Clinical trial NCT02381795
Conditions: Cluster Headache
Sponsor: Cady, Roger, M.D.
Start date: 2015-07-01; Completion date: 2017-04-01
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, investigator-sponsored, pilot study. Subjects agreeing to participate in the study and meeting the eligibility criteria assessed at the screening visit will be enrolled in the study. The length of time between screening and treatment will last between 0 days to a maximum of 12 weeks. Subjects who enter the screening phase during a cluster headache episode and meet the study eligibility criteria can immediately enter the treatment phase and may opt to treat their cluster headache episode in the clinic. Subjects who are not in a cluster headache episode, who meet initial screening eligibility criteria, can remain in the screening phase for up to 12 weeks until their next cluster episode begins. Upon initiation of a cluster headache episode, subjects will enter the treatment period. Subjects will be trained on the proper use of the hand-held dispenser containing carbon dioxide (CO2 )calibrated to deliver 0.5 standard liters per minute (SLPM). This dispenser will be provided for use in the clinic or home. Subjects will be instructed to use the nasal CO2 dispenser, 10 seconds/nostril, as needed up to 6 times to treat one attack. Each dose must be separated by 3-5 minutes. Subjects should treat only one attack in a 24-hour period. Subjects may treat up to three cluster headache attacks during the treatment phase of this study. One hour after the first dose, subjects can choose to treat with investigator-approved rescue medication. Subjects will be asked to complete an online diary after the completion of the dosing. Diary assessments will collect pain severity, nasal CO2 usage, acute medication usage, satisfaction of treatment, number of cluster attacks, and unusual symptoms. Subjects will be contacted by phone within 3 days of the first use of the nasal CO2 dispenser to assess adverse events (AEs) and medication usage. A total of 25 subjects will enter the treatment period and be instructed to treat up to 3 cluster headaches with nasal CO2. Within 7 days of treating their last cluster headache episode, subjects will return for an end of study visit.

Detailed description:

Arms: arm 1: 0.17 liters (L) of carbon dioxide (CO2) will be delivered through two 10 second administrations in each nostril, up to 6 times, to treat one attack (total of 1.0 L CO2). Subjects may treat up to three cluster headache attacks during the treatment phase of this study (total of 3.0 L (CO2).
Interventions: intervention 1: Nasal Carbon Dioxide
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 15-001CA 
Nasal CO2 
CLINICAL PROTOCOL 
Protocol No. 
15-001CA
Title: 
An Open Label, Pilot Study Evaluating the Efficacy and Safety of the Use of 
Nasal Carbon Dioxide for the Treatment of Cluster Headache 
Version: 
Original 
Amendment 1 
Amendment 2 
10 March 2015 
30 November 2015 
28 April 2016 
Sponsor:            Dr.  Timothy Smith 
Clinvest Research, LLC.  
3805 South Kansas Expressway, Suite B 
Springfield, MO 65807   
Phone: 417-883-7889 
Approval: 
Investigator Printed Name 
Signature 
_________________________________ 
Date 
CONFIDENTIAL 
This document contains proprietary and confidential information about Nasal CO2 Dispenser.  
Acceptance of this document constitutes agreement by the recipient that no previously unpublished 
information contained herein will be published or disclosed without the prior written approval of the 
manufacturer, Capnia, Inc. (Capnia), with the exception that this document may be disclosed to study 
personnel under your supervision who need to know the contents for conducting the study and 
appropriate Institutional Review Boards (IRBs)/Ethics Committees (ECs) under the condition that the 
personnel have agreed to keep this information confidential. The foregoing shall not apply to disclosure 
required by governmental regulations or laws; however, Capnia shall be promptly notified of any such 
disclosure. 


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TABLE OF CONTENTS 
 
CLINICAL PROTOCOL ..............................................................................................................1 
1.0 
STUDY SYNOPSIS ..............................................................................................................6 
2.0 
LIST OF ABBREVIATIONS ............................................................................................12 
3.0 
BACKGROUND .................................................................................................................14 
3.1 
Investigational Product ...............................................................................................14 
3.2 
Cluster Headache ........................................................................................................14 
3.3 
Non-Clinical and Clinical Data ..................................................................................15 
3.3.1 
In Vitro Non-Clinical Evaluations ................................................................15 
3.3.2 
In Vivo Non-Clinical Evaluations ................................................................15 
3.3.3 
Clinical Evaluation in Healthy Volunteers ...................................................15 
3.3.4 
Clinical Evaluations in Acute Migraine .......................................................16 
3.3.4.1 
CH-2000-02 (Migraine Phase 1) ................................................16 
3.3.4.2 
CH-2002-01 (Migraine Phase 2a) ..............................................17 
3.3.4.3 
CH-2004-03 (Migraine Phase 2b) ..............................................17 
3.3.4.4 
C112 (Mild Headache Study) .....................................................18 
3.3.4.5 
C113 (Phase 3, Moderate to Severe Migraine Study) ................18 
3.3.5 
Clinical Evaluations in Allergic Rhinitis .....................................................19 
3.3.5.1 
SAR-2005 (Seasonal Allergic Rhinitis Single-Dose Study) ......19 
3.3.5.2 
C211 (Perennial Allergic Rhinitis Single-Dose Study) ..............20 
3.3.5.3 
C213 (Perennial Allergic Rhinitis Multi-Dose Study) ...............20 
3.3.5.4 
C215 (Seasonal Allergic Rhinitis Multi-Dose Study) ................21 
3.3.5.5 
C216 (Phase 2, Seasonal Allergic Rhinitis) ...............................21 
3.3.5.6 
C218 (Phase 2, Seasonal Allergic Rhinitis) ...............................22 
3.3.5.7 
RH01910 (Phase 2, Nasal Congestion) ......................................22 
3.3.6 
Clinical Evaluation in Temporomandibular Disorders ................................23 
3.4 
Risk/Benefits ...............................................................................................................23 
3.5 
Dose Rationale ............................................................................................................23 
3.6 
Trial Conduct ..............................................................................................................24 
3.7 
Population ...................................................................................................................24 
4.0 
TRIAL OBJECTIVES .......................................................................................................24 
4.1 
Primary Objective .......................................................................................................24 
4.2 
Secondary Objectives .................................................................................................24 


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5.0 
TRIAL DESIGN .................................................................................................................24 
5.1 
Primary, Secondary, and Exploratory Endpoints .......................................................25 
5.1.1 
Primary Endpoint .........................................................................................25 
5.1.2 
Secondary Endpoints ....................................................................................25 
5.2 
Study Treatment ..........................................................................................................26 
5.2.1 
Dose Description ..........................................................................................26 
5.2.1.1 
Nasal CO2 Dispensers .................................................................26 
5.2.2 
Packaging and Labeling ...............................................................................26 
5.2.3 
Storage and Handling ...................................................................................27 
5.3 
Duration ......................................................................................................................27 
5.4 
Discontinuation ...........................................................................................................27 
5.5 
Investigational Product Accountability ......................................................................28 
5.6 
Data Identification ......................................................................................................28 
6.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................29 
6.1 
Inclusion Criteria ........................................................................................................29 
6.2 
Exclusion Criteria .......................................................................................................29 
6.3 
Subject Withdrawal ....................................................................................................30 
6.4 
Screen Failures ............................................................................................................31 
7.0 
TREATMENT OF SUBJECTS ........................................................................................31 
7.1 
Treatments to be Administered ...................................................................................31 
7.1.1 
Nasal CO2 Dispenser ....................................................................................31 
7.2 
Medication ..................................................................................................................32 
7.2.1 
Concomitant Medication ..............................................................................32 
7.2.2 
Medications Not Permitted ...........................................................................32 
7.2.3 
Rescue Medication .......................................................................................33 
7.3 
Monitoring for Subject Compliance ...........................................................................33 
8.0 
STUDY PROCEDURES ....................................................................................................33 
8.1 
Description of Study Procedures and Assessments ....................................................33 
8.1.1 
Informed Consent .........................................................................................33 
8.1.2 
Medical History, Medications and Demographics .......................................34 
8.1.3 
Physical Examination ...................................................................................34 
8.1.4 
Vital Signs ....................................................................................................34 
8.1.5 
Nasal Mucosal Examination .........................................................................34 
8.1.6 
Urine Pregnancy Test ...................................................................................35 


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8.1.7 
Enrollment ....................................................................................................35 
8.1.8 
Training ........................................................................................................35 
8.1.9 
Subject Diary and Assessments ....................................................................35 
8.1.10 
Treatment of Cluster Headaches ..................................................................36 
8.1.11 
Adverse Events .............................................................................................36 
8.1.12 
Concomitant Medications / Procedures ........................................................37 
8.1.13 
Telephone Contact ........................................................................................37 
8.2 
Schedule of Events .....................................................................................................38 
9.0 
ASSESSMENT OF SAFETY ............................................................................................39 
9.1 
General Guidelines .....................................................................................................39 
9.2 
Definitions ..................................................................................................................39 
9.2.1 
Adverse Event ..............................................................................................39 
9.2.2 
Suspected Adverse Reaction ........................................................................39 
9.2.3 
Serious Adverse Event .................................................................................39 
9.2.3.1 
Hospitalizations as Serious Adverse Events ..............................40 
9.2.4 
Unanticipated Adverse Device Effect ..........................................................40 
9.3 
Reporting of Safety Information .................................................................................40 
9.3.1 
Adverse Event Reporting .............................................................................40 
9.3.2 
Serious Adverse Event Reporting ................................................................41 
9.4 
Adverse Event Follow-up ...........................................................................................43 
10.0 STATISTICAL METHODS AND ANALYSIS ...............................................................43 
10.1 General Considerations ...............................................................................................43 
10.2 Handling of Dropouts or Missing Data ......................................................................43 
10.3 Endpoints ....................................................................................................................43 
10.3.1 
Primary Efficacy Endpoint ...........................................................................43 
10.3.2 
Method and Timing of Assessing Efficacy ..................................................43 
10.3.3 
Secondary Efficacy Endpoints .....................................................................43 
10.3.4 
Exploratory Efficacy Endpoints ...................................................................44 
10.3.5 
Safety Endpoint ............................................................................................44 
10.4 Analysis Sets ...............................................................................................................44 
10.4.1 
Intent-to-Treat (ITT) Population ..................................................................44 
10.4.2 
Modified Intent-to-Treat (mITT) Population ...............................................45 
10.4.3 
Per Protocol (PP) Population ........................................................................45 
10.4.4 
Safety Analysis Set .......................................................................................45 


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10.5 Primary Efficacy Analysis ..........................................................................................45 
10.6 Secondary Efficacy Analyses .....................................................................................45 
10.7 Exploratory Efficacy Analyses ...................................................................................45 
10.8 Safety Analysis ...........................................................................................................46 
10.8.1 
Adverse Events .............................................................................................46 
10.8.2 
Vital Signs ....................................................................................................46 
10.8.3 
Concomitant Medications ............................................................................46 
10.8.4 
Other Observations Related to Safety ..........................................................46 
10.9 Termination Criteria ...................................................................................................46 
10.10 Accountability Procedure ...........................................................................................46 
10.11 Deviation Reporting ....................................................................................................46 
11.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ...................................47 
12.0 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................47 
13.0 ETHICAL CONSIDERATIONS ......................................................................................47 
14.0 DATA HANDLING AND RECORD KEEPING ............................................................48 
15.0 REFERENCE LIST ...........................................................................................................50 
 


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1.0 
 STUDY SYNOPSIS 
Title of Study: 
An Open Label, Pilot Study Evaluating the Efficacy and Safety 
of the Use of Nasal Carbon Dioxide for the Treatment of Cluster 
Headache 
Sponsor: 
Dr. Timothy Smith 
Clinvest Research LLC  
3805 South Kansas Expressway, Suite B 
Springfield, MO 65807                           
Phone: 417-883-7889 
 
Indication: 
For the treatment of cluster headaches in adults. 
Primary Objectives: 
To evaluate the safety and efficacy of nasal CO2 for the treatment 
of cluster headache.  


