A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine
Phase: PHASE2
Conditions: Chronic Migraine
Sponsor: Smith, Timothy R., M.D.

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 1 of 54 
Clinvest Research, LLC. 
Clinical Study Protocol 
 
Study Title: 
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Efficacy and Safety of ISIS 
546254 for Preventive Treatment of Chronic Migraine 
Protocol Number: 
15-001IS 
Sponsor: 
Timothy R. Smith MD, RPh, FACP 
4350 S. National Ave. 
Suite C100 
Springfield, MO 65810 
Phone: (417) 883-7889 
Email: timothy.smith.md@gmail.com 
Medical Monitor: 
Timothy R. Smith MD, RPh, FACP 
4350 S. National Ave. 
Suite C100 
Springfield, MO 65810 
Phone: (417) 883-7889 
Email: timothy.smith.md@gmail.com 
To Report Pregnancy or 
Serious Adverse Event: 
Clinvest Research, LLC. 
Phone: (417) 883-7889 
Email: study@clinvest.com 
Date of Original Protocol 
(Version No. 1.0): 
13-Dec-2016 
Date of Amendment 1 
(Version No. 1.1): 
12-Jun-2017 
  
 
 
 
 
Confidential Information 
 
The information contained in this document is the property or under the control of IONIS 
Pharmaceuticals and is provided to you in confidence as an Investigator, potential Investigator, 
or consultant for review by you, your staff and applicable Institutional Review Board.  You shall 
not disclose this information to others without prior written authorization from IONIS 
Pharmaceuticals, except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered, and except as may be required by federal, state, or local 
laws or regulations. 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 2 of 54 
INVESTIGATOR SIGNATURE PAGE 
  
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy and Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
 
I agree to: 
 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Clinvest Research, LLC. in confidence and, when 
this information is submitted to an Institutional Review Board (IRB), it will be submitted 
with a designation that the materials are confidential. 
 
 
I have read and agree to follow this protocol. 
 
 
______________________________ 
____________________________ ____________ 
Investigator Printed Name 
 
 
Signature 
 
 
 
Date 
 
 
Sponsor Protocol Approval 
 
 
____________________________________ 
 
Date: ________________________ 
Timothy R. Smith, MD, RPh, FACP 
Medical Director, Clinvest Research, LLC.

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 3 of 54 
SUMMARY OF CHANGES FOR 15-001IS PROTOCOL 
Amendment 1 (Version No. 1.1, 12-Jun-2017) 
Section 
Pg Change From 
Change To 
Justification 
Header 
All 
12/13/2016 
Protocol No.: 15-001IS 
Title: A Multicenter, 
Randomized, Double-
Blind, Placebo-
Controlled Study 
Evaluating the Efficacy 
and Safety of ISIS 
546254 for Preventive 
Treatment of Chronic 
Migraine 
Date: 12-Jun-2017 
Clarification of study 
information across all 
pages. 
Footer 
All 
[Current page number] 
Version No.: 1.1 
CONFIDENTIAL 
[Current page number] 
of 54 
Clarification of study 
information across all 
pages, as well as total 
page count. 
Cover page 
1 
 
 
Revised Protocol 
Template Cover page to 
better detail 
Sponsor/Medical 
Monitor contact 
information, and 
protocol version history. 
Investigator signature 
page 
2 
Separate Investigator 
and Sponsor signature 
pages (pp. 2-3) 
Combined Investigator 
and Sponsor signature 
pages (p. 2) 
Consolidate all required 
signatures on one page. 
Summary of changes for 
15-001IS Protocol  
3-8 
 
 
Addition of changes to 
protocol by revision 
number. 
6. Study Drug 
14 
Subjects will receive 
Investigational Drug 
Product ISIS 546254, 
200 mg/mL, 2 mL (to be 
provided by Ionis 
Pharmaceuticals, Inc.) or 
matching placebo, 
which will be provided 
by the sponsor.  All 
doses (200mg) will be 
given by subcutaneous 
(SC) injection at a 
volume of 1.00 mL 
(200mg) ISIS 546254 or 
placebo and will be 
administered at 200mg 
weekly thereafter 
through week 16.  
 
Those randomized to 
ISIS 546254 will receive 
subcutaneous injections 
Subjects will receive 
study drug (ISIS 
546254, 200 mg/mL, 1 
mL or  placebo) which 
will be provided by Ionis 
Pharmaceuticals, Inc.  
All doses will be given 
by subcutaneous (SC) 
injection at a volume of 
1.00 mL  and will be 
administered at  the 
same volume weekly 
thereafter through week 
16.  
 
Those randomized to 
ISIS 546254 will receive 
subcutaneous injections 
containing 1.00 mL 
(200mg) weekly for 
weeks 1-16 of ISIS 
546254. 
Clarification of study 
drug units, and 
procedures.  

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 4 of 54 
containing 1.00 mL 
(200mg) weekly for 
weeks 1-16 of ISIS 
546254. 
 
Those randomized to 
placebo will receive 
1.00 mL during weeks 
1-16 subcutaneous 
injections of 0.9% sterile 
saline.  
 
Unblinded personal will 
label and package all 
study kits provided to 
subejcts following 
standard operating 
proceudes.  The 
investigational product 
(IP) and matching 
placebo will be drawn 
by an unblinded staff 
member. The first dose 
of investigational 
product (IP) will be 
administered under 
supervision of the 
unblinded staff at the 
study site.  Thereafter 
the IP may be self-
administered per dosing 
schedule if desired by 
the subject. All subjects 
will have the option to 
return to the site for 
injections by the 
unblinded staff member 
if they prefer. 
 
Those randomized to 
placebo will receive 1.00 
mL during weeks 1-16  
 
Unblinded personnel 
will label and package 
all study kits provided to 
subjects following 
standard operating 
procedures.  The study 
drug will be drawn by an 
unblinded staff member. 
The first dose of study 
drug will be 
administered under 
supervision of the 
unblinded staff at the 
study site.  Thereafter 
the study drug may be 
self-administered per 
dosing schedule if 
desired by the subject. 
All subjects will have 
the option to return to 
the site for injections by 
the unblinded staff 
member if they prefer 
 
7. Background & Study 
Rationale 
17 
CGRP 
calcitonin gene-related 
peptide (CGRP) 
Full name at first 
instance of abbreviation. 
12.2 Visit 2 - 
Randomization (Day 0) 
23 
8. Clinical laboratory 
sample collection for 
testing hematology, 
chemistry, PK, 
biomarkers and 
urinalysis . 
8. Clinical laboratory 
sample collection for 
testing hematology, 
chemistry, PK, 
biomarkers, plasma for 
anti-drug antibody 
screening, and 
urinalysis. 
Addition of plasma for 
anti-drug antibody 
screening at Visit 2. 
12.2 Visit 2 - 
Randomization (Day 0) 
24 
13. Dispense and 
instruct subjects on how 
to inject study drug. 
Subjects will also be 
educated on prohibited 
medications, dosage 
13. Dispense and 
instruct subjects on how 
to inject study drug. 
Subjects will also be 
educated on prohibited 
medications, dosage 
Addition of “unblinded 
staff.” 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 5 of 54 
limitations of study 
drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit and 
drug reconciliation will 
be performed. 
limitations of study 
drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit to the 
unblinded staff and drug 
reconciliation will be 
performed. 
12.6 Visit 3 - End of 
Treatment Month 1 
(Day 28 +/- 3 Days) 
24 
6. Clinical laboratory 
sample collection for 
testing hematology, 
chemistry, PK, 
biomarkers and 
urinalysis . 
6. Clinical laboratory 
sample collection for 
testing hematology, 
chemistry, PK, 
biomarkers, plasma for 
anti-drug antibody 
screening, and 
urinalysis. 
Addition of plasma for 
anti-drug antibody 
screening at Visit 3. 
12.6 Visit 3 - End of 
Treatment Month 1 
(Day 28 +/- 3 Days) 
24 
8. Perform drug 
accountability.   
8. Unblinded staff to 
perform drug 
accountability.   
Addition of “unblinded 
staff.” 
12.6 Visit 3 - End of 
Treatment Month 1 
(Day 28 +/- 3 Days) 
24 
10. Dispense and review 
how to inject study drug, 
prohibited medications, 
dosage limitations of 
study drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit. 
10. Dispense and review 
how to inject study drug, 
prohibited medications, 
dosage limitations of 
study drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit to 
unblinded staff . 
Addition of “to 
unblinded staff.” 
12.8 Visit 4 - End of 
Treatment Month 2 
(Day 56 +/- 3 Days) 
25 
• Collect unused study 
drug and used 
packaging. 
7. Unblinded staff to 
collect unused study 
drug and used 
packaging. 
Addition of “Unblinded 
staff to.” 
12.8 Visit 4 - End of 
Treatment Month 2 
(Day 56 +/- 3 Days) 
25 
• Perform drug 
accountability. 
8. Unblinded staff to 
perform drug 
accountability. 
Addition of “Unblinded 
staff to.” 
12.8 Visit 4 - End of 
Treatment Month 2 
(Day 56 +/- 3 Days) 
25 
• Dispense and review 
how to inject study drug, 
prohibited medications, 
dosage limitations of 
study drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit. 
10. Dispense and review 
how to inject study drug, 
prohibited medications, 
dosage limitations of 
study drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit to 
unblinded staff. 
Addition of “to 
unblinded staff.” 
12.10 Visit 5 – End Of 
Treatment Month 3 
(Day 84 +/- 3 Days) 
25 
6. Clinical laboratory 
sample collection for 
testing hematology, 
6. Clinical laboratory 
sample collection for 
testing hematology, 
Addition of plasma for 
anti-drug antibody 
screening at Visit 5. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 6 of 54 
chemistry, PK, 
biomarkers and 
urinalysis . 
chemistry, PK, 
biomarkers, plasma for 
anti-drug antibody 
screening, and 
urinalysis. 
12.10 Visit 5 – End Of 
Treatment Month 3 
(Day 84 +/- 3 Days) 
25 
7. Collect unused study 
drug and used 
packaging. 
7. Unblinded staff to 
collect unused study 
drug and used 
packaging. 
Addition of “Unblinded 
staff to.” 
12.10 Visit 5 – End Of 
Treatment Month 3 
(Day 84 +/- 3 Days) 
25 
8. Perform drug 
accountability. 
8. Unblinded staff to 
perform drug 
accountability. 
Addition of “Unblinded 
staff to.” 
12.10 Visit 5 – End Of 
Treatment Month 3 
(Day 84 +/- 3 Days) 
25 
10. Dispense and review 
how to inject study drug, 
prohibited medications, 
dosage limitations of 
study drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit. 
10. Dispense and review 
how to inject study drug, 
prohibited medications, 
dosage limitations of 
study drug, and storage 
requirements. Subjects 
will be instructed to 
return all used/partially 
used/unused study drug 
at next office visit to 
unblinded staff. 
Addition of “to 
unblinded staff.” 
12.12 Visit 6 – End Of 
Treatment/Et (Day 112 
+/- 3 Days) 
26 
7. Clinical laboratory 
sample collection for 
testing hematology, 
chemistry, PK, 
biomarkers and 
urinalysis . 
7. Clinical laboratory 
sample collection for 
testing hematology, 
chemistry, PK, 
biomarkers, plasma for 
anti-drug antibody 
screening, and 
urinalysis. 
Addition of plasma for 
anti-drug antibody 
screening at Visit 5. 
12.12 Visit 6 – End Of 
Treatment/Et (Day 112 
+/- 3 Days) 
26 
8. Collect unused study 
drug and used 
packaging. 
8. Unblinded staff to 
collect unused study 
drug and used 
packaging. 
Addition of “Unblinded 
staff to.” 
12.12 Visit 6 – End Of 
Treatment/Et (Day 112 
+/- 3 Days) 
26 
10. Perform drug 
accountability. 
10. Unblinded staff to 
perform drug 
accountability. 
Addition of “Unblinded 
staff to.” 
12.14 Visit 7 – Follow 
Up Visit (Day 140 +/- 3 
Days) 
26 
4. Administer 
Columbia-Suicide 
Severity Rating Scale 
(C-SSRS). 
4. Administer Columbia-
Suicide Severity Rating 
Scale (C-SSRS), and 
MSQ. 
Addition of MSQ to 
Visit 7. 
12.16 Phone Call 3 – 
Safety Follow Up (Day 
196 +/- 3 Days) 
26 
1. Record any AEs. 
 
