 
profile. 
1.3.3 
Research Hypothesis 
Rimegepant will have efficacy superior to placebo in the acute treatment of Temporomandibular 
Disorders with a favorable safety profile. 
1.3.4 
Benefit/Risk 
1.3.4.1 
Benefit/Risk Assessment 
As of the approval in February 2020 of Nurtec® ODT, more than 6,000 subjects have 
participated in Phase 1 studies in healthy subjects or Phase 2 and 3 studies in subjects with 
migraine. Among these subjects, more than 3,569 unique subjects have received the rimegepant 
clinical dose of 75 mg in Phase 2b/3 studies. Additionally, at the time of the Nurtec® ODT sNDA 
submission for the treatment of prevention in migraine, the pivotal prevention study had a total 
of 526 subjects received rimegepant (EOD or EOD plus as needed [EOD + PRN] up to once 
daily) for at least 6 months, and 138 subjects received rimegepant for at least 1 year. 
Collectively, the current data demonstrate a favorable benefit-risk profile for rimegepant in 
adults for the acute and preventative treatment of migraine and suggests a favorable benefit/risk 
assessment for the acute treatment of Temporomandibular Disorders. 


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2 STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
Temporomandibular Disorders on the time-weighted sum of pain intensity difference from 
baseline scores for the first 2 hours post-dose (SPID-2). 
2.2 
Secondary Objective(s) 
1. To evaluate rimegepant compared with placebo on the time-weighted sum of pain intensity 
difference (SPID) from baseline scores for the first 24 hours post-dose (SPID-24). 
2. To evaluate rimegepant compared to placebo on change from baseline of pain on NRS (0-10) 
score at 2 hours post-dose. 
3. To evaluate rimegepant compared to placebo on the proportion of subjects that are pain free 
at 2 hours post-dose. 
4. To evaluate rimegepant compared to placebo on time to onset of meaningful pain relief post- 
dose. 
5. To evaluate rimegepant compared to placebo on time to onset of initial pain relief post-dose. 
6. To evaluate rimegepant compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment. 
 
 
 
 
 
 
 


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3 STUDY ENDPOINTS 
3.1 
Primary Endpoint(s) 
 
Difference in SPID-2 scores between treatment groups will be assessed across the first 2 hours 
post-dose using the number of randomized and treated subjects. 
 
3.2 
Secondary Endpoint(s) 
1. Difference in SPID-24 scores between treatment groups will be assessed across the first 24 
hours post-dose using the number of randomized and treated subjects on NRS (0-10). 
2. Change from baseline will be assessed at 2 hours post-dose using the number of randomized 
and treated subjects. 
3. Pain freedom will be assessed using the number of evaluable subjects that report no pain at 
2 hours post-dose. Pain will be measured on NRS (0-10). 
4. Onset of meaningful pain relief will be assessed by the first nominal timepoint at which the 
pain on NRS (0-10) decreases by 30% from baseline. 
5. Onset of initial pain relief will be assessed by the first nominal timepoint at which the pain 
on NRS (0-10) decreases by 1 point from baseline. 
6. The probability of requiring rescue medication will be assessed using the number of 
subjects that take rescue medication within 24 hours after administration of study medication 
(rimegepant or placebo). 
3.3 
Measures of interest 
 
Safety and Other assessments: 
 
 
Adverse Events 
 
ECG assessments 
 
Vital Sign and Physical Measurements 
 
Routine Laboratory Tests 
 
Columbia Suicidality Rating Scale 
 
Assessment of TMD-associated Pain and Symptoms 
 
CCI 
 


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4 STUDY PLAN 
4.1 
Study Design and Duration 
This is a double-blind, randomized, multicenter, outpatient evaluation of the safety and efficacy 
of rimegepant as compared to placebo in the acute treatment of Temporomandibular Disorders. 
Subjects will be dispensed one dose of study medication consisting of a rimegepant 75 mg ODT 
(administered sublingually) or a matching placebo. The total duration of the study will be up to 
approximately 66 days. This includes a 3 to 14 day (+2 days for scheduling purposes, if needed) 
Screening Period, an Acute Treatment Phase that can last up to 45 days or until the subject has a 
TMD-associated pain that reaches intensity of  6 on the NRS (0-10), followed by an End of 
Treatment Visit 7 days after the administration of the study medication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1 
BHV3000-317 Schedule of Assessments 
 
Procedure 
Screening 
Visit 
(3-14 days) 
Baseline 
Visit 
(Randomizat 
ion) 
TMD- 
associated 
pain  6 on 
NRS (0-10) 
During 
Treatment 
15, 30, 45, 60 
and 90 mins 
Post-Dose 
During 
Treatment 
2, 4, 8 
hours Post- 
Dose 
During 
Treatment 24 
hours Post- 
Dose 
End of 
Treatment 
Visit (within 7 
(+2) days of 
treating TMD- 
associated pain) 
Comments 
Eligibility Assessments 
Informed Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
Medical History 
X 
Collect Daily Use of 
Medications / Oral 
Devices to Reduce 
Intensity of TMD 
Symptoms / 
Concomitant 
Medications 
X 
X 
X 
Subjects will be given a paper 
diary to track of concomitant 
medications, including rescue 
medications, and use of oral 
devices. All medications taken 
for any reason should be 
documented. Site staff should 
instruct subjects on proper use 
of the paper diary(ies) and 
instruct subjects that the 
diary(ies) will be collected, 
reviewed, and discussed with 
the subject at each visit. 
Assessment of 
TMD History 
(Signs and 
Symptoms) 
X 
Paper source document will 
be used to capture TMD 
History and entered in eCRF 


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Procedure 
Screening 
Visit 
(3-14 days) 
Baseline 
Visit 
(Randomizat 
ion) 
TMD- 
associated 
pain  6 on 
NRS (0-10) 
During 
Treatment 
15, 30, 45, 60 
and 90 mins 
Post-Dose 
During 
Treatment 
2, 4, 8 
hours Post- 
Dose 
During 
Treatment 24 
hours Post- 
Dose 
End of 
Treatment 
Visit (within 7 
(+2) days of 
treating TMD- 
associated pain) 
Comments 
Safety Assessments 
Physical 
Examination 
X 
X 
Vital Signs/Physical 
Measurements 
X 
X 
X 
Vital Signs consist of sitting 
arterial systolic and diastolic 
blood pressure, heart rate, oral 
body temperature, body weight 
and height. Height and weight 
will only be measured at 
Screening. 
Clinical Safety 
Laboratory Testing 
X 
X 
All Screening visit laboratory 
test results must be received 
prior to Baseline Visit 
(randomization) 
Urine drug screen 
for drugs of abuse 
X 
X 
HbA1c, Lipid 
Panel, FSH 
X 
ECG 
X 
X 
Pregnancy Test 
X 
X 
X 
X 
A serum pregnancy test will be 
completed at Screening and 
End of Treatment Visits as part 
of the standard laboratory tests 
(if appropriate). Confirmatory 
urine pregnancy test for 
WOCBP should be completed 
on site at the Baseline Visit 
and any subsequent visits for 
confirmation at the 
Investigator’s discretion. 
Home pregnancy test will be 


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Procedure 
Screening 
Visit 
(3-14 days) 
Baseline 
Visit 
(Randomizat 
ion) 
TMD- 
associated 
pain  6 on 
NRS (0-10) 
During 
Treatment 
15, 30, 45, 60 
and 90 mins 
Post-Dose 
During 
Treatment 
2, 4, 8 
hours Post- 
Dose 
During 
Treatment 24 
hours Post- 
Dose 
End of 
Treatment 
Visit (within 7 
(+2) days of 
treating TMD- 
associated pain) 
Comments 
provided to WOCBP after 
completion of baseline visit. 
Subjects will be provided with 
the accompanying package 
insert that contains instructions 
for use and interpretation of 
results. WOCBP subjects must 
complete the urine pregnancy 
test at home. WOCBP must 
have a negative serum or urine 
pregnancy test at the Screening 
Visit, Baseline Visit, and prior 
to taking study medication. 
Adverse Event and 
Serious Adverse 
Event Assessment 
X 
X 
X 
X 
X 
X 
X 
SAEs are reported from the 
time of informed consent and 
non-serious AEs are reported 
from baseline. See Section 8 
of the protocol for further 
information. 
Columbia 
Suicidality Rating 
Scale 
X 
X 
X 
This scale will be clinician 
administered, completed on 
site, and will be in paper. The 
source document will be 
provided by Biohaven. At the 
Screening Visit, the recall 
period for completing is 12 
months for suicidal ideation 
and 10 years for suicidal 
behavior; at all other visits, the 
recall period for completing 
the C-SSRS is since the last 
visit. 


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Procedure 
Screening 
Visit 
(3-14 days) 
Baseline 
Visit 
(Randomizat 
ion) 
TMD- 
associated 
pain  6 on 
NRS (0-10) 
During 
Treatment 
15, 30, 45, 60 
and 90 mins 
Post-Dose 
During 
Treatment 
2, 4, 8 
hours Post- 
Dose 
During 
Treatment 24 
hours Post- 
Dose 
End of 
Treatment 
Visit (within 7 
(+2) days of 
treating TMD- 
associated pain) 
Comments 
Clinical Drug Supplies/Study Supplies 
Randomize 
X 
Subjects will be randomized in 
the IWRS system at the 
Baseline Visit 
(Randomization) 
Dispense Study 
Medication 
X 
Administer 1 dose 
of study medication 
X 
Instruct subjects: STUDY 
DRUG only to be taken to treat 
a TMD-associated pain  6 
on NRS (0-10) AND after the 
subject has completed all 
required assessments in the 
eDiary. The eDiary will 
prompt the subject to take 
study medication. 
Return used study 
medication 
packaging or 
unused study 
medication 
X 
eDiary returned/ 
reviewed for 
completeness 
X 
Staff to review eDiary entries 
with subjects, confirm all data 
points are transferred to the 
system, and reset eDiary for 
future subject use, PRIOR to 
the subject leaving the clinic 


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X 
X 
 
 
Procedure 
Screening 
Visit 
(3-14 days) 
Baseline 
Visit 
(Randomizat 
ion) 
TMD- 
associated 
pain  6 on 
NRS (0-10) 
During 
Treatment 
15, 30, 45, 60 
and 90 mins 
Post-Dose 
During 
Treatment 
2, 4, 8 
hours Post- 
Dose 
During 
Treatment 24 
hours Post- 
Dose 
End of 
Treatment 
Visit (within 7 
(+2) days of 
treating TMD- 
associated pain) 
Comments 
Efficacy Assessments 
(±windows for timeframe around efficacy assessments (15, 30, 45, 60, 90 min, 2, 4, 8, and 24 hours) will be automated and captured in the eDiary.) 
Assessment of 
TMD-associated 
pain 
X 
X 
X 
X 
This scale is captured in the 
eDiary, 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.1.1 
Screening Phase (3-14 days) 
All subjects who are screened will be entered into the IWRS system and assigned a patient 
identifier. After obtaining informed consent, subjects will undergo all screening procedures 
as detailed in Table 1. After all screening procedures are complete, subjects may return 3 to 
14 days (+2 days if needed for scheduling purposes) from signing informed consent to be 
randomized at the Baseline visit if they meet all eligibility criteria. 
Subjects in this study may be screened only once. Rescreening is not permitted. 
4.1.2 
Acute Treatment (Randomization) Phase 
If the subject meets all eligibility criteria, they will be randomized at the Baseline Visit via 
the IWRS. The subjects will be provided with an eDiary. Study personnel will educate the 
subject on the proper use of the eDiary, accurate reporting, and placebo response prior to the 
subject leaving the office. 
After randomization via the IWRS, the subject will be dispensed a single dose of the double- 
blind study medication to take home for up to 45 days. This study medication is to be taken 
when an TMD-associated pain in the jaw and/or temple area on either side which reaches 
pain intensity of  6 on the NRS (0-10) in the eDiary. The subject will be instructed to take 
their study medication, as an outpatient, when (if) they have an TMD-associated pain in the 
jaw and/or temple area on either side which reaches pain intensity of  6 on the NRS (0-10) 
after they answer eDiary questions about their current pain and symptoms. The subject will 
complete an eDiary for 24 hours after taking study medication to record efficacy and other 
quality of life measures. 
Subjects in this study may be randomized only once. Under no circumstances may a subject 
be re-randomized. 
4.1.2.1 
eDiary Data Collection 
Subjects will record efficacy and other quality of life measures in their eDiary. This includes 
the following: onset time of TMD-associated pain, intensity of the TMD-associated pain prior 
to and at time of taking study medication. The subjects should not dose with study medication 
until the TMD-associated pain in the jaw and/or temple area on either side which reaches 
pain intensity of  6 on the NRS (0-10). TMD-associated pain severity will be recorded using 
a NRS (0-10) at the onset of the pain and after dosing at time points of 15, 30, 45, 60, and 90 
minutes and 2, 4, 8, and 24 hours. Subjects will record the date and time study therapy was 
 
 
 
 
After dosing with study medication, all other medication to relieve TMD-associated 
symptoms is prohibited during the 2 hours post dose. At the end of 2 hours after dosing with 
study medication (and after the 2-hour assessments have been completed on the eDiary) 
subjects will be permitted to use the following rescue medication: acetaminophen (up to 1000 
mg/day); or aspirin, ibuprofen, naproxen (or any other type of non- steroidal anti- 
taken in their eDiary according to the eDiary vendor’s specifications. CCI 


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inflammatory [NSAID]), or cyclobenzaprine (all up to the daily recommended dose indicated 
on the drug packaging). Subjects may administer whichever protocol permitted standard of 
care rescue medication they choose to reduce symptoms and that they have available. These 
are the only medications allowed for rescue treatment after 2 hours post dose of study 
medication. However, if needed, after 24 hours of administering the one dose of study 
medication (and before returning for the End of Treatment Visit) subject may take their 
prescribed standard of care medications for treatment of TMD-associated pain provided all 
the assessments have been completed on the eDiary. Exclusionary rescue medication such as, 
opioids, butalbital compounds, and muscle relaxants (except cyclobenzaprine used as rescue 
medication, see above) are not allowed on this study. Similarly, if the TMD-associated pain is 
relieved by study medication at 2 hours after dosing but then recurs to intensity level of  6 
on the NRS (0-10) between 2 and 24 hours, the subject will be permitted to take the same 
rescue therapy as outlined above. 
Subjects should be encouraged to treat the first qualifying TMD-associated pain (intensity 
level of  6 on the NRS (0-10)) that occurs during the treatment phase. If subjects are unable 
to treat their first qualifying TMD-associated pain due to scheduling, etc. the same 
medication restrictions would still apply (i.e., acetaminophen [up to 1000 mg/day]; or aspirin, 
ibuprofen, naproxen (or any other type of non- steroidal anti-inflammatory [NSAID]), or 
cyclobenzaprine [all up to the daily recommended dose indicated on the drug packaging]). 
Subjects may administer whichever protocol permitted standard of care medication they 
choose to reduce symptoms and that they have available. 
Similarly, for treatment of non-qualifying TMD-associated pain (i.e., pain of < 6 on the NRS 
(0-10), or other non-TMD related pain in the jaw and/or temple area on either side) that occur 
during the randomization period before a qualifying TMD-associated pain is reported, subject 
will only be permitted to use the medications listed above. Acetaminophen (over 1000 
mg/day) is prohibited after randomization except as rescue medication as described in Section 
5.5. In all circumstances, the subject will continue to complete his or her eDiary for up to 24 
hours after consuming the study medication. 
4.1.3 
Extension Phase 
Not applicable. 
4.1.4 
Washout Phase 
Not applicable. 
4.1.5 
End of Treatment 
Subjects will return to the study site within 7 days of study treatment (+2 days) for review of 
the eDiary assessment, of medication compliance, and monitoring of tolerability and safety 
(including vital signs, laboratory tests, and electrocardiography). If a subject has NOT 
experienced a TMD-associated pain of sufficient severity within 45 days after randomization, 
they still are required to complete all EOT visit procedures. All subjects must return unused 
study medication and eDiary to the study center. 


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4.2 
Post Study Access to Therapy 
At the end of the study, the Sponsor will not continue to supply study drug to 
subjects/Investigators. The Investigator should ensure that the subject receives the 
appropriate standard of care to treat the condition under study. 
5 POPULATION 
Individuals entered in this trial will be subjects who suffer from temporomandibular disorders 
as specified under Section 5.2. The treatment setting for these subjects may include clinics, 
institutions, or private office practices. Subjects may be recruited through a variety of 
sources, including referral from physicians and other health care professionals. 
5.1 
Number of Subjects 
It is anticipated that approximately 200 subjects will be randomized to result in 
approximately 160 evaluable subjects. The subjects will be randomized in a 1:1 ratio to the 
rimegepant or placebo treatment groups. It is anticipated that enrollment will occur at 
approximately 25 sites in the United States over a period of approximately 10 months during 
this trial. 
5.2 
Inclusion Criteria 
1. Signed Written Informed Consent 
a. Written informed consent must be obtained from the subject in accordance with 
requirements of the study center’s Institutional Review Board (IRB) or Ethics 
Committee prior to the initiation of any protocol-required procedures. 
b. Subject must agree to provide all requested demographic information (i.e. gender, 
race). 
c. Subject must be able to read and understand English or Spanish. 
2. Target population 
a. Subject has a minimum 3-month to a maximum 5-year history of temporomandibular 
disorder diagnosed by a healthcare provider, including the following: 
i. 
Meets criteria consistent with a diagnosis according to the DC / TMD (Diagnostic 
Criteria for Temporomandibular Disorders)3 that include at least one of the 
following: 
(1) Arthralgia (I.1.A.) 
(2) Myalgia (II.1.A.1-3) 
b. At least one instance of pain  6 on a Numeric Rating Scale (0-10) in the jaw and/or 
temple area on either side in the past 30 days prior to the Screening Visit. 


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c. Subject with daily use of medications to reduce intensity of TMD symptoms is 
permitted to remain on therapy if they have been on a stable dose for at least 3 months 
prior to the Screening Visit, and the dose is not expected to change during the course 
of the study. 
d. Subject with daily use of oral devices to reduce intensity of TMD symptoms is 
permitted to remain on therapy if they have been using them consistent for at least 3 
months prior to the Screening Visit, and the regimen is not expected to change during 
the course of the study. 
e. Subject agrees to not commence new pain medication, injection therapy, occlusal 
splint therapy or any other pain management techniques during the course of the 
study. 
3. Age and Reproductive Status 
a. Male and Female subjects ≥ 18 years and older. 
b. Women of childbearing potential (WOCBP) with male partners and men with women 
partners of childbearing potential must be using two acceptable methods of 
contraception to avoid pregnancy throughout the study in such a manner that the risk 
of pregnancy is minimized. See Section 5.5 for the definition of WOCBP. WOCBP 
must agree to use an acceptable contraceptive method or abstinence to avoid 
pregnancy from the Screening Visit through 60 days after dosing with study drug. 
Males with vasectomy are considered surgically sterile provided the procedure 
occurred greater than 6 months prior to the Screening Visit. 
c. No clinically significant abnormality identified on the medical or laboratory 
evaluation. A subject with a clinical abnormality or laboratory parameters outside the 
reference range may be included only if the Investigator considers that the finding is 
not clinically significant and will not introduce additional risk factors and will not 
interfere with the study procedures. 
d. WOCBP must have a negative serum or urine pregnancy test at the Screening Visit, 
Baseline Visit, and prior to taking study medication. 
e. Women must not be breastfeeding. 
5.3 
Exclusion Criteria 
1. Disease Target Exclusion 
a. Subject has a history of primary headache disorder consistent with diagnostic criteria 
according to the International Classification of Headache Disorders, 3rd Edition. If 
the majority of pain associated with tension-type headache diagnosis is attributable to 
TMD by the site PI, then it is not exclusionary. 
b. Subject has a history of headache disorder attributed to trauma or injury to the head 
and/or neck consistent with diagnostic criteria according to the International 
Classification of Headache Disorders, 3rd Edition. 