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Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is an open label, investigator-sponsored, pilot study.  
Subjects agreeing to participate in the study and meeting the 
eligibility criteria assessed at the screening visit will be enrolled 
in the study.  The length of time between screening and treatment 
will last between 0 days to a maximum of 12 weeks.  Subjects 
who enter the screening phase during a cluster headache episode 
and meet the study eligibility criteria can immediately enter the 
treatment phase and may opt to treat their cluster headache 
episode in the clinic.  Subjects who are not in a cluster headache 
episode, who meet initial screening eligibility criteria, can remain 
in the screening phase for up to 12 weeks until their next cluster 
episode begins. Upon initiation of a cluster headache episode, 
subjects will enter the treatment period. Subjects will be trained 
on the proper use of the hand-held dispenser containing CO2 
calibrated to deliver 0.5 standard liters per minute (SLPM).  This 
dispenser will be provided for use in the clinic or home.  Subjects 
will be instructed to use the nasal CO2 dispenser,                         
10 seconds/nostril, as needed up to 6 times to treat one attack.  
Each dose must be separated by 3-5 minutes.  Subjects should 
treat only one attack in a 24-hour period.  Subjects may treat up 
to three cluster headache attacks during the treatment phase of 
this study. One hour after the first dose, subjects can choose to 
treat with investigator-approved rescue medication.  Subjects will 
be asked to complete an online diary after the completion of the 
dosing. Diary assessments will collect pain severity (0=none, 
1=mild, 2=moderate, 3=severe), symptoms (such as tearing, nasal 
congestion, and running nose), nasal CO2 usage, acute 
medication usage, satisfaction of treatment, number of cluster 
attacks, and unusual symptoms.  Subjects will be contacted by 
phone within 3 days of the first use of the nasal CO2 dispenser to 
assess adverse events (AEs) and medication usage.  A total of 25 
subjects will enter the treatment period and be instructed to treat 
up to 3 cluster headaches with nasal CO2.  Within 7 days of 
treating their last cluster headache episode, subjects will return 
for an end of study visit. 


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Number of Subjects: 
Up to 25 subjects enrolled and treating up to 3 cluster headaches 
in one cluster headache period. 
Study Population: 
 
Subjects must meet all of the following inclusion criteria to be 
considered eligible for study entry: 
1. Male and female, 18 years of age and older. 
2. History of cluster headache, as defined by International 
Classification of Headache Disorders (ICHD), third edition, 
beta version guidelines (ICHD-3 beta, Cephalalgia 2013). 
3. Stable on concomitant medications, excluding those for the 
treatment of cluster headache, for at least 60 days prior to 
enrollment. 
Note: Subjects are allowed to use their usual standard of care 
for the preventative treatment for their cluster headache.  
Acute/abortive medications maybe used 60 or more minutes 
after the initial dose, limited to the following: triptans; high-
flow oxygen. 
4. If female and of childbearing potential, have a negative urine 
pregnancy test at the time of Screening. 
a. To not be considered childbearing potential a subject 
must be surgically sterile, have had a hysterectomy or 
tubal ligation, post-menopausal for at least 1 year, or 
otherwise incapable of pregnancy. 
5. Capable of completing online headache diary with access to 
internet. 
6. Able to provide written Informed Consent. 
 


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Study Population (Cont’d): 
 
Subjects must not meet any of the following exclusion criteria to 
be considered eligible for study entry:   
 
1. Recent nasal/midface trauma (< 3 months) 
2. Recent nasal/sinus surgery (< 3 months). 
3. Severe respiratory distress in the last 6 months.  
4. Neoplasm such as Angiofibroma, sinus tumor, granuloma. 
5. Nasal congestion present more than 10 days with fever 
(temperature ≥ 100.4 °F) and nasal mucous is an abnormal 
color. 
6. Surgery to treat cluster headache. 
7. History of aneurysm, intracranial hemorrhage, brain tumors 
or significant head trauma. 
8. Structural intracranial or cervical vascular lesions that may 
potentially cause headache attacks. 
9. Other significant pain problems (including cancer pain, 
fibromyalgia, and trigeminal neuralgia) that might confound 
the study assessments in the investigator opinion. 
10. Psychiatric disorder, which in the opinion of the Investigator, 
may interfere with the study. 
11. Pregnant, actively trying to become pregnant, or 
breastfeeding, and/or is unwilling to use an accepted form of 
birth control. 
12. Skin around and inside the nasal passage that is dry, cracked, 
oozing, or bleeding. 
13. Recurrent nose bleeds, which in the opinion of the 
Investigator, may interfere with the study. 
14. Is participating in any other therapeutic clinical investigation 
or has participated in a clinical trial and received treatment in 
the preceding 30 days. 
 


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Investigational Product: 
0.17 L CO2 delivered through two 10 second administrations in 
each nostril, up to 6 times, to treat one attack (total of 1.0 L CO2). 
Subjects may treat up to three cluster headache attacks during the 
treatment phase of this study (total of 3.0 L CO2). 
Efficacy Evaluation: 
Primary Endpoints: 
Greatest change from pre-treatment headache pain intensity to 
post treatment at any time point within 30 minutes of Nasal CO2 
administration. 
Secondary Endpoints: 
• 
Percentage of subjects experiencing headache pain freedom 
at 5-60 minutes within the treated attack 
• 
Percentage of subjects with headache relief at 5-60 minutes 
within the treated attack  
• 
Rescue medication usage for treated attack 
• 
Subject satisfaction   
• 
Cluster recurrence 
Safety Evaluation: 
Safety assessments will include: 
• 
Monitoring adverse events (AEs) 
• 
Concomitant medications 
Statistical Methods:  
Descriptive statistics will establish baseline characteristics and 
adverse event frequency. Data for each of the primary and 
secondary outcome measures will be statistically analyzed for 
within group changes via a 2-tailed repeated measures ANOVA 
and or independent or dependent t-tests as appropriate.  All 
ANOVAs will be followed by univariate post-hoc tests. 
 


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Schedule of Events: 
Study Procedures 
Screening 
Treatment 
End of Study 
Visit1 
 Informed Consent   
X 
 Eligibility  
X 
 Medical History/ Medications / Demographics  
X 
 Physical Examination with Neurological and Nasal 
Mucosal Exam  
X 
X 
 Vital Signs  
X 
X 
 Urine Pregnancy Test  
X 
X 
 Subject Training   
X 
 Subject eDiary, AE/ConMed diary, and Questionnaire 
Instruction 
X 
 Investigational Product Dispensation  
X 
X2 
 Accountability of Investigational Product and Study 
Supplies  
X 
X 
Diary Completion 
 
X 
 
 Adverse Event Assessment  
X 
X 
 Concomitant Medications Assessment  
X 
X 
X 
 Telephone Contact  
X3 
X 
 eSource Document and eCRF Completion  
X 
X 
1 The End of Study Visit should occur within 7 days after the subject treats up to his/her third 
headache or within 7 days after the completion of the 84-day treatment period, whichever 
occurs first. 
2 Subjects will return to the clinic at 4 and 8 weeks after Screening Visit as necessary for a 
replacement dispenser.   
3 Subjects will be contacted by telephone within 3 days of treating their 1st attack to answer any 
questions, assess if there are any problems with compliance or any concerning AEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 
LIST OF ABBREVIATIONS 
 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
AR 
Allergic Rhinitis 
ºC 
Degrees Celsius 
CDDS 
Carbon Dioxide Drug Delivery System 
CFR 
Code of Federal Regulations 
CGRP 
Calcitonin Gene-Related Peptide 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
EU 
European Union 
ºF 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H+ 
Proton  
H2CO3 
Carbonic Acid  
HCO3- 
Bicarbonate  
ICH 
International Conference on Harmonization 
ICHD-II 
International Classification of Headache Disorders-II  
IHS 
International Headache Society 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
L 
Liter 
MedDRA® 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
NSAIDS 
Non-Steroidal Anti-Inflammatory Drugs 


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Abbreviation or Term 
Definition/Explanation 
NSAE 
Non-Serious Adverse Event 
PAR 
Perennial Allergic Rhinitis 
pCO2 
Partial Pressure of Carbon Dioxide 
PE 
Physical Examination 
pH 
Log of the Hydrogen Ion Concentration 
PP 
Per Protocol Population 
SAE 
Serious Adverse Event 
SAR 
Seasonal Allergic Rhinitis 
Sec 
Second 
SLPM 
Standard Liters Per Minute, flow rate measured at a standard condition (25 °C and 
1 bar) 
TMD 
Temporomandibular Disorder 
TNSS 
Total Nasal Symptom Score 
TSA 
Transportation Security Administration  
US 
United States 
WHO-DRL 
World Health Organization-Drug Reference List 
 
 
 


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3.0 
BACKGROUND 
3.1 
Investigational Product 
Capnia, Inc. is developing nasal, non-inhaled carbon dioxide (CO2) for the symptomatic relief of 
diseases which may be mediated by the trigeminal nerve, including acute migraine and allergic 
rhinitis.  Carbon dioxide, the active pharmaceutical ingredient, is CO2 at ≥ 99.0% volume.  
Carbon dioxide is a naturally occurring gas that readily diffuses across body tissues and 
membranes.  Although the exact mechanism of action(s) of CO2 is unknown, in vitro studies 
with cultured neurons have shown that CO2 reduces intracellular pH while simultaneously 
suppressing neuropeptide secretion, in particular calcitonin gene-related peptide (CGRP).1  It is 
hypothesized that upon application to the nasal mucosa, CO2 diffuses into local tissue and upon 
interaction with water, forms carbonic acid (H2CO3), which subsequently releases a proton (H+) 
and bicarbonate (HCO3-).  The locally-released protons cause a drop in local tissue pH, which 
leads to depolarization and subsequent inactivation of local neurons.  The inactivation of neurons 
likely coincides with inhibition of the release from the trigeminal nerve of CGRP and other 
inflammatory mediators implicated in the pathogenesis of migraine and other trigeminally-
mediated diseases. 
3.2 
Cluster Headache 
Cluster headache is a seriously debilitating disorder with 14 million individuals worldwide 
currently seeking treatment.2 Characterized by recurrent bouts of excruciating unilateral pain 
with accompanying ipsilateral autonomic symptoms such as lacrimation, conjunctival erythema, 
nasal congestion, rhinorrhea, and occasionally a partial Horner’s syndrome.3  Cluster headaches 
typically last between 15-180 minutes with 75% of attacks lasting less than 60 minutes if left 
untreated.4   They occur at a frequency of several times per day to several times a week with a 
cluster period typically lasting 8-12 weeks.  
Cluster headaches are classified separately from migraine on the basis of more severe pain, more 
frequent attacks, shorter duration of attacks, different autonomic symptoms, and a different 
underlying pathophysiology. Interestingly, while migraine headaches are more commonly 
diagnosed in women, cluster headaches are up to 3 times more prevalent in men.3,4 Currently, the 
etiology cause of cluster headaches is not fully understood, however, there has been an increased 
interest in the role of the sphenopalatine ganglion (SPG) and trigeminal ganglion in cluster 
headache.6  Both of these ganglion innervate the sinuses and offer a potential therapeutic target 
for the treatment of cluster headache. Current standard of care treatments included both abortive 
and prophylactic medications; both with limited efficacy. During the onset of headache, many 
people respond to high flow oxygen and triptans have been shown to reduce severity and 
duration of attack, although do not demonstrate long-term prophylactic effects. 