1. Record any AEs. 
2. Administer MSQ. 
Addition of MSQ to 
Phone Call 3 
Schedule of Events 
Table 
27-
30 
 
 
Addition of Plasma 
Collection for ADA 
Screening to Visit 2, 3, 
5, and 6 
Schedule of Events 
Table 
27-
30 
 
 
Addition of MSQ to 
Visit 7 and Phone Call 3 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 7 of 54 
15 Study Drug 
Randomization and 
Training 
31-
32 
Eligible subjects will be 
randomized 1:1 to 
receive ISIS 546254, 
200 mg/mL, 2 mL or 
placebo at Visit 2 by 
unblinded staff.  If at 
any time during the 
study the subject 
withdrawals from the 
study, they will be 
instructed to return all 
used packaging and 
unused medication. All 
doses (200mg 
ISIS546254 or placebo 
will be given by 
subcutaneous (SC) 
injection at a 
standardized volume of 
1.00 mL ISIS 546254 or 
placebo weekly through 
week 16.  All dosing 
after the first injection at 
the site may be self-
administered per dosing 
schedule if desired by 
the subject. All subjects 
will have the option to 
return to the site for 
injections administered 
by the unblinded staff if 
they desire.  Subjects 
will receive training on 
proper administration of 
IP, storage requirements, 
and will be asked to 
return all used/partially 
used/unused medication 
containers at the next 
office visit. Any subject 
self-administering IP 
will call site to confirm 
most recent lab report 
values are within 
allowable rages dosing.  
 
Adjustments of dose 
and/or treatment 
schedule should occur 
only on rare occasions. 
Adjustments in the dose 
and/or treatment 
schedule may be 
allowed only with 
Eligible subjects will be 
randomized 1:1 to 
receive ISIS 546254, 
200 mg/mL, 1 mL or 
placebo at Visit 2 by 
unblinded staff.  If at 
any time during the 
study the subject 
withdrawals from the 
study, they will be 
instructed to return all 
used packaging and 
unused medication to 
unblinded staff. All 
doses (200mg 
ISIS546254 or placebo 
will be given by 
subcutaneous (SC) 
injection at a 
standardized volume of 
1.00 mL ISIS 546254 or 
placebo weekly through 
week 16.  All dosing 
after the first injection at 
the site may be self-
administered per dosing 
schedule if desired by 
the subject. All subjects 
will have the option to 
return to the site for 
injections administered 
by the unblinded staff if 
they desire.  Subjects 
will receive training on 
proper administration of 
IP, storage requirements, 
and will be asked to 
return all used/partially 
used/unused medication 
containers at the next 
office visit to unblinded 
staff. Any subject self-
administering IP will 
call site to confirm most 
recent lab report values 
are within allowable 
rages dosing.  
 
Adjustments of dose 
and/or treatment 
schedule should occur 
only on rare occasions. 
Adjustments in the dose 
and/or treatment 
Addition of “to 
unblinded staff.” 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 8 of 54 
consent of the study 
medical monitor 
following discussion 
with the investigator for 
subjects that are unable 
to tolerate the once 
weekly dose. 
schedule may be allowed 
only with consent of the 
study medical monitor 
following discussion 
with the investigator for 
subjects that are unable 
to tolerate the once 
weekly dose. 
28. Storage 
Requirements 
39-
40 
Study drug will be 
inventoried and 
accounted for 
throughout the study.  
Drug Accountability 
will be maintained for 
subjects randomized in 
the study.  Study staff 
will record the amount 
of study drug dispensed 
and amount returned at 
each appropriate office 
visit.  Any missing 
devices or discrepancies 
will be addressed and 
reconciled as needed. 
Study drug will be 
inventoried and 
accounted for 
throughout the study.  
Drug Accountability will 
be maintained for 
subjects randomized in 
the study.  Unblinded 
study staff will record 
the amount of study drug 
dispensed and amount 
returned at each 
appropriate office visit.  
Any missing devices or 
discrepancies will be 
addressed and reconciled 
as needed. 
Addition of “Unblinded 
study.” 
36.6 List of Laboratory 
Analytes 
45 
Hematology, clinical 
chemistry, urinalysis 
laboratory, urine drug 
screen, HIV, HbsAg, 
and HCV serology will 
be performed at sites 
local laboratory.  
Reference ranges will be 
supplied by local 
labratory and used by 
the Investigator to assess 
the laboratory data for 
clinical significance and 
pathological changes. 
Hematology, clinical 
chemistry, urinalysis 
laboratory, urine drug 
screen, HIV, HbsAg, 
and HCV serology will 
be performed at sites 
local laboratory. Plasma 
samples for anti-drug-
antibody screening will 
also be collected and 
stored for potential 
future analysis. 
Reference ranges will be 
supplied by local 
laboratory and used by 
the Investigator to assess 
the laboratory data for 
clinical significance and 
pathological changes. 
Addition of “. Plasma 
samples for anti-drug-
antibody screening will 
also be collected and 
stored for potential 
future analysis.” 
 