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c. Meets criteria consistent with a diagnosis according to the DC / TMD (Diagnostic 
Criteria for Temporomandibular Disorders)3 that include at least one of the following: 
i. Joint Pain: 
(1) Arthritis (I.1.B) 
ii. Joint Disorders: 
(1) Disc disorders (I.2.A.1-4) only when associated with mechanically induced 
arthralgia 
(2) Other hypomobility disorders (I.2.B), such as adhesions/adherence, ankylosis 
(3) Hypermobility disorders (I.2.C.), such as subluxation, luxation 
iii. Joint Diseases: 
(1) Systemic arthritides (I.3.B) 
(2) Condylysis/idiopathic condylar resorption (I.3.C) 
(3) Osteochondritis dissecans (I.3.D) 
(4) Ostonecrosis (I.3.E) 
(5) Neoplasm (I.3.F) 
(6) Synovial chondromatosis (I.3.G) 
iv. Fractures: 
(1) Fractures (I.4) 
v. Congenital/Developmental Disorders: 
(1) Aplasia (I.5.A) 
(2) Hypoplasia (I.5.B) 
(3) Hyperplasia (I.5.C) 
vi. Muscle Pain: 
(1) Myositis (II.1.C) 
(2) Spasm (II.1.D) 
vii. Contracture (II.2) 
viii. 
Neoplasm: 


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(1) Neoplasm (II.4) 
ix. Movement Disorders: 
(1) Orofacial dyskinesia (II.5.A) 
(2) Oromandibular dystonia (II.5.B) 
x. Masticatory Muscle Pain Attributed to Systemic/Central Pain Disorders: 
(1) Fibromyalgia/widespread pain (II.6.A) 
xi. Associated Structures: 
(1) Coronoid hyperplasia (IV.1) 
d. Subject has a history of neuropathic (e.g., trigeminal neuralgia, postherpetic 
neuralgia) or idiopathic pain disorder. 
e. Subject has a history of pain of dental origin within the 3 months prior to the 
Screening Visit. 
f. Subject has a history of trauma in the craniocervical area, including joint sprain/strain, 
within the 3 months prior to the Screening Visit. 
g. Subject has a history of or is planning TMJ surgery (e.g., arthrocentesis, arthroscopy, 
TMJ implants) or ear surgery. 
h. Subject has a history of radiation treatment to head and neck. 
i. Subject has a history of connective tissue disorders. 
2. Medical History and Concurrent Diseases 
a. Body Mass Index  33kg/m2 
b. Subject history of HIV disease. 
c. Subject history with current evidence of uncontrolled, unstable, or recently diagnosed 
cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, 
and cerebral ischemia. Subjects with Myocardial Infarction (MI), Acute Coronary 
Syndrome (ACS), Percutaneous Coronary Intervention (PCI), cardiac surgery, stroke 
or transient ischemic attack (TIA) during the 6 months prior to the Screening Visit. 
d. Uncontrolled hypertension (high blood pressure) or uncontrolled diabetes (however 
subjects can be included who have stable hypertension and/or diabetes for at least 3 
months prior to the Screening Visit). 
e. Subject has a current diagnosis of major depression, other pain syndromes, psychiatric 
conditions (e.g., schizophrenia), dementia, or significant neurological disorders that, 
in the Investigator’s opinion, might interfere with study assessments. 


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f. Subject has a history of gastric or small intestinal surgery (including Gastric Bypass, 
Gastric Banding, Gastric Sleeve, Gastric Balloon, etc.), or has a disease that causes 
malabsorption. 
g. The subject has a history or current evidence of any significant and/or unstable 
medical conditions (e.g., history of congenital heart disease or arrhythmia, known 
suspected infection, hepatitis B or C, or cancer) that, in the Investigator’s opinion, 
would expose them to undue risk of a significant adverse event (AE) or interfere with 
assessments of safety or efficacy during the course of the trial. Severe hepatic 
impairment (Child-Pugh C) is exclusionary in all cases. 
h. Subjects with a history of, treatment for, or evidence of, alcohol or drug abuse or who 
have met DSM-V criteria13 for any significant substance use disorder within the past 
12 months from the date of the Screening Visit. 
i. Subjects should be excluded if they have a positive drug screen for drugs of abuse that 
in the Investigator’s judgment is medically significant, in that it would impact the 
safety of the subject or the interpretation of the study results. In addition: 
Detectable levels of cocaine, amphetamine, and phencyclidine (PCP) in the drug 
screen are exclusionary. Subjects who are positive for amphetamines, and who are 
on a prescribed amphetamine medication for an approved indication (e.g., ADHD) 
will be allowed into the study at the Investigator’s discretion. This determination 
by the Investigator must be well documented in the subject’s source medical 
records. The stimulant dose must be stable from 3 months prior to the Screening 
Visit until the end of treatment visit occurs. 
Detectable levels of cannabinoids (e.g., marijuana, CBD) in the drug screen at the 
Screening Visit are not exclusionary, if in the Investigator’s documented opinion 
the subject does not meet DSM-V criteria13 for substance use disorder, and the 
positive test does not signal a clinical condition that would impact the safety of the 
subject or interpretation of the study results. 
j. Hematologic or solid malignancy diagnosis within 5 years prior to the Screening 
Visit. 
3. Allergies and Adverse Drug Reactions 
a. History of drug or other allergy which, in the opinion of the Principal Investigator, 
makes the subject unsuitable for participation in the study. 
4. ECG and Laboratory Test Findings 
a. Estimated glomerular filtration rate (eGFR) according to the re-expressed abbreviated 
(four-variable) Modification of Diet in Renal Disease (MDRD) Study equation ≤ 40 
ml/min/1.73m2. 
b. Corrected QT interval > 470 msec (QTc by method of Frederica), at Screening. 
c. Left Bundle Branch block. 


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d. Right Bundle Branch Block with a QRS duration ≥ 150 msec. 
e. Intraventricular Conduction Defect with a QRS duration ≥ 150 msec. 
f. Serum bilirubin (Total, Direct or Indirect) > 1 x ULN (Only abnormal values of 
between 1-1.5x ULN may be repeated once for confirmation during the screening 
period). 
g. Neutrophil count ≤ 1000/μL (or equivalent). 
h. HbA1c ≥ 6.5%. 
i. AST (SGOT) or ALT (SGPT) > 1 x ULN (Only abnormal values of between 1-1.5x 
ULN may be repeated once for confirmation during the screening period). 
5. Excluded Current or Recent Treatments 
a. Subject has a history of new or recently modified use of night guards, splints, dental 
orthotics, or dental appliances within the 3 months prior to the Screening Visit. 
b. Subject has a history of dental orthodontic use within the 3 months prior to the 
Screening Visit. 
c. Subject has a history of dental restorative care (e.g., crowns, bridges) within the 3 
months prior to the Screening Visit. 
d. Subject has a history of new or recently modified physical therapy treatment in the 
head and/or neck area within the 3 months prior to the Screening Visit. 
e. Subject has a history of new or recently modified botulinum therapy (e.g., 
onabotulinum toxin A, abobotulinum toxin A, and incobotulinum toxin A) within the 
3 months prior to the Screening Visit. 
f. Subject has a history of injection therapy other than botulinum therapy (e.g., 
lidocaine, corticosteroids, hyaluronic acid) within the 30 days prior to the Screening 
Visit. 
g. Subject has a history of Transcutaneous Electrical Nerve Stimulation (TENS) use 
within the 3 months prior to the Screening Visit. 
6. Other Exclusion Criteria 
a. Prisoners or subjects who are involuntary incarcerated. 
b. Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
c. Participation in clinical trial with non-biological investigational agents or 
investigational interventional treatments within the 30 days prior to Screening Visit. 


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d. Subjects who have previously participated in any BHV-3000/ BMS-927711/ 
rimegepant study. 
e. Participation in clinical trial with biological investigational agents within the 3 
months prior to Screening Visit. 
f. Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 
12 months prior to the Screening Visit, OR subjects who endorse any of the five C- 
SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, 
preparatory acts, or behavior) within the last 10 years prior to the Screening Visit, OR 
subjects who, in the opinion of the Investigator, present a serious risk of suicide (See 
Section 6.3.5). 
g. Planned participation in any other investigational clinical trial while participating in 
this clinical trial. 
h. Subjects engaged in, or with plans to engage in, litigation or Worker’s Compensation 
in which monetary gain or loss (or other compensation) may affect their objective 
participation in the trial. 
See Section 5.4 for prohibited medications and Section 5.5 for allowable medications to 
consider when evaluating subject eligibility. 
Subjects must be willing to comply with all concomitant medication requirements and study 
procedures. 
5.4 
Prohibited and Restricted Concomitant Medications 
The below medications are prohibited prior to randomization and during the course of this 
study or as specified. 
1. History of non-narcotic analgesic intake on greater than/equal to 15 days per month for 
greater than/equal to 3 months (e.g., acetaminophen, NSAIDs, gabapentin etc.) for other 
pain indications. (Please refer to Section 5.5 for rescue medication). 
2. Use of all acetaminophen or acetaminophen containing products must be discontinued at 
least 2 days prior to randomization (acetaminophen < 1000 mg/day is allowed as rescue 
medication, see Section 5.5). During the screening phase (3-14 days) use of 
acetaminophen or acetaminophen containing products at daily dosing levels of greater 
than 1000 mg/day is prohibited. 
3. Muscle relaxants should not be taken 14 days prior to randomization and throughout the 
study (cyclobenzaprine is allowed as rescue medication, see Section 5.5). 
4. Systemic corticosteroids should not be taken 30 days prior to randomization and 
throughout the study. 
5. Benzodiazepines should not be taken 14 days prior to randomization and throughout the 
study. 


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6. St. John’s Wort should not be taken 14 days prior to randomization and throughout the 
study. 
7. Barbiturate-containing products (e.g., Fioricet, Fiorinal, butalbital, phenobarbital) should 
not be taken 14 days prior to randomization and throughout the study. 
8. Modafinil (PROVIGIL®) should not be taken 14 days prior to randomization and 
throughout the study. 
9. The use of CGRP antagonists (biologic or small molecule) is prohibited during the study. 
CGRP antagonist biologics must be discontinued 3 months prior to screening. CGRP 
small molecule antagonists must be discontinued 2 weeks prior to screening and 
throughout the course of the study. 
10. Use of narcotic medication, such as opioids (e.g., morphine, codeine, oxycodone and 
hydrocodone) is prohibited for at least 30 days prior to the Screening Visit and throughout 
the study. 
11. Use of cannabinoids (e.g., marijuana, CBD) is prohibited during the study. 
12. Concomitant use of strong CYP3A4 inhibitors, such as HIV Protease Inhibitors, Hepatitis 
C protease inhibitors, certain azole antifungals, or clarithromycin, is prohibited during the 
study. Strong CYP3A4 inhibitors must be discontinued 14 days prior to screening and 
throughout the course of the study. Please see Section 17.1, Appendix I, for additional 
resources. 
13. Concomitant use of moderate to strong CYP3A4 inducers, such as carbamazepine, 
phenytoin, or rifampin, is prohibited during the study. Moderate or strong CYP3A4 
inducers must be discontinued 14 days prior to screening and throughout the course of the 
study. Please see Section 17.1, Appendix I, for additional resources. 
14. Atypical antipsychotics such as Abilify (aripiprazole), Zyprexa (olanzapine), Seroquel 
(quetiapine), Geodon (ziprasidone), or Risperdal (risperidone) or Depakote/Depakene 
(valproic acid/valproate) should not be taken 3 months prior to randomization and 
throughout the study. 
15. LAMICTAL (lamotrigine) should not be taken 3 months prior to randomization and 
throughout the study. 
16. Subjects with daily use of medications to reduce intensity of TMD symptoms are 
permitted to remain on therapy provided they have been on a stable dose for at least 3 
months prior to study entry (see Section 5.5. Daily and Rescue Medications and Oral 
Devices) 
Low dose aspirin (e.g., 81 mg or less) for documented cardiovascular prophylaxis is allowed. 
5.5 
Daily and Rescue Medications and Oral Devices 
Subjects may not use more than 1 of the following medications and not more than 1 of the 
oral devices if not otherwise prohibited by the protocol. Medication doses must be stable 


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within 3 months prior to the Screening Visit and throughout the study. Use of oral devices 
must be consistent (i.e., non-active) within 3 months prior to the Screening Visit and 
throughout the study. 
Daily medications and therapy that are permitted during the study include: 
 
Tricyclic antidepressants (such as: amitriptyline, nortriptyline) 
 
Venlafaxine, desvenlafaxine, duloxetine, milnacipran 
 
Gabapentin, pregabalin 
 
Feverfew, magnesium (≥ 600 mg/day), riboflavin (≥ 100 mg/day) 
 
Botulinum therapy (e.g., onabotulinum toxin A, abobotulinum toxin A, and 
incobotulinum toxin A) 
Oral devices that are permitted during the study include: 
 
Night guards, splints, dental orthotics, dental appliances 
 
Dental orthodontics 
The use of CGRP antagonists (biologic [e.g., Aimovig®, Ajovi®, Emgality®, Vyepti®] or 
small molecule) other than rimegepant is prohibited during the study. 
After dosing with study medication, all other pain medication is prohibited during the 2 hours 
post dose. However, a subject who does not experience relief of their pain at the end of 2 
hours after dosing with study medication (and after the 2-hour assessments have been 
completed on the eDiary), will be permitted to use the following rescue medication: 
acetaminophen (up to 1000 mg/day); or aspirin, ibuprofen, naproxen (or any other type of 
non- steroidal anti-inflammatory [NSAID]), or cyclobenzaprine (all up to the daily 
recommended dose indicated on the drug packaging). Subjects may administer whichever 
protocol permitted standard of care rescue medication they choose to reduce symptoms and 
that they have available. These are the only medications allowed for rescue treatment after 2 
hours post dose of study medication. 
However, if needed, after 24 hours of administering the one dose of study medication (and 
before coming in for the End of Treatment Visit) subject may take their prescribed standard 
of care medications for treatment of TMD provided all the assessments have been completed 
on the eDiary. Exclusionary rescue medication such as opioids, butalbital compounds, and 
muscle relaxants (except cyclobenzaprine as a rescue medication, see above) are not allowed 
on this study. Similarly, if the pain is relieved by study medication at 2 hours after dosing but 
then recurs to intensity level of  6 on NRS (0-10) between 2 and 24 hours, the subject will 
be permitted to take the same rescue therapy as outlined above. In all circumstances, the 
subject will always continue to complete his or her eDiary entries through the 24-hour 
assessment after consuming the study medication. Use of concomitant medication after 
randomization, including rescue medication, will be recorded by the subject on a paper diary 
and reported to the site. The site will record medications that were taken within 14 days of 
dosing with study medication (or until the End of Treatment Visit). 


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During the [up to] 66 days the subject is participating in the study, if the subject has a non- 
qualifying TMD-associated pain (i.e., pain < 6 on a NRS (0-10) in the jaw and/or temple area 
on either side), the subject is permitted to use only the following medications: acetaminophen 
(up to 1000 mg/day); or aspirin, ibuprofen, naproxen (or any other type of non- steroidal anti- 
inflammatory [NSAID]), or cyclobenzaprine (all up to the daily recommended dose indicated 
on the drug packaging). Subjects may administer whichever protocol permitted standard of 
care medication they choose to reduce symptoms and that they have available. 
After completing all assessments (through 24 hours and before End of Treatment Visit) in 
their eDiary, if subjects experience pain they are allowed to take their prescribed standard of 
care medication. 
5.6 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) includes any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy) or is not postmenopausal. Tubal ligation 
is considered one form of contraception; therefore, one additional form of contraception must 
be used to fulfill contraception requirements for the study. Essure, tubal occlusion and 
endometrial ablation are not acceptable methods of contraception. Menopause is defined as: 
Amenorrhea greater than or equal to 12 consecutive months without another cause 
and a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. 
NOTE: FSH level testing is not required for women greater than or equal to 62 years 
old with amenorrhea of greater than or equal to 1 year. 
OR 
Woman on hormone replacement therapy (HRT) who no longer menstruate. 
Women of childbearing potential (WOCBP) and all men must understand the following 
requirements and use an acceptable method of contraception to avoid pregnancy throughout 
the study and for up to 60 days for WOCBP and 90 days for male subjects after the last dose 
of investigational product in such a manner that risk of pregnancy is minimized. 
It is required that all WOCBP use 2 methods of contraception to prevent pregnancy, for the 
duration of the study (i.e., this study begins with signed consent form through 60 days after 
dosing with study drug). The 2 methods should include 1 barrier method (ex. condom with 
spermicidal gel, non-hormonal intrauterine devices, cervical cap etc.) and 1 other method. 
The other method could include another barrier method or hormonal contraceptives (e.g., oral 
contraceptives, injectable contraceptives, patch, or contraceptive implant [e.g., hormonal 
intrauterine device]) used since at least 4 weeks prior to sexual intercourse. 
WOCBP and all male subjects must be counseled on the requirements to avoid pregnancy 
throughout the study and for 60 days for WOCBP and 90 days for male subjects after the last 
dose of study drug, as well as acceptable methods of contraception to use during the study. 
Subjects who report abstinence, or who report exclusively being in same-sex relationships are 
still required to understand the contraception requirements in this study to prevent pregnancy. 


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If subjects who report abstinence or who report exclusively being in a same-sex relationship 
engage in heterosexual activity, then the contraception requirements must be followed. 
Males with vasectomy are considered surgically sterile provided the procedure occurred 
greater than 6 months (24) weeks prior to the screening visit. Vasectomy is considered one 
form of contraception; therefore, one additional form of contraception must be used to fulfill 
the contraception requirements for the study. Male subjects must not donate sperm until 90 
days following the last study drug administration. 
 
All WOCBP must complete the pregnancy test schedule in Table 1. 
 
5.7 
Other Restrictions and Precautions 
Not applicable. 
5.8 
Protocol Deviations 
Any significant event that does not comply with the inclusion / exclusion criteria, study 
conduct, or study procedures will be documented as a deviation. Deviations will be 
documented and reported throughout the clinical monitoring of the trial. Deviations will be 
reported to the IRB/EC at the frequency required by the IRB/EC. Prospective approval of 
protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, is not permitted. See Section 10.1 for further information on serious breaches of 
the protocol. 


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6 STUDY CONDUCT AND DESCRIPTION OF STUDY 
PROCEDURES 
6.1 
Study Materials 
The following study materials may be provided at the study start: 
 
Investigator File/Regulatory Binder 
 
Pharmacy Binder 
 
Drug Accountability Logs 
 
Sample source documents, where applicable 
 
Concomitant and Rescue Medication Logs (take home for subject) 
 
Investigator Brochure 
 
Interactive Web-based Response System (IWRS) 
 
Electronic Case Report Form (eCRF) instructions 
 
Electronic Diary (eDiary): 1 will be given to each randomized subject 
 
Instructions for the ePRO device and access to the portal 
 
Laboratory Kits and Laboratory Manual 
 
Pregnancy Test 
 
ECG Machine and Instructions 
 
Serious Adverse Event (SAE) forms 
 
Pregnancy Surveillance Forms 
 
Symptom Questionnaire – DC/TMD 
 
Clinical Exam Form (NA) – DC/TMD 
 
 
CCI 
 
All sites will use an Electronic Data Capture (EDC) tool to submit study data to the Sponsor’s 
CRO. Electronic Case Report Forms (eCRFs) will be prepared for all data collection fields. 
SAE data (including responses to queries) will be submitted to the CRO using a paper SAE 
report form. Electronic Patient Reported Outcomes (ePRO) will be used for all patient-rated 
scales and will be captured on an eDiary. Any assessment completed by the subject in the 
eDiary will be transferred from the site/subject to the vendor and from the vendor to the CRO 


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and/or Sponsor. No additional source documents are required for scales and assessments 
completed by the subject in eDiary. 
Safety laboratory, plasma, serum, instructions for all specimens collected will be provided by 
a designated central laboratory. ECG equipment, supplies, instructions, and training materials 
will be supplied by a centralized ECG vendor. 
6.2 
Eligibility Assessments 
6.2.1 
Symptom Questionnaire – DC/TMD 
Subjects will undergo an assessment using the DC/TMD Symptom Questionnaire during the 
Screening Phase as outlined in Table 1. 
6.2.2 
Clinical Exam Form (NA) – DC/TMD 
Subjects will undergo an assessment during the Screening Phase using the DC/TMD 
Symptom Questionnaire at the scheduled visits as outlined in Table 1. 
6.3 
Safety Assessments 
6.3.1 
Vital Signs and Physical Measurements (Height and Weight) 
Sitting arterial systolic and diastolic blood pressure and pulse rate, height, weight and body 
temperature will be measured at Screening and End of Treatment. Height and weight will be 
done at Screening only see Table 1. 
6.3.2 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be recorded during the Screening Phase and at the scheduled 
visits as outlined in Table 1. A central ECG service will be utilized for all ECGs and the 
Investigator will determine if any abnormalities are clinically significant or not. 
6.3.3 
Physical Exam 
Subjects will undergo a routine physical examination during the Screening Phase and at the 
scheduled visits as outlined in Table 1. Physical examinations include examination of the 
heart, abdomen, lungs, and any other body system to be guided by symptoms. 
6.3.4 
Laboratory Assessments 
6.3.4.1 
Safety Laboratory Testing 
Blood and urine samples will be obtained as outlined in Table 1 for clinical laboratory 
evaluations. A central laboratory vendor will be utilized for this study and a laboratory 
manual will be provided to each site. If possible, subjects should be fasting for a minimum of 
8 hours prior to all blood draws. However, if a subject is not fasting at a given visit, the blood 
draw should still be performed, and the non-fasting status should be documented. 
Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count (WBC) 
with differential, and platelets. 


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Blood chemistry/electrolyte: Sodium, potassium, chloride, bicarbonate, calcium; glucose, 
BUN (urea), serum creatinine, uric acid, ALT, AST, alkaline phosphatase, LDH, total 
protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, CK. End of Treatment 
Visit – elevations in CK (>5x ULN) may have further CK fractionation tests performed 
through the central lab. 
Lipid Panel: Total cholesterol, LDL, HDL and triglycerides will be performed through the 
central lab at screening. 
HbA1c: measured at screening only. 
Estimated glomerular filtration rate: eGFR using the estimated MDRD formula will be 
calculated and reported by the central lab at each visit that clinical laboratory tests are 
collected as outlined in Table 1. 
Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, protein, 
glucose, and blood. If blood, protein, or leukocytes are positive, reflex to microscopic 
examination. 
Urine Drug Screen: For drugs of abuse. 
 