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The social and economic burden of cluster headache is significant. Patients with chronic and 
active episodic cluster headache are severely impacted in non-economic and economic of their 
lives. A study by D’Amico et al found a 36% of cluster headache patients have lost their jobs and 
half the patients have reduced work time by at least 50%.7 
Considering the inadequacy of current pharmacological therapy at considerable economic and 
social burden of this debilitating disorder, further research is warranted on alternative treatment 
options. 
3.3 
Non-Clinical and Clinical Data 
 
This section provides a brief summary of non-clinical and clinical data obtained to date.  
Additional Pharmacology/Toxicology as well as clinical safety information are summarized in 
the Investigator’s Brochure.  Toxicology studies have been conducted in rats as well as rabbits.  
Preliminary data is summarized in the Investigator’s Brochure.   
3.3.1 
In Vitro Non-Clinical Evaluations  
Experiments in primary cultures of rat trigeminal ganglia showed that CO2 treatment of culture 
under isohydric conditions (i.e., buffered to prevent extracellular acidification), significantly 
suppressed the stimulatory effects of various stimuli on CGRP release.   
These experiments provide evidence of a potentially unique mechanism of action by which CO2 
inhibits sensory nerve activation and subsequent release of CGRP.1    
3.3.2 
In Vivo Non-Clinical Evaluations 
Experiments in a hyperalgesic rat model have shown normalization of withdrawal latency of 
experimentally-induced ear pain with the administration of nasal CO2.  Subsequent experiments 
reported that this effect was decreased to a small extent if the duration of CO2 administration was 
decreased by half the time, but there was a much more significant decrease in the anti-
hyperalgesic effect if the flow rate was decreased by half.8  
These experiments show that CO2 had an anti-hyperalgesic effect in non-clinical models of pain, 
and that flow rate may be a significant determinant of the magnitude of this effect.   
3.3.3 
Clinical Evaluation in Healthy Volunteers 
Study C011 was a randomized, double-blind, placebo-controlled study in healthy human 
volunteers designed to assess the tolerability of nasal CO2 at different flow rates (0.22 L/min and 
0.44 L/min) and using different nosepieces (direct versus indirect flow).  Twenty-three subjects 


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were assigned to receive combinations of high or low flow rate (and placebo) with each type of 
nosepiece.   
In C011, the most common AEs reported were related to the administration site (described in 
different terms such as nasal discomfort, tingling, burning, pain, stinging, irritation, etc.), 
lacrimation, rhinalgia, ear/nose/throat discomfort or pain, unusual/unpleasant taste, headache, 
and rhinorrhea.  Additional AEs reported were dizziness/lightheadedness, post-nasal drip, nasal 
congestion, pressure at forehead or sinus, local hypothesia, left-side facial pain, numbness in 
throat, wheezy cough, and hot flashes.  In general, subjects were able to tolerate the nasal CO2 
administrations, with approximately 90% of administrations being completed.  The higher flow 
rate and direct flow nosepiece were not as well-tolerated as the lower flow rate and diffuse flow 
nosepieces. 
3.3.4 
Clinical Evaluations in Acute Migraine 
To date, approximately 820 subjects with acute migraine have participated in clinical trials to 
evaluate the safety and preliminary efficacy of nasal CO2 compared to a placebo control.  
Experience with nasal CO2 to date support that nasal CO2 can be administered safely at the doses 
planned for the current protocol.  The data from these studies are summarized briefly below.   
3.3.4.1 
CH-2000-02 (Migraine Phase 1) 
Study CH-2000-02 was a randomized (1:1), double-blind, placebo-controlled study conducted at 
three centers and examined the safety and efficacy of nasal CO2 in the treatment of acute 
migraine.  The CO2 or nitrogen (control) was administered from hospital medical gas cylinders 
using disposable nosepieces.  Subjects (n=54) self-selected a gas flow rate ranging from 
0.20 L/min (3.3 mL/sec) to 0.69 L/min (11.4 mL/sec), depending on their own preference.  
Subjects were continuously monitored for pCO2 levels, heart rate, electrocardiogram (ECG), 
respiratory rate, respiratory pattern, and blood pressure. 
There were no SAEs reported in this study.  Adverse events were mostly limited to application 
site irritation and included atypical sensations in the nasal cavity (discomfort, burning, stinging), 
watery eyes, throat discomfort, bad or unusual taste or smell, and dizziness/lightheadedness/ 
vertigo.  Compared to pre-dose control, the study showed no clinically meaningful differences in 
the pCO2 of subjects who received CO2.  There were no significant differences between CO2 and 
placebo gases in any of the physiologic parameters measured at any time point.   
The study provided preliminary evidence that nasal CO2 is not systemically absorbed to any 
measurable degree and appears to be safe.    


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3.3.4.2 
CH-2002-01 (Migraine Phase 2a) 
Study CH-2002-01 was a randomized (1:1), double-blind, placebo-controlled, multi-center study 
and examined the safety and efficacy of nasal CO2 in the treatment of acute migraine.  The gas 
was delivered via hand-held dispenser (CAP-2, an earlier design of the current CO2 drug delivery 
system) at a subject-selected flow rate of either approximately 0.3 L/min or approximately 
0.9 L/min.  Subjects were known International Headache Society (IHS)-defined migraineurs who 
were allowed to treat at any severity of pain at baseline (i.e., pain could be mild, moderate or 
severe), across multiple migraines.  
There were no SAEs reported in this study.  Adverse events most frequently reported included 
administration site reactions (irritation) and nausea.  
The study demonstrated a 2-hour pain-free response of 36% in the CO2 group (55 subjects) 
compared with 10% in placebo group (60 subjects), p<0.01, for the first attack.  Relief was rapid 
with the majority of all responders in the CO2 group reporting no pain at 30 minutes.  
Stratification according to pain at baseline showed a substantial improvement in the 2-hour 
pain-free response rate (52% CO2, 10% placebo, p<0.01) for subjects with mild pain at baseline.   
This study therefore provided preliminary evidence that nasal CO2 is a potentially effective 
treatment for acute migraine.   
3.3.4.3 
CH-2004-03 (Migraine Phase 2b) 
A randomized (2:1), double-blind, placebo-controlled, multi-center study examined the safety 
and efficacy of nasal CO2 in the treatment of acute migraine.  The gas was delivered via a hand-
held dispenser (CAP-3, an earlier design of the current CO2 drug delivery system) at flow rate of 
approximately 0.6 L/min.  Subjects were known IHS-defined migraineurs treating a typical 
migraine at moderate or severe pain.   
There were no SAEs reported.  The most common AEs were administration site irritation (i.e., 
stinging, burning, numbness, tingling).   
The study showed a 2-hour pain-free response of 23% for CO2 (89 subjects) versus 4% for 
placebo (45 subjects), p<0.01.  The trial included a pulsed dosing arm where the efficacy 
comparison to placebo was not statistically significant.  
The trial provided further evidence that nasal CO2 may be an effective treatment for acute 
migraine.  Statistically significant efficacy was observed at 2 hours with rapid onset of effect and 
the effect was sustained at 24 hours. 


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3.3.4.4 
C112 (Mild Headache Study) 
Study C112 was a randomized, double-blind, placebo-controlled study to evaluate the safety and 
efficacy of nasal CO2 in the treatment of mild headache in migraineurs.  This was an adaptively 
designed study that used a two-step randomization process.  First, eligible subjects were assigned 
to either active or placebo.  Then, upon experiencing a qualifying headache, subjects would call 
into the Interactive Voice Response System (IVRS) to receive their dosing regimen assignment.  
Two-hundred ninety-two subjects were randomized into Study C112 and 244 completed the 
study.  Of the 244 subjects, 102 subjects (69 active and 33 placebo) dosed 10 sec/nostril 1 time, 
49 subjects (29 active and 20 placebo) dosed 20 sec/nostril 1 time, 21 subjects (15 active and 6 
placebo) dosed 40 sec/nostril 1 time, 42 subjects (31 active and 11 placebo) dosed 10 sec/nostril 
4 times, and 30 subjects (21 active and 9 placebo) dosed 20 sec/nostril 4 times.   
The safety profile of nasal CO2 was similar to what has been seen in prior studies with the most 
common adverse events being nasal discomfort and lacrimation. There were no serious adverse 
events in subjects who treated a headache with the study drug and no discontinuations due to 
adverse events. 
The study showed that lower doses appear to be efficacious, and higher doses do not seem to add 
to efficacy.  The 10 sec/nostril 1 time dose group was the most efficacious in this study (showing 
a 38.5% pain-free at 2 hours versus 25.8% for placebo), with the 10 sec/nostril 4 times showed 
similar efficacy (showing a 36.7% pain-free at 2 hours versus 18.2% for placebo).  None of the 
groups achieved statistical significance against corresponding placebo, but the 10 sec/nostril 
1 time dose group showed strong statistical trends towards efficacy (Bayes p=0.09).  The study 
was primarily designed to select the appropriate dose for future studies, and determined that dose 
to be 10 sec/nostril which can be repeated up to 4 times. 
3.3.4.5 
C113 (Phase 3, Moderate to Severe Migraine Study) 
Study C113 was a multi-center, double-blind, placebo-controlled, parallel group trial that 
evaluated the safety and efficacy of nasal, non-inhaled administration of CO2 in the treatment of 
moderate to severe migraine.    
 
Subjects were allowed to treat up to a total of 4 moderate to severe migraines within a 56-day 
treatment period.  Headaches treated with the study drug (nasal CO2 or placebo) were to be at 
least 48 hours apart. 
 
Each dose consisted of an administration of 10 sec/nostril.  If subjects still had pain and/or any 
other symptoms after the initial dose then they were permitted to take a dose after completing the 
symptom assessment at 15, 30, and/or 60 minutes after the initial dose.  Thus, subjects could 


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have taken up to 4 doses of study drug to treat a headache.  Subjects with an ongoing headache at 
2 hours were permitted to take rescue medication. 
 
A total of 35 subjects were enrolled in this study.  This study was performed in collaboration 
with the Navy’s Advanced Medical Development Program and medicated through the Omnibus 
program.  Due to a low enrollment rate and limited funding available to conduct this study, this 
study was closed prior to meeting the enrollment goal of 450 subjects.   
 
The analysis of all subjects treated (CO2 = 17; Placebo = 13) did not show statistical significance 
in any of the four co-primary endpoints (pain free, nausea/vomiting free, photophobia free, or 
phonophobia free) at two hours after the initiation of treatment. 
 
The safety profile of nasal CO2 was similar to what has been seen in prior studies.  The most 
common adverse event reported was nasal discomfort (CO2 = 36.8%, placebo = 12.5%). All 
reported events typically resolved with cessation of administration. There were one SAE; it was 
due to a bicycle accident and unrelated to the study drug.    
 