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 9 of 54 
Table of Contents 
1 
ABBREVIATIONS ........................................................................................................................... 12 
2 
INDICATION .................................................................................................................................... 13 
3 
STUDY PURPOSE ........................................................................................................................... 13 
4 
SUMMARY OF STUDY DESIGN .................................................................................................. 13 
5 
POPULATION SAMPLE ................................................................................................................ 14 
6 
STUDY DRUG .................................................................................................................................. 14 
7 
BACKGROUND & STUDY RATIONALE ................................................................................... 15 
8 
PRIMARY OBJECTIVES ............................................................................................................... 19 
9 
SECONDARY OBJECTIVES ......................................................................................................... 19 
10 
SUBJECT SELECTION .................................................................................................................. 19 
11 
INCLUSION/EXCLUSION CRITERIA ........................................................................................ 20 
11.1 
INCLUSION CRITERIA .................................................................................................................. 20 
11.2 
EXCLUSION CRITERIA................................................................................................................. 21 
12 
STUDY DESIGN ............................................................................................................................... 22 
12.1 
VISIT 1 – SCREENING (DAY -28)............................................................................................ 23 
12.2 
VISIT 2 – RANDOMIZATION (DAY 0) ................................................................................... 23 
12.3 
PHONE CALL 1 – SAFETY FOLLOW UP (DAY 1) .............................................................. 24 
12.4 
PHONE CALL 2 – SAFETY FOLLOW UP (DAY 2) .............................................................. 24 
12.5 
HEMATOLOGY SAMPLE COLLECTION (DAY 14 +/- 3 DAYS) ....................................... 24 
12.6 
VISIT 3 – END OF TREATMENT MONTH 1 (DAY 28 +/- 3 DAYS) ................................... 24 
12.7 
HEMATOLOGY SAMPLE COLLECTION (DAY 42 +/- 3 DAYS) ....................................... 24 
12.8 
VISIT 4 – END OF TREATMENT MONTH 2 (DAY 56 +/- 3 DAYS) ................................... 24 
12.9 
HEMATOLOGY SAMPLE COLLECTION (DAY 70 +/- 3 DAYS) ....................................... 25 
12.10 
VISIT 5 – END OF TREATMENT MONTH 3 (DAY 84 +/- 3 DAYS) ............................... 25 
12.11 
HEMATOLOGY SAMPLE COLLECTION (DAY 98 +/- 3 DAYS)................................... 25 
12.12 
VISIT 6 – END OF TREATMENT/ET (DAY 112 +/- 3 DAYS).......................................... 25 
12.13 
HEMATOLOGY SAMPLE COLLECTION (DAY 126 +/- 3 DAYS)................................. 26 
12.14 
VISIT 7 – FOLLOW UP VISIT (DAY 140 +/- 3 DAYS) ..................................................... 26 
12.15 
HEMATOLOGY SAMPLE COLLECTION (DAY 154 +/- 3 DAYS)................................. 26 
12.16 
PHONE CALL 3 – SAFETY FOLLOW UP (DAY 196 +/- 3 DAYS) .................................. 26 
13 
CONTRACEPTION REQUIREMENTS ....................................................................................... 31 
14 
INFORMED CONSENT .................................................................................................................. 31 
15 
STUDY DRUG RANDOMIZATION AND TRAINING .............................................................. 31 
16 
DOSING ERRORS ........................................................................................................................... 32 
17 
RESCUE MEDICATION................................................................................................................. 32 
18 
CONCOMITANT MEDICATIONS ............................................................................................... 32 
18.1 
ALLOWED MEDICATIONS ........................................................................................................... 32 
18.2 
PROHIBITED MEDICATIONS ........................................................................................................ 32 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 10 of 54 
19 
HEADACHE DIARY ....................................................................................................................... 32 
20 
UNSCHEDULED VISITS ................................................................................................................ 33 
21 
BLINDING/UNBLINDING ............................................................................................................. 33 
22 
DISCONTINUATION/WITHDRAWAL FROM STUDY ........................................................... 33 
23 
ADVERSE EVENTS......................................................................................................................... 34 
23.1 
NON-SERIOUS ADVERSE EVENT (NSAE)................................................................................... 34 
23.2 
SERIOUS ADVERSE EVENT (SAE) .............................................................................................. 35 
24 
SAFETY MONITORING RULES .................................................................................................. 36 
24.1 
SAFETY MONITORING RULES FOR LIVER CHEMISTRY TESTS .................................................... 36 
24.2 
SAFETY MONITORING RULES FOR PLATELET COUNT RESULTS ................................................ 37 
24.3 
SAFETY MONITORING FOR  BLEEDING EVENTS ......................................................................... 37 
24.3.1 
Defination of Major Bleeding Events ................................................................................ 37 
24.3.2 
Defination of Clinically Relevent, Non-Major Bleeding Events........................................ 37 
25 
STOPPING RULES .......................................................................................................................... 38 
25.1 
LIVER CHEMISTRY ELEVATIONS ................................................................................................ 38 
25.2 
RENAL FUNCTION TEST RESULTS .............................................................................................. 38 
25.3 
PLATELET COUNT RESULTS ....................................................................................................... 38 
26 
PREGNANCY ................................................................................................................................... 39 
27 
CLINICAL SUPPLIES..................................................................................................................... 39 
28 
STORAGE REQUIREMENTS ....................................................................................................... 39 
29 
CONFIDENTIALITY ...................................................................................................................... 40 
30 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT ..................................................... 40 
31 
QUALITY CONTROL/ASSURANCE ........................................................................................... 41 
32 
STUDY DOCUMENTATION ......................................................................................................... 41 
33 
RECORD RETENTION .................................................................................................................. 42 
34 
INSTITUTIONAL REVIEW BOARD ........................................................................................... 42 
35 
TRAINING ........................................................................................................................................ 43 
36 
SAFETY MEASURES ...................................................................................................................... 43 
36.1 
ADVERSE EVENTS ...................................................................................................................... 43 
36.2 
PHYSICAL EXAMINATION ........................................................................................................... 43 
36.3 
VITAL SIGNS ............................................................................................................................... 43 
36.4 
ECG ............................................................................................................................................ 44 
36.5 
LABORATORY ASSESSMENTS ..................................................................................................... 44 
36.6 
LIST OF LABORATORY ANALYTES ............................................................................................. 44 
37 
FUTURE BIOMEDICAL RESEARCH ......................................................................................... 45 
38 
SUMMARY OF METHODS OF DATA COLLECTION ............................................................ 45 
39 
STATISTICAL ANALYSIS............................................................................................................. 46 
39.1 
MODIFIED INTENT-TO-TREAT POPULATION (MITT) .................................................................. 46 
39.2 
SAFETY POPULATION ................................................................................................................. 46 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 11 of 54 
40 
PRIMARY ENDPOINTS ................................................................................................................. 46 
41 
SECONDARY ENDPOINTS ........................................................................................................... 46 
42 
COLLECTION AND DERIVATION OF ENDPOINTS .............................................................. 47 
42.1 
PRIMARY EFFICACY VARIABLE .................................................................................................. 47 
42.2 
SECONDARY EFFICACY VARIABLES ........................................................................................... 47 
43 
APPENDIX A .................................................................................................................................... 49 
44 
APPENDIX B .................................................................................................................................... 50 
45 
APPENDIX C .................................................................................................................................... 51 
46 
REFERENCES .................................................................................................................................. 52 
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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Page 12 of 54 
1 
ABBREVIATIONS  
Abbreviation or Term 
Definition/Explanation 
ADD 
Attention-Deficit Disorder 
ADHD 
Attention-Deficit/Hyperactivity Disorder 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BK 
Bradykinin 
CV 
Curriculum Vitae 
DSM-IV-TR 
The Diagnostic and Statistical Manual of Mental Disorders Version 
4 Text Revision 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ET 
Early Termination 
FDA 
Food And Drug Administration 
g/kg 
Gram Per Kilogram 
GCP 
Good Clinical Practices 
HbsAg 
Hepatitis B Surface Antigen  
HCV 
Hepatitis C Virus  
HIPPA 
Health Insurance Portability and Accountability Act of 1996  
HIV 
Human Immunodeficiency Virus  
HMWK 
High Molecular Weight Kininogen  
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonization 
ICHD 
Classification Of Headache Disorders 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MAO-A 
Monoamine Oxidase A 
MOH 
Medication Overuse Headache 
mg 
Milligram 
mg/dL 
Milligrams Per Deciliter 
mITT 
Modified Intent To Treat 
mmHg 
Millimeter of Mercury 
NSAE 
Non-Serious Adverse Event 
QTcF 
Fridericia's Corrected QT Interval 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SOP 
Standard Operating Procedure 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 13 of 54 
2 
INDICATION 
The prophylaxis of chronic migraine in adults ages 18 - 65 
 
3 
STUDY PURPOSE 
• 
To evaluate the safety, tolerability, and changes in the number of migraine and 
headache days with repeated subcutaneous administration of ISIS 546254  or placebo 
in subjects with chronic migraine. 
 
4 
SUMMARY OF STUDY DESIGN 
This is a double-blind, placebo-controlled, randomized, multi-center study in subjects with 
chronic migraine.  The study will consist of 7 office visits, 6 Sample collection visits and 3 
phone call assessments.  Subjects agreeing to participate in the study and meeting the entry 
criteria assessed at the screening visit, will begin a 28 day baseline period to confirm their 
diagnosis, and establish a baseline frequency of migraine and headache days.  During the 
baseline period, subjects will continue treating their migraines in their usual manner.  They will 
monitor headache activity, migraine related symptoms, and medication usage with an electronic 
daily headache diary.   
Subjects who, after completing the baseline, continue to meet entrance criteria will be eligible to 
enter into the 4 month treatment phase.  They will be randomized according to the Clinvest 
generated randomization schedule.  A total of 30 randomized subjects  will enter the treatment 
phase receiving ISIS 546254 (SC) or placebo in a 1:1 design. Study drug or placebo will be 
administered weekly for 16 weeks.  A short phone call to assess any treatment related adverse 
events will take place 1 and 2 days after randomization.  Daily electronic diary assessments will 
collect headache frequency and severity, associated migraine symptoms, acute medication usage, 
and the emergence of unusual symptoms and adverse events.  Subjects will return to the site at 
weeks 4, 8, and 12 for investigational product (IP) accountability/dispensing, medication and 
medication updates, biomarker/lab sample collection, and assessment of adverse events. An end 
of treatment visit will take place 16 weeks after randomization.  Subjects will have a follow-up 
safety visit one month after their last dosage of IP ) for assessment of any adverse events (AE) 
and satisfaction and a final safety phone call 2 months following their last office visit (3 months 
after last dose of IP) for assessment of any adverse events (AE).  Subjects will continue to 
complete headache diaries through Visit 7.  Subjects will also have hematology samples 
collected every other week starting after Visit 2 through Day 154. 
The study consists of 3 phases (Table 1): 
Baseline Phase: 
Visit 1 (Screening/Baseline Period – Day -28) 
Treatment Phase:  
Visit 2 (Randomization/Treatment Month 1/Day 0) 
 
 
 
Phone Call Visit 1 (Randomization/Treatment Month 1/Day 1) 
Phone Call Visit 2 (Randomization/Treatment Month 1/Day 2) 
 
 
 
Sample Collection – Day 14 
 
 
 
Visit 3 (Treatment Period Month 2/Day 28) 
 
 
 
Sample Collection – Day 42 
 
 
 
Visit 4 (Treatment Period Month 3/Day 56)  
 
 
 
Sample Collection – Day 70 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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CONFIDENTIAL 
Page 14 of 54 
 
 
 
Visit 5 (Treatment Period Month 4/Day 84) 
 
 
 
Sample Collection – Day 98 
Follow-up Phase: 
Visit 6 (End of Treatment/ET/Day 112) 
 
 
 
Sample Collection – Day 126 
Visit 7 (Follow up one month after last IP dosage/Day 140 ) 
Sample Collection – Day 154 
 
 
 
Phone Call Visit (3 months after last IP dosage/Day 196) 
 
Safety and tolerability will be monitored by the Investigators.  Patients who discontinue study 
treatment prematurely should complete any follow-up visits associated with the most recent dose 
and should move into and complete the Follow-up Phase. 
Subjects will undergo sampling for (pharmacokinetics) PK, coagulation,  chemistry, hematology, 
and optional future biomedical research, as specified in the schedule of procedures.   
 
5 
POPULATION SAMPLE 
Subjects included in the study are those: 
• 
who have at least a 3 month history of chronic migraine meeting the diagnostic 
criteria listed in the International Classification of Headache Disorders (ICHD)-3 beta 
(Appendix B) 
• 
who migraine started prior to the age of 50. 
• 
not currently taking a migraine preventive or has been taking preventive for at least 
30 days prior to screening and agrees to not start, stop, or change any medications 
and/or dosage during the study period. 
 
6 
STUDY DRUG 
 
Subjects will receive study drug (ISIS 546254, 200 mg/mL, 1 mL or  placebo) which will be 
provided by Ionis Pharmaceuticals, Inc.  All doses will be given by subcutaneous (SC) injection 
at a volume of 1.00 mL  and will be administered at  the same volume weekly thereafter through 
week 16.  
 
Those randomized to ISIS 546254 will receive subcutaneous injections containing 1.00 mL 
(200mg) weekly for weeks 1-16 of ISIS 546254. 
 