Reflex tests: If ALT or AST ≥ 3 x ULN OR total bilirubin ≥ 2 x ULN at any visit after the 
baseline visit, the central laboratory will perform reflex tests that may include: CK, GGT, and 
anti-viral serologies. Subjects may have to return to the study site to provide additional blood 
samples for these laboratory tests. 
 
FSH: A confirmatory FSH level will be measured at screening on post-menopausal women 
(as defined in Section 5.6) to confirm post-menopausal status. FSH level testing is not 
required for women greater than or equal to 62 years old with amenorrhea of greater than or 
equal to 1 year. 
Additional laboratory tests may be required. 
6.3.4.2 
Pregnancy Testing 
Pregnancy tests will be conducted on women of childbearing potential as outlined in Table 1. 
Women of childbearing potential must have a negative serum or urine pregnancy test at the 
Screening Visit, Baseline Visit, and prior to taking study medication. Subjects will be 
provided with the accompanying package insert that contains instructions for use and 
interpretation of results. 
6.3.5 
Columbia Suicidality Severity Rating Scale (CSSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide 
assessment.14 The C-SSRS “Screening version” will be used at the Screening Visit and the 
“Since Last Visit version”15 will be used at subsequent visits in this study. 
The C-SSRS Assessment is intended to help establish a person’s immediate risk of suicide. 
The C-SSRS is a clinician administered scale that should be administered by a certified rater. 


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This scale will be collected on site with a paper form. The C-SSRS should be reviewed by the 
Investigator or designee before the subject is allowed to leave clinic. 
At the Screening Visit, the recall period for completing is 12 months for suicidal ideation and 
10 years for suicidal behavior; at all other visits, the recall period for completing the C-SSRS 
is since the last visit (Table 1). 
Any “Yes” responses must be immediately evaluated by the investigator. If the Investigator 
determines that a participant is at risk of suicide, self-harm, appropriate measures to ensure 
the participant’s safety and obtain mental health evaluation must be implemented. In such 
circumstances, the participant must immediately be discontinued from the study. The event 
should be recorded as either an AE or SAE as determined by the Investigator and reported 
within 24 hours to the Sponsor. 
6.4 
Efficacy Assessments 
6.4.1 
Pain 
Subjects are given an eDiary to record their current TMD-associated pain score, on a NRS (0- 
10) at the time points indicated in Table 1. 
6.4.2 
Rescue Medication 
The subject’s use of rescue medication is recorded by the subject in a paper diary. 
CCI 
 
 
 
6.5 
Early Discontinuation from the Study 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the Investigator) for any of the following reasons: 
 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 


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 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the Investigator or Sponsor, indicates that continued participation in the 
study is not in the best interest of the subject. 
 
Pregnancy. 
 
Termination of the study by Biohaven Pharmaceuticals. 
 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
All subjects who discontinue should comply with protocol specified End of Treatment 
procedures as outlined in Table 1. The only exception to this requirement is when a subject 
withdraws consent for all study procedures or loses the ability to consent freely (i.e., is 
incapacitated, imprisoned, or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness). 
6.5.1 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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7 
STUDY DRUG MANAGEMENT 
7.1 
Description of Study Drug 
7.1.1 
Investigational Product 
An investigational product, also known as investigational medicinal product in some regions, 
is defined as follows: 
 
A pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization 
but used or assembled (formulated or packaged) in a way different from the authorized 
form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form. 
The investigational product should be stored in a secure area according to local regulations. It 
is the responsibility of the Investigator to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations. 
In this protocol, investigational product is/are: 
 
Rimegepant ODT and matching placebo. The rimegepant ODT and the matching placebo 
appear identical visually, via touch, smell, and taste. 
7.1.2 
Non-Investigational Product 
Other medications used as support or rescue medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered non-investigational products. 
In this protocol, non-investigational product(s) is/are: 
 
Standard of care / rescue medications and/or oral devices for the treatment of TMD- 
associated symptoms. 
7.1.3 
Packaging, Shipment and Storage 
The investigational product storage manager should ensure that the study drug is stored in 
accordance with the environmental conditions (temperature, light, and humidity) as 
determined by the Sponsor. Please see the Pharmacy Manual/Investigator Brochure for 
specific conditions. If concerns regarding the quality or appearance of the study drug arise, do 
not dispense the study drug and contact the Sponsor/CRO immediately. 
7.2 
Dose and Administration 
One dose of rimegepant ODT (75 mg) or matching placebo will be dispensed to the subject 
and will be taken at the time the subject has a TMD-associated pain that reaches intensity of  
6 on a NRS (0-10) and after completing the eDiary questions. 


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7.2.1 
Method of Assigning Subject Identification 
Immediately after written informed consent is obtained and before performing any study- 
related procedures, each subject will be assigned a unique sequential subject number for 
identification throughout the study through an IWRS. This subject number must not be reused 
for any other subject in the study. The physician/coordinator must contact the IWRS to enroll 
each subject into a centralized database after signing consent. 
After completion of all screening evaluations, all eligible subjects will be randomized in a 1:1 
ratio to the rimegepant or matching placebo treatment groups. The randomization will be 
stratified by the daily use of medications / oral devices to reduce intensity of TMD symptoms 
(yes or no). It is important to correctly enter subjects who are using daily medications / oral 
devices in the IWRS system. Once a subject is stratified in the IWRS, this cannot be changed. 
Randomization schedules will be generated and kept by the IWRS vendor in a secure network 
folder with access limited to only unblinded team members. Each subject who is qualified for 
treatment will be randomized via the IWRS randomization option. Subjects will maintain 
their subject number assigned at screening throughout the trial. The IWRS will provide the 
double-blind treatment assignments. 
The randomization will trigger dispensation for the subject and assign a bottle number for the 
appropriate randomized treatment type. The drug is dispensed at the time of randomization. 
7.2.2 
Selection and Timing of Dose and Administration 
Study medication (one 75 mg orally disintegrating tablet or matching placebo) will be 
packaged in a single blister in a subject-specific bottle. There are no dose adjustments in this 
study and subjects will receive one dose to treat TMD-associated pain of  6 on a NRS (0-10) 
within 45 days of randomization (Baseline Visit). Subjects will be dispensed the study 
medication at randomization (Baseline Visit) and will take the ODT from the blister/bottle at 
the time of TMD-associated pain of  6 on a NRS (0-10) onset ONLY after answering 
questions regarding their TMD-associated symptoms in the eDiary device. The ODT should 
be placed on or under the tongue until fully dissolved then swallowed. Subjects should be 
instructed to use dry hands when handling the study medication. 
7.2.3 
Dose Modifications 
There will be no dose adjustments in this study. 
7.3 
Blinding and Unblinding 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that subject may be broken by 
the treating physician. 
Before breaking the blind of an individual subject’s treatment, the Investigator should have 
determined that the information is necessary, (i.e., that it will alter the subject’s immediate 
management). In many cases, particularly when the emergency is clearly not investigational 


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product related, the problem may be properly managed by assuming that the subject is 
receiving active product without the need for unblinding. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt to 
preserve the blind is made. 
7.4 
Treatment Compliance 
Responsible study personnel will dispense the study drug. Accountability and compliance 
verification should be documented in the subject’s study records. 
Subjects have to be counseled on the importance of taking the study drug as directed when a 
TMD-associated pain occurs and reaches intensity of  6 on a NRS (0-10). If the subject does 
not have a TMD-associated pain of  6 on a NRS (0-10) or take their study medication within 
45 days of the Baseline Visit, they should return to the clinic for their End of Study Visit and 
return their unused study medication. 
7.5 
Destruction and Return of Study Drug 
Subjects will be instructed to return all unused study drug or packaging from used study drug 
to the study site for drug accountability. All unused study drug can be sent back to the drug 
depot for destruction only after being inspected and reconciled by the responsible Study 
monitor or the Sponsor’s designee. If it is site policy to destroy study drug on site, it is the 
Investigator’s responsibility to ensure that arrangements have been made for the disposal, 
procedures for proper disposal have been established according to the applicable regulations, 
guidelines and institutional procedures, and appropriate records of the disposal have been 
documented. The used study drug packaging can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor or the Sponsor’s designee. 


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8 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a subject or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding for example) symptom, or disease temporally associated with 
the use of the investigational product, whether or not considered related to the investigational 
product. 
Adverse events can be spontaneously reported or elicited during an open-ended questioning, 
examination, or evaluation of a subject. In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs. 
If a specific diagnosis or syndrome is identified by the Investigator, this should be recorded 
as the AE, rather than recording (as separate AEs) the individual signs/symptoms or clinically 
significant laboratory abnormalities known to be associated with, and considered by the 
Investigator to be a component of, the disease/syndrome. 
Definition of terms related to all Adverse Events (serious and non-serious): 
Mild: Is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
Moderate: Is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject. 
Severe: Interrupts usual activities of daily living, significantly affects clinical status, or may 
require intensive therapeutic intervention. 
Life threatening AEs that are considered life threatening should be considered SAEs. An AE 
is life threatening if the subject was at immediate risk of death from the event as it occurred, 
i.e., it does not include a reaction that if it had occurred in a more serious form might have 
caused death. For example, drug induced hepatitis that resolved without evidence of hepatic 
failure would not be considered life threatening even though drug induced hepatitis can be 
fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization 
for elective surgery or routine clinical procedures that are not the result of AE (e.g., elective 
surgery for a pre-existing condition that has not worsened) need not be considered AEs or 
SAEs. If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE, either 'serious' or 'non-serious' according to the usual criteria. 


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Assessment for Determining Relationship of AE to Study Drug: 
The relatedness of each AE to study drug must be classified based on medical judgement and 
according to the following categories. The definitions are as follows: 
Related: This category applies to AEs that are considered, with a high degree of certainty, to 
be related to the study drug. An AE may be considered related when it follows a temporal 
sequence from the administration of study drug, it cannot reasonably be explained by the 
known characteristics of the subject’s clinical state, environment, or toxic factors, or other 
modes of therapy administered to the subject. An AE may be considered related when it 
follows a known pattern of response to the study drug, or if the AE reappears upon re- 
challenge. This category also applies to AEs that are considered to have an unlikely 
connection to study drug, but a relationship cannot be ruled out with certainty. 
Unrelated: This category applies to AEs that are considered with a high degree of certainty to 
be due only to extraneous causes (e.g., subject’s clinical state, environment, toxic factors, 
disease under study, etc.) and does not meet the criteria of other categories above. 
There are two types of adverse events, Serious Adverse Events (SAE) and Non-Serious 
Adverse Events (AEs). 
8.1 
Serious Adverse Events 
8.1.1 
Definition of Serious Adverse Event (SAE) 
An SAE is any event that meets any of the following criteria at any dose: 
 
Death 
 
Life-threatening 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
Persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect in the offspring of a subject who received rimegepant 
 
Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events are (but not limited to): 
○ Intensive treatment in an emergency room or at home for allergic bronchospasm 
○ Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
○ Development of drug dependency or drug abuse 


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○ Potential drug induced liver injury (see Section 8.5) 
○ Abuse or Overdose of medication 
▪ 
Potential study medication abuse (including cases of excessive non-compliance 
with study medication dosing instructions or subjects who discontinue treatment 
without returning study medication) should be documented in the source record 
and reported as an AE or SAE as appropriate. Investigators must monitor subjects 
for possible cases of abuse of study medication (subjects taking study drug for 
non-therapeutic purposes, e.g., for psychoactive effects such as high or euphoria). 
Investigators should obtain more information and explanation from subjects when 
there are study drug accountability discrepancies. 
▪ 
Potential study medication overdose is defined in Section 8.3. 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician's office or outpatient setting. When in 
doubt as to whether 'hospitalization' occurred or was necessary, the AE should be considered 
serious. 
The following hospitalizations are not considered SAEs in Biohaven clinical studies (but may 
be considered non-serious AEs): 
 A visit to the emergency room or other hospital department for <24 hours that does not 
result in an admission (unless considered “important medical event” or event that is life 
threatening). 
 
Elective surgery planned prior to signing consent. 
 
Admissions as per protocol for a planned medical/surgical procedure. 
 
Routine health assessment requiring admission (i.e., routine colonoscopy). 
 
Admission encountered for another life circumstance that carries no bearing on health and 
requires no medical intervention (i.e., lack of housing, care-giver respite, family 
circumstances). 
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions. 
8.1.2 
Collection and Reporting Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specific procedures. All SAEs must be collected that occur during the screening 
period and throughout the course of the study up to and including the End of Treatment Visit 
/ 30 days after last dose. The Investigator should report any SAE occurring after this time 
period that is believed to be related to study drug or protocol-specific procedures. 


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All SAEs should be followed to resolution or stabilization. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
If the Investigator believes that an SAE is not related to the study drug, but is potentially 
related to the conditions of the study (such as a withdrawal of previous therapy or a 
complication related to study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
SAEs, whether related or not related to study drug, overdose (see Section 8.3), potential drug 
induced liver injury (see Section 8.5) and pregnancies (see Section 8.4) must be reported 
within 24 hours of the Investigator becoming aware of the event. The Investigator is 
responsible for submitting all applicable events to the Independent Review Board (IRB) as 
per the IRB’s reporting requirements. Additionally, the Investigator, or designated staff, is 
responsible for entering the SAE information into the Case Report Form (CRF) and/or system 
(i.e., event term, start/stop dates, causality, and severity). 
Any serious adverse event must be reported immediately or no later than 24 hours after 
awareness of the event to PPD Pharmacovigilance (PVG). A written description of any 
serious adverse event, using the PPD SAE report form, must be sent to PPD PVG by 
facsimile (fax), which is the preferred method of submission, within 24 hours after awareness 
of the event: 
 
North America - 1-888-488-9697 
If a form is unable to be submitted within 24 hours, the SAE may be reported by telephone 
via the Safety Hotline Number: 
 
North America – 1-800-201-8725 
If only limited information is initially available, follow-up reports are required. If an ongoing 
SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours of the Investigator 
becoming aware of the updated information using the same procedure used for the 
transmission of the initial SAE and the same event term should be used. 
The minimum information required for an initial SAE report is: 
 
Sender of report (Site number, Investigator name) 
 
Subject identification (subject number) 
 
Protocol number 
 
SAE term (if an SAE is being reported) 
8.2 
Non-serious Adverse Events 
A non-serious adverse event is an AE not classified as serious. 


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8.2.1 
Collection and Reporting of Non-Serious Adverse Events 
The collection of non-serious AE information should begin at the initiation of study drug 
through the Follow up Safety Visit (End of Treatment Visit). 
Non-serious adverse events should be followed until conclusion or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug or those that are present at the end of study 
treatment. 
8.2.2 
Laboratory Test Abnormalities 
The following laboratory test abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate: 
 
Any laboratory test result that is clinically significant or meets the definition of an SAE. 
 
Any laboratory abnormality that required the subject to have the study drug discontinued 
or interrupted. 
 
Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
8.3 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. 
All occurrences of medically significant overdose (suspected or confirmed and irrespective of 
whether it involved BHV-3000) must be communicated to Biohaven or a specified designee 
within 24 hours and be fully documented as an SAE. Details of any signs or symptoms and 
their management should be recorded including details of any treatments administered. 
Asymptomatic dosing errors (e.g., accidentally taking two tablets instead of prescribed dose 
of one tablet in one calendar day) should be reported as deviations. 
8.4 
Pregnancy 
If, following the Baseline Visit, it is subsequently discovered that a study subject is pregnant 
or may have been pregnant at the time of the investigational product exposure, including 
during at least 6 half-lives after the product administration, the investigational product will be 
permanently discontinued in an appropriate manner (i.e., dose tapering if necessary for 
subject safety). Protocol-required procedures for study discontinuation and follow-up must 
be performed on the subject unless contraindicated by the pregnancy (i.e., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated. 
Sites should instruct subjects to contact the Investigator if they become pregnant during the 
course of the study. The Investigator must immediately notify the Biohaven (or designee) 
Medical Monitor and PPD of the event and complete the Pregnancy Form in accordance with 
SAE reporting procedures as described in Section 8.1.2. The pregnancy should be reported 


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using paper forms, which should be faxed to PPD PVG by facsimile (fax), which is the 
preferred method of submission, within 24 hours after Investigator/site awareness of the 
event: 
 
North America - 1-888-488-9697 
Or if the form cannot be faxed or emailed (wilsafety@ppdi.com; subject line must include 
“Biohaven Protocol BHV3000-314”), reported via phone to the PPD Safety Hotline at North 
America: 1-800-201-8725. 
Once the paper form is available, the data must be reported per standard procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome, and where applicable offspring information must also be reported on a 
Pregnancy Report Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to the Sponsor/PPD. Information on this pregnancy will be collected on the Pregnancy 
Report Form, as appropriate. 
8.5 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of the initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs as per Section 8.1.2. 
Potential drug induced liver injury is defined as: 
1. ALT or AST elevation > 3 times the upper limit of normal (ULN). 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase). 
AND 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
If any potential DILI is identified and meets the criteria above, the Biohaven Medical 
Monitor (or designee) should immediately be contacted for further instruction and whether 
the subject must discontinue from the trial and appropriate follow up requirements. 
8.6 
Adverse Events of Special Interest 
None 


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9 STATISTICS 
Complete details on the statistical methods for this study may be found in the Statistical 
Analysis Plan (SAP). 
9.1 
General Procedures 
Categorical variables are tabulated with counts and percentages. Continuous variables are 
summarized with univariate statistics (e.g., n, mean, standard error, median, minimum and 
maximum). 
For the calculation of descriptive statistics of observed data, subjects must have a baseline 
value to be evaluable for endpoints based on values and changes from baseline over time. 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; interruptions of study therapy; non-study medications; adverse events; 
and laboratory abnormalities. Thus, for these endpoints, multiple occurrences of the same 
event are counted only once per subject. 
9.2 
Sample Size 
If 80% of the 200 randomized (100 per treatment arm) treat with study drug, we expect 
roughly 160 total or 80 per treatment group in the randomized and treated population for 
analysis. 
Assuming rimegepant provides a 2-point reduction in NRS pain, and a 1.5-point advantage 
over placebo on the primary endpoint, and a common standard deviation of 3.0, then the 
study will have roughly 88% power on the primary endpoint. 
9.3 
Populations for Analysis 
The set of enrolled subjects consists of all subjects who signed the informed consent form 
and were assigned a subject identification number. 
The set of randomized subjects consists of enrolled subjects who were assigned a randomized 
treatment group. 
The set of treated subjects consists of all randomized subjects who take study therapy 
(rimegepant or placebo). 
9.4 
Statistical Methods 
9.4.1 
Demographic and Baseline Characteristics 
Tabulations of demographic and baseline characteristics are made for: subjects randomized 
but not treated; subjects randomized and treated; and overall. A separate set of tabulations are 
made for subjects enrolled but not randomized. 


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9.4.2 
Primary Endpoint(s) 
The SPID-2 will be calculated by multiplying the PID score (difference between NRS at each 
time point and baseline NRS) at each post-dose timepoint by the duration (in hours) since the 
preceding timepoint, then summing the values over the 2 hours. This is analyzed on the 
treated population using an analysis of covariance (ANCOVA) model that includes the 
baseline NRS (0-10) value as a covariate, and main effects for treatment group and 
stratification factor (use of daily medications / oral devices to reduce the intensity of TMD 
symptoms). 
The least squares mean (LS mean), standard error (SE), and 95% confidence interval (CI) for 
each treatment group will be reported, as well as the difference estimate (rimegepant - 
placebo), SE, 95% CI, and p-value. 
Intercurrent events will be treated as failures, with the assumption that the subject does not 
improve once the intercurrent event occurs. In the event a subject uses a non-study rescue 
medication on or before 2 hours post-dose, all data points after rescue medication was 
administered will be set to the last available observation prior to rescue medication usage 
(RM = Rescue medication use: F = Failure). Likewise, if a subject fails to log their pain score 
at any time after study drug is administered, through 2 hours post-dose, this data will be 
imputed to the last available observation (NC = Non-completers; F = Failure). 
Sensitivity analyses will be described in the SAP. 
9.4.3 
Secondary Endpoint(s) 
If the primary endpoint test is significant at alpha  0.05, then the secondary endpoints will 
be analyzed at an alpha level of  0.05 using Hochberg’s procedure. Secondary endpoints 
will be analyzed on the treated population. 
9.4.3.1 
SPID-24 
The SPID-24 will be analyzed in the same manner as the primary endpoint, with the SPID 
calculated by multiplying the PID score at each post-dose timepoint by the duration (in hours) 
since the preceding timepoint, then summing the values over the 24 hour period. 
9.4.3.2 
Change from Baseline of Pain on NRS 
The change from baseline of pain on NRS score at 2 hours post-dose will be analyzed with a 
generalized linear mixed effect model that includes subject as a random effect, the baseline 
NRS (0-10) value as a covariate, and fixed effects for treatment group, stratification factor 
(use of daily medications / oral devices to reduce the intensity of TMD symptoms), scheduled 
time point, and time point by treatment group interaction. Time points included in the model 
are nominally at 15, 30, 45, 60, 90 and 120 minutes post-dose. Repeated measurements 
within-subject will be modeled using an unstructured covariance structure for within-subject 
error. In the case that the model fails to converge, a Huynh-Feldt error structure will be 
attempted, followed by an AR(1) structure. Error degrees of freedom will be calculated using 
a Kenward-Roger approximation. The difference estimate (rimegepant - placebo), SE, 95% 
CI, and p-value will be reported for 2 hours post-dose. 