The most reported AEs were mild or moderate in severity. Of the 15 severe AEs reported, only 4 
(nausea [n=1], nasal discomfort [n=2], and migraine [n=1]) were deemed related to study drug or 
study device; however, all 4 of these AE resolved with the cessation of application of the study 
drug/device.  There were 2 discontinuations due to AEs.  One was due to severe nausea and 
identified as being probably related to study drug; however, this subject was assigned to placebo.  
The other was due to neck pain and deemed unrelated to study drug and/or study device; the 
subject withdrew from the study because non-allowed medication was required for the treatment 
of the neck pain. 
 
3.3.5 
Clinical Evaluations in Allergic Rhinitis 
To date, approximately 975 subjects with allergic rhinitis have participated in clinical trials to 
evaluate the safety and preliminary efficacy of single doses of nasal CO2 compared to a placebo 
control.  In addition, a study was conducted to assess the consumer experience of CO2 nasal 
spray in subjects with nasal congestion.  One-hundred forty-seven subjects participated in that 
study.  The doses administered in the allergic rhinitis studies have been smaller than those used 
for migraine, with the highest being approximately 1.2 L.   The data from these studies are 
summarized briefly below. 
3.3.5.1 
SAR-2005 (Seasonal Allergic Rhinitis Single-Dose Study) 
Study SAR-2005 was a double-blind, placebo-controlled, in-clinic, single-center study conducted 
to evaluate the safety and efficacy of a single dose of nasal CO2 on the symptoms of seasonal 
allergic rhinitis (SAR).9   Eighty-nine subjects were treated with 60 seconds per nostril of either 
CO2 (60 subjects) or placebo (29 subjects).  The study tested one CO2 dose of approximately 
1.2 L (60 sec/nostril, approximately 0.6 L/nostril) versus placebo (air).  There were no serious 


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adverse events (SAEs) reported.  Nasal stinging or burning and watery eyes were the most 
common adverse events observed in this study.   
In this study, a single dose (two 60-second nasal CO2 administrations) resulted in 
rapid (10 minutes) and sustained (≥ 4 hours) relief of nasal symptoms (i.e., rhinorrhea, nasal 
congestion, nasal itching, and sneezing) compared to placebo.   
3.3.5.2 
C211 (Perennial Allergic Rhinitis Single-Dose Study) 
Study C211 was a randomized (2:1), double-blind, placebo-controlled, in-clinic, multi-center 
study and examined the safety and efficacy of nasal CO2 on the symptoms of perennial allergic 
rhinitis (PAR).  The study tested two dose durations (10 and 30 sec/nostril) and two flow rates 
(0.3 and 0.6 L/min) for CO2 versus placebo (no gas).1  The primary endpoint was mean change 
from baseline in total nasal symptom score (TNSS, the sum of the scores of rhinorrhea, average 
score the right and left nostril congestion, nasal itching, and sneezing) at 30 minutes, separately 
comparing the 10 and 30 sec/nostril dosing groups.  A total of 348 subjects (previously 
diagnosed with PAR) were randomized and treated.   
There were no SAEs reported in this study.  The treatment was generally well-tolerated and the 
most frequent AEs reported were nasal discomfort, lacrimation increased, headache, rhinalgia, 
rhinorrhea, and throat irritation.   
The study provided further evidence that nasal CO2 may be a safe and effective treatment for 
both the nasal and non-nasal symptoms (i.e., lacrimation, eye redness, ear/throat itching, eye 
itching) of PAR.  It had a rapid onset of effect that was sustained for several hours compared to 
placebo.    
3.3.5.3 
C213 (Perennial Allergic Rhinitis Multi-Dose Study) 
Study C213 was a randomized, double-blind, placebo-controlled, single-center, cross-over study 
to evaluate the effect of nasal, non-inhaled CO2 on nasal congestion using acoustic rhinometry in 
subjects with PAR.  Twenty (20) subjects were randomized to receive study drug in one of four 
treatment sequences.  Each sequence consisted of the same four treatments in different order. 
These four treatments were:  
Dose A:  Nasal CO2 (0.5 SLPM) for 5 sec/nostril 
Dose B:  Nasal CO2  (0.5 SLPM) for 10 sec/nostril 
Dose C:  Nasal CO2  (0.5 SLPM) for 30 sec/nostril 
Dose D:  Placebo (0.0 SLPM, no gas) for 30 sec/nostril 
All 20 subjects completed all four treatments and completed the study. 
 


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CO2 was delivered via a nosepiece that was attached to a CO2 cylinder by plastic tubing.  The 
flow rate was controlled by a flow control valve at 0.0 SLPM for the placebo dose for (Dose D) 
and 0.5 (± 0.05) SLPM for the active doses (Doses A, B, and C). 
No consistent changes in nasal congestion were seen as measured by acoustic rhinometry.   
3.3.5.4 
C215 (Seasonal Allergic Rhinitis Multi-Dose Study) 
Study C215 was a randomized, double-blind, placebo-controlled, multi-center study to evaluate 
the efficacy and safety of nasal CO2 administered twice daily for 14 days in the treatment of 
seasonal allergic rhinitis.  Four-hundred fifty-three (453) subjects met the randomization 
criterion of a minimum average score of 6 on the total nasal-symptom score (TNSS, a 0 - 3 scale 
to evaluate the severity of congestion, runny nose, itchy nose, and sneezing) and were 
randomized, 229 to the CO2 treatment and 224 to the placebo treatment.  Of the subjects 
randomized, 451 (99.6%) had at least one administration of the study drug and 447 (98.7%) 
completed the study.  
CO2 and placebo (no gas) were administered via hand-held dispensers.  Subjects completed 
symptom diaries every morning and evening over the 14-day treatment period.   
The baseline characteristics were similar between the two groups with respect to age, sex, 
ethnicity, and race.  The reflective Total Nasal Symptom Score (TNSS) at baseline was 9.6 ± 1.7 
in the CO2 group and 9.3 ± 1.7 in the placebo group. 
An analysis of treatment effects over the entire 14-day treatment period noted that the change 
from baseline in reflective total nasal symptom scores for treatment compared to control subjects 
were 2.0 and 1.7, respectively (p=0.1440).   
While the primary analysis of efficacy for the 14-day treatment did not show a significant 
benefit, statistically significant changes from baseline in TNSS were seen after the first dose on 
Day 0.  The changes from baseline in instantaneous TNSS for treatment compared to control 
subjects at 30 minutes were -2.4 and -1.6, respectively (p=0.0001), and at 6 hours were -2.2 
and -1.5, respectively (p=0.0139). 
3.3.5.5 
C216 (Phase 2, Seasonal Allergic Rhinitis) 
Study C216 was a randomized (2:1), double-blind, placebo-controlled, multi-center, parallel 
group, pilot study to evaluate the efficacy and safety of nasal, non-inhaled carbon dioxide used 
as-needed, up to 6 times per day, for 14 days in subjects with SAR.  Thirty-two (32) subjects 
who completed at least 2 SAR episode diaries per day and had a TNSS of 8 out of a maximum of 
12 for at least 2 of the SAR episodes during the 3 days prior to randomization were randomized, 
19 to the CO2 treatment and 13 to the placebo treatment.  All 32 subjects completed the study.  


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Carbon dioxide and placebo (no gas) were administered via hand-held dispensers.  Subjects 
completed instantaneous symptom diaries immediately prior to dosing (pre-dose assessment), 
30 minutes after dosing (post-dose assessment) as well as reflective diaries in the mornings and 
evenings during the 14-day treatment period.   
The baseline characteristics were similar between the two groups with respect to age, sex, 
ethnicity, and race.  Subjects in both groups dosed an average of 3 times per day.  Analysis of all 
treated episodes (CO2=816, placebo=516) showed a statistically significant beneficial change in 
pre-dose TNSS and 30-minute post dose TNSS for CO2 (-2.00) versus placebo (-1.49), effect 
size=-0.51, p<0.0001. 
3.3.5.6 
C218 (Phase 2, Seasonal Allergic Rhinitis)  
Study C218 was a randomized (2:1), double-blind, placebo-controlled, multi-center, parallel 
group, pilot study to evaluate the efficacy and safety of nasal, non-inhaled carbon dioxide 
administered four times per day, for 14 days in subjects with SAR.  Thirty-three (33) subjects 
met the randomization criterion of a minimum average reflective TNSS of 8 out of a maximum 
of 12 and were randomized, 22 to the CO2 treatment group and 11 to the placebo group.  All 33 
subjects completed the study.  
Carbon dioxide and placebo (no gas) were administered via handheld dispensers.  Subjects 
completed instantaneous symptom diaries immediately prior to dosing (pre-dose assessment), 
30 minutes after dosing (post-dose assessment) as well as reflective diaries in the mornings and 
evenings during the 14-day treatment period.   
The baseline characteristics were similar between the two groups with respect to age, sex, 
ethnicity, and race.  Analysis of all treated episodes (CO2=1220, placebo=602) did not show a 
statistically significant beneficial change in pre-dose TNSS and 30-minute post-dose TNSS for 
CO2 (-0.78) versus placebo (-0.65), effect size=-0.13, p<0.6302. 
3.3.5.7 
RH01910 (Phase 2, Nasal Congestion) 
Study RH01910 was a multi-center, monadic, open-label two-part repeat-dose, consumer 
experience study in subjects with nasal congestion.  In the first part of the study, recruited 
subjects were provided a description of a new treatment option.  Interested subjects were offered 
the opportunity to enter the clinical study.  Eligible subjects received one dose, 10 sec/nostril of 
nasal CO2 in the study clinic under medical supervision. Afterward, subjects who wished to 
continue in the study were allowed to take the nasal CO2 product home for an additional six days 
of use, 10 sec/nostril up to 4 times daily.  Subjects used a diary to record the number of times the 
product was used and their nasal congestion symptoms before and after use.   
 
This study showed that nasal CO2 was perceived well in subjects with nasal congestion. 


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The nasal CO2 was tolerated well in this study. Adverse events were mild and consistent with 
previous studies. No serious or unexpected adverse events were reported. 
 
3.3.6 
Clinical Evaluation in Temporomandibular Disorders 
Study C301 was a randomized, placebo-controlled study to evaluate the safety and efficacy of 
nasal, non-inhaled administration of CO2 in subjects with pain and other symptoms related to 
temporomandibular disorders (TMD).  One-hundred (100) subjects were randomized and treated 
with CO2 or placebo in a 2:1 randomization respectively.  For both treatment groups, a single 
dose consisted of 2 sequential administrations which were to last for 30 seconds in each nostril 
(60 sec/dose).  Subjects in the CO2 group received up to 3.6 L of CO2; subjects in the placebo 
group received up to 3.6 L of Air.  The data from this study are summarized in the current 
Investigator’s Brochure for Carbon Dioxide Drug Delivery System.   
3.4 
Risk/Benefits 
The adverse events anticipated with nasal CO2 include: administration site reactions (such as 
nasal passage irritation, tingling, burning, pain, rhinorrhea, congestion, etc.), increased 
lacrimation, nausea, headache, throat irritation, dysgeusia, dizziness, pharyngolaryngeal pain, 
epistaxis, parosmia, post-nasal drip, rhinalgia, rhinorrhea, migraine headache, upper respiratory 
tract infection and feeling cold.  There is minimal risk of systemic effects of CO2 as relatively 
small volumes are administered locally to the nasal cavity.  Even if the product were 
inadvertently inhaled, the amount of CO2 is minimal compared to the minute volume of 
respiration.   
3.5 
Dose Rationale  
The trial is designed to evaluate a dose of nasal CO2 at 10 sec/nostril administered up to 
6 times for one attack in a cluster period.  
The dose selected for evaluation in this study are based on safety data from the Phase 2      
single-dose studies in SAR and PAR, the multi-dose study in SAR, as well as from three studies 
in patients with migraine, and a study in healthy volunteers as described in Sections 3.3.3, 
Section 3.3.4, and Section 3.3.5, respectively. Prior migraine studies evaluated a wide range of 
doses (from 10 sec/nostril 1 time [0.17 L] to 20 sec/nostril 4 times [1.67 L]).  Single doses 
evaluated in allergic rhinitis (AR) studies have ranged from 0.1 L to 1.2 L of CO2.  In a SAR 
study, subjects were allowed to administer up to 1.0 L of CO2 per day for two-weeks. Thus, the 
dose selected for evaluation in this study is within the range of doses used in previous studies.  In 
these previous studies, nasal CO2 was found to be safe.      