Those randomized to placebo will receive 1.00 mL during weeks 1-16  
 
Unblinded personnel will label and package all study kits provided to subjects following 
standard operating procedures.  The study drug will be drawn by an unblinded staff member. The 
first dose of study drug will be administered under supervision of the unblinded staff at the study 
site.  Thereafter the study drug may be self-administered per dosing schedule if desired by the 
subject. All subjects will have the option to return to the site for injections by the unblinded staff 
member if they prefer.  
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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Page 15 of 54 
7 
BACKGROUND & STUDY RATIONALE 
Migraine is a highly prevalent neurovascular disorder that affects a significant proportion of the 
adult population worldwide: up to 6% of males and 18% of females, with the highest prevalence 
occurring between 25 and 55 years of age.  Migraine represents an enormous socio-economic 
burden to the individual as well as to the society and affects the quality of life. A migraine attack 
is characterized by recurrent, severe, debilitating headache associated with nausea, vomiting, 
photophobia, phonophobia, and/or osmophobia, and fatigue, along with other disturbances in 
autonomic, mental, sensory and motor functions.  Migraine attacks typically last 4 to 72 hours 
and may be precipitated by endogenous factors (i.e., hormonal changes, psychosocial stress, 
sleep deficit or surplus, hunger), or by exogenous factors (i.e., certain kinds of food; stimulation 
of different sensory modalities).  Migraine attacks can be preceded by abnormal visual, sensory, 
motor and/or speech functions (migraine with aura) or start with no warning signs (migraine 
without aura). 
Chronic migraine (CM), defined as migraine occurring on ≥ 15 days per month, is a disabling 
neurological condition with an estimated global prevalence of up to 4 - 5%, and represents 
approximately half of all cases of chronic primary headache (Stovner et al. 2006; Stovner et al. 
2007; Diener et al. 2012; Paemeleire et al. 2014).  Episodic migraine (EM) has a complex 
relationship with CM as approximately 2.5–3 % of EM patients per year evolve into a CM state 
(‘‘progression’’) and CM can remit back to EM, with a 2-year remission rate of around 
25%(Bigal 2008; Manack 2011).  CM patients are most commonly females in their 40s and have 
longer attacks, experience greater pain severity, are more disabled, and more likely to have a 
lower quality of life than patients with EM (Paemeleire et al. 2014).  Mood and anxiety 
disorders, respiratory disorders and cardiac risk factors, including hypertension, diabetes mellitus 
and high cholesterol, were also reported significantly more by CM patients (Buse et al. 2010). 
Treatment of Chronic Migraine 
The goal of CM treatment is to reduce the frequency and severity of attacks and return the 
patient to an episodic pattern and includes counseling on risk factors such as caffeine and 
analgesic use and stress management.  Drug therapy for prevention of migraine revolves around 
a variety of nonspecific drugs that primarily reduce neuronal hyperexcitability, the putative 
pathophysiological hallmark for migraine. 
Various pharmacologic classes of medication are used for migraine prophylaxis.  Four of the 
more effective classes include effective classes include beta blockers, anticonvulsants, calcium 
antagonists, tricyclic antidepressants.  In the US, topiramate and valproate sodium are approved 
for migraine prophylaxis, and botulinum toxin type A (BoNT-A) is approved for prophylaxis of 
CM. Regardless of class, effect sizes are modest and data from randomized, placebo-controlled 
trials (RCT) is scant.  Topiramate, one of the best-studied medications, established efficacy at a 
daily dose of 100 mg during 16 weeks via two multicenter, parallel-group RCT in Europe (59 
patients) and the USA (328 patients) (Diener et al. 2007; Silberstein et al. 2007).  The topiramate 
studies demonstrated a mean reduction in monthly migraine days of 3.5 (versus a reduction of 
0.2 for placebo) and a number needed-to-treat of 12.5.  There is no standard definition for drug 
refractory CM, but generally at least three or four drugs should have been adequately tested 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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before a migraineur is declared refractory.  Other therapies for CM include peripheral nerve 
stimulation (both invasive and non-invasive), central neurostimulation, transcranial magnetic 
stimulation, cranial osteopathic manipulative treatment, and cognitive-behavioral therapy.   
The various effective preventive agents used in migraine prophylaxis, such as topiramate, 
valproate, b-blockers, and tricyclic antidepressants, appear to have in common the effect of 
suppressing cortical excitability. 
Migraine Pathophysiology 
CM is a chronic pain disorder where migraine attacks coexist with almost daily head pain: its 
pathophysiology is complex, with features of migraine attacks overlapping with those of acute 
head pain and chronic pain disorders.  Structural, physiologic, and biochemical alterations in the 
brains of patients with CM have been documented.  Migraine has a genetic basis in that common 
genetic variants set a ‘‘migraine threshold’’ that is modulated by endogenous and exogenous 
factors and characterized by an abnormal pattern of sensory processing.  Neurophysiological 
studies have shown that for a number of different sensory modalities the migrainous brain is 
characterized by a lack of habituation to evoked responses (Coppola et al. 2007).  Whether this is 
due to increased cortical hyperexcitability, possibly due to decreased inhibition, or to an 
abnormal responsivity of the cortex due a decreased preactivation level remains disputed.  
Sensitization of central trigeminovascular neurons in nucleus caudalis mediates cutaneous 
allodynia (Burnstein and Jakubowski 2005). 
Kallikrein-Kinin System 
Plasma prekallikrein (PKK) is a glycoprotein that is predominantly synthesized in the liver.  Low 
levels of PKK mRNA are also found in the epithelial cells of the kidney, adrenal gland and 
placenta.  PKK is secreted into the circulation as a single chain zymogen that has an apparent 
molecular weight of approximately 85-88 kDa.  The major physiological activator of PKK, 
activated factor XII (FXIIa), cleaves a single peptide bond to generate the active form of plasma 
kallikrein.  Kallikrein is anchored to cell surfaces by binding to its substrate HMWK (Björkqvist 
et al. 2013). 
PKK is a key component of the kallikrein-kinin system (KKS) signaling cascade.  Kallikrein 
cleaves HMWK to release the potent inflammatory vasodilator peptide hormone bradykinin 
(BK).  BK acts through stimulation of G-protein coupled B1 receptors (B1R) or B2 receptors 
(B2R).  B2R are constitutively expressed in multiple tissues, whereas B1R are typically 
expressed in very low numbers but rapidly increase in response to tissue injury, inflammation, or 
other pathophysiological events.  B2R mediate bronchoconstriction, local blood flow regulation, 
hypotension, acute inflammatory reactions, pain, and hyperalgesia.  B1R mediate short-lived 
arachidonic acid release and prostaglandin (PG) synthesis and B1R activation leads to elevation 
of intracellular free calcium activity by increasing calcium entry into the cell (Sharma et al. 
2012).  B1R affect natriuresis and glomerular filtration, contribute in the pathogenesis of 
diabetes, support leucocyte recruitment and the initiation of inflammatory responses and pain, 
and are mitogenic in fibrotic tissue (Sharma et al. 2012). 
Bradykinin and Migraine 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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Increased production of BK is the main characteristic of the well-known genetic deficiency of 
C1-INH in HAE patients.  BK might also influence migraine.  As an inflammatory agent, it 
directly activates the trigeminal system when applied to the meninges.  Furthermore, BK 
stimulates the increase of intracellular Ca2+.  Ca2+ has a key function in hemiplegic migraines 
and in cortical spreading depression.  Via calcium, the signaling cascade leads to increased nitric 
oxide (NO) production and calcitonin gene-related peptide (CGRP) release.  Both NO and CGRP 
are intensely discussed elements of migraines.  BK stimulates endothelial cell prostacyclin 
synthesis leading to inhibition of platelet function and the formation of nitric oxide (Palmer et al. 
1987) 
BK is involved in numerous signaling pathways, including involvement with g-coupled receptors 
that modulate pain and inflammation.  Stimulation of the BK receptor leads to activation of a 
phosphoinositide signaling pathway, the release of intracellular calcium, and the activation of a 
kinase system.  Various signal transduction mechanisms have been described for kinins, e.g.  the 
activation of phospholipases A2, C, and D with the subsequent release of prostaglandins, NO, 
inositol phosphates and diacylglycerol leading to the mobilization of intracellular calcium and 
activation of protein kinase C (Engeli 2004).  This leads to the opening of the nociceptors 
TRPV1 channels in the sensory nerve cell membrane, enhancing nociception.  Generated during 
inflammation and tissue injury, BK is a prominent algogenic mediator and regulator of the 
noxious heat sensitivity of nociceptors.  Two (2) receptor types have been described: B1 and B2.  
B2 is constitutive in numerous tissues, including neurons, whereas B1 is typically inducible and 
its activation can generate both pain and inflammation.  BKs numerous physiological functions 
might also be implicated in migraine headache (Engeli 2004). 
The activation of B2 receptors, constitutively expressed in primary sensory neurons, promotes 
polymodal nociceptor activation and hyperalgesia through the production of diacylglycerol and 
activation of protein kinase C (Engeli 2004).  BK can sensitize nociceptors following the release 
of inflammatory mediators such as prostaglandins, cytokines and NO either from sensory 
neurons or endothelial and immune cells.  BK is also known to facilitate the release of substance 
P and CGRP from rat sensory neurons in culture (Engeli 2004).  However, the type of BK 
receptor responsible for pain and inflammation in humans has not been adequately defined. 
Studies have substantiated the binding of BK to cortical astrocytes and indicated that stimulation 
with BK causes calcium turnover, suggesting a role for BK in central nervous transmission 
(Stephens et al. 1993).  BK increases Ca2+-levels in sensory neurons (Linhart et al. 2003).  BK 
activation simulates the release of Ca2+ from intracellular stores and Ca2+ supply through Ca2+ 
entry pathways in the plasma membrane.  BK regulates systemic and local hemodynamics by 
turning on NO production (Engeli 2004). 
HAE and Migraine 
Chung and Kim reported on an HAE patient manifesting migraine-like episodes of headache, 
effectively prophylaxed with Danazol.  The patient, a 44-yr-old Korean man, suffered from 
frequent attacks of migraine-like headache (3-7 per month), pulsating in nature, associated with 
nausea, and aggravated by activity.  His headache had shown recent progression with abdominal 
pain.  No remarkable findings were observed on radiologic examination, including brain MRI 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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and intracranial and extracranial MRA.  Danazol 200 mg every other day prevented the 
migraine-like episodes for about 2 years.  A single moderate migraine-like headache was 
resolved with administration of naratriptan 2.5 mg (Chung and Kim 2012).   It suggests that 
pathogenic mechanism of headache in hereditary angioedema may be mediated by the 
neurogenic inflammatory-like physiology of migraine.  Hoxha et al. reported on 38-old female 
HAE patient presenting facial paralysis and hemiparesis, persistent headache, nausea, and 
vomiting who also responded to Danazol with resolution of her symptoms (Hoxha et al. 2013). 
Current clinical studies are underway investigating inhibitors of calcitonin gene-related peptide 
(CGRP) as prophylactic agents for chronic migraine.   Due to the role that BK plays in the 
stimulating the release of CGRP via its increasing prostaglandin production through binding to 
BK BR2, it is thought that the systemic reduction of circulating PKK, and therefore the reduction 
of plasma’s potential to produce BK, could greatly reduce the contribution of BK and its 
associated downstream effects in chronic migraine (Ceruti et al. 2011; Supowit et al. 2011; Petho 
and Reeh 2012; Gangadha et al. 2014).  This, combined with the known long tissue half-life of 
ASOs, supports ISIS 546254 as a potentially attractive once-weekly, self-administered, 
subcutaneous treatment for the prevention, or amelioration, of symptoms associated with chronic 
migraine. 
 
ISIS 546254 
Antisense oligonucleotides are short synthetic strings of nucleotides that selectively bind to 
mRNA and prevent the expression of a targeted protein encoded by that specific segment of 
mRNA. These compounds bind to RNA with high affinity and selectivity. Antisense 
technologies offer a number of potential advantages over more traditional approaches for drug 
discovery and development including: (1) greatly improved specificity allowing discrimination 
between closely related gene products; (2) predictability due to some similarities in 
pharmacokinetics, toxicology and manufacturing; and (3) versatility allowing inhibition of “non-
druggable” targets, such as transcription factors, adapter proteins and other proteins with no 
intrinsic enzymatic activity or proteins with unknown function. Antisense oligonucleotides have 
been tested clinically for the treatment of a wide variety of diseases including viral disease, 
cancer, cardiovascular, metabolic and inflammatory diseases.  
 