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CCI 
Interurrent events of use of a non-study rescue medication at or before 2 hours post-dose, or 
if a subject fails to log their pain score at any time after study drug is administered through 2 
hours post-dose, will be handled in the same manner as they are for the primary endpoint. 
9.4.3.3 
Pain Freedom at 2 Hours 
The number of subjects that are pain free at 2 hours post-dose will be analyzed after first 
imputing missing data at 2 hours to be failure (NC = F). Additionally, subjects who use 
rescue medication on or before assessment of pain at 2 hours will also be assigned as failures 
(RM = F). The analysis will be done using a stratified Cochran-Mantel-Haenszel (CMH) test 
after imputation is done, with the stratification factor as use of daily medications / oral 
devices to reduce the intensity of TMD symptoms. 
9.4.3.4 
Time to Onset of Meaningful Pain Relief 
Time to onset of meaningful pain relief post-dose will be defined as the first nominal 
timepoint at which a 30% reduction of pain from baseline on NRS is achieved. This will be 
analyzed using Kaplan-Meier methods for a “time to event” analysis. Rimegepant will be 
compared to placebo using a log-rank test which will compare the survival distributions. 
Intercurrent events will be handled in the same manner as they are for the primary endpoint. 
9.4.3.5 
Time to Onset of Initial Pain Relief 
Time to onset of initial pain relief post-dose will be defined as the first nominal timepoint at 
which a 1-point reduction of pain from baseline on NRS is achieved. This will be analyzed 
using Kaplan-Meier methods for a “time to event” analysis. Rimegepant will be compared to 
placebo using a log-rank test which will compare the survival distributions. Intercurrent 
events will be handled in the same manner as they are for the primary endpoint. 
9.4.3.6 
Rescue Medication Use through 24 Hours 
The number of subjects that use rescue medication through 24 hours post-dose will be 
analyzed using a stratified CMH test, with the stratification factor as use of daily 
medications/oral devices to reduce the intensity of TMD symptoms. 
9.4.4 
Adjustment for Multiplicity 
Type 1 error is addressed in this study using a gatekeeping procedure. The significance of 
the primary endpoint is evaluated at the two-sided alpha level of 0.05. If the primary 
endpoint is significant, then the secondary endpoints are tested using Hochberg’s procedure. 
 
9.4.5 
Missing Data 
For the primary and secondary endpoints of SPID-2, SPID-24, change in NRS from baseline, 
time to onset of meaningful pain relief, and time to onset of initial pain relief, subjects who 
fail to record their pain during the timeframe of interest for each endpoint will be considered 


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failures (NC = F) and this data will be imputed to the last available observation prior to the 
missing data occurrence. 
For the secondary endpoint of proportion of subjects that are pain free at 2 hours post-dose, 
missing data at 2 hours post-dose will be imputed as a failure (NC = F), and these subjects 
will not be considered as having achieved pain freedom. 
For the secondary endpoint of proportion of subjects who use rescue medication through 24 
hours-post dose, there will be no imputation for missing data, the analysis will be based on 
non-missing, observed data. 
Additional methods for handling of missing data, including sensitivity analyses, will be 
described in detail in the SAP. 
9.4.6 
Rescue Medication 
For the primary and secondary endpoints of SPID-2, SPID-24, change in NRS from baseline, 
time to onset of meaningful pain relief, and time to onset of initial pain relief, use of non- 
study rescue medications on or before the time point of interest (2 hours post-dose or 24 
hours post-dose) will be handled as failures (RM = F). Specifically, the assumption will be 
that once the subject has used a rescue medication, their pain will not improve any further 
and these data points will be set to the last value recorded prior to the use of the rescue 
medication. 
For the secondary endpoint of pain freedom at 2 hours post-dose, subjects that take rescue 
medication on or before the time point of interest (2 hours post-dose) will be considered as 
failures (RM = F). 
Rescue medications are described in more detail in Section 5.5. 
9.4.7 
Analysis of Safety 
The Investigators determine the intensity of AEs and the relationship of AEs to study therapy. 
The Investigators’ terms are coded and grouped by system organ class using the latest version 
of the Medical Dictionary for Regulatory Activities (MedDRA) available. AEs are presented 
by system organ class and preferred term, ordered by the overall frequency of events. If a 
subject had an adverse event with different intensities over time, then only the greatest 
intensity is reported. 
AEs are tabulated in all treated subjects. SAEs occurring in subjects enrolled but not treated 
are listed. Deaths are listed for enrolled subjects without regard to onset. 
The frequencies of the following safety events are summarized by treatment regimen, and 
overall, for treated subjects: SAEs; all AEs, AEs by intensity; and AEs by relatedness. 
Clinically significant laboratory test abnormalities will be identified as Grade 3 to 4 
laboratory test results graded according to numeric laboratory test criteria in Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (2017), if available. 
Otherwise, if CTCAE grades are not available, then results will be graded according to 
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of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017). If a subject has a 
laboratory test abnormality with different toxicity grades over time, then only the highest 
toxicity grade will be reported. 
Further safety analyses will be described in the statistical analysis plan. 
9.5 
Schedule of Analyses 
The data from this study may be locked and analyzed at any point after the last subject 
completes their end of treatment visit and adequate time has been allowed for follow-up. 


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10 ETHICS AND RESPONSIBILITIES 
10.1 
Good Clinical Practice 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Good Laboratory Practice (GLP), International Conference on Harmonization guidelines, and 
all applicable regulations, including the Federal Food, Drug and Cosmetic Act, U.S. 
applicable Code of Federal Regulations (title 21), any Independent Ethics Committee (IEC) 
requirements relative to clinical studies. The study will also be conducted in compliance with 
the recommendations laid down in the most recent version of the Declaration of Helsinki, 
with the exception that registration of such Phase 1 trials in a publicly accessible database is 
not mandatory. 
This study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to 
initiation of the study. 
As per Section 5.8, any significant event that does not comply with the inclusion / exclusion 
criteria, study conduct, or study procedures will be documented as a deviation. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. All serious breaches 
must be reported to Biohaven (or designee) immediately. Examples include (but are not 
limited to): 
 
Missing, inadequate, or delinquent informed consent. 
 
Randomization of a subject that does not meet key eligibility criteria. 
 
Failure to withdraw a subject meeting discontinuation criteria. 
 
Unreported serious adverse events. 
 
Improper breaking of the blind. 
 
Conducting the study without IRB approval. 
 
Working under an expired medical license, or a debarred or disqualified status. 
 
Falsifying research or medical records. 
Study personnel involved in conducting this study will be qualified by education, training, 
and experience to perform their respective task(s). 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). 


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The Principal Investigator and the Sponsor’s representative must sign the protocol and its 
amendments (if any) before initiating the study. 
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary. 
10.2 
Institutional Review Board/Independent Ethics Committee 
The Investigators agree to provide the IRB/IEC with all appropriate documents, including a 
copy of the protocol/amendments, ICFs, advertising text (if any), Investigator’s brochure (if 
any) and any other written information provided to study subjects. The trial will not begin 
until the Investigators have obtained the IRB/IEC favorable written approvals for the above- 
mentioned study documents. 
In the event that the protocol is amended, the revised protocol must be approved by the 
IRB/IEC prior to its implementation, unless the changes involve only logistical or 
administrative aspects of the trial. 
10.3 
Informed Consent 
Investigators must ensure that subjects, or, in those situations where consent cannot be given 
by subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
Biohaven (or designee) will provide the Investigator with an appropriate (i.e., Global or 
Local) sample informed consent form which will include all elements required by ICH, GCP 
and applicable regulatory requirements. The sample informed consent form will adhere to 
the ethical principles that have their origin in the Declaration of Helsinki. 
Before the potential subject has undergone any study-related screening procedures, the nature 
of the study and the potential risks associated with it will be explained to the subject, and the 
subject will be given an opportunity to ask questions to his or her satisfaction. After the 
questions are answered, but before proceeding further, the subject must read, sign and date an 
IRB/IEC approved written informed consent form for study. The signed and dated ICF will 
be retained at the Investigator’s site, with a copy provided to the study subject and date will 
be entered in his or her CRF or appropriate system. The IRB/IEC must review and approve 
all protocol versions and informed consent form versions and a copy of each version of the 
IRB/IEC approved protocol and informed consent form is to be retained in the Study Master 
file. Any revisions to the protocol or ICF will be reviewed and approved by the IRB/IEC and 
subjects will be informed of ICF changes and document continuing consent by signing and 
dating the revised version of the ICF. 
If a revised ICF is introduced during the study, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IRB/IEC, prior to 
subsequently obtaining each subject’s consent. 
The informed consent form must also include a statement that Biohaven and its 
representatives and regulatory authorities may have direct access to subject records. 


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10.4 
Case Report Forms 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation of each study 
subject. Data reported on the CRF that are derived from source documents must be consistent 
with the source documents or the discrepancies must be explained. 
Electronic CRFs will be prepared for all data collection fields when EDC is being used. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The Investigator must retain a copy of the CRFs including records of changes and 
corrections. If EDC is being used, signatures will be obtained electronically and a copy of 
the electronic CRFs will be provided (or the data from the CRFs) for future reference. 


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11 RECORDS MANAGEMENT 
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and CRO. The Sponsor is entitled to access information about the 
status of the study and to review the original documents of the study. 
The Investigator must retain all study records and source documents for the maximum time 
period required by the applicable regulations and guidelines, or institution procedures or for 
the period of time specified by the Sponsor, whichever is longer. The Investigator must 
contact the Sponsor prior to destroying any records associated with this study. 
Biohaven will notify the Investigators when the study files for this study are no longer 
needed. 
If the Investigator withdraws from the study (i.e., retirement, relocation), the records shall be 
transferred to a mutually agreed upon designee. Notice of such transfer will be given in 
writing to Biohaven. 
It is the responsibility of the Investigator to ensure that the current disposition record of 
investigational product (may be supplied by the Sponsor) is maintained at each study site 
where the study drug is inventoried and dispensed. Records or logs must comply with 
applicable regulations and guidelines and should include: 
 
amount of study drug received and placed in storage area 
 
label ID number or batch number or Kit number as specified for the protocol 
 
amount dispensed to and returned from each subject 
 
amount transferred to another area or site for dispensing or storage if applicable 
 
amount of drug lost or wasted 
 
amount destroyed at the site if applicable 
 
amount returned to sponsor, if applicable 
 
retain samples for bioavailability/bioequivalence, if applicable 
 
record of dates and initials of personnel responsible for IM dispensing and accountability 
11.1 
Source Documentation 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent for all subjects on study. 
If source documents are created to support the collection of study information, this must be 
retained with the other pertinent medical records for each subject for verification of data 


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points, unless otherwise instructed by the Sponsor or designee to enter data directly on the 
eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
11.2 
Study Files and Record Retention 
The Sponsor does not require original documents that have already been scanned and entered 
into the eTMF system to be forwarded to the Sponsor. Any original documents (i.e., 1572, 
signed financial disclosure, signed ICF, etc.) will be retained in the regulatory binder at the 
study site. The CRO will conduct a final TMF reconciliation to ensure all study files and 
regulatory documents have been correctly uploaded to the TMF prior to the close or 
termination of the study. Any materials or documents to support the clinical trial outside of 
the eTMF (i.e., rater training tapes) should be maintained by the CRO. The Sponsor will be 
contacted to determine whether the study documents/materials that are retained outside of the 
TMF will be forwarded to the Sponsor, destroyed or kept at the CRO or at another facility for 
a longer period of time at the Sponsor's expense. 
The CRO will maintain adequate study records after completion or termination of study. 
After that period, the Sponsor will be contacted to determine whether the study records will 
be forwarded to the Sponsor, destroyed or kept at CRO or at another facility for a longer 
period of time at the Sponsor's expense. 


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12 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may 
be made only by Biohaven (or specified designee). A protocol change intended to eliminate 
an apparent immediate hazard to subjects may be implemented immediately, provided the 
IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the Investigator must await approval 
before implementing the changes. Biohaven or specified designee will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the Investigator, and/or Biohaven, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the 
subject and/or has an impact on the subject's involvement as a study participant, the currently 
approved written informed consent form will require similar modification. In such cases, 
informed consent will be renewed for subjects enrolled in the study before continued 
participation. 


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13 STUDY REPORT AND PUBLICATIONS 
Biohaven (or specified designee) is responsible for preparing and providing the appropriate 
regulatory authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication policy of Biohaven is discussed in the Investigator's Clinical Research 
Agreement. 


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14 STUDY DISCONTINUATION 
Both Biohaven and the Principal Investigator reserve the right to terminate the study at the 
Investigator’s site at any time. Should this be necessary, Biohaven or a specified designee 
will inform the appropriate regulatory authorities of the termination of the study and the 
reasons for its termination, and the Principal Investigator will inform the IRB/IEC of the 
same. In terminating the study, Biohaven and the Principal Investigator will assure that 
adequate consideration is given to the protection of the subjects’ interests. 


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15 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Biohaven. However, authorized regulatory officials, IRB/IEC 
personnel, Biohaven and its authorized representatives are allowed full access to the records. 
Identification of subjects and CRFs shall be by initials (when allowed), screening and 
treatment numbers only. If required, the subject's full name may be made known to an 
authorized regulatory agency or other authorized official. 
The Sponsor may approve the sharing of de-identified data from this study to be made 
available to researchers for the purpose of advancing the understanding of neurologic or 
psychiatric illness, rating scales, or trial methodology for the affected population. In any 
publication of this data, confidentiality of individual subjects will be protected. 


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Protocol Title: A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Safety and Efficacy Trial 
of BHV-3000 (rimegepant) Orally Disintegrating Tablet (ODT) for the Treatment of 
Temporomandibular Disorders (TMD) 
Study No: BHV3000-317 
Original Protocol Date: 09 Dec 2021 
Protocol Version No: V3.0 
Protocol Version Date: 31 Mar 2022 
Name and Title 
Author: 
Signature Approval 
Date 
PPD 
PPD 
MBA 
PPD 
Clinical Operations 
Clinical Operations: 
PPD 
Clinical Operations 
Biometrics: 
PPD 
PPD 
Ph.D 
Biostatistics 
PPD 
Ph.D. PPD 
 
Medical Lead: 
PPD 
PPD 
MD 
PPD 
Regulatory Affairs: 
PPD 
MA 
Regulatory Affairs 
PPD 
PPD 
PPD 
PPD 
 
16 CLINICAL PROTOCOL APPROVAL FORM 
 
 
 
 
The current risk-benefit evaluation of the investigational product. 
 The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of GCP as described in 21 CFR parts 50, 54, 56 
and 312 and according to applicable local requirements. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 


Study BHV3000-317 Clinical Protocol, Version 3.0 
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boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, 
indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and 
ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole, clarithromycin, 
nefazodone, nelfinavir, tacrolimus, mifepristone, mibefradil. 
Strong CYP3A4 inhibitors 
apalutamide, carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, St. John’s Wort 
Strong CYP3A4 inducers 
 
17 APPENDICES 
17.1 
APPENDIX I – Strong Inhibitors and inducers of CYP3A4 protein (Not all- 
inclusive) 
The following medications and medication combinations are some of the strong inhibitors of 
CYP3A4). This list should not be considered all-inclusive. As described in the study protocol, 
concomitant use of strong CYP3A4 inhibitors is prohibited. Individual drug labels should be 
reviewed for specific information on propensity to inhibit CYP3A4 enzymes for a specific 
compound. 
 
 
 
 
Resources: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter  
actionsLabeling/ucm093664.htm#table3-2 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter  
actionsLabeling/ucm093664.htm#table3-3 
Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: the 
University of Washington Metabolism and Transport Drug Interaction Database. Hum 
Genomics. 2010 Oct;5(1):61-72. 
University of Washington Metabolism and Transport Drug Interaction Database accessible at 
https://www.druginteractioninfo.org/ 


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18 REFERENCES 
1 
Gauer, R. L. & Semidey, M. J. Diagnosis and treatment of temporomandibular 
disorders. Am Fam Physician 91, 378-386 (2015). 
2 
Scrivani, S. J., Keith, D. A. & Kaban, L. B. Temporomandibular disorders. N Engl J 
Med 359, 2693-2705, doi:10.1056/NEJMra0802472 (2008). 
3 
Schiffman, E. et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) 
for Clinical and Research Applications: recommendations of the International 
RDC/TMD Consortium Network* and Orofacial Pain Special Interest Groupdagger. J 
Oral Facial Pain Headache 28, 6-27, doi:10.11607/jop.1151 (2014). 
4 
Bitiniene, D. et al. Quality of life in patients with temporomandibular disorders. A 
systematic review. Stomatologija 20, 3-9 (2018). 
5 
Buescher, J. J. Temporomandibular joint disorders. Am Fam Physician 76, 1477-1482 
(2007). 
6 
Mehta, N. R. & Keith, D. Temporomandibular disorders in adults. www.uptodate.com 
(2020). 
7 
National Academies of Sciences, E., and Medicine; Health and Medicine Division; 
Board on Health Care Services; Board on Health Sciences Policy; Committee on 
Temporomandibular Disorders (TMDs): From Research Discoveries to Clinical 
Treatment. in Temporomandibular Disorders: Priorities for Research and Care The 
National Academies Collection: Reports funded by National Institutes of Health (eds 
O. Yost et al.) (2020). 
8 
Cady, R. J., Glenn, J. R., Smith, K. M. & Durham, P. L. Calcitonin gene-related 
peptide promotes cellular changes in trigeminal neurons and glia implicated in 
peripheral and central sensitization. Mol Pain 7, 94, doi:10.1186/1744-8069-7-94 
(2011). 
9 
Romero-Reyes, M., Pardi, V. & Akerman, S. A potent and selective calcitonin gene- 
related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to 
nociceptive trigeminal activation: Role of CGRP in orofacial pain. Exp Neurol 271, 
95-103, doi:10.1016/j.expneurol.2015.05.005 (2015). 
10 
Shu, H. et al. A Pre-Existing Myogenic Temporomandibular Disorder Increases 
Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced 
Hypersensitivity in Mice. Int J Mol Sci 21, doi:10.3390/ijms21114049 (2020). 
11 
Sato, J. et al. Relationship of calcitonin gene-related peptide in synovial tissues and 
temporomandibular joint pain in humans. Oral Surg Oral Med Oral Pathol Oral 
Radiol Endod 98, 533-540, doi:10.1016/j.tripleo.2004.02.057 (2004). 
12 
Appelgren, A., Appelgren, B., Kopp, S., Lundeberg, T. & Theodorsson, E. 
Neuropeptides in the arthritic TMJ and symptoms and signs from the stomatognathic 


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BHV3000 (rimegepant) – Temporomandibular Disorders 
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system with special consideration to rheumatoid arthritis. J Orofac Pain 9, 215-225 
(1995). 
13 
APA. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 5th 
Edition. 5th edn, (American Psychiatric Publishing, 2013). 
14 
Posner, K. et al. The Columbia-Suicide Severity Rating Scale: initial validity and 
internal consistency findings from three multisite studies with adolescents and adults. 
Am J Psychiatry 168, 1266-1277, doi:10.1176/appi.ajp.2011.10111704 (2011). 
15 
Posner, K. et al. Columbia-Suicide Severity Rating Scale. The Research Foundation 
for Mental Hygiene, inc. Version 1/14/09 (2009). 