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3.6 
Trial Conduct 
This trial will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB), Good Clinical Practice (GCP), and applicable regulatory requirements and 
standards.  No amendment to the protocol or deviation from the protocol will be implemented 
without the prior review and approval of the IRB except where it may be necessary to eliminate 
an immediate hazard to a research subject.  In such a case, the deviation will be reported to the 
IRB as soon as possible. 
3.7 
Population 
The trial population will include men and women ages 18 years old and above who have an 
established diagnosis of cluster headache, as defined by International Classification of Headache 
Disorders (ICHD), third edition, beta version guidelines (ICHD-3 beta, Cephalalgia 2013.3   
4.0 
TRIAL OBJECTIVES 
4.1 
Primary Objective 
The primary objective of this trial is to evaluate the safety and efficacy of nasal CO2 for the 
treatment of cluster headache.  
4.2 
Secondary Objectives 
Key secondary objectives are to determine the effect of nasal CO2 in the treatment of cluster 
headache: 
• freedom from pain at 5-60 minutes 
• headache relief at 5-60 minutes 
• rescue medication usage 
• subject satisfaction 
5.0 
TRIAL DESIGN 
This is an open-label, investigator-sponsored, pilot study.  Subjects agreeing to participate in the 
study and meeting the eligibility criteria assessed at the screening visit will be enrolled in the 
study.  The length of time between screening and treatment will last between 0 days to a 
maximum of 12 weeks.  Subjects who enter the screening phase during a cluster headache 
episode and meet the study eligibility criteria can immediately enter the treatment phase and may 
opt to treat their cluster headache episode in the clinic.  Subjects who are not in a cluster 


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headache episode, who meet initial screening eligibility criteria, can remain in the screening 
phase for up to 12 weeks until their next cluster episode begins.  Upon initiation of a cluster 
headache episode, subjects will enter the treatment period.  
Subjects will be trained and demonstrate the proper use of the hand-held dispenser containing 
CO2 calibrated to deliver 0.5 standard liters per minute (SLPM).  This dispenser will be provided 
to subjects for use in the clinic or home.  Subjects will be instructed to use the nasal CO2 
dispenser, 10 sec/nostril, as needed up to 6 times to treat one attack.  Each dose must be 
separated by 3-5 minutes.  Subjects should treat only one attack in a 24-hour period.  Subjects 
may treat up to three cluster headache attacks during the treatment phase of this study.  One hour 
after the first dose subjects can choose to treat with investigator-approved rescue medication.  
Subjects will be asked to complete an online diary after the completion of the dosing.  Diary 
assessments will collect pain severity (0=none, 1=mild, 2=moderate, 3=severe), symptoms (such 
as tearing, nasal congestion, and running nose), nasal CO2 usage, acute medication usage, 
satisfaction of treatment, number of cluster attacks, and unusual symptoms.  Subjects will be 
contacted by phone within 3 days of the first use of the nasal CO2 dispenser to assess adverse 
events (AEs) and medication usage.   A total of 25 subjects will enter the treatment period and be 
instructed to treat up to three cluster headaches with nasal CO2.  Within 7 days of treating their 
last cluster headache episode, subjects will return for an end of study visit. 
 
5.1 
Primary, Secondary, and Exploratory Endpoints 
5.1.1 
Primary Endpoint 
Greatest change from pre-treatment headache pain intensity to post treatment at any time point 
within 30 minutes of Nasal CO2 administration. 
 
5.1.2 
Secondary Endpoints 
• Percentage of subjects experiencing headache pain freedom at 5-60 minutes within the 
treated attack 
• Percentage of subjects with headache relief at 5-60 minutes within the treated attack 
• Rescue medication usage 
• Subject satisfaction   
• Cluster recurrence 


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Exploratory endpoints include but not limited to: 
• Number of doses per treated attack 
• Consistency of response with repeated treated attacks 
All primary, secondary, and exploratory efficacy endpoints will be analyzed for the all headaches 
analyses as well.       
5.2 
Study Treatment 
5.2.1 
Dose Description 
This is an open-label study so all eligible subjects will receive a nasal CO2 hand-held dispenser.  
One dose will consist of a 10 second administration of nasal CO2 to each nostril.  Subjects will 
be instructed to use the nasal CO2 dispenser, 10 sec/nostril, as needed up to 6 times to treat one 
attack.  Each dose must be separated by 3-5 minutes.  Subjects should treat only one attack 
during a 24-hour period with the investigational product.  Subjects may treat up to three cluster 
headache attacks during the treatment phase of this study.      
Subjects may receive up to a total of 1.0 L of CO2 if they treat one attack with 6 doses.  Subjects 
may receive a total of 3.0 L of CO2 if they treat three headache attacks with 6 doses of CO2 
during this study.   
 
5.2.1.1 
Nasal CO2 Dispensers 
The dispensers are calibrated to deliver CO2 at a target flow rate of 0.5 standard liters per 
minute (SLPM).    
5.2.2 
Packaging and Labeling 
Treatment kits will consist of one (1) dispenser and the Directions for Use.  The directions will 
specify that the dispensers cannot be taken aboard an airplane.  There will be replacement 
dispensers available in the event subjects damage or misplace their dispensers.  When subjects 
are enrolled, they will be assigned a unique subject identification number and a unique kit 
number.     
Once eligibility is confirmed, the study site personnel will review the Directions for Use with the 
subjects and will give the copy of the Directions for Use to the subjects to take with them.  


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5.2.3 
Storage and Handling 
The dispenser should be stored at room temperature (59 – 86 °F / 15 – 30 °C).  Prolonged 
exposure to temperatures above or below ambient conditions should be avoided. 
The contents of the dispenser are under pressure.  Therefore, exposure of the dispenser to 
temperatures ≥ 120 °F (50 °C), puncture, or other damage to the dispenser may cause injury 
and/or loss of contents.   
At this time, the Transportation Security Administration (TSA) does not allow the dispenser to 
be carried aboard any commercial aircraft.  If the dispenser is carried through TSA security or 
onto any commercial flight, it will be confiscated.    
Neither the dispenser nor its packaging is child-resistant.  It has not been tested in children for 
safety.  Therefore, the dispenser should be kept out of the reach of children. 
The dispenser is an investigational drug product and must be stored, handled, and administered 
in accordance with this protocol, the Investigator’s Brochure and labeling, as well as all 
applicable laws, regulations, and institution requirements.   
5.3 
Duration 
Once enrolled, each subject’s participation in the trial may last up to 84 days (12 weeks) or once 
the subject treats up to 3 cluster headache attacks with the nasal CO2 dispenser, whichever occurs 
first.  There will be two scheduled clinic visits, Screening and End of Study Visit.  The subject 
may return to the clinic 4 weeks and 8 weeks after the screening visit as necessary for a 
replacement dispenser.  The End of Study Visit should occur within 7 days after the subject 
treats his/her last cluster headache attack or within 7 days after the completion of the 84-day 
treatment period, whichever occurs first.  If a subject has not treated any cluster headaches 
during the 12 weeks treatment phase they can be allowed to continue in the study for an 
additional 12 weeks at the discretion of the Investigator.    
5.4 
Discontinuation 
Based on trials conducted with nasal CO2 to date, it is not expected that serious safety issues will 
arise that would require a discontinuation of the study.  If such issues do arise, the sponsor, Dr. 
Cady, will, in consultation with the Capnia, appropriate regulatory authority(ies), and/or IRB, 
take the steps necessary to modify or discontinue the trial.   
 
Since this is an open-label, pilot study, there will be an ongoing review of the data.  The trial 
may also be discontinued or modified in the event that the study treatment is not showing any 
signs of efficacy.    


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The criteria for the discontinuation of the participation of individual subjects are explained in 
Section 6.3. 
5.5 
Investigational Product Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain an 
inventory record to document the receipt and dispensation of each nasal CO2 dispenser.  All used 
and unused investigational product will be returned to Capnia or designee.  Investigational 
product will not be dispensed to any person who is not a qualified study subject under this 
protocol.  The investigational product will be dispensed only by study site personnel designated 
by the Investigator in writing on the Study Site Personnel Signature Log.  The investigational 
product must be dispensed only within and from the institution listed in the study contract and 
Form FDA 1572.  The maintenance of study-related investigational product accountability 
records does not preclude the Investigator’s responsibilities to maintain additional records in 
accordance with all national and/or local institutional requirements for investigational 
medication. 
 
Subjects are required to return the used and/or unused dispensers to the study site at the End of 
Study Visit.  Upon completion or termination of the study or on request, all used and unused 
investigational product will be accounted for and returned to Capnia or designee. 
 
5.6 
Data Identification 
Clinical data will be directly entered into the combined eSource/CRF forms by members of the 
study site personnel.  Site personnel will be responsible for instructing subjects on the 
requirement for timely and daily completion of the electronic diary (eDiary).  Subject-reported 
adverse events and concomitant medications collected during the out-subject treatment period 
will be recorded by the subject in the eDiary.  This diary will be reviewed by the Investigator 
and/or the appropriate study site personnel, applicable information will be collected, recorded 
into the subject’s eSource/eCRF.  The electronic diaries will be automatically collected after the 
completion of each diary and stored with the subject’s eSource/CRF documents.  Subjects will 
record their headache-related symptom assessments as well as the details regarding the nasal 
CO2 administration in an electronic diary.   


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6.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be considered eligible for study 
entry:   
• Male or female, 18 years of age and older. 
• History of cluster headache, as defined by International Classification of Headache Disorders 
(ICHD), third edition, beta version guidelines (ICHD-3 beta, Cephalalgia 2013). 
• Stable on concomitant medications, excluding those for the treatment of cluster headache, for 
at least 60 days prior to enrollment. 
Note: Subjects are allowed to use their usual standard of care for the preventative treatment 
for their cluster headache.  Acute/abortive medications maybe used 60 or more minutes after 
the initial dose, limited to the following: triptans; high-flow oxygen. 
 
• If female and of childbearing potential, have a negative urine pregnancy test at the time of 
Screening. 
 
o To not be considered childbearing potential a subject must be surgically sterile, 
have had a hysterectomy or tubal ligation, post-menopausal for at least 1 year, or 
otherwise incapable of pregnancy.   
   
• Capable of completing online headache diary with access to internet. 
• Able to provide written Informed Consent. 
6.2 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria to be considered eligible for study 
entry: 
• Recent nasal/midface trauma (< 3 months). 
• Recent nasal/sinus surgery (< 3 months). 
• Severe respiratory distress in the last 6 months. 
• Neoplasm such as Angiofibroma, sinus tumor, granuloma. 