The investigational product, ISIS 546254, is a chimeric 2′-O-(2-methoxyethyl) (2′-MOE) 
antisense oligonucleotide (ASO) targeted to human prekallikrein (PKK) mRNA. As such, it is a 
highly specific inhibitor of PKK synthesis which should result in reduced BK generation. The 
antisense concept is based upon Watson-Crick hybridization. Antisense oligonucleotides are 
designed to inhibit the translation of mRNA by binding with high affinity and selectivity to their 
RNA targets. Antisense oligonucleotides exert their inhibitory effects on mRNA translation by a 
number of mechanisms, the most studied of which includes breakdown of steady-state mRNA 
levels through the utilization of endogenous RNase H1 enzyme.(Monia et al. 1993) ISIS 546254 
was designed to function through an RNase H1-dependent terminating mechanism. (Baker and 
Monia 1999)RNase H1 efficiently induces antisense-mediated cleavage of mRNA and is present 
in most mammalian cells. Antisense-mediated reduction of target mRNA levels is typically 85-
90% of control levels.(Crooke and Bennett 1996) Furthermore, reduction in target mRNA levels 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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using this approach correlates directly with a subsequent reduction in target protein levels. ISIS 
546254 is a very potent antisense inhibitor of human PKK expression and has demonstrated an 
ED50 of 2.5-5 mg/kg/week in transgenic animal models. 
 
After systemic administration, the primary mechanism of ISIS 546254 is to reduce circulating 
prekallikrein (PKK) levels, therefore reducing the plasma’s ability to produce kallikrein which in 
turn will reduce bradykinin formation and vascular permeability. Preclinical data indicate that 
reduction of PKK by administering a specific antisense oligonucleotide (ASO) targeting PKK 
mRNA (ISIS 546254) leads to reduced ability of treated plasma to produce bradykinin and 
reduced vascular permeability in animal models. (Revenkop et al. 2011) 
 
This, combined with the known long tissue half-life of ASOs, supports ISIS 546254 as a 
potentially attractive  self-administered, SC treatment for the prophylaxis of chronic migraine.  
 
8 
PRIMARY OBJECTIVES 
1. To evaluate the safety and tolerability of ISIS 546254 in the preventive treatment of 
chronic migraine 
2. To evaluate the efficacy of ISIS 546254 in the preventive treatment of chronic migraine, 
measured by change in migraine days 
9 
SECONDARY OBJECTIVES 
1. To evaluate the efficacy of ISIS 546254 in the preventive treatment of chronic migraine, 
measured by change in average headache severity from baseline 
2. To evaluate the efficacy of ISIS 546254 in the preventive treatment of chronic migraine, 
measured by change in headache days from baseline 
3. To evaluate the proportion of patients reporting a ≥ 50% reduction in the number of 
migraine headaches from baseline 
4. To evaluate the frequency of migraine headache days requiring use of acute and rescue 
migraine medication as compared to baseline 
5. To evaluate changes in the Migraine Specific Quality of Life (MSQ) Questionnaire from 
baseline 
6. To evaluate changes in physician global impress of change (PGIC) from baseline 
7. To evaluate changes in subject global impress of change (SGIC) from baseline 
 
10 SUBJECT SELECTION 
The study population will be composed of approximately 30 randomized female and male 
patients, aged 18 to 65 years, with a history of migraine for at least 1 year and chronic migraine 
(CM) (as defined by International Classification of Headache Disorders, 3
rd revision [ICHD-3] 
criteria [IHS 2013]) for at least 3 months prior to screening. The diagnosis will be prospectively 
confirmed via a review of headache data recorded in an electronic daily headache diary during a 
28-day run-in period. Subjects on migraine preventative medications will be required to be on a 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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Page 20 of 54 
stable regimen for 30 days prior to and throughout the study period and to be experiencing ≥15 
headaches per month despite prophylaxis.  
 
11 INCLUSION/EXCLUSION CRITERIA 
Subjects who meet all of the following inclusion criteria and none of the exclusion criteria will 
be enrolled. 
 
11.1 Inclusion Criteria  
Potential subjects must meet the following criteria at the screening visit to enter this 
study: 
1. male or female, in otherwise good health, 18 to 65 years of age. 
2. history of chronic migraine meeting the diagnostic criteria listed in the 
International Classification of Headache Disorders (ICHD-III beta version, 2013), 
as follows: 
a. 
History of frequent headaches suggestive of chronic migraine (15 or 
greater days of qualifying headaches per month) for at least three months 
prior to screening 
b. 
Verification of headache frequency through prospectively collected 
baseline information during the 28-day run-in phase demonstrating 
headaches on at least 15 days, with at least 8 days per month fulfilling any 
ONE of the following; 
i. 
Qualify as being a migraine attack 
ii. 
Relieved by migraine specific acute medications 
3. onset of migraine before age 50. 
4. stable pattern of migraine pattern for at least 3 months prior to screening. 
5. not currently taking a migraine preventive OR has been taking a stable dose of a 
preventive for at least 30 days prior to screening and agrees to not start, stop, or 
change medication and/or dosage during the study period. 
i. 
Subjects on migraine preventative should have stable headache 
pattern 
ii. 
Injections of onabotulinumtoxinA are allowable if subject has 
completed at least 2 injection cycles and agrees to maintain a regular 
injection cycle for the duration of the study 
6. females must be either surgically sterile (e.g., tubal occlusion such as bilateral 
tubal ligation, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) OR 
post-menopausal (>12 months since last period) OR if of child-bearing potential, 
using an acceptable contraceptive method during, and for 97 days (approximately 
5 half-lives of ISIS 546254) after the last dose of study drug.  
7. males must be surgically sterile, abstinent, OR if engaged in sexual relations of 
child-bearing potential, the subject must be using an acceptable contraceptive 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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method as defined in Section 14 during and for at least 97 days after the last dose 
of study drug. 
8. completion of online diary must be ≥ 80 % compliance, unless otherwise 
approved by Clinvest. 
9. must have given written, informed consent and obtain any authorizations required 
by local law.  
10. be able and willing to comply with all study requirements.  
  
11.2 Exclusion Criteria 
Potential subjects meeting any of the following criteria will be excluded from entering this study: 
 
1. unable to understand the study requirements, the informed consent, or complete headache 
records as required per protocol. 
2. pregnant, actively trying to become pregnant, or breast-feeding. 
3. history of medication overuse (MO) of opioids, or butalbital, as defined by ICHD-3 beta 
criteria and/or MO during baseline period (Appendix C). 
4. history of substance abuse and/or dependence, in the opinion of the Investigator. 
5. unstable neurological condition or a significantly abnormal neurological examination 
with focal signs or signs of increased intracranial pressure. 
6. suffers from a serious illness, or an unstable medical condition, one that could require 
hospitalization, or could increase the risk of adverse events. 
7. any psychiatric condition with psychotic features, and/or any other psychiatric disorder 
not stable or well controlled, that would interfere in the ability to complete study 
activities.  
8. history of thrombocytopenia. 
9. history of bleeding, diathesis or coagulopathy 
10. use of any anticoagulant 
11. received any investigational agents within 30 days prior to Visit 1, or 5 half-lives of study 
drug, whichever is longer. 
12. has significant risk of suicide, defined as a “yes” answer to any of the following questions 
on the Columbia-Suicide Severity Rating Scale (C-SSRS), either at the screening visit 
(when assessing the prior 12 months) or at visit 2 (when assessing time since the 
screening visit): 
a. Questions 4 or 5 on the suicidal ideation section 
b. Any question on any item in the suicidal behavior section 
13. plans to participate in another clinical study at any time during this study. 
14. malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated. 
15. treatment with any non-Ionis oligonucleotide (including siRNA) at any time or prior 
treatment with an Ionis oligonucleotide within 6 months of screening. Subjects that have 
previously received only a single dose of an ISIS oligonucleotide as part of a clinical 
study may be included as long as a duration ≥4 months elapsed since dosing. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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16. unwillingness or inability to comply with study procedures, including follow-up, as 
specified by this protocol. 
17. electrocardiogram (ECG) showing a clinically significant abnormality at screening.   
18. screening laboratory results that would render a subject unsuitable for study participation 
including, but not limited to: 
a. ALT/AST > 1.5 x ULN 
b. Bilirubin ≥ 1.2 x ULN 
i. Study Medical Monitor may allow subjects with bilirubin ≥ 1.2 x ULN on 
study if all of the following are satisfied: 
1. indirect bilirubin only is elevated 
2. ALT/AST is ≤ ULN 
3. genetic testing confirms Gilbert’s disease 
c. Platelets < 150 x 109/L 
d. Alkaline phosphatase > 2.0 x ULN  
e. Cockcroft-Gault calculated GFR < 60 mL/min 
f. INR > 1.2 
g. aPTT > ULN 
h. PT > ULN 
i. 
Serum creatinine > 1.1 x ULN 
j. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg. 
i. In the event of P/C ratio above this threshold eligibility may be confirmed 
by a quantitative total urine protein measurement of < 200 mg/24hr with 
prior Sponsor approval 
k. Urine blood ≥ trace by dipstick 
i. Subjects with positive dipsticks are eligible if urine microscopy shows ≤ 5 
red blood cells per high power field. 
19. have any other conditions, which, in the opinion of the Investigator would make the 
subject unsuitable for inclusion, or could interfere with the subject participating in or 
completing the study. 
20. active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
21. positive urine drug screen for substances not otherwise prescribed. 
22. suffers from human compromised immune system including immunodeficiency virus 
(HIV), Hepatitis B or C. 
 
12 STUDY DESIGN 
This is a double-blind, placebo-controlled, randomized, multi-center study in subjects with 
chronic migraine. Approximately 30 randomized female and male patients, aged 18 to 65 years, 
inclusive, with a history of migraine for at least 1 year and chronic migraine (CM) (as defined by 
International Classification of Headache Disorders, 3
rd revision [ICHD-3] criteria [IHS 2013]) 
for at least 3 months prior to screening. Subjects will complete a 1-month baseline prior to 
randomization to confirm their diagnosis, as well as establish baseline migraine characteristics.  
Eligible subjects will enter a four month treatment phase receiving ISIS 546254 (200mg SC) or 
placebo in a 1:1 design. Following the treatment phase subjects will return to the site one month 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 23 of 54 
after their last dosage of IP and receive a phone call at 3 months after last dose to complete for 
safety assessments. During the treatment and follow-up phases of the study, all patients will have 
samples taken every two weeks for hematology testing to monitor platelet levels. 
 