SAP_001.pdf: 
Pfizer, Inc. 
Statistical Analysis Plan for Protocol BHV3000-317 
Confidential 
Page 1 of 51 
Pfizer Confidential 
 
 
 
 
Protocol BHV3000-317 
 
 
A Phase 2/3, Double-Blind, Randomized, Placebo- Controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) Orally Disintegrating Tablet (ODT) 
for the Acute Treatment of Temporomandibular Disorders (TMD) 
 
Statistical Analysis Plan 
 
 
 
 
Version 2.0 
Date: 14-Jun-2023 


Pfizer, Inc. 
Statistical Analysis Plan for Protocol BHV3000-317 
Confidential 
Page 2 of 51 
Pfizer Confidential 
 
 
SIGNATURE PAGE 
 
Protocol Title: 
A Phase 2/3, Double-Blind, Randomized, Placebo- 
Controlled, Safety and Efficacy Trial of BHV-3000 
(rimegepant) Orally Disintegrating Tablet (ODT) for the 
Acute Treatment of Temporomandibular Disorders (TMD) 
Sponsor: 
Pfizer, Inc. 
Document Version: 
V2.0 
Date: 
14-Jun-2023 
Author: 
PPD 
 Biostatistics 
Rho, Inc. 
Signature:_ 
Date: 
 
Sponsor 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study/project, are in accordance with the study/project objectives, and are 
consistent with the statistical methodology described in the protocol, clinical development 
plan, and all applicable regulatory guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments. All changes to the 
planned analyses will be described in the Clinical Study Report (CSR). 
Sponsor Signatories: 
 
PPD 
PPD 
Lead 
Pfizer, Inc 
 
Statistics Group 
Signature: 
Date: 
 
PPD 
PPD 


Pfizer, Inc. 
Statistical Analysis Plan for Protocol BHV3000-317 
Confidential 
Page 3 of 51 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ..........................................................................................................2 
LIST OF TABLES .............................................................................................................5 
LIST OF FIGURES ...........................................................................................................6 
REVISION HISTORY .......................................................................................................7 
ABBREVIATIONS ............................................................................................................8 
1 
BACKGROUND AND RATIONALE .....................................................................10 
1.1 
RESEARCH HYPOTHESIS ...............................................................................10 
1.2 
SCHEDULE OF ANALYSES .............................................................................10 
2 
STUDY DESCRIPTION ..........................................................................................11 
2.1 
STUDY DESIGN ..................................................................................................11 
2.2 
TREATMENT ASSIGNMENT ..........................................................................12 
2.3 
BLINDING AND UNBLINDING .......................................................................12 
2.4 
PROTOCOL AND PROTOCOL AMENDMENTS .........................................13 
3 
STUDY OBJECTIVES AND ESTIMANDS ..........................................................14 
3.1 
OBJECTIVES.......................................................................................................14 
3.1.1 
PRIMARY OBJECTIVES ............................................................................14 
3.1.2 
SECONDARY OBJECTIVES ......................................................................14 
CCI 
3.2 
ESTIMANDS ........................................................................................................15 
3.2.1 
PRIMARY OBJECTIVE ESTIMAND ........................................................16 
3.2.2 
SECONDARY OBJECTIVE ESTIMANDS ................................................16 
CCI 
4 
ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS ....................18 
4.1 
ANALYSIS SETS .................................................................................................18 
4.2 
TREATMENT GROUPS ....................................................................................19 
4.3 
SUBGROUPS .......................................................................................................19 
5 
SAMPLE SIZE, POWER, AND TYPE I ERROR ................................................19 
6 
STATISTICAL ANALYSES ...................................................................................19 
6.1 
GENERAL ............................................................................................................19 
6.1.1 
PROGRAMMED OUTPUT ..........................................................................19 
6.1.1.1 
TABLES ....................................................................................................20 
6.1.1.2 
LISTINGS .................................................................................................20 
6.1.2 
STATISTICAL METHODS .........................................................................20 
6.1.3 
HANDLING OF MISSING DATA ...............................................................21 
6.2 
STUDY POPULATION .......................................................................................21 
6.2.1 
ANALYSIS SETS ...........................................................................................21 
6.2.2 
ENROLLMENT .............................................................................................21 
6.2.3 
SUBJECT DISPOSITION .............................................................................21 
6.2.3.1 
SUBJECT DISPOSITION AT STUDY MILESTONES ..................... 21 
6.2.3.2 
OVERALL PREMATURE STUDY TERMINATION DUE TO 
COVID-19 .................................................................................................22 
6.2.4 
PROTOCOL DEVIATIONS .........................................................................22 
6.2.4.1 
RELEVANT PROTOCOL DEVIATIONS ...........................................22 
6.2.4.2 
SIGNIFICANT PROTOCOL DEVIATIONS .......................................22 


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CCI 
6.2.5 
BASELINE CHARACTERISTICS ..............................................................23 
6.2.5.1 
DEMOGRAPHICS AND OTHER RELEVANT BASELINE 
CHARACTERISTICS .............................................................................23 
6.2.5.2 
BASELINE DISEASE CHARACTERISTICS ......................................23 
6.2.5.3 
MEDICAL HISTORY .............................................................................27 
6.2.5.4 
NON-STUDY PRIOR MEDICATIONS ................................................27 
6.2.6 
EXPOSURE ....................................................................................................28 
6.2.6.1 
STUDY THERAPY ..................................................................................28 
6.2.6.2 
MEASUREMENTS OF TREATMENT COMPLIANCE....................29 
6.2.6.3 
CONCOMITANT AND RESCUE MEDICATIONS ............................29 
6.2.6.4 
CONCOMITANT ORAL DEVICES .....................................................30 
6.3 
EFFICACY ...........................................................................................................30 
6.3.1 
RESCUE MEDICATION ..............................................................................31 
6.3.2 
PRIMARY EFFICACY ENDPOINT ...........................................................31 
6.3.2.1 
PRIMARY ANALYSIS ...........................................................................31 
6.3.3 
SECONDARY EFFICACY ENDPOINTS ...................................................33 
6.3.3.1 
SUM OF PAIN INTENSITY DIFFERENCE AT 24 HOURS (SPID- 
24) ..............................................................................................................33 
6.3.3.2 
CHANGE FROM BASELINE OF PAIN ON NRS AT 2 HOURS ......33 
6.3.3.3 
PAIN FREEDOM AT 2 HOURS ............................................................33 
6.3.3.4 
TIME TO ONSET OF MEANINGFUL PAIN RELIEF ......................34 
6.3.3.5 
TIME TO ONSET OF INITIAL PAIN RELIEF ..................................35 
6.3.3.6 
RESCUE MEDICATION USE WITHIN 24 HOURS ..........................35 
6.4 
SAFETY ................................................................................................................36 
6.4.1 
ADVERSE EVENTS ......................................................................................37 
6.4.1.1 
DEATHS ...................................................................................................37 
6.4.1.2 
AE OVERVIEW .......................................................................................38 
6.4.1.3 
ON-TREATMENT AES BY SOC AND PT ..........................................38 
6.4.2 
LABORATORY TESTS ................................................................................38 
6.4.2.1 
LABORATORY TEST ABNORMALITIES .........................................39 
6.4.2.2 
LIVER FUNCTION TEST ELEVATIONS ..........................................39 
6.4.2.3 
LFT PLOTS ..............................................................................................39 
6.4.2.4 
LABORATORY TEST CHANGES FROM BASELINE TABLE ......39 
6.4.2.5 
LABORATORY TEST LISTINGS ........................................................40 
6.4.3 
VITAL SIGNS AND PHYSICAL MEASUREMENTS ..............................40 
6.4.3.1 
VITAL SIGN CHANGES FROM BASELINE .....................................40 
6.4.3.2 
VITAL SIGNS ABNORMALITIES .......................................................40 
6.4.3.3 
VITAL SIGNS AND PHYSICAL MEASUREMENTS LISTING ......41 
6.4.4 
PROCEDURES ..............................................................................................41 
6.4.5 
SUICIDALITY ...............................................................................................41 
6.4.6 
SAFETY NARRATIVE SUBJECT IDENTIFIERS LISTING .................41 
7 
CONVENTIONS. ......................................................................................................42 
7.1 
DERIVED DATES ...............................................................................................42 
7.1.1 
ANALYSIS PERIOD REFERENCE DATES .............................................42 


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7.1.1.1 
STUDY DRUG DATES ........................................................................... 42 
7.1.2 
IMPUTED DATES ......................................................................................... 43 
7.1.3 
LAST CONTACT DATE .............................................................................. 43 
7.1.4 
COVID-19 VISIT DATE ............................................................................... 43 
7.1.5 
OTHER DERIVED/IMPUTED DATES ..................................................... 43 
7.2 
ANALYSIS PERIODS ......................................................................................... 44 
7.3 
ANALYSIS VISIT WINDOWS .......................................................................... 45 
7.4 
SUBGROUPS ....................................................................................................... 46 
7.5 
BASELINE VALUE ............................................................................................ 46 
8 
CONTENT OF REPORTS ...................................................................................... 47 
9 
APPENDICES ........................................................................................................... 48 
9.1 
RELEVANT PROTOCOL DEVIATIONS ....................................................... 48 
10 REFERENCES .......................................................................................................... 51 
LIST OF TABLES 
Table 1: 
Primary Objective Estimand ................................................................... 16 
Table 2: 
Secondary Objective Estimands ............................................................. 16 
Table 3: 
NRS Collection Nominal Timepoints ...................................................... 32 
Table 4: 
Analysis Visit Windows for Safety Parameters ..................................... 45 
Table 5: 
Evaluation Intervals for Efficacy Analyses ............................................ 46 


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LIST OF FIGURES 
Figure 1: Study Schematic ...............................................................................................12 


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REVISION HISTORY 
 
 
Version 
Description of Change 
 
0.1 
Created 
0.2 
Updated after initial review by PP  
0.3 
Incorporated Core SAP VersionD2 updates 
1.0 
Final version after final sponsor review 
2.0 
Signature: Updated Author and Signatory from Pfizer 
Section 1: Added text on the study termination prematurely 
Section 2.4: Added SAP version 2.0 is also based on Protocol version 3.0 
Section 3.2.2 Table 2 Objective 3: Corrected stratified CMH into Mantel-Haenzel risk 
estimation 
Section 3.2.2 Table 2 Objective 4: Removed comparison using log-rank test 
Section 3.2.2 Table 2 Objective 5: Removed comparison using log-rank test 
Section 3.2.2 Table 2 Objective 6: Corrected stratified CMH into Mantel-Haenzel risk 
estimation 
Section 3.2.3: Removed all CCI 
 except forCCI  
Section 4.3: Removed text on p-values 
Section 5: Removed text on multiplicity when testing CCI 
 
Section 6.2.4.2: Added a listing of significant protocol deviations based on CTMS. 
Section 6.3.1: Updated Table 6 to Table 5 
Section 6.3.2.1: Updated Table 4 to Table 3 and removed text on p-value for the 
ANCOVA 
Section 6.3.2.2: Removed section on sensitivity analyses as no sensitivity analysis will 
be done 
Section 6.3.3: Removed texts on p-values and texts on sensitivity analysis. 
Section 6.3.3.3: Corrected stratified CMH into Mantel-Haenzel risk estimation 
Section 6.3.3.4: Removed comparison using log-rank test 
Section 6.3.4: CCI 
 are not assessed 
Section 6.4: Removed ECG to be analyzed. 
Section 6.4.4: Removed section on ECG 
Section 6.4.5: Updated to Section 6.4.4 
 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ASE 
asymptotic standard error 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BUN 
Blood Urea Nitrogen 
CI 
Confidence interval 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Technical Criteria for Adverse Events 
CTMS 
clinical trial management system 
ECG 
electrocardiogram 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOT 
End of Treatment 
FESS 
functional endoscopic sinus surgery 
ICH 
International Conference on Harmonization 
IP 
investigational product 
IWRS 
Interactive web response system 
LFT 
Liver function test 
LS 
Least squares 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov Chain Monte Carlo 
MI 
Multiple imputation 
MNAR 
Missing not at random 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 


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CCI  
 
PT 
Preferred term 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SI 
Systeme Internationale 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TBL 
Total bilirubin 
TLF 
Table listing figure 
TMD 
Temporomandibular Disorder 
TMJ 
Temporomandibular joint 
ULN 
Upper limit of normal 
US 
United States 
WHO-DD 
World Health Organization-Drug Dictionary 


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1 BACKGROUND AND RATIONALE 
This document presents the statistical analysis plan (SAP) for Protocol BHV3000-317: A Phase 
2/3, Double-Blind, Randomized, Placebo-Controlled, Safety and Efficacy Trial of BHV-3000 
(rimegepant) Orally Disintegrating Tablet (ODT) for the Acute Treatment of 
Temporomandibular Disorders (TMD). 
This SAP contains the analysis details and methodology to answer the study objectives, 
including planned tables, listings, and figures (TLFs), which provide the basis for the results 
section of the clinical study report (CSR). 
The Rimegepant (BHV3000)/Zavegepant (BHV3500) Core Statistical Analysis Plan, v3.0 (the 
“Core SAP”) describes analysis details and methodologies common to the BHV3000 program 
and is incorporated by reference. The Core SAP assumes primacy for any matter where this SAP 
is silent (and the relevant content of the Core SAP could feasibly apply) or where the Core SAP 
is directly referenced as applicable. Otherwise, should any discrepancy exist between the Core 
SAP and this SAP, this SAP assumes primacy. 
For purposes of applying the Core SAP, the following applies: 
• BHV3000-317 is a single-dose study 
• BHV3000-317 is not a study with a follow-up phase 
• References in the Core SAP to “studies with a COVID-19 Visit Impact CRF” will not 
necessarily apply to BHV3000-317. COVID-19 impact will be addressed as specified in 
this SAP. 
Note that the study was terminated prematurely in 1Q2023 due to low enrollment. As a result, 
the SAP is being amended from Version 1.0 to 2.0 to reduce the number of TLFs to focus only 
on the most important outputs. 
1.1 
Research Hypothesis 
Rimegepant will have efficacy superior to placebo in the acute treatment of temporomandibular 
disorders (TMD) with a favorable safety profile. 
1.2 
Schedule of Analyses 
During this study, safety and exposure data are monitored on an ongoing basis. The CSR is 
produced after the last patient last visit and final database lock. All analyses described in this 
SAP are performed after the final database lock. No interim unblinded analyses are planned. 


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CCI 
 
2 STUDY DESCRIPTION 
2.1 
Study Design 
This is a Phase 2/3, double-blind, randomized, multicenter, outpatient evaluation of the safety 
and efficacy of rimegepant as compared to placebo for the acute treatment of temporomandibular 
disorders (TMD). The study drug will be rimegepant presented in a 75 mg ODT or matching 
placebo. 
After obtaining informed consent, subjects will undergo all screening procedures as detailed in 
the schedule of assessments. After all screening procedures are complete, subjects may return 3 
to 14 days (+2 days if needed for scheduling purposes) from signing informed consent to be 
randomized at the Baseline visit if they meet all eligibility criteria. 
After randomization, the subject will be dispensed a single dose of the double-blind study 
medication to take home for up to 45 days. The subject will be instructed to take their study 
medication, as an outpatient, when (if) they have a TMD-associated pain in the jaw and/or 
temple area on either side which reaches pain intensity of 2: 6 on the NRS (0-10) after they 
answer eDiary questions about their current pain and symptoms; they should not dose until 
TMD-associated pain reaches a current intensity of 2: 6. The subject will complete an eDiary for 
24 hours after taking study medication. The subject will be instructed to telephone the study 
center immediately if a severe or serious adverse event occurs. 
Subjects will record efficacy data in their eDiary. 
 
Pain severity will be recorded using an NRS (0-10) at time of 
taking study medication and at 15, 30, 45, 60, and 90 minutes and 2, 4, 8 and 24 hours after 
dosing. 
Subjects will return to the study site within 7 days (+2) after 
taking study treatment for review of the eDiary, assessment of medication compliance, and 
monitoring of tolerability and safety. If a subject has NOT experienced a TMD-associated pain 
of sufficient severity within 45 days after randomization, they still are required to complete all 
end of treatment (EOT) visit procedures. All subjects must return empty medication packaging, 
any unused study medication, and the eDiary to the study center. 
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CCI 
Figure 1: Study Schematic 
 
 
2.2 
Treatment Assignment 
After completion of all screening evaluations, all eligible subjects will be randomized in a 1:1 
ratio to the rimegepant or matching placebo treatment groups. Subjects will be randomized via 
the Interactive Web Response System (IWRS). The randomization will be stratified by the daily 
use of medications / oral devices to reduce intensity of TMD symptoms (yes or no) and will 
utilize block randomization with varying block sizes of 4 or 8. The number of blocks of each 
size will be blinded. It is important to correctly enter subjects who are using daily medications / 
oral devices in the IWRS system. Once a subject is stratified in the IWRS, this cannot be 
changed. Further detail is provided in the Randomization Plan v1.0, dated December 13, 2021. 
2.3 
Blinding and Unblinding 
The study is double-blinded. 
Randomization schedules are generated and kept by the IWRS vendor in a secure network folder 
with access limited to only unblinded team members. Each subject who is qualified for 
treatment is randomized via the IWRS randomization option. Subjects will maintain their 
subject number assigned at screening throughout the trial. The IWRS provides the double-blind 
treatment assignments. Further detail is provided in the BHV3000-317 Unblinding Plan v1.0 (as 
amended). 
Dummy coding of treatment groups is used for purposes of blinded statistical programming and 
data review. Blinding of subjects is maintained until the database has been locked and 
unblinding has been approved. 


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Unblinding of individual subject(s) may occur in events of medical emergencies or pregnancies 
as specified in Section 7.3 of the protocol. 
2.4 
Protocol and Protocol Amendments 
The versions 1.0 and 2.0 of the SAP are based on Version 3.0 of the protocol (31 March 2022). 


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3 STUDY OBJECTIVES AND ESTIMANDS 
3.1 
Objectives 
3.1.1 
Primary Objectives 
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
Temporomandibular Disorders on the time-weighted sum of pain intensity difference (SPID) 
from baseline scores for the first 2 hours post-dose (SPID-2). 
3.1.2 
Secondary Objectives 
1. To evaluate rimegepant compared with placebo on the time-weighted sum of pain intensity 
difference from baseline scores for the first 24 hours post-dose (SPID-24). 
2. To evaluate rimegepant compared to placebo on change from baseline of pain on NRS (0-10) 
score at 2 hours post-dose. 
3. To evaluate rimegepant compared to placebo on the proportion of subjects that are pain free 
at 2 hours post-dose. 
4. To evaluate rimegepant compared to placebo on time to onset of meaningful pain relief 
post-dose. 
5. To evaluate rimegepant compared to placebo on time to onset of initial pain relief post-dose. 
6. To evaluate rimegepant compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment. 
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3.2 
Estimands 
An estimand is the target of estimation to address the scientific question of interest posed by a 
study objective. The four attributes of an estimand include the population of interest, endpoint of 
interest, summary of the endpoint, and specification of how intercurrent events are reflected in 
the scientific question of interest. 
For all objectives, the population of interest is defined through appropriate inclusion/exclusion 
criteria to reflect the targeted patient population for approval. Refer to the protocol for 
inclusion/exclusion criteria. 
Intercurrent Events 
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the endpoint or affect its interpretation. Use of non-study rescue medications on or before the 
time point of interest is considered an intercurrent event; intercurrent events are discussed in 
Table 1, Table 2 and Section 3.2.3 as applicable. 
Refer to the specific sections below for additional detail on estimands for each endpoint. Refer 
to Section 4.1 for analysis sets that are used to assess endpoints. 
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3.2.1 
Primary Objective Estimand 
Table 1: 
Primary Objective Estimand 
Objective 
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment 
of temporomandibular disorders on the time-weighted sum of pain intensity difference 
from baseline scores for the first 2 hours post-dose (SPID-2). 
Efficacy Endpoint 
Difference in SPID-2 scores between rimegepant and placebo groups assessed across 
the first 2 hours post-dose in treated subjects. 
Summary 
Difference in time-weighted SPID-2 between the rimegepant and placebo groups using 
an analysis of covariance (ANCOVA) model. 
Intercurrent Events 
1) Use of non-study rescue medications on or before two hours post-dose 
Composite strategy: All data points after rescue medication use are set to the last 
available observation prior to rescue medication usage when a subject uses a rescue 
medication on or before two hours post-dose. It is assumed that subjects who use 
rescue medication within the first two hours after dosing would not have experienced 
additional pain relief without the use of rescue medication. 
2) Failure to log pain score at any time after study drug is administered through two 
hours post dose 
Composite strategy: All missing data points are set to the last available observation for 
subjects that fail to enter pain score(s) in the eDiary any time on or before the two hour 
post-dose pain assessment. It is assumed that subject who fail to enter pain scores 
would not have experienced additional efficacy at the missing timepoints. 
3) All other intercurrent events 
Treatment policy strategy: All available assessments on the subject are used 
regardless of other intercurrent events. 
 
3.2.2 
Secondary Objective Estimands 
Table 2: 
Secondary Objective Estimands 
 
1 
Objective 
To evaluate rimegepant compared with placebo on the time-weighted sum of pain 
intensity difference (SPID) from baseline scores for the first 24 hours post-dose 
(SPID-24). 
Efficacy 
Endpoint 
Difference in SPID-24 scores between rimegepant and placebo assessed across the first 
24 hours post-dose in treated subjects 
Summary 
Same as that of primary estimand, with respect to time-weighted SPID-24. 
Intercurrent 
Events 
Same as that of primary estimand. 
 
 
2 
Objective 
To evaluate rimegepant compared to placebo on change from baseline on NRS (0-10) 
score at 2 hours post-dose. 
Efficacy 
Endpoint 
Change from baseline in NRS score to 2 hours post-dose in treated subjects. 
Summary 
Difference in change from baseline in the NRS score between the rimegepant and 
placebo groups using a generalized linear mixed effect model. 


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Intercurrent 
Events 
Same as that of primary estimand. 
3 
Objective 
To evaluate rimegepant compared to placebo on the proportion of subjects that are pain 
free at 2 hours post-dose. 
Efficacy 
The percentage of treated subjects that report no pain at 2 hours post-dose 
Endpoint 
Summary 
The difference between the rimegepant and placebo group in the percentage of subjects 
who are pain-free at 2 hours post-dose, analyzed using Mantel-Haenszel risk estimation. 
The definition of “pain free” is a subject that reports a zero on their 2 hour post-dose 
NRS assessment. 
Intercurrent 
1) Use of non-study rescue medications on or before two hours post-dose 
Events 
Composite strategy: Subjects who use rescue medication on or before assessment of 
pain at two hours are imputed as a failure. 
2) Failure to report eDiary assessments at two-hours post-dose 
Composite strategy: Subjects with missing data at two hours post-dose are imputed as a 
failure. 
3) All other intercurrent events: 
Treatment policy strategy: All available assessments on the subject are used regardless 
of other intercurrent events. 
4 
Objective 
To evaluate rimegepant compared to placebo on time to onset of meaningful pain relief 
post-dose. 
Efficacy 
Endpoint 
The time to first nominal timepoint at which pain on NRS (0-10) decreases by 30% 
from baseline in treated subjects. 
Summary 
Descriptive analysis by treatment group of the time to first nominal timepoint at which 
pain on NRS (0-10) decreases by 30% from baseline using Kaplan-Meier method. 
Meaningful pain reduction will be measured as a two-point reduction in NRS (0-10) 
score for subjects with a baseline pain score of 6, 7, or 8 and a 3 point reduction in NRS 
(0-10) score for subjects with a baseline pain score of 9 or 10. 
Intercurrent 
Events 
1) Use of non-study rescue medications on or before onset of meaningful pain relief 
Composite strategy: Subjects who use rescue medication on or before onset of 
meaningful pain relief are censored at the time of rescue medication use. 
2) Failure to report eDiary assessments. 
Composite strategy: Subjects who do not complete all post-dose assessment will be 
censored at the time of the last completed NRS pain assessment. 
3) All other intercurrent events: 
Treatment policy strategy: All available assessments on the subject are used regardless 
of other intercurrent events. 
5 
Objective 
To evaluate rimegepant compared to placebo on time to onset of initial pain relief 
post-dose. 
Efficacy 
The time to first nominal timepoint at which pain on NRS (0-10) decreases by 1 point 
Endpoint 
from baseline in treated subjects. 
Summary 
Descriptive analysis by treatment group of the time to first nominal timepoint at which 
pain on NRS (0-10) decreases by 1 point from baseline using the Kaplan-Meier method. 


