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 10 March 2015 Amendment 1 30 November 2015 Amendment 2 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 Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of the manufacturer, Capnia, Inc. (Capnia), with the exception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. Protocol 15-001CA Nasal CO2 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 2 Confidential Information 28 April 2016 Protocol 15-001CA Nasal CO2 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 3 Confidential Information 28 April 2016 Protocol 15-001CA Nasal CO2 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