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• Nasal congestion present more than 10 days with fever (temperature ≥ 100.4 °F) and nasal 
mucous is an abnormal color. 
• Surgery to treat cluster headache. 
• History of aneurysm, intracranial hemorrhage, brain tumors or significant head trauma. 
• Structural intracranial or cervical vascular lesions that may potentially cause headache 
attacks. 
• Other significant pain problem (including cancer pain, fibromyalgia and trigeminal 
neuralgia) which in the opinion of the clinician, may interfere with the study.  
• Psychiatric disorder which in the opinion of the Investigator may interfere with the study. 
• Pregnant, actively trying to become pregnant, or breastfeeding, and/or is unwilling to use an 
accepted form of birth control. 
o Acceptable forms include: complete abstinence from intercourse from 2 weeks 
prior to administration of study drug, throughout the study, and for 7 days after 
completion or premature discontinuation from the study; sterilization of male 
partner when in a monogamous relationship; intrauterine device or implant with 
published data showing lowest expected failure rate is less than 1% per year; 
double barrier method (i.e., 2 physical barriers OR 1 physical barrier plus 
spermicide) for a least 1 month prior to Screening Visit and throughout study; or 
hormonal contraceptives for at least 3 months prior to Screening Visit and 
throughout study.   
• Skin around and inside the nasal passage that is dry, cracked, oozing, or bleeding. 
• Recurrent nose bleeds which in the opinion of the Investigator, may interfere with the study. 
• Is participating in any other therapeutic clinical investigation or has participated in a clinical 
trial and received treatment in the preceding 30 days  
6.3 
Subject Withdrawal 
Subjects are free to withdraw consent and discontinue participation in the study at any time 
without prejudice to further treatment.  A subject’s participation in the study may be 
discontinued at any time at the discretion of the Investigator.  Justifiable reasons for the removal 
of a subject from the study include but are not limited to:  


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• The subject’s request 
• The subject is non-compliant in the opinion of the Investigator  
• The subject resumes or initiates other medication not permitted in this study 
• The subject experiences an adverse event which, regardless of seriousness or severity, 
prohibits further participation in the study 
• The subject does not have a cluster headache episode within 84 days (12 weeks) after 
Enrollment 
• The subject becomes pregnant, at which time she is to inform the study site personnel  
Enrolled subjects who withdraw from the study must return to the study site for the End of Study 
Visit.  If during this visit, the Investigator determines that the subject has an ongoing study drug-
related or study device-related adverse event, the subject will be followed until resolution or 
stabilization.   
The reasons for withdrawal must be documented accordingly in the subject’s eSource 
documents/eCRF.  Subjects who withdraw early from the study may be replaced. 
6.4 
Screen Failures 
Subjects who do not meet the eligibility criteria at the Screening Visit will be considered screen 
failures.  These subjects will be instructed by the study site, if the Investigator is the subject’s 
doctor, how to manage their cluster headaches (i.e., continue to use the medication they were 
previously taking for their cluster headaches prior to being screened for this study) or be referred 
to their regular physician for management of their cluster headaches.  These subjects will not be 
required to undergo the End of Study Visit procedures. 
7.0 
TREATMENT OF SUBJECTS 
Below is a brief description of the treatments to be administered in this study.  Please refer to 
Section 5.5 Trial Treatment and the Investigator’s Brochure for more information regarding 
nasal CO2. 
7.1 
Treatments to be Administered 
7.1.1 
Nasal CO2 Dispenser 
The subject will administer the nasal CO2 to one nostril and then to the second nostril (i.e., 
10 seconds to the right nostril then 10 seconds to the left nostril).  The administrations should 


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occur in succession and there should be no more than one (1) minute delay between 
administration each nostril.  One dose consists of a 10-second administration of CO2 to each 
nostril.  If subjects still have pain and/or any other symptoms after the initial dose then they may 
take up to 5 doses after the initial dose.  Each dose must be separated by 3-5 minutes. Thus, 
subjects may take up to 6 doses of study drug to treat an attack.   
If the subject is feeling congested at the time of the study drug administration, he/she may blow 
his/her nose prior to each dose.  The subject will be informed to hold his/her breath or to breathe 
in and out of his/her mouth during the administration, whichever is more comfortable to the 
individual subject.  
Subjects will treat up to 3 cluster headache attacks within a 84-day period (12 weeks) of their 
Screening Visit (i.e., when they were enrolled into the study).  Subjects will return to the clinic   
4 weeks and 8 weeks after the Screening Visit for a replacement dispenser, as necessary.      
7.2 
Medication 
7.2.1 
Concomitant Medication 
Concomitant medications required by subjects must be documented on their eSource/CRF 
documents.  Patients must be stable on concomitant medications, excluding those for the 
treatment of cluster headache, for at least 60 days prior to enrollment    
Subjects are allowed to take their prescription migraine and cluster prophylaxis medication.  
    
7.2.2 
Medications Not Permitted 
The investigator or designee will instruct the subjects NOT to treat a cluster headache with the 
study drug if, within 12 hours prior to the onset of the attack, they used any of the following:  
• Non-steroidal anti-inflammatory drugs (NSAIDS) 
• Non-prescription analgesics 
• Narcotic analgesics 
• Triptans 
• Ergotamine medication or derivatives  


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• Any other medications or treatments for headache (e.g., homeopathy, natural health products, 
acupuncture, etc.) 
7.2.3 
Rescue Medication 
Subjects will be allowed to take rescue medication as prescribed by their physician if the 
headache(s) does/do not resolve or worsen(s) after completing the one-hour assessment.  
Subjects who take rescue medication will be asked to record the details of all medication taken 
through the 24-hour assessment (e.g., what medication they took, dose, when they took it, etc.) in 
the eDiary. The data recorded by the subjects in the diaries will be discussed at the End of Study 
Visit and all rescue medication taken by the subjects will be recorded on the subjects’ 
appropriate eSource/eCRFs. If a subject uses rescue mediation they are not allowed to treat the 
same headache again with Investigational Product.  
Subjects who take rescue medication shall record the severity of their headache and associated 
symptoms at the 1 hour assessment.    
7.3 
Monitoring for Subject Compliance 
Subjects return to the site approximately 4 weeks after enrollment to exchange study drug and 
determine the subjects’ compliance with nasal CO2 administration and eDiary completion.  If 
necessary, at these visits subjects can receive re-training if it is determined there are issues with 
study drug administration and/or diary completion.    
8.0 
STUDY PROCEDURES 
The following sections describe the procedures and assessments that will be performed during 
the study.  The Schedule of Events, located in Section 8.2, indicates the frequency of these 
procedures and assessments.  
8.1 
Description of Study Procedures and Assessments 
8.1.1 
Informed Consent  
At the beginning of the Screening Visit, potential participants will be given an IRB-approved 
informed consent form by a member of the study site personnel (i.e., study coordinator, 
Investigator, or other study site personnel).  Potential participants will be provided time to read 
the consent form as well as the opportunity to ask questions and have their questions answered 
prior to the initiation of any study-specific assessments.  Subjects must voluntarily provide 
written informed consent before any study-related assessments are performed.  Once signed by 
the subject and the study site personnel performing the consent process, a copy of the consent 
form will be given to the subject and the original will be stored in the study site’s files.  The 


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subject’s medical records/source documents must include documentation that written informed 
consent was obtained from the subject, and that the subject received copies of the signed, fully-
executed informed consent form.   
8.1.2 
Medical History, Medications and Demographics 
Subjects will be asked about their medical history and any medication and supplements they are 
currently taking or have taken within 30 days of the Screening Visit.  Subjects will also be asked 
about their cluster headache history (e.g., age of diagnosis, typical associated symptoms, cluster 
headache pattern, etc.) and the pharmacotherapy and/or alternative treatment (e.g., homeopathy, 
natural health products, etc.) they have taken for their cluster headaches.  In addition, the 
subject’s demographic information (age, gender, race, and ethnicity) will be collected.     
8.1.3 
Physical Examination 
A full physical exam, including all major body systems and neurological exam, will be 
performed at the Screening Visit and at the End of Study Visit.  Any conditions or symptoms 
reported after the subject is enrolled will be recorded as an AE on the AE eCRF.  This includes 
new events after nasal CO2 administration, conditions that become more severe or increase in 
frequency, any disease-related signs or symptoms present at the Screening Visit (see 
Section 8.1.2) that have worsened in severity or frequency, as well as any event or finding that 
the Investigator feels is clinically significant.   
8.1.4 
Vital Signs 
Vital signs include temperature, systolic and diastolic blood pressure, and pulse rate will be 
measured at the Screening Visit and at the End of Study Visit.  Unscheduled vital signs may be 
measured as clinically necessary and shall be reported in the subject’s eSource/eCRF form.  
Height and body weight will be measured at the Screening Visit only.   
8.1.5 
Nasal Mucosal Examination 
A nasal mucosal examination will be performed at the Screening Visit and at the End of Study 
Visit to determine presence of polyps, nasal passage redness, deviated septum, purulence or other 
abnormalities.  Subjects with the presence of any of these that are considered clinically 
significant prior to enrollment at the Screening Visit will be excluded from participation in the 
study.  The results of the examination shall be reported in the subject’s eSource/eCRF.  
Clinically significant changes that are noted at the End of Study Visit and/or during an 
unscheduled nasal mucosal examination will be recorded as an AE on the AE eCRF.  If 
significant abnormalities are found, then the subject may be referred to an ear, nose and throat 
specialist.    


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8.1.6 
Urine Pregnancy Test 
Female subjects of childbearing potential will be given a urine pregnancy test at the Screening 
Visit and at the End of Study Visit.  Subjects with a positive urine pregnancy test will be 
excluded or withdrawn from the study.   
8.1.7 
Enrollment  
Subjects who sign the informed consent form, complete all screening evaluations, and meet the 
eligibility criteria outlined in Sections 6.1 and 6.2 will be eligible for enrollment into the study.   
8.1.8 
Training 
A member of the study site personnel, the trainer, will train enrolled subjects on the following: 
• How to complete the headache-related symptom assessments and enter the nasal CO2 
administration details in eDiaries 
• How and when to administer the nasal CO2 using the Directions for Use as a guide 
– This includes using the activated device one time 5 seconds/nostril 
• How to enter data (e.g.,  to medical problems, medications/treatments, etc.) in the eDiary 
• When it is acceptable to take rescue medication, if needed 
• When the dispenser is operating properly (i.e., makes a hissing sound, which will be 
demonstrated by the trainer during the Screening Visit) and to contact the site if the dispenser 
is not operating properly 
• Contact site if experiencing any significant AEs and, if after hours, subject should go to the 
emergency room 
It is the responsibility of the study site personnel to ensure that each subject completely 
understands how to do all of these tasks.  This training should be documented in the subject’s 
eSource/eCRF documents.   
8.1.9 
Subject Diary and Assessments 
The primary and most of the secondary endpoint data will be collected from the electronic daily 
headache diary.  Site personnel will be responsible for instructing subjects on the requirement for 
timely completion of the electronic diary.  An email will be sent to subjects for completion of 
their headache diary containing a link to the diary. This link will take them to a survey queue 


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where all diaries will be available for completion. The diary for each headache should be 
completed during or immediately after each headache treated with nasal CO2 and will document: 
• Pain severity: (0=none, 1=mild, 2=moderate, 3=severe) 
• Baseline pain severity 
• Study medication usage 
• Rescue medication usage 
• Pain severity after initial treatment with nasal CO2, symptoms at 5, 15, 30, and 60 minutes 
following treatment 
• Headache resolution 
• Unusual symptoms 
All assessments must be completed as close as possible to the protocol-specified time of the 
assessment. 
8.1.10 
Treatment of Cluster Headaches  
Subjects will be allowed to treat up to 3 cluster attacks during this study.   
If subjects still have pain and/or any other symptoms after the initial dose then they may take up 
to 5 more doses (each dose must be separated by 3-5 minutes).  Thus, subjects may take up to 6 
doses of nasal CO2 to treat a headache. 
Subjects will record the details about each dose taken (i.e., time of nasal CO2 administration, 
duration of administration) in the eDiary.      
8.1.11 
Adverse Events 
Subjects will be monitored for safety from the time they are enrolled until the End of Study Visit.   
Non-serious adverse events (NSAEs) will be collected beginning after the first dose of study 
medication through the End of Study Visit and will include any change from the subject’s 
condition at Screening.   
SAEs will be collected following enrollment and will include any change from the subject’s 
baseline condition at Screening.  SAE collection will conclude at End of Study or until resolution 
of the SAE if it extends beyond the End of Study Visit.  