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Intercurrent 
Events 
Same as secondary endpoint # 4 
 
 
6 
Objective 
To evaluate rimegepant compared to placebo on the probability of requiring rescue 
medication within 24 hours of initial treatment. 
Efficacy 
Endpoint 
Percentage of treated subjects that use rescue medication within 24 hours after 
administration of study drug. 
Summary 
The difference in the percentage of subjects that take study drug and then take rescue 
medication within 24 hours, analyzed using Mantel-Haenszel risk estimation. 
Intercurrent 
Events 
Treatment policy strategy: All available assessments on the subject are used regardless 
of intercurrent events. 
 
 
 
 
CCI 
 
 
 
 
 
 
4 ANALYSIS SETS, TREATMENT GROUPS, AND SUBGROUPS 
4.1 
Analysis Sets 
The following analysis sets are evaluated and used for presentation and analysis of the data: 
• Enrolled: Subjects who signed the informed consent form and were assigned a subject 
identification number by the IWRS; i.e., non-missing informed consent date. This analysis 
set is used mainly to assess study population and in by-subject listings. 
• Full: Enrolled subjects who were assigned a randomized treatment group; i.e., non-missing 
IWRS randomization date. This analysis set is used mainly to assess study population. 
• Treated: Enrolled subjects who took study therapy (rimegepant or placebo); i.e., non-missing 
study drug start date. This is the primary efficacy analysis set and used to assess study 
population, exposure, and on-treatment safety, and produce select by-subject listings. 


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4.2 
Treatment Groups 
The two treatment groups are rimegepant 75 mg and placebo. The treated analysis set is 
assessed by the as-randomized treatment group for efficacy presentations and as-treated for 
safety presentations. The randomized analysis set is assessed by as-randomized treatment 
groups. The enrolled analysis set is assessed overall. If there are non-randomized subjects who 
took study drug, then the treatment group of “not randomized” is included in the full analysis set. 
4.3 
Subgroups 
Stratification factor (use of daily medications / oral devices to reduce the intensity of TMD 
symptoms), as randomized is a subgroup of interest for the treated analysis set. 
Subgroup analyses are performed for the primary efficacy endpoint only, following the methods 
specified in Section 6.3.2.1 with respect to each subgroup level. Stratification factor is removed 
as a covariate from the model as appropriate. 
5 SAMPLE SIZE, POWER, AND TYPE I ERROR 
If 80% of the 200 randomized (100 per treatment arm) treat with study drug, we expect roughly 
160 total or 80 per treatment group in the randomized and treated population for analysis. 
Assuming rimegepant provides a 2-point reduction in NRS pain, and a 1.5-point advantage over 
placebo on the primary endpoint, and a common standard deviation of 3.0, then the study will 
have roughly 88% power on the primary endpoint. 
Type 1 error is not applicable. The significance of the primary and secondary endpoints will not 
be evaluated. 
6 STATISTICAL ANALYSES 
All statistical analyses are performed using SAS statistical software (Version 9.4 or later). 
6.1 
General 
6.1.1 
Programmed Output 
A list of TLFs and corresponding templates, attributes, and programming notes are presented 
separately in a mock TLF document corresponding to this SAP. 
Refer to the Core SAP for additional details about programmed output. 
Adverse event (AE), medical history, medications, and procedures are coded using Medical 
Dictionary for Regulatory Activities (MedDRA) v. 25.0 and World Health Organization-Drug 
Dictionary (WHO-DD) version March 2022 B3. 


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6.1.1.1 
Tables 
Treatment Group Presentation 
Tables present results by treatment group (i.e., rimegepant 75 mg and placebo) with the 
following exceptions: 
• Results for the enrolled analysis set are presented only by overall, without treatment group. 
• Results for study population parameters (see Section 6.2) and pre-treatment safety also 
include overall. 
Time-to-event Tables 
Time-to-event endpoints are summarized with Kaplan-Meier tables. Refer to the Core SAP for 
additional details. 
Time-to-event distributions of endpoints are tabulated with the following descriptive statistics: 
number and percentage of subjects with events; number and percentage of subjects censored in 
or before the last time interval; number and percentage of subjects censored in the last time 
interval; time-to-event median with 95% CI, first quartile, and third quartile. The 95% CI for the 
median is estimated using the method of Brookmeyer and Crowley. 
6.1.1.2 
Listings 
In general, by-subject listings are sorted by randomization status (randomized, not randomized), 
which is not displayed, followed by site-subject ID and visit and/or date/time, as applicable. 
Unless specified otherwise, listings of significant protocol deviations, safety parameters, efficacy 
parameters, and COVID-19 visit impact include the following: analysis visit or assessment in 
which the measurement was slotted (where applicable); event or finding date/time (where 
applicable); and study day and/or treatment day derived using the event or finding date/time (see 
Section 7.2 of the Core SAP). Listings of significant protocol deviations, safety parameters, and 
COVID-19 visit impact also include the abbreviated name of the analysis period in which the 
measurement was slotted (i.e., PRETRT for pre-treatment and ONTRT for on-treatment; see 
Section 7.2). 
Refer to the Core SAP for additional details about listings. The footnote for race abbreviations is 
provided in Section 3.6.2. of the Biohaven Biostatistics Global TLF Standards - GD-0056 and 
does not include ‘U’ for Unknown. 
6.1.2 
Statistical Methods 
Refer to the Core SAP for descriptive statistics in summary tables, counting rules in frequency 
tables, and rounding rules. 
Notwithstanding Section 7.6 of the Core SAP, age in all instances is age recorded on the case 
report form (CRF). 


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6.1.3 
Handling of Missing Data 
All safety analyses are based on observed data without using imputation, except that partial or 
missing start and stop dates or datetimes for non-study medications and AEs are imputed solely 
for purposes of categorizing the events. See Section 7.1.2 for the imputation of partial or 
missing non-study medications and AE dates (except rescue medications). 
Missing efficacy data are handled in the respective subsections of Section 6.3. 
6.2 
Study Population 
6.2.1 
Analysis Sets 
The number of subjects in each analysis set described in Section 4.1 is tabulated by treatment 
group (as-randomized for the full analysis set; as-treated for the treated analysis set), not 
randomized, and overall. 
A by-subject listing of analysis sets is provided for the enrolled analysis set, and an 
administrative listing of randomization scheme and codes is provided for all randomization 
numbers and block numbers, even those not assigned to a subject. Refer to the Core SAP for 
listing contents. 
6.2.2 
Enrollment 
Enrollment by country and site is tabulated for the enrolled analysis set. Refer to the Core SAP 
for additional details. 
6.2.3 
Subject Disposition 
6.2.3.1 
Subject Disposition at Study Milestones 
Subject disposition is based on the Disposition CRF, unless noted otherwise. 
A subject disposition table is provided for treatment to completion/discontinuation for the treated 
analysis set. This includes the number and percentage of treated subjects completing the study 
(i.e. study status is marked “Complete” in the Disposition CRF) and not completing the study 
with reasons for non-completion, including whether or not the subject discontinued due to 
COVID-19. 
A by-subject listing of subject disposition is provided for the enrolled analysis set based on the 
Disposition CRF and includes the following: date randomized (as applicable), date/time the study 
drug was administered (as applicable), an indication whether the subject completed the study (yes, 
no), reason for discontinuation if applicable (including an indication if the subject discontinued 
due to COVID-19), and last contact date (see Section 7.1.3). Notwithstanding Section 6.2.3 of the 
Core SAP, this listing will not be provided separately for each phase, and study milestone 
parameters will not be included. 


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A listing would be provided for all visits and assessments impacted by COVID-19 for the 
enrolled analysis set. The listing would include the visits and assessments that were impacted by 
COVID-19, impact (e.g. missed), and relationship to COVID-19 (e.g. subject diagnosed with 
COVID-19). 
6.2.3.2 
Overall Premature Study Termination due to COVID-19 
Notwithstanding Section 6.2.3.2 of the Core SAP, a frequency table of overall premature study 
termination due to COVID-19 will not be produced. 
6.2.4 
Protocol Deviations 
6.2.4.1 
Relevant Protocol Deviations 
A relevant protocol deviation is a deviation from the protocol which is programmed from the 
database and which could potentially affect the interpretability of the study results. This type of 
deviation includes but is not limited to: eligibility and subject management. 
For purposes of identifying relevant protocol deviations related to medication use, partial or 
missing non-study medication dates are imputed as set forth in Section 7.1.2. Medical history 
dates are not imputed; however, ongoing medications with partial start dates will be considered 
ongoing for purposes of categorizing relevant protocol deviations related to medical history if the 
partial date(s) are consistent with the medication being ongoing at the time of Screening, or as 
specified in the relevant protocol deviation criteria (see Section 9.1 for further detail). 
Relevant Protocol Deviation Frequency Table 
The frequency table of relevant protocol deviations displays the number and percentage of 
subjects in deviation categories and subcategories by deviation type (e.g., eligibility, subject 
management) for the full analysis set. Categories and subcategories are displayed in the order 
provided in specified in Section 9.1. Results are displayed for all deviations, even those with 0 
counts, unless otherwise specified. See Section 6.2.4.1 of the Core SAP for further details. 
Relevant Protocol Deviation Listing 
The by-subject listing of relevant protocol deviations is provided for the full analysis set. This 
includes deviation type, category, and subcategory, which are additional sorting variables. 
Footnotes describe the medical dictionary and the drug dictionary as applicable. 
6.2.4.2 
Significant Protocol Deviations 
A by-subject listing of significant protocol deviations is provided for the enrolled analysis set. 
This includes visit, category, subcategory, and description, which are used as additional sorting 
variables. 


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A Microsoft Excel file of protocol deviations is provided by the data management vendor from 
the clinical trial management system (CTMS). This file serves as the raw data source of protocol 
deviations, and classifies deviation severity as major or minor. Significant protocol deviations 
are defined as those with major severity. A footnote describes the raw data source and how 
significant protocol deviations are identified, e.g., “Significant protocol deviations are those with 
major severity reported by the data management vendor in the clinical trial management system.” 
6.2.5 
Baseline Characteristics 
Baseline characteristics include (1) demographics and other relevant baseline characteristics, (2) 
baseline disease characteristics (i.e., Diagnostic Criteria for TMD Symptom Questionnaire, 
DC/TMD Examination), (3) medical history, and (4) prior non-study medications. These are 
tabulated by the treated analysis set. 
By-subject listings are provided for the enrolled analysis set for the following: demographics, 
medical history, Diagnostic Criteria for TMD Symptom Questionnaire, and DC/TMD 
Examination. 
See Section 7.5 for the derivation of the baseline value for a parameter (e.g., weight). 
6.2.5.1 
Demographics and Other Relevant Baseline Characteristics 
Refer to the Core SAP (Section 6.2.5.1) for the table of demographics and other relevant baseline 
characteristics, with the following adjustments: 
• Country is not tabulated. 
• Triptan non-responders and cardiovascular risk factors contraindicating triptans are not 
tabulated, as these data are not directly collected. 
• “Unknown” is not included as a race category. 
 
 
Randomization Stratum Frequency Table 
A frequency table of randomization stratum displays the number and percentage of subjects in 
each randomization stratum for the full analysis set to confirm whether balance was achieved 
across treatment groups. 
Demographics Listing 
Refer to Section 6.2.5.1 of the Core SAP for specifications on the demographics listings. 
6.2.5.2 
Baseline Disease Characteristics 
With respect to reporting baseline disease characteristics, Section 6.2.5.2 “Baseline Disease 
Characteristics” of the Core SAP does not apply in its entirety; the following applies instead. 


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Diagnostic Criteria for TMD 
 
Results are based on the Diagnostic Criteria for Temporomandibular Disorders Symptom 
Questionnaire CRF. Results will be tabulated and include the following parameters summarized 
as categorical or continuous variables, as applicable. The table includes a “not reported” 
category for missing categorical variables for any categories with at least one record of “not 
reported”. For each high-level category, the denominator is the number of subjects in the 
relevant population. For each sub-level category the denominator is the number of subjects 
responding “yes” in the related high-level category. 
• Ever had pain in jaw, temple, in the ear, or in the front of the ear (yes, no) 
o Number of years and/or months since pain onset (continuous) 
o Pain in the last 30 days (no pain, pain comes and goes, pain always present) 
■ 
Chewing hard or tough food 
■ 
Opening mouth, or moving jaw forward or to the side 
■ 
Jaw habits such as holding teeth together, clenching/grinding teeth, or 
chewing gum 
■ 
Other jaw activities such as talking, kissing, or yawning 
• Headaches in the last 30 days that included the temple areas (yes, no) 
o Number of years and/or months since temple headache first begin (continuous) 
o Activities in the last 30 days that changed any headache (better or worse) in the 
temple area 
■ 
Chewing hard or tough food 
■ 
Opening mouth, or moving jaw forward or to the side 
■ 
Jaw habits such as holding teeth together, clenching/grinding teeth, or 
chewing gum 
■ 
Other jaw activities such as talking, kissing, or yawning 
• Jaw joint noise(s) in the last 30 days when the jaw is moved or used (yes/no) 
• Closed locking of the jaw so that it would not open all the way (yes, no) 
o Severe enough to interfere with eating (yes, no) 
o Jaw locked in the last 30 days and then unlocked (yes/no) 


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■ 
Jaw currently locked (yes, no) 
• Open locking of jaw in the last 30 days so that it could not close from a wide-open 
position (yes, no) 
o Intervened to allow jaw to close including resting, moving, pushing, or 
maneuvering (yes, no) 
 
A by-subject listing of responses to all Diagnostic Criteria for TMD is provided for 
enrolled subjects. 


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DC/TMD Examination 
 
Results are based on the DC/TMD Examination CRF. Results are tabulated and includes the 
following parameters summarized as categorical or continuous variables, as applicable. The 
table includes a “not reported” category for missing categorical variables for any categories with 
at least one record of “not reported.” For each high-level category, the denominator is the 
number of subjects in the relevant population. For each sub-level category, the denominator is 
the number of subjects responding “yes” the related high-level category. 
• DC/TMD examination completed in entirety (yes, no) 
• Opening movements 
o Pain free opening (mm) (continuous) 
o Maximum unassisted opening (mm) (continuous) 
o Maximum assisted opening (mm) (continuous) 
o Terminated (yes, no) 
• Diagnoses – pain disorders 
o None (n, %) 
o Myalgia (n, %) 
o Myofascial pain with referral (n, %) 
o Right arthralgia (n, %) 
o Left arthralgia (n, %) 
o Headache attributed to TMD (n, %) 
• Right temporomandibular joint (TMJ) disorders 
o None (n, %) 
o Disc displacement with reduction (n, %) 
o Disc displacement with reduction and intermittent locking (n, %) 
o Disc displacement without reduction, with limited opening (n, %) 
o Disc displacement without reduction, without limited opening (n, %) 


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o Degenerative joint disease (n, %) 
o Subluxation (n, %) 
• Left TMJ disorders 
o None (n, %) 
o Disc displacement with reduction (n, %) 
o Disc displacement with reduction and intermittent locking (n, %) 
o Disc displacement without reduction, with limited opening (n, %) 
o Disc displacement without reduction, without limited opening (n, %) 
o Degenerative joint disease (n, %) 
o Subluxation (n, %) 
• Other diagnoses (non-primary) 
o Tendonitis (n, %) 
o Contracture (n, %) 
o Hypertrophy (n, %) 
 
A by-subject listing of DC/TMD Examination is provided for enrolled subjects. 
 
6.2.5.3 
Medical History 
Refer to the Core SAP (Section 6.2.5.3) for medical history. 
6.2.5.4 
Non-Study Prior Medications 
The following prior non-study medications are tabulated by therapeutic class and preferred 
name: 
• Previous medications 
• Current medications 
• Stable medications to reduce intensity of TMD symptoms through end of treatment. 


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The definitions of medication types in Section 6.2.6.3 of the Core SAP, as applicable to single- 
dose studies, applies. For clarity, prior (previous and current) medications do not include rescue 
medications (see Section 6.2.6.3). 
Medications are displayed in descending order of overall frequency within therapeutic class and 
preferred name. See Section 6.2.6.3 for further detail on medication types. 
Stable TMD medications through Screening are defined as TMD medications taken > 3 months 
before informed consent and through completion or discontinuation of the study, with no change 
in dose amount or frequency, i.e., (1) informed consent date – imputed medication start date > 91 
days, and (2) completion or discontinuation  imputed medication stop date, with no change in 
dose amount or frequency. For purposes of this analysis, TMD medications are defined as 
follows: 
• Tricyclic antidepressants (such as: amitriptyline, nortriptyline) 
• Venlafaxine, desvenlafaxine, duloxetine, milnacipran 
• Gabapentin, pregabalin 
• Feverfew, magnesium (2: 600 mg/day), riboflavin (2: 100 mg/day) 
• Botulinum therapy (e.g., onabotulinum toxin A, abobotulinum toxin A, and 
incobotulinum toxin A) 
6.2.6 
Exposure 
6.2.6.1 
Study Therapy 
Study drug is dispensed in a subject-specific bottle containing one blister unit of drug. Exposure 
is measured by subjects providing self-reported study drug exposure information (see Section 
7.1). As a check on this exposure data, study drug accountability data are provided on the Drug 
Accountability CRF. 
The date/time of exposure is defined in Section 7.1. 
The self-reported study drug exposure data are tabulated by treatment group and overall for 
randomized subjects and includes: 
• The number (and percentage) of randomized subjects that took study medication 
o The number and percentage who mistakenly took drug. A medication is deemed 
taken mistakenly if the subject entered “Yes” to “Did you mistakenly take your 
study medication already?” in the “Initial pain” eDiary, or if the subject reported 
having mistakenly taken drug to the site without interacting with the eDiary. 
o The number and percentage that took study medication immediately after 
providing a qualifying pain NRS score (侔 6) (i.e. the subject responded “Yes” to 
the question “Please confirm you took your Study Medication” in the “Initial 
pain” eDiary. 


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• The number and percentage of randomized subjects who never reported taking study 
medication 
 
o The number and percentage who never reported a qualifying pain NRS score (侔 
6) 
o The number and percentage who reported a qualifying pain NRS score (2: 6) at 
least once 
An administrative listing of investigational product (IP) batch numbers is provided for the 
randomized analysis set. Refer to the Core SAP for listing contents. 
6.2.6.2 
Measurements of Treatment Compliance 
Section 6.2.6.2 of the Core SAP does not apply. 
The study drug accountability data are tabulated by treatment group and overall, for randomized 
subjects and includes: 
• The number and percentage of randomized subjects to whom kits were dispensed 
• The number and percentage of randomized subjects who returned kits 
o The number and percentage of subjects with returned kits from which the IP was 
used 
o The number and percentage of subjects with returned kits from which the IP was 
not used 
o The number and percentage of subjects with returned kits from which IP use not 
reported (i.e., missing) 
• The number and percentage of subjects who did not return kits 
• The number and percentage of subjects who did not report returning kit (i.e., missing) 
A by-subject listing is prepared that indicates the study drug exposure and accountability status 
for the treated analysis set; this listing includes study drug start date/time and study day, drug 
accountability kit dispensed date, kit returned date, kit ID, and IP used status (IP taken, IP not 
taken). A patient identifier listing is prepared if subjects had unknown exposure data, unknown 
accountability data, or for whom the exposure and accountability data did not match. 
6.2.6.3 
Concomitant and Rescue Medications 
Concomitant non-study medications are tabulated by therapeutic class and preferred name for the 
treated analysis set. The definition of concomitant medication in Section 6.2.6.3 of the Core 
SAP, as applicable to single-dose studies, applies. For clarity, concomitant medications include 


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both medications recorded on the Concomitant Medications CRF that meet the definition of 
“concomitant” (see Section 6.2.6.3 of the Core SAP) and all rescue medications (defined below). 
Sites are instructed to exclude medications reported on the Rescue Medication CRF from the 
Concomitant Medications CRF. 
Medications are displayed in descending order of overall frequency within therapeutic class and 
preferred name. Refer to the Sections 6.2.6.3 of the Core SAP for non-study medication 
counting rules in frequency tables. 
Rescue medications include any non-study medication recorded on the Rescue Medication CRF 
with complete medication dates, and either (1) medication date/time is after the study drug start 
date/time if the medication time and study drug start time are both not missing, or (2) medication 
date is on or after study drug start date if the medication time or study drug start time is missing. 
Rescue medication dates are not imputed. Rescue medication times are not imputed, except as 
provided in Section 7.1.5 for time-to-event analyses. Rescue medications are separately 
tabulated and displayed in descending order of overall frequency within therapeutic class and 
preferred name for the treated analysis set. Any medication recorded on the Rescue Medication 
CRF that does not meet the above definition of a “rescue medication” will be treated as a current 
or concomitant medication, as appropriate, based on the imputed medication start date. 
A by-subject listing of non-study medications is provided by therapeutic class and preferred 
name for the enrolled analysis set. The listing displays medication type and treatment days 
derived from the imputed start date. For purposes of this listing, the start date/time of rescue 
medication use is the date/time of rescue medication use, and rescue medications are identified. 
Refer to the Core SAP for additional listing contents, except AE and medical history terms are 
not included. 
Non-study medications are classified according to the World Health Organization Drug 
Dictionary (WHO-DD) and Anatomical Therapeutic Chemical (ATC) classification system B3 
global format (March 2022). 
6.2.6.4 
Concomitant Oral Devices 
Concomitant oral devices are tabulated by system organ class (SOC) and preferred term (PT) for 
the treated analysis set. The definition of concomitant oral devices is the same as that used for 
concomitant medication in Section 6.2.6.3 of the Core SAP, as applicable to single-dose studies. 
A by-subject listing of concomitant oral devices is provided for the enrolled analysis consistent 
with section 6.2.5.3 of the Core SAP, as applicable for oral devices. 
6.3 
Efficacy 
Unless otherwise noted, all efficacy analyses are conducted using the treated analysis set as 
outlined below. Efficacy tabulations present results by as-randomized treatment group only 
(excluding overall), unless specified otherwise. All key efficacy data are included in listings by 
subject, treatment group, and time point (as applicable). 