12.1 VISIT 1 – SCREENING (Day -28)  
The following will be completed at Visit 1: 
1. Obtain written Informed Consent. The informed consent will be obtained in 
accordance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements from each subject prior to participation in the study.   
2. Verify Inclusion/Exclusion Criteria.  Subjects will meet all the inclusion and none of 
the exclusion criteria. 
3. Obtain demographics. 
4. Obtain medical, medication, and headache history. Data collected will include 
medical history and diagnoses, age at onset of migraine and other pertinent 
migraine/headache history, history of acute and prophylactic headache medications 
within the past 30 days, and history of other recent/concomitant medications. 
5. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
6. Perform physical and neurological examinations. 
7. Measure vital signs. 
8. Perform electrocardiogram (ECG). 
9. Perform urine drug screen. 
10. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
11. Clinical laboratory sample collection for testing hematology, chemistry, PK, 
biomarkers and urinalysis. 
12. Serology for human immunodeficiency virus (HIV), Hepatitis B and C. 
13. Instruct subject on diary completion. 
 
 
12.2 VISIT 2 – RANDOMIZATION (Day 0) 
1. Verify Inclusion/Exclusion Criteria. Subjects must continue to meet all inclusion and 
none of the exclusion criteria.  
2. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
3. Perform brief physical and collect vital signs. 
4. Record any changes to concomitant medications. 
5. Record any Adverse Events (AE) since signing the Informed Consent. 
6. Review Baseline Headache Diary for completeness and continuing eligibility.  
7. Perform urine drug screen. 
8. Clinical laboratory sample collection for testing hematology, chemistry, PK, 
biomarkers, plasma for anti-drug antibody screening, and urinalysis. 
9. Randomize subject. 
10. Review Diary instruction (same instructions as Baseline Headache Diary). 
11. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
12. Administer first dose of study drug (1.00 mL). 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 24 of 54 
13. Dispense and instruct subjects on how to inject study drug. Subjects will also be 
educated on prohibited medications, dosage limitations of study drug, and storage 
requirements. Subjects will be instructed to return all used/partially used/unused 
study drug at next office visit to the unblinded staff and drug reconciliation will be 
performed.  
14. Administer MSQ. 
15. Schedule Visit 3. 
   
12.3 PHONE CALL 1 – SAFETY FOLLOW UP (DAY 1) 
1. Record any changes to concomitant medications. 
2. Record any Adverse Events. 
3. Answer any subject questions on IP administration. 
 
12.4 PHONE CALL 2 – SAFETY FOLLOW UP (DAY 2) 
1. Record any changes to concomitant medications. 
2. Record any AEs. 
3. Answer any subject questions on IP administration. 
 
12.5 HEMATOLOGY SAMPLE COLLECTION (DAY 14 +/- 3 DAYS) 
1.  Patient to submit sample through contract lab  
12.6 VISIT 3 – END OF TREATMENT MONTH 1 (DAY 28 +/- 3 DAYS) 
1. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
2. Perform brief physical and collect vital signs. 
3. Record any changes to concomitant medications. 
4. Record any AEs. 
5. Review Diary for completeness maintaining an 80% compliance and continuing 
eligibility.  
6. Clinical laboratory sample collection for testing hematology, chemistry, PK, 
biomarkers, plasma for anti-drug antibody screening, and urinalysis. 
7. Collect unused study drug and used packaging. 
8. Unblinded staff to perform drug accountability.   
9. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
10. Dispense and review how to inject study drug, prohibited medications, dosage 
limitations of study drug, and storage requirements. Subjects will be instructed to 
return all used/partially used/unused study drug at next office visit to unblinded staff .  
11. Schedule Visit 4. 
 
12.7 HEMATOLOGY SAMPLE COLLECTION (DAY 42 +/- 3 DAYS) 
1. Patient to submit sample through contract lab  
 
12.8 VISIT 4 – END OF TREATMENT MONTH 2 (DAY 56 +/- 3 DAYS) 
1. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
2. Perform brief physical and collect vital signs. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 25 of 54 
3. Record any changes to concomitant medications. 
4. Record any AEs. 
5. Review Diary for completeness maintaining an 80% compliance and continuing 
eligibility.  
6. Clinical laboratory sample collection for testing hematology, chemistry, PK, 
biomarkers and urinalysis . 
7. Unblinded staff to collect unused study drug and used packaging. 
8. Unblinded staff to perform drug accountability. 
9. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
10. Dispense and review how to inject study drug, prohibited medications, dosage 
limitations of study drug, and storage requirements. Subjects will be instructed to 
return all used/partially used/unused study drug at next office visit to unblinded staff.  
11. Schedule visit 5. 
 
12.9 HEMATOLOGY SAMPLE COLLECTION (DAY 70 +/- 3 DAYS) 
  1. Patient to submit sample through contract lab. 
 
12.10 VISIT 5 – END OF TREATMENT MONTH 3 (DAY 84 +/- 3 DAYS) 
1. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
2. Perform brief physical and collect vital signs. 
3. Record any changes to concomitant medications. 
4. Record any AEs. 
5. Review Diary for completeness maintaining an 80% compliance and continuing 
eligibility.  
6. Clinical laboratory sample collection for testing hematology, chemistry, PK, biomarkers, 
plasma for anti-drug antibody screening, and urinalysis. 
7. Unblinded staff to collect unused study drug and used packaging. 
8. Unblinded staff to perform drug accountability. 
9. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
10. Dispense and review how to inject study drug, prohibited medications, dosage 
limitations of study drug, and storage requirements. Subjects will be instructed to return 
all used/partially used/unused study drug at next office visit to unblinded staff.  
11. Schedule visit 6 
 
12.11 HEMATOLOGY SAMPLE COLLECTION (DAY 98 +/- 3 DAYS) 
   1. Patient to submit sample through contract lab  
 
12.12 VISIT 6 – END OF TREATMENT/ET (DAY 112 +/- 3 DAYS) 
1. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
2. Perform physical and neurological examinations. 
3. Measure vital signs. 
4. Perform electrocardiogram (ECG).  
5. Record any changes to concomitant medications. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 26 of 54 
6. Record any AEs.   
7. Clinical laboratory sample collection for testing hematology, chemistry, PK, 
biomarkers, plasma for anti-drug antibody screening, and urinalysis. 
8. Unblinded staff to collect unused study drug and used packaging. 
9. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
10. Unblinded staff to perform drug accountability. 
11. Administer MSQ, PGIC, and SGIC.  
12. Schedule Visit 7  
 
12.13 HEMATOLOGY SAMPLE COLLECTION (DAY 126 +/- 3 DAYS) 
   1. Patient to submit sample through contract lab  
 
12.14 VISIT 7 – FOLLOW UP VISIT (DAY 140 +/- 3 DAYS) 
1. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be 
negative to continue in study.  
2. Collect vital signs. 
3. Record any changes to concomitant medications. 
4. Administer Columbia-Suicide Severity Rating Scale (C-SSRS), and MSQ. 
5. Record any AEs.   
6. Clinical laboratory sample collection for testing hematology, chemistry, PK, 
biomarkers and urinalysis.. 
12.15 HEMATOLOGY SAMPLE COLLECTION (DAY 154 +/- 3 DAYS) 
  1. Patient to submit sample through contract lab  
 
12.16 PHONE CALL 3 – SAFETY FOLLOW UP (DAY 196 +/- 3 DAYS) 
           1. Record any AEs. 
           2. Administer MSQ. 
 
 
 
 
 
 
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of ISIS 546254 for Preventive 
Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 27 of 54 
  
  
Screening 
Randomization 
Treatment 
Visit 1 
Day -28 
  
Visit 2 
 Day 0 
(+3) 
Phone 
Call 
1&2  
Day 1 
& 2 
Sample 
Collection 
Day 14 
(+/- 3) 
Visit 3 
Day 28 
 (+/- 3) 
Sample 
Collection 
Day 42 
(+/- 3) 
Visit 4 
Day 56 
(+/- 3) 
Sample 
Collection 
Day 70 
(+/-3) 
Visit 5 
Day 84 
(+/-3) 
Sample 
Collection 
Day 98 
(+/-3) 
Informed Consent 
X 
  
 
 
  
 
  
 
 
 
Physical/Neurologic
al Exam 
X 
  
 
 
  
 
  
 
 
 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
Verify 
Inclusion/Exclusion 
X 
X 
 
 
  
 
 
 
 
Subject 
Randomization 
  
X 
 
 
  
 
  
 
  
 
Medical History 
X 
  
 
 
  
 
  
 
  
 
Migraine History 
X 
  
 
 
  
 
  
 
  
 
Medication History 
X 
  
 
 
  
 
  
 
  
 
Update 
Concomitant 
Medications 
  
X 
X 
 
X 
 
X 
 
X 
 
Urine Drug Screen 
X 
X 
 
 
  
 
  
 
  
 
Clinical Labs*  
X 
X 
 
X† 
X 
X† 
X 
X† 
X 
X† 
Plasma Collection 
for ADA Screening 
 
X 
 
 
X 
 
 
 
X 
 
ECG 
X 
X 
 
 
X 
 
X 
 
X 
 
Serology (HIV/ Heb 
B and C) 
X 
  
 
 
  
 
  
 
  
 
Pregnancy Test  
X 
X 
 
 
 X 
 
X  
 
X  
 
SGIC 
  
  
 
 
  
 
  
 
  
 
PGIC 
  
  
 
 
  
 
  
 
  
 
Dispense Study 
Medication 
  
X 
 
 
X 
 
X 
 
X 
 
Drug 
Accountability 
  
  
 
 
X 
 
X 
 
X 
 
Headache Diary 
X 
X 
 
 
X 
 
X 
 
X 
 
Review Diary 
  
X 
 
 
X 
 
X 
 
X 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of ISIS 546254 for Preventive 
Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 28 of 54 
Collect Adverse 
Events 
  
X 
X 
 
X 
 
X 
 
X 
 
Administer MSQ 
  
X 
 
 
  
 
  
 
 
 
Administer C-SSRS 
X 
X 
 
 
X 
 
X 
 
X 
 
Follow-Up Phone 
Call 
 
 
X 
 
 
 
 
 
 
 
*Clinical chemistry, hematology, inflammation panel, PK and PD biomarkers (see table 2).  Any missing or unreportable value should 
be repeated as soon as possible (within 1 week) using a clinic local to the patient if necessary 
†Hematology panel only. Any missing or unreportable value should be repeated as soon as possible (within 1 week) using a clinic 
local to the patient if necessary 
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of ISIS 546254 for Preventive 
Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 29 of 54 
  
  
EOT/
ET 
Follow-Up 
Visit 6 
Day 
112 
(+/- 3) 
Sample 
Collection 
Day 126 
(+/-3) 
Visit 7 
Day 140  
 (+/- 3) 
Sample 
Collection 
Day 154 
(+/-3) 
Phone Call 3 
Day 196 
(+/- 3) 
Informed Consent 
 
 
  
 
 
Physical/Neurological 
Exam 
X 
 
 
 
Vital Signs 
X 
 
X 
 
 
Verify 
Inclusion/Exclusion 
 
 
 
 
Subject Randomization 
 
 
  
 
 
Medical History 
 
 
  
 
 
Migraine History 
 
 
  
 
 
Medication History 
 
 
 
 
Update Concomitant 
Medications 
X 
 
X 
 
X 
Urine Drug Screen 
 
 
  