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Subjects will be instructed to record in the eDiary any adverse events they experience from the 
time they are enrolled at the Screening Visit until their End of Study Visit.  Any conditions or 
symptoms reported will be recorded as an AE in the subject’s AE eCRF page.  Subjects who 
have an ongoing AE related to study drug and/or study device will be followed until resolution or 
stabilization of the event.   
At the End of Study Visit, subjects will be asked by the Investigator or an appropriate member of 
the study site personnel about any AEs they have experienced since the previous visit.  All AEs 
recorded by the subject in the eDiary will be discussed and reviewed by the Investigator or an 
appropriate member of the study site personnel, recorded in the subject’s source documents, and 
on the appropriate eCRF.  Subjects will be instructed to contact the study site in the event they 
experience any significant AEs.  At the discretion of the Investigator, the subject may be asked to 
come to the study site for an Unscheduled Visit.  Additional information regarding AEs is 
provided in Section 9.0. 
8.1.12 
Concomitant Medications / Procedures 
Medications taken and procedures performed, within 30 days prior to the Screening Visit will be 
recorded in the subject’s eSource/eCRF.  Medications taken after the Screening Visit and until 
the end of the subject’s participation in the study (End of Study Visit) will be recorded by the 
subject in the eDiary.  Any rescue medication taken will also be recorded in the subject’s eDiary.  
At the End of Study Visit as well as at any unscheduled visits, subjects will be asked about the 
medications, procedures and/or alternative treatments (e.g., homeopathy, natural health products, 
etc.) they have taken since their previous visit.  All medication and procedures including rescue 
medication recorded by the subject on the diary will be discussed and reviewed by the 
Investigator or an appropriate member of the study site personnel, recorded in the subject’s 
eSource/eCRF.   
8.1.13 
Telephone Contact 
Subjects will be contacted within 3 days of treating their first headache attack with nasal CO2 to 
answer any questions the subject may have, to assess if there are any problems with compliance, 
or any concerning AEs.  Furthermore, during the treatment period, approximately at 4 and 8 
weeks after the Screening Visit, a member of the study site personnel will follow-up with the 
subject via telephone to answer any questions the subject may have, to assess if there are any 
problems with compliance or any concerning AEs and, as necessary, to request that the subject 
return to the clinic for a replacement dispenser.   
If it is determined that the subject is non-compliant with the requirements of this study, then it is 
the Investigator’s discretion whether or not to withdraw the subject from the study.      


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8.2 
Schedule of Events  
Study Procedures 
Screening 
Treatment 
End of 
Study Visit1 
Informed Consent   
X 
 
 
Eligibility  
X 
 
 
Medical History/ Medications / Demographics  
X 
 
 
Physical Examination including Neurological and 
Nasal Mucosal Exam  
X 
 
X 
Vital Signs  
X 
 
X 
Urine Pregnancy Test  
X 
 
X 
Subject Training   
X 
 
 
Subject eDiary, AE/ConMed diary, and 
Questionnaire Instruction  
X 
 
 
Investigational Product Dispensation  
X 
X2 
 
Accountability of Investigational Product Study 
Drug and Study Supplies  
X 
 
X 
Diary Completion 
 
X 
 
Adverse Event Assessment  
 
X 
X 
Concomitant Medications Assessment  
X 
X 
X 
Telephone Contact  
 
X3 
X 
 Source Document and eCRF Completion  
X 
 
X 
1 The End of Study Visit should occur within 7 days after the subject treats up to his/her third 
headache or within 7 days after the completion of the 84-day treatment period, whichever 
occurs first. 
2 Subjects will return to the clinic at 4 and 8 weeks after the Screening Visit as necessary for a 
replacement dispenser.   
3 Subjects will be contacted by telephone within 3 days of treating their 1st attack to answer any 
questions, assess if there are any problems with compliance or any concerning AEs. 
 
   


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9.0 
ASSESSMENT OF SAFETY 
9.1 
General Guidelines 
All AEs (NSAEs and SAEs), regardless of causality or severity, will be recorded in the subject’s 
AE eCRF document according to Section 8.1.11.  Appropriate medical intervention should be 
provided if required.   
9.2 
Definitions 
The following definitions, developed in accordance with the International Committee on 
Harmonization (ICH) Clinical Safety Data Management Guidance for Industry, E2A, and 
21 CFR Parts 312.32 and 812.3 will be used for the purpose of identifying AEs in this clinical 
study.   
9.2.1 Adverse Event  
An adverse event (AE) is any untoward medical occurrence in a subject, or clinical investigation 
subject, administered a pharmaceutical product which does not necessarily have to 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 increase in severity or 
frequency of a pre-existing abnormality, temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product.   
9.2.2 Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is reasonable possibility that 
the drug caused the adverse event.  Suspected adverse reactions will consist of the adverse events 
that are evaluated by the investigator as possibly related or probably related to the study drug 
and/or study device.   
9.2.3 Serious Adverse Event  
A serious adverse event (SAE) is any adverse experience occurring after randomization at any 
dose that results in any of the following outcomes: 
 
• Death 
• Is life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 


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• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly/birth defect (in an offspring) 
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, the 
event may jeopardize the subject and/or the subject may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.   
9.2.3.1 
Hospitalizations as Serious Adverse Events 
All AEs requiring hospitalization or prolongation of hospitalization should be reported as SAEs.   
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate CRF: short-term administrative hospitalization for procedures, tests 
or treatments of conditions that would not otherwise constitute an SAE, or elective 
hospitalizations.   
9.2.4 
Unanticipated Adverse Device Effect  
A serious adverse effect on health or safety or any life-threatening problem or death caused by, 
or associated with, a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
9.3 
Reporting of Safety Information 
9.3.1 
Adverse Event Reporting 
All AEs, regardless of causality, severity, whether expected or not, must be entered on the AE 
CRF.  Disease-related signs and symptoms that are present at baseline should not be reported as 
AEs unless they worsen in severity or frequency.  Information collected concerning AEs will 
include the following:   
• Name of the event 
• Start date 
• Stop date or if the event is continuing 
• Intensity 


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– Mild (does not interfere with subject’s usual function) 
– Moderate (interferes to some extent with the subject’s usual function) 
– Severe (interferes significantly with subject’s usual function) 
• Relationship to investigational product (drug, device or both) 
• Seriousness of event 
• Outcome 
• Action taken 
Non-serious adverse events will be collected beginning after the first dose of study medication 
through the End of Study Visit and will include any change from the subject’s condition at 
Screening. All NSAE that are deemed related to study drug and/or study device will be followed 
until resolution or stabilization of the event.  SAEs will be collected following enrollment and 
will include any change from the subject’s baseline condition at Screening.  SAE collection will 
conclude at End of Study or until resolution of the SAE if it extends beyond the End of Study 
Visit.      
9.3.2 
Serious Adverse Event Reporting 
All SAEs must be reported to Capnia within 24 hours of first knowledge of the event.  All SAEs 
that occur from the time the subject is enrolled through the End of Study Visit are reportable 
within 24 hours.   
The procedure for reporting an SAE is as follows: 
• Within 24 hours of first knowledge of the event, the site must contact Capnia by telephone or 
facsimile to report the event. 
• The initial report should include all information known at the time of the report (additional 
information can be reported as discovered).  Initial reporting should not be delayed in order 
to obtain resolution or follow-up information. 
• The site will fax an SAE report, or similar form, that includes the following information, as 
available: 
– Subject ID 
– Basic demographic information (age, gender, weight) 


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– Relationship to investigational product (drug, device or both) 
– The outcomes attributed to the event (death, life-threatening, hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to prevent 
permanent impairment/damage, etc.) 
– The onset date and severity of the event 
– A brief description of the event including frequency and severity of symptoms leading to 
diagnosis 
– A list of relevant test results and lab data 
– Any other relevant history 
– Date of  investigational product  administration 
– Whether the investigational product was discontinued prematurely  
– Investigator’s assessment of causality 
The completed SAE report should be faxed as soon as possible (within 24 hours) to: 
CAPNIA, Inc. 
Attn:  Anish Bhatnagar, MD 
1235 Radio Road, Suite 110 
Redwood City, CA 94065 USA 
(+1) 650-213-8444 ext. 19 Telephone 
(+1) 650-619-3449 Mobile 
(+1) 866-286-1332 Fax 
 
Dr. Bhatnagar or another representative of Capnia may contact the Investigator to request 
additional information regarding the event or to confirm information.  All SAEs will be entered 
on the AE eCRF.  The same nomenclature should be used on both the SAE report and the AE 
CRF.   
The Investigator is responsible for the complete and timely reporting of all SAEs to Capnia, 
following up on resolution of the SAE, and expeditiously and simultaneously notifying the 
responsible IRB of the occurrence and details of the event according to institutional standard 
procedures.  In the event there is a question as to whether the experience is serious, the event 
should be reported.   


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9.4 
Adverse Event Follow-up 
All AEs that are deemed by the Investigator to be related to study drug and/or study device will 
be followed until resolution or stabilization of the event. 
10.0 
STATISTICAL METHODS AND ANALYSIS 
10.1 
General Considerations 
Tests will be conducted with a two-sided alpha = 0.05.  Descriptive statistics and 95% 
confidence intervals will be presented with all analyses. 
One interim analyses will be performed after 12 subjects have completed the study.  All efficacy 
and safety analyses will be performed at the conclusion of the study. 
10.2 
Handling of Dropouts or Missing Data 
Efficacy analyses (primary and key secondary endpoints) may be performed using the last value 
carried forward (LVCF) method. 
LVCF will be used only for pain scores up to the specified time point that occurred after the first 
headache treated with the study drug.  All other analysis will be performed on observed values.  
The following rules will be applied for LVCF method for pain scores: 
• If there is only baseline headache pain score available prior to rescue or prior to missing 
headache pain score, the baseline value will be carried forward as the LVCF. 
10.3 
Endpoints 
10.3.1 
Primary Efficacy Endpoint 
Greatest change from pre-treatment headache pain intensity to post treatment at any time point 
within 30 minutes of Nasal CO2 administration. 
10.3.2 
Method and Timing of Assessing Efficacy 
Since this is an open-label, pilot study, all efficacy analyses will be performed after 12 subjects 
have treated at least 1 cluster attack.   
 