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Summary statistics (n, mean, median, SD, minimum, maximum) are reported for continuous 
variables at each time point, along with change from baseline, as applicable. 
6.3.1 
Rescue Medication 
Rescue medications are defined in Section 6.2.6.3. For efficacy evaluations (except for the 
analysis set forth in Section 6.3.3.6), a rescue medication is considered used as of a given time 
point if the date/time of first rescue medication use is on or prior to the date/time of that efficacy 
evaluation or, if the eDiary assessment is missing at that time point, if the date/time of first 
rescue medication use is :S the upper limit of the window for that assessment as specified in 
Table 5. For instance, a subject is treated as having used rescue medication as of 2 hours post- 
dose if the date/time of first rescue medication use is prior or equal to the date/time of the 2-hour 
assessment, even if the date/time of first rescue medication is more than 2 hours post-dose, or, if 
the eDiary assessment at 2 hours is missing, if the date/time of first rescue medication use is :S 
135 minutes. If the time of first rescue medication is missing, the rescue medication is 
considered used as of a given time point if the date of rescue medication is on or prior to the date 
of that efficacy evaluation. 
For efficacy evaluations (except for the analysis set forth in Section 6.3.3.6), the first rescue 
medication date/time is defined as the earliest rescue medication date/time, where missing time is 
considered to be earlier than non-missing time on the same date. 
For clarity, assessments after rescue medication administration are not set to missing for 
purposes of calculating summary statistics, even when the assessments are set to missing for 
model evaluation. 
6.3.2 
Primary Efficacy Endpoint 
6.3.2.1 
Primary Analysis 
TMD pain is assessed using an NRS score ranging in integers from 0 to 10, with 0 being “no 
pain” and 10 being “worst imaginable pain.” Each subject indicates pain using the eDiary at 
each of the following nominal timepoints: 0 (baseline), 15, 30, 45, 60, 90 and 120 minutes post- 
dose. 
The pain intensity difference at each post-baseline timepoint (PIDi) is calculated by finding the 
difference between the NRS score at each timepoint (PIi) from the baseline NRS score (PIo). 
PIDi = PIi - PIO 
The SPID-2 will be calculated by multiplying the PID score at each post-dose timepoint by the 
duration (in hours) since the preceding timepoint, then summing the values over the 2 hours. 
 
6 
SPID - 2 = I 
(Ti - T(i-1))* PIDi 
i=1 


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Where T0 = 0, Ti = the nominal time as described in Table 3, T(i-1) = the preceding nominal time, 
PIDi = PID score at time Ti 
Table 3: 
NRS Collection Nominal Timepoints 
 
NRS collection 
 timepoint 
i 
Ti (hours) 
 
 
15 minutes 
1 
0.25 
30 minutes 
2 
0.50 
45 minutes 
3 
0.75 
60 minutes 
4 
1.00 
90 minutes 
5 
1.50 
2 hours 
6 
2.00 
4 hours 
7 
4.00 
8 hours 
8 
8.00 
 24 hours 
9 
24.00 
 
The SPID-2 will be analyzed on the treated population using an analysis of covariance 
(ANCOVA) model, estimated by Restricted Maximum Likelihood (REML) that includes 
baseline NRS value as a covariate and treatment group and stratification factor (use of daily 
medications / oral devices to reduce the intensity of TMD symptoms) as the main effects. The 
least squares mean (LS mean), standard error (SE), and 95% confidence intervals (CI) for each 
treatment group will be estimated and reported, as well as the LS mean, SE, and 95% CI for the 
difference between treatment groups (rimegepant – placebo). Descriptive summaries of PID 
value at each measured timepoint will be presented by treatment group to include mean, SD, 
median, minimum, and maximum. 
The intercurrent events of non-study rescue medication and failure to log NRS pain score are 
treated with a composite strategy. All assessments after rescue medication administration are set 
to the last observation prior to the time of rescue medication use. Any missing NRS 
assessment(s) will be imputed to the last non-missing observation prior to the missing 
assessment. For clarity, in the case of intermittent missing values, missing values will be 
imputed based on the last non-missing observation prior to the missing value or consecutive 
series of missing values; any subsequent non-missing values will not be imputed unless rescue 
medication was administered prior to that assessment. Subjects who mistakenly dose and thus 
have a missing baseline NRS assessment will have the missing baseline assessment imputed as 
the mean of the non-missing baseline assessments across subjects. 


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6.3.3 
Secondary Efficacy Endpoints 
Secondary endpoints will be analyzed on the treated population. 
6.3.3.1 
Sum of Pain Intensity Difference at 24 Hours (SPID-24) 
The analysis in Section 6.3.2.1 is repeated for the SPID-24 on the treated population, with SPID- 
24 being calculated by multiplying the PID score at each post-dose timepoint by the duration (in 
hours) since the preceding timepoint, then summing the values over a 24-hour period. 
Each subject indicates pain using the eDiary at each of the following nominal timepoints: 0 
(baseline), 15, 30, 45, 60, 90 and 120 minutes, and 4, 8, and 24 hours post-dose. 
6.3.3.2 
Change from Baseline of Pain on NRS at 2 Hours 
Change from baseline pain on NRS score is analyzed on the treated population using a 
generalized linear mixed effect model that includes the baseline NRS (0-10) value as a covariate, 
and fixed effects for treatment group, stratification factor (use of daily medications / oral devices 
to reduce the intensity of TMD symptoms), scheduled time point, and time point by treatment 
group interaction. Time points included in the model are nominally at 15, 30, 45, 60, 90 and 120 
minutes post-dose. 
Repeated measures within subject are modeled using an unstructured covariance structure for 
within subject error. In the case the model fails to converge, a Huynh-Feldt error structure is 
utilized, followed by an AR(1) structure. Error degrees of freedom are calculated using the 
Kenward-Rogers approximation if an unstructured covariance structure fits appropriately; 
otherwise, a sandwich estimator is utilized to estimate the covariance structure, and the degrees 
of freedom are calculated using the between-within method. 
Restricted maximum likelihood (REML) estimation is utilized; should the model fail to converge 
under REML, maximum likelihood estimation is utilized. 
Least squares (LS) means, SE, and 95% CIs are reported for each treatment group at 2 hours 
post-dose, along with LS mean difference estimate (rimegepant - placebo) and associated SE and 
95% CI. 
Intercurrent events will be handled in the same way as in the primary analysis described in 
Section 6.3.2.1. 
6.3.3.3 
Pain Freedom at 2 Hours 
The number and percentage of subjects in the treated population that experience pain freedom at 
2 hours post-dose are analyzed after first imputing missing data at 2 hours to be failure (NC 
[Non-completer] = F [Failure]). Additionally, subjects who use rescue medication on or before 
assessment of pain at 2 hours are also assigned as failures (RM [Rescue medication use] = F). If 
the time of first rescue medication is missing, subjects are considered as failures if the date of 
rescue medication is the same as the date of dosing. 


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The analysis is done using Mantel-Haenszel risk estimation after imputation is done, with the 
stratification factor as yes/no for use of daily medications / oral devices to reduce the intensity of 
TMD symptoms. If one category of stratification factor has sparse data (less than 5 subjects), 
then the stratification factor is removed. Pain freedom is defined as an NRS score of zero at 2 
hours post-dose (yes or no). 
Results presented from the analysis includes the following: 
• Response rate (i.e., “n/N” and percentage), asymptotic standard error (ASE), and 95% CI 
by randomization stratum for each treatment group 
• Response rate (i.e., “n/N” and percentage), ASE, and 95% CI for each treatment group 
• Percentage difference between treatment groups (rimegepant – placebo), ASE and 95% 
CI by randomization stratum 
• Stratified percentage difference between treatment groups (rimegepant – placebo), ASE 
and 95% CI 
A forest plot is produced depicting the risk difference for pain freedom at 2 hours post dose. The 
risk difference for each stratum will be presented, as well as the overall common risk difference. 
6.3.3.4 
Time to Onset of Meaningful Pain Relief 
Time to onset of meaningful pain relief post-dose is analyzed descriptively for the treated 
population using Kaplan-Meier methods. Meaningful pain relief is considered the event in these 
analyses and is defined as the first nominal timepoint at which a 30% reduction of pain from 
baseline on the NRS is achieved. For clarity, meaningful pain relief is a 2-point reduction in NRS 
(0-10) score for subjects with a baseline pain score of 6, 7, or 8, and a 3-point reduction in NRS 
(0-10) score for subjects with a baseline pain score of 9 or 10. 
The survival distributions will be described at the nominal timepoints of 15, 30, 45, 60, 90, and 
120 minutes, and 4, 8, and 24 hours post-dose. Subjects are considered to have an event through 
24 hours if the first post-dose eDiary finding date/time where meaningful pain relief is achieved 
is (1) at or before the upper bound of the 24-hour analysis window in minutes (see Table 5: 
Analysis Visit Windows for Safety Parameters), and (2) is before the imputed rescue medication 
start date/time, if not missing (see Section 7.1). Subjects who do not have the event through 24 
hours (even in the case of missing data) are censored at the earliest of the following: (1) upper 
bound of the 24-hour analysis window + 1 minute; (2) time from the study drug start date/time to 
the imputed rescue medication start date/time, if the time is at or before the upper bound of the 
24-hour analysis window in minutes; (3) time from the study drug start date/time to the last non- 
missing eDiary date/time defining the endpoint, if the time was before the lower bound of the 24- 
hour analysis window in minutes. Likewise, subjects who take rescue medication will be 
censored at the time of first rescue medication use, if rescue medication is taken before 
meaningful pain relief is recorded. 


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A Kaplan-Meier (KM) plot and table using the following time intervals post-dose will be 
generated: using the following time intervals post-dose: 0 to 15, >15 to 30, > 30 to 45, > 45 to 
60, > 60 to 90, > 90 to 120, > 120 to 180, > 180 to 240, > 240 to 360, > 360 to 495, and > 495 
minutes. The KM plot displays the percentage of subjects with meaningful pain relief within 24 
hours on the y-axis versus time in minutes on the x-axis. Refer to Core SAP for more details. 
A time-to-event distribution table will be generated. This includes number and percentage of 
subjects with events; number and percentage of subjects censored in or before the last time 
interval; number and percentage of subjects censored in the last time interval; time-to-event 
median with 95% CI, first quartile, and third quartile. The 95% CI for the median is estimated 
using the method of Brookmeyer and Crowley. 
6.3.3.5 
Time to Onset of Initial Pain Relief 
The analysis in Section 6.3.3.4 will be repeated with respect for the time to onset of initial pain 
relief. Initial pain relief will be defined as the timepoint at which a 1-point reduction of pain from 
baseline NRS is achieved. 
6.3.3.6 
Rescue Medication Use within 24 Hours 
The number and percentage of subjects that use rescue medication within 24 hours post-dose are 
analyzed. Subjects who used rescue medication as of 24 hours post-dose are deemed failures, and 
subjects who did not use rescue medication as of 24 hours are deemed successes. For clarity, 
failure is the event being modeled (i.e. rescue medication use within 24 hours) in this analysis. 
Refer to Section 6.2.6.3 for the definition of rescue medication. A rescue medication would be 
deemed used as of 24 hours post-dose if the date/time of first rescue medication use is strictly  
24 hours after the date/time of dosing, notwithstanding Section 6.3.1 of the SAP. Subjects with a 
rescue medication start date on or before study drug start date/time + 24 hours and missing 
rescue medication start time are excluded. Subjects who report non-study medication on the 
Rescue Medication CRF with a missing rescue medication date, or a partial medication date that 
is consistent with being used within 24 hours of dosing, are also excluded. Regardless of the 
foregoing, if a subject has at least one rescue medication use with non-missing start time that is  
24 hours after the date/time of dosing, the subject will be included in the analyses and deemed a 
failure. 
No analysis window around the 24-hour post-dose time point is used. 
The analysis follows the same methodology set forth in Section 6.3.3.3. A forest plot is 
produced depicting the risk difference for rescue medication use within 24 hours post dose. The 
risk difference for each strata will be presented, as well as the overall common risk difference. 
Time to rescue medication use through 24 hours post-dose is assessed by treatment group as 
follows: 
• Kaplan-Meier plot and table using 2-hour time intervals (i.e., 0 to 2, > 2 to 4, … , > 24). 
The Kaplan-Meier plot displays the percentage of subjects taking rescue medication 


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e. 
within 24 hours post-dose on the y-axis versus time in hours on the x-axis. Refer to Core 
SAP for more details. 
• Time-to-event distribution table (hours). This includes number and percentage of subjects 
with events; number and percentage of subjects censored in or before the last time 
interval; number and percentage of subjects censored in the last time interval; time-to- 
event median with 95% CI, first quartile, and third quartile. The 95% CI for the median is 
estimated using the method of Brookmeyer and Crowley. 
Rescue medication use through 24 hours post-dose is considered as an event in these time-to- 
event analyses. See Section 7.1.5 for imputing missing rescue medication start time for purposes 
of time to rescue medication analyses. Subjects who do not take rescue medication within 24 
hours post-dose are censored at 24 hours and 1 minute. 
CCI 
 
 
 
 
6.4 
Safety 
Safety analyses are based on the treated analysis set by as-treated treatment group (i.e., the actual 
treatment received). Results for the overall treatment group are also presented in pre-treatment 
safety summaries. 
Safety parameters include deaths, AEs, and the following findings: laboratory tests; vital signs; 
physical measurements; procedures and C-SSRS. 
Analysis periods are pre-treatment and on-treatment (see Section 7.2). Refer to the Core SAP for 
slotting safety parameters into analysis periods. 
Values and changes from baseline in safety findings (e.g., laboratory tests, vital signs and 
physical measurements) and C-SSRS endpoints are tabulated as continuous variables 
descriptively at baseline and the end of treatment visit. These analyses are based on observed 


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data without imputation and regardless of rescue medication use. In these tables of safety 
parameters, if a subject has multiple values in the end of treatment analysis visit window (see 
Section 7.3), then the last non-missing value measured in the analysis period is used. See 
Sections 6.3.4.1, 6.4.4.1, and 6.4.2.4 for further handling of ties on the same measurement date 
or time. 
By-subject listings of safety parameters are described in subsections and identify on-treatment 
data. 
6.4.1 
Adverse Events 
AEs are displayed in tables and listings by SOC and PT, unless specified otherwise. 
Refer to the Core SAP for AE start date imputation, AE counting rules and frequency table 
specifications, definition of related to study drug, definition of treatment-emergent adverse 
events (TEAEs), definition of AEs of special interest, reporting of deaths, and AE listing 
contents. Exposure-adjusted multiple occurrences of unique AEs (Section 6.4.1.5 of the Core 
SAP) does not apply. 
For purposes of applying Section 6.4.1.2 of the Core SAP (definition of TEAE), an AE with non- 
missing start time is considered pre-treatment if the start date/time of the AE is prior to treatment 
start date/time. Furthermore, the “first occurrence” of an AE means the earliest imputed start 
date or earliest start date/time, where an AE with non-missing start date/time is deemed prior to 
an AE with missing start time and an imputed start date on the same date. 
A by-subject AE listing is provided for the enrolled analysis set. Notwithstanding Section 6.4.1.7 
of the Core SAP, “treatment of event” is not listed. 
6.4.1.1 
Deaths 
Deaths are identified from any the following sources: 
• AE CRF with any of the following: PT of “death”; reported term containing “death”; 
outcome of fatal; “yes” response to any death-related question (e.g., “Did the AE result in 
death?”; “Is a death certificate available?”; “Is an autopsy report available?”); complete or 
partially complete death date (see Section 7.1) 
• Disposition CRF: subject status of “Death.” 
The by-subject listing of deaths is provided for the enrolled analysis set, and displays all CRF 
sources of death, safety analysis period, death date (see Section 7.1), study day derived from the 
death date, treatment day derived from the death date, and the following AE parameters: non- 
imputed start date and end date; SOC; PT; verbatim term; outcome; and response to the question 
“Fatal”. 


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6.4.1.2 
AE Overview 
An AE overview without SOC and PT presents the number and percentage of subjects with any 
of the following AEs: any AE; mild AE; moderate AE; severe AE; moderate or severe AE; AE 
related to study drug; SAE; SAE related to study drug; AE leading to study drug discontinuation; 
hepatic-related AE; cardiovascular AE; and suicidality AE. 
An AE overview is produced for each analysis period (pre-treatment, on-treatment) for the 
treated analysis set. 
6.4.1.3 
On-treatment AEs by SOC and PT 
On-treatment AEs are tabulated by SOC and PT for the treated analysis set for the following 
endpoints: 
• AEs by intensity 
• AEs associated with study drug by intensity 
• AEs by relationship to study drug (related, not related, not reported) 
• SAEs 
• AEs leading to study drug discontinuation 
• Hepatic-related AEs by intensity * 
• Cardiovascular AEs * 
• Suicidality AEs *. 
AEs of special interest are asterisked (“*”). AEs are displayed in descending order of 
rimegepant frequency within SOC and PT. 
6.4.2 
Laboratory Tests 
Laboratory tests are analyzed using results from a central laboratory and are collected at the 
following visits: Screening, EOT and Unscheduled. Laboratory tests are slotted into safety 
analysis periods (pre-treatment and on-treatment) according to the laboratory collection date and 
time, as available. Some tabulations are provided for the on-treatment period only, as specified 
below. 
Fasting time is not collected; therefore, cholesterol and triglycerides are analyzed as separate 
laboratory test parameters according to fasting status (last 8 hours): fasting; non-fasting; overall 
(see Section 6.4.2 of the Core SAP). 
Clinically significant laboratory abnormalities are identified as grade 3 to 4 laboratory test 
results. Refer to Section 6.4.2.1 of the Core SAP for laboratory tests of clinical interest for 
analyses, including identification of those with toxicity grades. If a toxicity grade depends on 
age, then age is defined as age recorded on the CRF. 


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Estimated glomerular filtration rate (eGFR) is derived using the modification of diet in renal 
disease (MDRD) formula. Notwithstanding Section 2.2 of the Core SAP, eGFR is not separately 
derived but is provided as reported by the central laboratory. 
Laboratory test groups of clinical interest includes hematology, serum chemistry, and urinalysis. 
TLFs show data in the Systeme International (SI) unit system, if applicable. Tables present 
results by treatment group and overall, and laboratory tests alphabetically within laboratory test 
group, as applicable. 
6.4.2.1 
Laboratory Test Abnormalities 
Laboratory test abnormalities are tabulated as the number and percentage of subjects in the 
treated analysis set in the frequency tables specified in Section 6.4.2.2 of the Core SAP. This is 
provided for the on-treatment period only. 
6.4.2.2 
Liver Function Test Elevations 
Liver function test (LFT) elevations are tabulated for laboratory tests as specified in Section 
6.4.2.3 of the Core SAP (as applicable to single-dose studies). 
LFT Elevations: Cumulative, Mutually Exclusive, and Composite 
The number and percentage of subjects with LFT elevations are tabulated separately for each 
analysis period (pre-treatment, on-treatment) for the treated analysis set. LFT elevations are 
based on fold changes above ULN. 
LFT ULN Shifts from Baseline to Worst Elevation 
LFT ULN shifts from baseline to the worst (highest) on-treatment LFT elevation are tabulated as 
the number and percentage of subjects in the treated analysis set in pre-specified elevation 
categories. 
6.4.2.3 
LFT Plots 
An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot is produced, as 
specified in Section 6.4.2.4 of the Core SAP, separately for each analysis period (pre-treatment, 
on-treatment). By-subject longitudinal LFT plots are not produced. 
6.4.2.4 
Laboratory Test Changes from Baseline Table 
Values and changes from baseline in laboratory tests are tabulated descriptively as continuous 
variables over time at baseline and EOT. 
The table displays results by laboratory tests alphabetically within laboratory test group. 
Multiple values in analysis visit windows are handled as set forth in Section 7.3. 