 
 
Clinical Labs*  
X 
X† 
X 
X† 
 
Plasma Collection for 
ADA Screening 
X 
 
 
 
 
ECG 
X 
 
X 
 
 
Serology (HIV/ Heb B 
and C) 
 
 
  
 
 
Pregnancy Test  
X 
 
X 
 
 
SGIC 
X 
 
 
 
PGIC 
X 
 
 
 
Dispense Study 
Medication 
 
 
  
 
 
Drug Accountability 
X 
 
 
 
Headache Diary 
 
 
  
 
 
Review Diary 
X 
 
 
 
Collect Adverse Events 
X 
 
X 
 
X 
Administer MSQ 
X 
 
X 
 
X 
Administer C-SSRS 
X 
 
X 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of ISIS 546254 for Preventive 
Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 30 of 54 
Follow-Up Phone Call 
 
 
 
 
X 
*Clinical chemistry, hematology, inflammation panel, PK and PD biomarkers (see table 2).  Any missing or unreportable value should 
be repeated as soon as possible (within 1 week) using a clinic local to the patient if necessary 
†Hematology panel only. Any missing or unreportable value should be repeated as soon as possible (within 1 week) using a clinic 
local to the patient if necessary 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 31 of 54 
13 CONTRACEPTION REQUIREMENTS 
Male subjects must refrain from sperm donation and either be abstinent† or, if engaged in sexual 
relations with a female of child-bearing potential, they must use effective barrier contraception 
with their partner from the time of signing the informed consent form until at least 13 weeks 
after their last dose of Study Drug.  Effective contraception includes a vasectomy with negative 
semen analysis at follow-up, or the use of condoms together with spermicidal 
foam/gel/film/cream/suppository.  Male subjects engaged in sexual relations with a female of 
child-bearing potential must also encourage their female partner to use effective contraception 
from the time of signing the informed consent until 96 days  after the subject’s last dose of study 
treatment.   
Effective contraception for the female partner includes: surgical sterilization (e.g., bilateral tubal 
ligation), hormonal contraception, intrauterine contraception/device, or barrier methods (female 
condom*, diaphragm, sponge, cervical cap) together with spermicidal 
foam/gel/film/cream/suppository.  Male subjects with partners that are pregnant must use 
condoms to ensure that the fetus is not exposed to the Study Drug. 
†Note: Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception. 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
 
14 INFORMED CONSENT 
The investigator must obtain documented consent from each potential subject, or legally 
authorized representative, prior to any study related procedures being performed.  Consent must 
be documented by the subject’s dated signature on an Informed Consent Form (ICF) along with 
the dated signature of the persons conducting the consenting process.  A copy of the signed and 
dated consent form should be given to the subject before participating in the study.   
 
15 STUDY DRUG RANDOMIZATION AND TRAINING 
Eligible subjects will be randomized 1:1 to receive ISIS 546254, 200 mg/mL, 1 mL or placebo at 
Visit 2 by unblinded staff.  If at any time during the study the subject withdrawals from the 
study, they will be instructed to return all used packaging and unused medication to unblinded 
staff. All doses (200mg ISIS546254 or placebo will be given by subcutaneous (SC) injection at a 
standardized volume of 1.00 mL ISIS 546254 or placebo weekly through week 16.  All dosing 
after the first injection at the site may be self-administered per dosing schedule if desired by the 
subject. All subjects will have the option to return to the site for injections administered by the 
unblinded staff if they desire.  Subjects will receive training on proper administration of IP, 
storage requirements, and will be asked to return all used/partially used/unused medication 
containers at the next office visit to unblinded staff. Any subject self-administering IP will call 
site to confirm most recent lab report values are within allowable rages dosing.  
 
Adjustments of dose and/or treatment schedule should occur only on rare occasions. Adjustments 
in the dose and/or treatment schedule may be allowed only with consent of the study medical 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 32 of 54 
monitor following discussion with the investigator for subjects that are unable to tolerate the 
once weekly dose. 
 
16 DOSING ERRORS 
Study drug errors should be documented as protocol deviations.  A brief description should be 
provided in the deviation, including whether the subject was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
 
17 RESCUE MEDICATION 
Subjects will be instructed they may take their investigator approved rescue medications for 
headaches, if needed.  Rescue medication usage and dosage will be recorded on the headache 
diary. 
 
18 CONCOMITANT MEDICATIONS 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
Investigator. Concomitant medication usage and dosage will be recorded on the concomitant 
medication form. 
 
Routine medications, including migraine preventative medications, should be maintained on a 
stable dose and regimen for the duration of the study period.  Additionally, any concomitant 
chronic therapies should be maintained at a stable dose and dose regimen during the study. 
 
18.1  Allowed Medications 
1. All acute migraine medications currently taken by subject at Visit 1 will be 
allowed during the study as a rescue medication or if a subject does not treat with 
study drug for that specific headache. 
2. All migraine preventative medications, currently taken by subject at Visit 1, will 
be allowed if on a stable dose for at least 30 days prior to Visit 1 and subject 
agrees to continue at that dose throughout the study.   
 
18.2 Prohibited Medications 
1. Any anticoagulant during the study is prohibited  
 
19 HEADACHE DIARY 
The primary and much of the secondary endpoints will be derived from the electronic daily 
headache diary.  Site personnel will be responsible for instructing subjects on the requirement for 
timely and daily completion of the electronic diary.  Each day, the subject will be asked to record 
diary data for the previous day (24 hour period).  If a subject does not experience a headache in 
the previous 24 hour period, the diary must still be completed and recorded as no headache.  
Subject’s diaries may vary day to day based on their responses.  Subjects will be asked to 
document all headaches experienced regardless of severity for the duration of the study.  All 
subjects should have at least 80% compliance with diary completion throughout the length of the 
study.  Subjects will record headache severity, symptoms, use of acute medications, as well as 
additional questions as required.  Headache severity will be subjectively rated by the subject as 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 33 of 54 
follows: no pain, mild pain, moderate pain, or severe pain.  These ratings will be collected at pre-
defined time points.    
    
20 UNSCHEDULED VISITS 
If a subject has an unscheduled visit, the unscheduled visit form must be completed.  If the visit 
occurs for safety reasons, all relevant safety data should be captured and reported on the 
appropriate forms.  If the unscheduled visit results in an early termination, all applicable final 
study visit procedures will be performed and the early termination form will need to be 
completed as well. 
 
21 BLINDING/UNBLINDING 
At randomization (Visit 2), neither the subject nor the investigator will be aware to which 
treatment group the subject has been assigned.  Investigational product will be drawn and 
administered by an unblinded member of the staff. If needed, for safety and proper treatment of 
the subject, the investigator can unblind the subject’s treatment assignment to determine which 
treatment has been assigned and institute appropriate follow-up care.  When possible, Sponsor 
and Clinvest should be notified prior to unblinding study drug.    
 
Individual unblinding envelopes are shipped with study drug.  Each study drug kit has a 
corresponding unblinding envelope.  Unblinding will include matching the kit and unblinding 
envelope with the subject drug number. 
 
To unblind a subject without breaking the blind for remaining subjects’ treatment the following 
instructions described below will be followed: 
• 
Obtain the security envelope containing the unblinding envelopes. 
• 
Remove the unblinding envelope with the study drug number corresponding with the 
study drug kit dispensed to the subject. 
• 
Break the seal of the unblinding envelope and remove the subjects’ treatment label. 
• 
Return the subjects’ treatment label to the unblinding envelope. 
• 
Return the unblinding envelope to the security envelope. 
• 
Document on the unblinding form located in the eAdmin Binder.  
• 
Email copy of unblinding form to study@clinvest.com within 24 hours of unblinding. 
• 
Complete and email or fax the Sterling IRB, unanticipated problem report form, to 
Sterling IRB within 10 business days of unblinding.  
 
22 DISCONTINUATION/WITHDRAWAL FROM STUDY 
All subjects who withdraw from the study, for any reason, must return all study drug and 
supplies to the investigator or his/her delegate at the first available opportunity.  Subjects may 
withdraw at any time or be dropped from the study at the discretion of the investigator or 
Clinvest if he/she violates the study plan or for administrative and/or safety reasons.  When a 
subject discontinues/withdraws prior to study completion, all applicable activities scheduled for 
the final study visit should be performed at the time of discontinuation, as well as the completion 
of the early termination form and unscheduled visit form (if appropriate).  Any adverse 
experiences which are present at the time of discontinuation/withdrawal should be followed in 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 34 of 54 
accordance with the safety requirements outlined in the adverse event reporting section of this 
protocol.   
 
 
23 ADVERSE EVENTS 
The investigator will be responsible for the detection, collection, and evaluation of all events 
meeting the definition of an adverse event (AE).  An adverse event is defined as any untoward 
medical occurrence in a subject or clinical investigation subject administered a medicinal product 
and which does not necessarily have a causal relationship with the study product.  An adverse 
event can therefore be any unfavorable and unintended sign (including abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study product, whether 
or not related to the study product.   
 
An adverse event observed after the initial dose of the study product will be considered a 
“treatment-emergent adverse event”.  Treatment-emergent adverse events will be analyzed and 
discussed in the clinical study report for this study.  Adverse event terms should include a 
diagnosis, as available, in preference to the listing of individual signs and symptoms.  If a 
diagnosis is not possible, each sign and symptom should be recorded as an individual adverse 
event.   
 
All adverse events, whether or not related to the study drug, must be completely documented on 
the appropriate adverse event eCRF (electronic case report form) page.  If a subject is withdrawn 
from the study due to an adverse event, this must also be recorded on the appropriate eCRF 
pages.   
 
The site staff must record all directly observed AEs and all spontaneously reported AEs.  At each 
visit, the site staff will ask the subject a non-specific question (e.g., “Have you noticed any 
change in your health since your last visit?”) to assess AE occurrence since the last report or 
visit.   
 
23.1 Non-Serious Adverse Event (NSAE) 
Non-serious adverse events (NSAE) will be collected beginning after the first dose of 
study medication of treatment and will include any change from the subject’s condition at 
Visit 2 though the last follow up phone call 3 months post treatment.  These include 
physical findings, clinical signs and symptoms, or sequelae.  Any worsening (i.e. any 
clinically significant adverse change in the frequency and/or intensity) of a preexisting 
condition which is temporally associated with the use of the provided product, is also 
considered to be an adverse event.  Events such as elective medical/surgical procedures 
or anticipated day-to-day fluctuations of pre-existing conditions present at screening that 
do not worsen are not considered NSAE’s. 
 