10.3.3 
Secondary Efficacy Endpoints 
The key secondary endpoints are:   


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• Percentage of subjects experiencing headache pain freedom at 5-60 minutes within the 
treated attack 
• Percentage of subjects with headache relief at 5-60 minutes within the treated attack 
• Rescue medication usage 
• Subject satisfaction   
• Cluster recurrence  
This analysis will be assessed for the first headache treated with the investigational product. 
10.3.4 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will be assessed for the first headache and for all headaches.   
Exploratory efficacy endpoints include: 
• Number of doses per attack 
• Consistency of response with repeated treated attacks 
All primary, secondary, and exploratory efficacy endpoints will be analyzed for the all headaches 
analyses as well.     
The endpoint for extent of exposure will be the number of doses per subject per headache. 
10.3.5 
Safety Endpoint 
The safety endpoints are adverse events and concomitant medications.  Additional safety 
assessments will include changes from baseline in nasal mucosa. 
10.4 
Analysis Sets 
10.4.1 
Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) population will consist of all subjects enrolled in the study.  The ITT 
population will primarily be used to describe subject disposition and baseline characteristics. 


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10.4.2 
Modified Intent-to-Treat (mITT) Population  
The modified intent to treat (mITT) population will consist of all ITT subjects who treated a 
headache, received at least one dose of the study drug, and had at least one post treatment 
efficacy evaluation.  The mITT population will be used to conduct all efficacy analyses.  
 
10.4.3 
Per Protocol (PP) Population  
The per protocol (PP) population is defined as all mITT subjects who had no major protocol 
violations.  Subjects will be analyzed based on the treatment that they actually received.  The PP 
population will be used to analyze the primary and key secondary efficacy endpoints. 
10.4.4 
Safety Analysis Set 
The safety analysis set will consist of all subjects enrolled in the study who receive at least one 
administration of investigational product.  The safety population will be used for all safety 
analyses.  
10.5 
Primary Efficacy Analysis   
This analysis will be performed using the mITT population.  This analysis will be assessed for 
the first headache treated with the investigational product and all headaches treated as well. 
 
10.6 
Secondary Efficacy Analyses 
No adjustments will be made for multiplicity in the analyses of the secondary efficacy endpoints. 
This analysis will be performed using the mITT population.  This analysis will be assessed for 
the first headache treated with the investigational product and all headaches treated as well. 
10.7 
Exploratory Efficacy Analyses 
No adjustments will be made for multiplicity in the analyses of the exploratory efficacy 
endpoints. 
This analysis will be performed using the mITT population.  This analysis will be assessed for 
the first headache treated with the investigational product and all headaches treated as well. 
The extent of exposure will be compared between the two treatment groups descriptively for the 
first headache as well as the all headaches analysis. 


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10.8 
Safety Analysis 
All safety analyses will be performed on all enrolled subjects. 
10.8.1 
Adverse Events 
Adverse events (AEs) will be monitored throughout the study. All reported AEs will be 
documented on the appropriate eCRF. All similar AEs will be combined into one category and 
the frequency of all AEs occurring above 5% will be reported. 
 
10.8.2 
Vital Signs 
Vital signs will be summarized using descriptive statistics.  
10.8.3 
Concomitant Medications 
Concomitant medications, as well as rescue medications, will be summarized using descriptive 
statistics.  
10.8.4 
Other Observations Related to Safety 
Physical, neurological, and nasal examination results, as well as other observations related to 
safety will be summarized in data listings. 
10.9 
Termination Criteria 
Based on studies conducted with nasal CO2 to date, it is not expected that serious safety issues 
will arise that would require the sponsor to discontinue parts or all of the study.  If such issues do 
arise, the sponsor will, in consultation with Capnia, appropriate regulatory authority, and IRB 
take the steps necessary to discontinue the study. 
There will be an ongoing analysis of the data, and as such there is the possibility of terminating 
the study early due to efficacy or lack of efficacy.   
10.10 Accountability Procedure 
For primary efficacy analyses, no adjustment for missing values will be made.  Exploratory 
analyses may be performed using the last value carried forward (LVCF) method.  
10.11 Deviation Reporting 
Any significant deviations to the statistical analysis plan (Sections 10.1 through 10.11) will be 
addressed in the final report for this study. 


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11.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
During the trial, Clinvest will conduct remote monitoring and safety oversight periodically.  The 
clinical monitors may review eCRFs, at intervals throughout the study to verify appropriate 
inclusion of subjects, adherence to the protocol, and completeness, correctness, and accuracy of 
eCRF entries.  Any source upload should be reviewed for privacy elements and removed.  
Source uploads should only include the subject enrollment number as identifying information. 
 
The Investigator and Institution will permit authorized representatives of Capnia, its designees, 
the national health authorities, local authorities, and IRB direct access to source data/documents 
to conduct study-related monitoring, audits, IRB review, and regulatory inspections.   
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
It is Clinvest’s responsibility for implementing and maintaining quality control and assurance 
with written SOPs to ensure the trial is conducted in compliance with GCP standards and all 
applicable federal, state, and local laws, rules, and regulations.  Appropriate tools will be 
implemented by the site to facilitate quality management of the subject and continuity through 
the trial.   
  
Quality control should be applied by all parties and to each stage of subject management, 
investigational product management and data handling to ensure all data are reliable and have 
been processed correctly.  All clinical data are to be generated and processed by personnel with 
relevant clinical and GCP knowledge.  Subject generated data should be preceded with 
appropriate subject training and technical support for questions that arise during the trial.   
  
Agreements, made by Clinvest, the investigator, and Capnia, Inc. and/or with any other parties 
involved with clinical trial should be in writing in a separate agreement. 
  
Capnia, Inc. has provided Clinvest a Letter of Authorization so that Clinvest may cross-
reference, Capnia INDs #74,680 and 126,801.  As the investigator-sponsor of this study, the 
ultimate responsibility for the quality and integrity of the trial data also resides with Clinvest.  
The investigator agrees to be responsible for the integrity of all study conduct at their site.   
   
The study will be registered on ClinicalTrials.gov by Clinvest. 
 
13.0 
ETHICAL CONSIDERATIONS 
This study will be conducted according to the applicable regulations and international standards 
of GCP.   
All subjects for this study will be provided an informed consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 


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participation in this study.  This consent form will be submitted with the protocol for review and 
approval by the appropriate IRB.  The formal consent of a subject, using the IRB-approved 
informed consent form, will be obtained before that subject undergoes any study-specific 
procedure.  This informed consent form must be signed by the subject or legally acceptable 
surrogate, and the Investigator-designated research professional obtaining the informed consent.   
14.0 
DATA HANDLING AND RECORD KEEPING 
Data for this trial will be primarily collected in a web-based electronic data capture (EDC) 
REDCap platform.  The EDC access will be supplied by Clinvest with relevant training support 
to sites.  The site will be responsible for training study subjects in the EDC system.  All data 
specified should be captured by the site personnel or subjects in the EDC system.  All eCRFs are 
to be completely filled out by personnel administering the study procedures at the time of the 
visit.  The eCRF will be considered the source document for all data collected other than 
laboratory and procedure findings, which will be uploaded into the eCRF as source.  All data 
must be reviewed and signed by the investigator or sub-investigator at the conclusion of the 
study for each subject.  The eCRFs should not be made available in any form to third parties, 
without written permission from the sponsor.   
It is the investigator’s responsibility for the collection and reporting of all clinical, safety, and 
laboratory data entered on the eCRF and confirmation the data is accurate, authentic, attributable, 
complete, and consistent.  The investigator or sub-investigator must sign the eCRFs within the 
EDC system to attest the information contained with the eCRF is true and causality of any safety 
information has been assessed.   
Study documentation includes all workbooks, worksheets, forms, lab reports, logs, signature 
pages, appointment schedules, investigator correspondence, electronic data (i.e. data stored on 
cds, flash drives, etc.), and regulatory documents.  The original recording of an observation 
should be retained as the source document.   
1. 
Investigator will maintain essential documents for the conduct of a clinical study and any 
other documentation as specified by applicable regulatory requirements. 
2. 
Investigator will maintain a binder containing written informed consent records. 
3. 
Conduct of study visits will be maintained on appropriate Source Documentation/Case 
Report Forms.  Subject anonymity will be maintained on these forms by identification 
codes (i.e., subject initials and number).  The Investigator’s electronic signature will 
verify that all data entries in the CRF’s are complete and accurate. 


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4. 
Investigator will maintain a Subject Identification Log.  Information such as full name of 
subject, address, contact information, and additional subject identifiers will be recorded.  
This log will be kept confidential and not copied. 
5. 
Investigator will maintain a Subject Screening/Enrollment Record. This record will 
record chronologically subjects who were seen for Screening/Enrollment, additional 
visits conducted to replace Nasal CO2 dispensers, and completion/discontinuation 
information. 
6. 
Clinvest will maintain an Investigational Product Assignment Log.  This log will record 
chronologically study medication received from Capnia, Inc. as well as medication 
returned or destroyed at the completion of the study. 
Government agency regulation and directives require all study documentation pertaining to the 
conduct of a clinical trial must be retained by the investigator for at least 2 years after the last 
approval of a marketing application in an International Conference on Harmonization (ICH) 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product.  The investigator will maintain all study documentation on file in a 
secure and safe location.  Clinvest will notify the investigator in writing when retention is no 
longer necessary.  No study records will be destroyed without prior agreement between Capnia, 
Inc. and Clinvest.   
 
 
 
 


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15.0 
REFERENCE LIST 
 
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Vause C, Bowen E, Spierings E, Durham P. Effect of carbon dioxide on calcitonin gene-
related peptide secretion from trigeminal neurons. Headache. Nov-Dec 
2007;47(10):1385-1397. 
2. 
Bennett MH, French C, Schnabel A, Wasiak J, Kranke P. Normobaric and hyperbaric 
oxygen therapy for migraine and cluster headache. The Cochrane Database of Systematic 
Reviews. 2008(3):CD005219. 
3. 
Headache Classification Committee of the International Headache S. The International 
Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. Jul 
2013;33(9):629-808. 
4. 
Friedman BW, Grosberg BM. Diagnosis and management of the primary headache 
disorders in the emergency department setting. Emergency Medicine Clinics of North 
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Pringsheim T. Cluster headache: evidence for a disorder of circadian rhythm and 
hypothalamic function. Can J Neurol Sci. Feb 2002;29(1):33-40. 
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Lainez MJ, Puche M, Garcia A, Gascon F. Sphenopalatine ganglion stimulation for the 
treatment of cluster headache. Therapeutic Advances in Neurological Disorders. May 
2014;7(3):162-168. 
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D'Amico D, Rigamonti A, Solari A, et al. Health-related quality of life in patients with 
cluster headache during active periods. Cephalalgia. Dec 2002;22(10):818-821. 
8. 
Tzabazis AZ, Niv SH, Manering NA et al. Trigeminal antihyperalgesic effect of 
intranasal carbon dioxide. Life Sci 2010;87:36-41. 
9. 
Casale TB, Romero FA, Spierings EL. Intranasal noninhaled carbon dioxide for the 
symptomatic treatment of seasonal allergic rhinitis. The Journal of Allergy and Clinical 
Immunology. Jan 2008;121(1):105-109. 
10. 
Casale T, Onder R, Berkowitz R, Yen K, Bhatnagar A, Korenblat P. Nasal non-inhaled 
carbon dioxide for as-needed treatment of rhinitis symptoms [abstract]Casale T, Onder R, 
Berkowitz R, Yen K, Bhatnagar A, Korenblat P. Allergy 2010;65:35