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6.4.2.5 
Laboratory Test Listings 
By-subject Listings of Laboratory Test Results 
All laboratory test listings will be based on the enrolled analysis set. 
A by-subject listing of the following select laboratory tests is provided for subjects with at least 
one laboratory assessment of grade 3 or 4 abnormality or a positive pregnancy test result: 
hematology results, serum chemistry results, and urinalysis results. If there is a positive 
pregnancy test, defined as a serum or urine pregnancy test with either (1) “positive” character 
value, or (2) numeric value  25 U/L. the listing will also include all pregnancy test results over 
time. 
Refer to Section 6.4.2.6 of the Core SAP for listing contents as applicable to this study. 
By-subject Listing of LFT Values and Ratios to ULN 
Liver function test (LFT) values and ratios to upper limit of normal (ULN) (i.e., alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin [TBL] and alkaline 
phosphatase [ALP]) are displayed for SI units. The listing displays all LFT results over time for 
subjects with select LFT elevations (ALT or AST > 3x ULN; ALP or TBL > 2x ULN) at any 
time point. Refer to Section 6.4.2.6 of the Core SAP for listing contents as applicable to this 
study. 
6.4.3 
Vital Signs and Physical Measurements 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, and temperature. 
These parameters are measured at Screening, Baseline, and EOT. Vital signs are slotted into 
safety analysis periods (pre-treatment, on-treatment) according to the measurement date. Vital 
signs are tabulated for the on-treatment analysis period (see Section 7.2) for the treated analysis 
set. 
Physical measurements include height, weight, and body mass index (where height and weight 
are measured at Screening only). Physical measurements are slotted into safety analysis periods 
(pre-treatment, on-treatment) according to the measurement date. 
6.4.3.1 
Vital Sign Changes from Baseline 
Values and changes from baseline in vital signs are tabulated descriptively as continuous 
variables at baseline and EOT. Physical measurements (i.e. weight, height, and BMI) are not 
included in this display. 
Multiple values in analysis visit windows are handled as set forth in Section 7.3. 
6.4.3.2 
Vital Signs Abnormalities 
Vital sign abnormalities are tabulated as the number and percentage of subjects in the treated 
analysis set meeting categories specified in Section 6.4.3.2 of the Core SAP during the on- 


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treatment analysis period, except weight change from baseline is not calculated. Analyses are 
based on the subset of subjects with non-missing data in the on-treatment analysis period for a 
given parameter. 
6.4.3.3 
Vital Signs and Physical Measurements Listing 
Refer to Section 6.4.3.3 of the Core SAP for details on the by-subject vital signs and physical 
measurement listing, as applicable to this study. All vital signs and physical measurements 
listings will be based on the enrolled analysis set. 
6.4.4 
Procedures 
Procedures are listed for the enrolled analysis set using the Concomitant Procedures CRF. The 
listing includes the name of the procedure/surgery, SOC and PT, the date of the 
procedure/surgery, and analysis periods. See Section 6.4.5 of the Core SAP for further details. 
Procedures are slotted into safety analysis periods according to the procedure date. Note that 
procedures are slotted like AEs, but without date imputation (see Section 7.2). 
6.4.5 
Suicidality 
The C-SSRS is a clinician administered questionnaire used for suicide assessment. The C-SSRS 
Screening version is used at the Screening Visit and the Since Last Visit version is used at 
subsequent visits. C-SSRS is measured at Screening, Baseline and EOT. The C-SSRS 
Assessment is intended to help establish a person’s immediate risk of suicide. 
At the Screening Visit, the recall period for completing the C-SSRS is past 12 months for 
ideation, and 10 years for attempt and behavior; at all other visits, the recall period for 
completing the C-SSRS is since the last visit. 
Refer to the Core SAP for the definitions of C-SSRS parameters and specifications for 
tabulation. However, notwithstanding Section 6.4.6.2 of the Core SAP, C-SSRS results are not 
separately tabulated by analysis periods but instead tabulated by visit (Screening, Baseline, and 
EOT). Unscheduled or early termination visits following treatment are reassigned as specified in 
Section 7.3; unscheduled or early termination visits prior to treatment are not reassigned or 
tabulated. 
6.4.6 
Safety Narrative Subject Identifiers Listing 
A by-subject listing of safety narrative subject identifiers is provided for the following select 
events and analysis sets as columns: 
• All deaths on-treatment or during follow-up, regardless of treatment 
• SAEs on-treatment or during follow-up for rimegepant-treated subjects, regardless of 
relationship to study drug 


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• Any AE leading to discontinuation of study drug for rimegepant-treated subjects, 
regardless of relationship to study drug 
• On-treatment events of special interest for rimegepant-treated subjects: 
o ALT or AST > 3x ULN 
o ALT or AST > 3x ULN concurrent with TBL > 2x ULN 
o TBL or ALP > 2x ULN 
o Select hepatic-related AE, i.e., PT containing cirrhosis, hepatic failure, hepatitis, 
jaundice, or liver failure 
o Cardiovascular AE 
o Suicidality AE 
Refer to the Core SAP for additional details. The listing flags subjects with select events. 
Should the criteria stated in the Biohaven Rimegepant Safety Narrative Scope conflict with the 
criteria above, the Biohaven Rimegepant Safety Narrative Scope will take precedence. 
7 CONVENTIONS 
7.1 
Derived Dates 
Refer to Section 7.1 of the Core SAP for the definition of complete dates, partially complete 
dates, and the term “date/time.” 
7.1.1 
Analysis Period Reference Dates 
Analyses periods are determined by analysis period reference date/times. The analysis period 
reference date/time for the pre-treatment and on-treatment analysis periods are the date of 
informed consent and the study drug date/time (see Section 7.2). 
Derived dates (or date/time values) are defined as follows. 
7.1.1.1 
Study Drug Dates 
• Study drug date/time: 
o For subjects who indicated that they took study medication (not mistakenly) on the 
“Initial Pain Diary,” the date/time that the “Initial Pain Diary” is saved. 
o For subjects who indicated that they mistakenly took study medication on the “Initial 
Pain Diary,” the date/time that the subject entered on the “Initial Pain Diary” in 


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response to the question “When did you take the Study Medication?” (Note that if 
the subject indicated that they dosed on the same day, only time is manually entered.) 
o For subjects who reported to the site that they took study medication without 
interacting with eDiary, the date/time recorded by the site and transmitted to the 
electronic patient-reported outcome vendor. 
7.1.2 
Imputed Dates 
Refer to Section 7.1.2 of the Core SAP for the imputation of non-study medication start dates 
(except rescue medications), non-study medication end dates, AE start dates, and AE end dates, 
with the following adjustment: with respect to the use of birth date in the imputation logic, the 
complete birth date is assumed to be January 1st of the birth year if the birth year is non-missing. 
7.1.3 
Last Contact Date 
The last contact date is used to determine select parameters (i.e., time on study, imputed non- 
study medication end dates, and death date), and is typically defined using non-imputed dates as 
follows: 
1. Earliest complete death date from all sources that collect death dates (e.g., AE CRF), if it 
exists. 
2. Otherwise, the maximum complete date of the following CRF or external data sources, as 
applicable: AE start or end; COVID-19 visit where the COVID-19 visit impact type is not a 
missed visit; ECG; efficacy assessment; informed consent; IWRS randomization; laboratory 
test collection; non-study medication start or end; physical exam; physical measurement; 
protocol deviation; questionnaire; study drug start; subject disposition 
completion/discontinuation; visit; vital sign. 
3. If the last contact date is after the most recent raw database creation date, then it is set to the 
most recent raw database creation date. 
7.1.4 
COVID-19 Visit Date 
COVID-19 visit dates are not derived and are not displayed on listings. 
7.1.5 
Other Derived/Imputed Dates 
Additional derived dates include. 
• Date/time of eDiary assessments: The date/time of a given assessment collected in the 
eDiary is the datetime the diary for that time point is saved (e.g., the date/time of all 
assessments collected on the 15 minute diary is the datetime the 15 minute diary is saved). 
• Rescue medication start date/time: Earliest rescue medication date/time. Missing time is 
considered to be earlier than non-missing time on the same date. Refer to Section 6.2.6.3. 


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• Imputed rescue medication start date/time: This is used only for time-to-event efficacy 
analyses in Section 6.3.3.5. 
o If the rescue medication start date and time are both not missing, then the imputed 
rescue medication start date/time is set to the rescue medication start date/time. 
o If the rescue medication start time is missing and the rescue medication start date is 
equal to the study drug dose date, then the imputed rescue medication start date/time 
is set to the study drug dose date/time. 
o Otherwise, if the rescue medication start time is missing and the rescue medication 
start date is equal to a post-dose eDiary finding date with non-missing efficacy data 
on that date (i.e., the day after dosing), then the imputed rescue medication start 
date/time is set to the first eDiary finding date/time on that date corresponding to non- 
missing efficacy data. 
o Otherwise, if the rescue medication start time is missing and rescue medication start 
date is equal to the study drug dose date + 1 day, with no eDiary efficacy data 
recorded the day after dosing, then the imputed rescue medication start date/time is 
set to the study drug start date/time + upper bound of the 24-hour analysis window 
(see Table 6). 
• Death date: Last contact date (see Section 7.1.3), derived only for subjects who died (see 
Section 6.4.1.1). 
No imputations are performed on these derived dates, except as specifically mentioned in this 
Section 7.1.5. Complete dates are those with valid, non-missing day, month, and year. 
7.2 
Analysis Periods 
Measurements are slotted into analysis periods by comparing both measurement date and time to 
analysis period reference date and time (i.e., study drug start date and time; see Section 7.1.1). 
Otherwise, if (1) time is missing or not available for either the measurement or the analysis 
period reference, or (2) time is not required for slotting, then only the measurement date is 
compared to the analysis period reference date. 
Note that the measurement date must be complete for the measurement to be slotted into an 
analysis period (see Section 7.1). Exceptions are noted for the pre-treatment analysis period for 
subjects in the enrolled analysis set who are not in the safety analysis set and for AEs, where 
imputed start dates are used if start date is incomplete. 
Analysis periods are defined as follows. 
• Pre-treatment: measurement date/time at or before the study drug dose date/time. This 
period is used to derive baseline values and to assess pre-treatment endpoints. Note that all 
measurements are pre-treatment for subjects in the enrolled analysis set with missing study 
drug dose date and that AEs with imputed start date prior to study drug dose date are 
included in this analysis period (or start date/time < study drug dose date/time if AE start 
time is non-missing). 


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• On-treatment: measurement date/time after the study drug dose date/time. This period is 
used to assess safety endpoints on treatment. Note that AEs with imputed start date equal to 
study drug dose date are included in this analysis period, unless start time is non-missing and 
start date/time is < study drug dose date/time. Baseline assessments are not count as “on 
treatment” but are included in “on treatment” tables that report change from baseline. 
See Section 7.1 for derived dates for determining analysis periods. 
7.3 
Analysis Visit Windows 
Refer to Protocol Section 4.2 for the schedule of assessments. 
Study days are calculated from the randomization date as follows: 
• Measurement date − randomization date + 1, if measurement date  randomization date 
• Measurement date − randomization date, if measurement date < randomization date. 
Treatment days are calculated from the study drug dose date as follows: 
• Measurement date − study drug dose date + 1, if measurement date  study drug dose date 
• Measurement date − study drug dose date, if measurement date < study drug dose date. 
Analysis visit windows for safety parameters are presented in Table 4. 
Table 4: 
Analysis Visit Windows for Safety Parameters 
 
 
Analysis Visit 
Analysis-Specified Interval 
Screening 
Baseline 
End of treatment 
• 
 Study day – 1 or both study day and treatment day missing 
• 
 Treatment day – 1 * 
Study day 1 
• 
 Study day 2 
• 
 Treatment day * 
*Applies only to subjects who took study drug but were not randomized 
Notwithstanding Sections 6.4.3.1 of the Core SAP, multiple values in analysis visit windows are 
handled as follows: 
• The scheduled visit takes priority over unscheduled or early termination visits. 
• If a subject does not have a scheduled visit, the unscheduled or early termination visit 
closest to the target date takes priority. 


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• If there are still multiple values on the same measurement date, then the last value 
collected timewise takes priority (if time is collected); if ties remain, the value with the 
highest ECG reference identifier, vital signs identifier, or laboratory barcode is used, as 
applicable. 
For clarity, displays that tabulate baseline values tabulate the baseline value as defined in Section 
7.5, rather than the value that maps to the Baseline Visit, unless otherwise explicitly noted (see 
Section 6.4.6). 
For efficacy assessments collected on the eDiary, windows are imposed by the eDiary, as shown 
in Table 5. No additional analysis windows are imposed. The anchor point for the windows is 
the date/time of exposure, as defined in Section 7.1. 
 
Table 5: 
Evaluation Intervals for Efficacy Analyses 
 
 
Post-dose Evaluation 
Analysis-Specified Interval 
Target Time 
15 min diary 
10-20 min 
Study medication start time + 15 min 
30 min diary 
25-35 min 
Study medication start time + 30 min 
45 min diary 
40-50 min 
Study medication start time + 45 min 
60 min diary 
55-65 min 
Study medication start time + 60 min 
90 min diary 
85-95 min (1hr 25 min – 1 hr 35 min) 
Study medication start time + 90 min 
2 hr diary 
115-135 min (1hr 55 min – 2 hr 15 min) 
Study medication start time + 2 hr 
4 hr diary 
225-255 min (3hr 45 min – 4 hr 15 min) 
Study medication start time + 4 hr 
8 hr diary 
465-495 min (7 hr 45 min – 8 hr 15 min) 
Study medication start time + 8 hr 
24 hr diary 
1380-1500 min (23 hr – 25 hr ) 
Study medication start time + 24 hr 
 
7.4 
Subgroups 
Section 7.4 of the Core SAP does not apply in its entirety. 
7.5 
Baseline Value 
The baseline value for a safety parameter collected with a measurement date/time (e.g., weight) 
is defined according to analysis set as follows: 
• Enrolled analysis set but not in the randomized analysis set: Last non-missing value 


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• Full analysis set but not in the treated analysis set: Last non-missing value at or before the 
IWRS randomization date 
• Treated analysis set: Last non-missing value in the pre-treatment analysis period 
“Last” is determined by the last complete measurement date/time. See Section 7.1 for complete 
dates, Section 7.2 for analysis periods, and Sections 6.4.2.4 and 6.4.3.1 for handling multiple 
values on the same measurement date. 
The baseline NRS pain score is the value collected on the “Initial pain” eDiary where the subject 
confirmed having dosed (not mistakenly). The date/time of the associated baseline value is the 
date and time that the “Initial pain” eDiary is saved. For subjects who mistakenly took drug and 
thus are missing baseline NRS pain scores (see Section 6.2.6), baseline NRS pain scores are 
imputed as the mean of the non-missing baseline NRS pain scores across subjects. 
8 CONTENT OF REPORTS 
The final CSR is produced after the final database lock, which occurs after last subject last visit. 
All TLFs described in this SAP are produced for the final CSR. No interim analyses are planned. 


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9 APPENDICES 
9.1 
Relevant Protocol Deviations 
Relevant eligibility protocol deviations include the following categories: 
• TMD history not aligned with eligibility requirements as any of the following: 
o TMD onset less than 3 months prior to Screening OR longer than 5 years 
o Qualifying TMD Pain Disorder not selected (myalgia AND Right arthralgia AND 
Left arthralgia not selected) 
• Finding out of range at Screening (or at Baseline, as applicable), defined as any of the 
following: 
o ALT/AST/Direct Bilirubin/Indirect Bilirubin/Total Bilirubin > ULN 
o ECG abnormalities as follows: 
■ 
Corrected QT interval > 470 msec (QTc by method of Frederica) 
■ 
Left Bundle Branch block 
■ 
Right Bundle Branch Block with a QRS duration 2: 150 msec 
■ 
Intraventricular Conduction Defect with a QRS duration 2: 150 msec 
o Neutrophil count :S 1000/µL (or equivalent) 
o HbA1c 2: 6.5% 
o Diastolic blood pressure > 100 mmHg after 10 mins of rest 
o Estimated glomerular filtration rate (eGFR) according to the re-expressed abbreviated 
(4-variable) Modification of Diet in Renal Disease (MDRD) Study equation  40 
mL/min/1.73m2 
o BMI  33 kg/m2 
o Positive for cocaine, cannabinoids, or PCPs at any visit 
o Females with a positive pregnancy test at Screening or Baseline 
o C-SSRS suicidal ideation with active intent or plan to act, or suicidal behavior present 
during screening. Defined as having a “yes” response to any of the following C-SSRS 
questions at Screening Visit or Baseline Visit: 
■ 
Suicidal ideation question 4 (active suicidal ideation with some intent to act, 
without specific) or 5 (active suicidal ideation with specific plan and intent) 
■ 
Suicidal behavior question 1 (actual attempt), 3 (interrupted attempt), 4 
(aborted attempt), 5 (preparatory acts or behavior), or 6 (suicidal behavior). 
 
Relevant subject management protocol deviations include the following: 


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• Prohibited non-study medications, procedures, or therapies defined as any of the following: 
o Daily medications with dose change or with start date < 3 months 
o Daily oral devices without consistent use or with start date < 3 months 
o Excluded current or recent treatments (Section 5.3.6 of the protocol) prior to the 
Screening Visit or throughout the study as follows: 
■ 
history of active dental orthodontic use within the 3 months prior to the 
Screening Visit, or new or recently modified use of non-active dental 
orthodontics. 
■ 
history of dental restorative care (e.g., crowns, bridges) within the 3 months 
prior to the Screening Visit. 
■ 
new or recently modified physical therapy treatment in the head and/or neck 
area within the 3 months prior to the Screening Visit. 
■ 
has a history of Transcutaneous Electrical Nerve Stimulation (TENS) within 
the 3 months prior to the Screening Visit. 
■ 
history of injection therapy other than botulinum therapy (e.g., lidocaine, 
corticosteroids, hyaluronic acid) within the 30 days prior to the Screening 
Visit. 
o Non-narcotic analgesic taken on 2: 15 days per month for greater 2: 3 month prior to 
the Screening Visit 
o Acetaminophen or acetaminophen containing products taken within 2 days before 
randomization. 
o Use of acetaminophen during the screening phase (3 to 14 days) or throughout the 
study at daily dosing levels of greater than 1000 mg/day 
o Muscle relaxants taken up to 14 days prior to randomization or afterward (except 
cyclobenzaprine) 
o Systemic corticosteroids taken up to 30 days prior to the Screening Visit or afterward 
o Narcotic medication, such as opioids, taken up to 30 days prior to the Screening Visit 
or afterward 
o Strong CYP3A4 inhibitors taken up to 14 days prior to the Baseline Visit or afterward 
o Moderate or strong CYP3A4 inducers taken up to 14 days prior to the Screening Visit 
or afterward 
o Atypical antipsychotics such as Abilify (aripiprazole), Zyprexa (olanzapine), 
Seroquel (quetiapine), Geodon (ziprasidone), or Risperdal (risperidone) or 
Depakote/Depakene (valproic acid/valproate) taken up to 90 days prior to the 
Baseline Visit or afterward 
 
Note: Medications taken up to X days before a reference date or afterward are defined 
as those with medication start date or stop date  reference date – X. Refer to the 
Core SAP for additional details about prohibited non-study medications. 
• Finding out of range during the study, defined as any of the following: 


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o C-SSRS suicidal ideation with active intent or plan to act, or suicidal behavior present 
during screening. Defined as having a “yes” response to any of the following C-SSRS 
questions at the Baseline Visit and the subject is randomized: 
■ 
Suicidal ideation question 4 (active suicidal ideation with some intent to act, 
without specific) or 5 (active suicidal ideation with specific plan and intent) 
■ 
Suicidal behavior question 1 (actual attempt), 3 (interrupted attempt), 4 
(aborted attempt), 5 (preparatory acts or behavior), or 6 (suicidal behavior). 
o Females with a positive pregnancy test at Baseline Visit and the subject is 
randomized 
o Positive for cocaine, cannabinoids or PCPs at any post-baseline visit, including End 
of Treatment visit 
 
• Medical history, defined as any of the following subcategories: 
o History of trigeminal neuralgia or postherpetic neuralgia 
o Trauma in the craniocervical area, including joint sprain/strain, within the 3 months prior 
to the Screening Visit 
o History of TMJ surgery (e.g., arthrocentesis, arthroscopy, TMJ implants) or ear surgery 
 
• Prescence of concomitant medications/devices discrepant between IWRS and CRF data, 
defined as any of the following subcategories: 
o IWRS randomization stratum of yes, but no concomitant oral medications reported AND 
no concomitant devices reported 
o IWRS randomization stratum of no, but concomitant oral medications reported OR 
concomitant devices reported 
• End of treatment visit outside of 9 days after treatment administered 


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10 REFERENCES 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York, NY USA, 
John Wiley & Sons Inc. 
Salaffi F, Stancati A, Silvestri CA, Ciapetti A, Grassi W. Minimal clinically important changes 
in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain 
2004;8:283-91.