All NSAE’s noted will be captured on the non-serious adverse events eCRF.  Information 
captured will include start date/time, end date/time, severity, relationship of causality to 
study drug, course of action taken, and outcome. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 35 of 54 
 
23.2 Serious Adverse Event (SAE) 
An serious adverse event (SAE) is defined as any untoward medical occurring after 
signing of the informed consent and until cessation of the study which: 
1. results in death. 
2. is life threatening (Note: The term “life-threatening” in the definition of 
“serious” refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe.). 
3. requires subject hospitalization or prolongation of existing hospitalization. 
4. results in persistent or significant disability/incapacity; or a congenital 
anomaly/birth defect. 
5. Important medical events that may not result in death, are not life-
threatening, or do not require hospitalization may also be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse 
 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition above.  These should also be considered serious. 
 
SAE’s will be reported in compliance with all applicable safety reporting requirements as 
set forth in the Code of Federal Regulations.  SAE’s assessed as life threatening or death 
“possibly related to the study medication” will be reported to Clinvest, Sponsor, and 
Sterling IRB within 24 hours of knowledge of the event by study staff.  All other SAE’s 
(such as hospitalization, disability, congenital anomaly, and an important medical event) 
will be reported to Clinvest, Sponsor, and Sterling IRB within 48 hours of knowledge of 
the event by study staff.  A MedWatch Form FDA 3500A will also be completed and 
forwarded to Sponsor and Clinvest.   
 
Included in the SAE Report Form will be an assessment of the causal relationship 
between the Study IP and the SAE.  SAE’s will be followed by study staff until the 
event(s) have returned to normal, stabilized, or have been otherwise explained, for at least 
2 weeks following the last dose of study drug. 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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If the investigator learns of any SAEs after a subject has been discharged from the study 
and he/she considers the event reasonably related to the investigational product, the 
investigator will notify Clinvest. 
 
24 SAFETY MONITORING RULES 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance: At any time during the Study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens.  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  For stopping rules, if the initial 
laboratory result is observed during the Treatment Period, the results from the retest must be 
available prior to administering the next dose of Study Drug (ISIS 546254 or placebo). 
Re-dosing Guidance:  Subjects with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, subjects who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and study drug 
manufacturer (Ionis Pharmaceuticals Inc.) should confer as to whether additional close 
monitoring of the subject is appropriate.  If any of the stopping criteria described below (Section 
25) are met, the subject will be permanently discontinued from further treatment with Study 
Drug, evaluated fully as outlined below and in consultation Ionis Pharmaceuticals or 
appropriately qualified designee, and will be followed up in accordance with Section 23 of the 
protocol. 
 
24.1 Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline, please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the Study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional, confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Subjects with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, ALP, INR and total bilirubin) retested at least once-weekly 
until ALT and AST levels become ≤ 1.2 x ULN ( or 1.2 x baseline value if the baseline value 
was > ULN). 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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Further Investigation into Liver Chemistry Elevations: For subjects with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was > 
ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody (ANA)) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with Ionis 
Pharmaceuticals.  Repetition of the above evaluations should be considered if a subject’s ALT 
and/or AST levels reach 5 x ULN. 
 
24.2 Safety Monitoring Rules for Platelet Count Results 
All patients will have platelet measures taken every two weeks for the duration of the study. 
 
24.3 Safety Monitoring for  Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically 
relevant, non-major bleeding events (which are defined below), for example excess bruising, 
petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the Investigator 
should notify Ionis Pharmaceuticles and additional testing of coagulation parameters (aPTT, PT, 
INR) and platelet count should be performed. 
24.3.1 Definition of Major Bleeding Events  
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with 
compartment syndrome, and/or 
3. Bleeding causing a fall in hemoglobin level of 2.0 mg/dL (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of two or more units of whole or red cells 
 
24.3.2 Definition of Clinically Relevant, Non-Major Bleeding Events  
 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitastaxis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
25 STOPPING RULES 
 
25.1 Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation, dosing of a subject with Study Drug will be stopped permanently; 
values that are not confirmed due failure to retest or missing lab values will be presumed 
confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the 
baseline value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR 
> 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the 
baseline value was > ULN), which is confirmed, and the new appearance (i.e. onset 
coincides with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or concomitant eosinophilia (> 
ULN) 
 
25.2 Renal Function Test Results 
In the event of laboratory results for either of the following criteria, dosing of a subject with 
Study Drug (ISIS 546254 or placebo) will be stopped permanently: 
1. Confirmed serum creatinine increase that is both ≥ 0.3 mg/dL (26.5 µmol/L) and ≥ 40% 
above Baseline creatinine values  
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
The follow-up schedule for any events meeting either of these stopping criteria will be 
determined by the Investigator in consultation with Ionis Pharmaceuticals or designee. 
 
25.3 Platelet Count Results 
In the event of a confirmed platelet count less than 100,000/mm3, dosing of a subject with Study 
Drug (ISIS 546254 or placebo) will be stopped permanently.  The follow-up schedule for any 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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events meeting this stopping criterion will be determined by the Investigator in consultation with 
Ionis Pharmaceuticles or designee. 
 
26 PREGNANCY 
All pregnancies of women participating in the study that occur during the study, are to be 
reported immediately, and the site must complete the pregnancy form. 
 
Any female patient becoming pregnant during the study will immediately discontinue the study 
drug. All 
patients who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous or voluntary termination). If the pregnancy continues to term, the outcome (health 
of the infant up to 8 weeks of age), including details of birth and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the investigator becomes aware of after termination from the study will be reported as an 
adverse event or serious adverse event, as appropriate. 
If the pregnancy does not continue to term, 1 of the following actions will be taken: 
 
1. For a spontaneous abortion, report as a serious adverse event. 
2. For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
3. For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
For pregnancies of partners of men participating in the study, Clinvest will determine the 
procedure to appropriately follow up after notification as described above. All partners who 
become pregnant and provide appropriate consent will be monitored until the completion or 
termination of the pregnancy. 
 
27 CLINICAL SUPPLIES 
Clinical supplies will be packaged for subjects in accordance to an allocation schedule generated 
by Clinvest.   
 
28 STORAGE REQUIREMENTS 
The study drug and clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
designated staff have access.  Clinical supplies and medications are to be dispensed only as 
defined in the protocol.  It is the Investigator’s responsibility to keep accurate records of the 
supplies received, the amount dispensed to and returned by subjects, and the remaining amount 
at the end of the study.  Study staff should not open individual study drug containers prior to 
dispensing to the subject.   
 
Study drug will be inventoried and accounted for throughout the study.  Drug Accountability will 
be maintained for subjects randomized in the study.  Unblinded study staff will record the 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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amount of study drug dispensed and amount returned at each appropriate office visit.  Any 
missing devices or discrepancies will be addressed and reconciled as needed. 
 
Study drug should be kept in a secure location and stored according to the package insert.    
 
The study drug storage area at the site must be monitored by the site staff for temperature 
consistency with the acceptable storage temperature range specified on study drug temperature 
log.  Documentation of temperature monitoring should be maintained.   
 
29 CONFIDENTIALITY 
By signing this protocol, the investigator affirms to Clinvest information furnished to the 
Investigator by Clinvest will be maintained in confidence.  Likewise, data generated by this 
study will be considered confidential by the Investigator, with the exception of information 
included in a publication or information shared with Ionis Pharmaceuticals.   
 
The Investigator also agrees that Clinvest, Institutional Review Board (IRB), or Regulatory 
Agency representatives may consult and/or copy study documents in order to verify data.  By 
signing the consent form, the subject agrees to this process.  Signing of this protocol also means 
the Investigator agrees to treat all subject data used and disclosed in connection with this study in 
accordance will all applicable privacy laws, rules and regulations, including applicable 
provisions of Health Insurance Portability and Accountability Act (HIPPA).   
 
30 COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT 
By signing the protocol, the Investigator agrees to conduct the study in a diligent manner and in 
conformance with the protocol, standards of the Declaration of Helsinki under its most recent 
amendment and including Good Clinical Practice (GCP) according to the International 
Conference on Harmonisation (ICH) guidelines, and all applicable federal, state, and local laws, 
rules and regulations relating to the conduct of the clinical study.   
 
Prior to trial initiation, the Investigator at each site will provide Clinvest a fully executed and 
signed Food and Drug Administration (FDA) Form 1572 and curriculum vitae (CV). 
 
The Investigator also agrees to allow monitoring, audits, IRB review, and regulatory agency 
inspection of trial-related documents and procedures.  Centralized monitoring will be performed 
to verify accuracy of data entered into the electronic data capture system (EDC).   
 
Additionally, the Investigator agrees not to seek reimbursement from subjects, their insurance 
providers, or from government programs for procedures included as part of the study that are 
reimbursed by Clinvest.   
 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on Clinvest studies.  The Investigator will 
immediately disclose in writing to Clinvest if any person who is involved in study conduct is 
debarred, or if any proceeding for debarment is pending or threatened.   

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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31 QUALITY CONTROL/ASSURANCE 
It is Clinvest’s responsibility for implementing and maintaining quality control and assurance 
with written standard operating procedures (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 provided to 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 the sponsor, or their designee, with the investigator, institution and/or with 
any other parties involved with clinical trial should be in writing in a separate agreement. 
 
The investigator agrees to be responsible for the integrity of all study conduct at their site.   
 
During the trial Clinvest will conduct remote monitoring and safety oversight periodically.  The 
clinical monitors may review eCRFs, etc. 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 study will be registered on www.clinicaltrials.gov by Clinvest. 
   
32 STUDY DOCUMENTATION  
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.  Sites 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 and the ICF, 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.   

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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33 RECORD RETENTION 
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.  Patient 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 (CRF) are complete and accurate. 
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 Visit 1, randomized at Visit 2, 
additional visits conducted during study, and completion/discontinuation information. 
6. Clinvest will maintain a Drug Assignment Log.  This log will record chronologically 
study drug received, as well as drug returned or destroyed at the completion of the 
study. 
7. Investigator will maintain a Site Drug Accountability Record.  This record will record 
chronologically study drug received from the Sponsor, as well as drug 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 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 Ionis Pharmaceuticals and Clinvest.   
 
34 INSTITUTIONAL REVIEW BOARD 
Clinvest is responsible for obtaining IRB approval of the protocol, informed consent document, 
written information provided to the subject, recruiting material, and all other appropriate 
documents.  The trial will not be initiated until IRB approval of all trial documents.  The 
investigator will provide Ionis Pharmaceuticals with documentation that the IRB has approved 
(such as the protocol, informed consent, and any study-related materials to be provided to the 
subject) before the study drug is shipped to the sites and study begins.  In the event an 
amendment is needed to any document, Clinvest will also be responsible for the approval of all 
subsequent major changes.  The investigator is responsible for obtaining initial and continuing 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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review (annually if necessary) of the study by an IRB.  Written approval must be forwarded to 
Clinvest before clinical supplies will be shipped.  For continuing studies, written approval from 
the IRB must be sent to Clinvest at intervals not to exceed 1 year.  All other appropriate reports 
on the progress of the study will be made to the IRB and the Sponsor by Clinvest in accordance 
with applicable governmental regulations and in agreement with the policy established by the 
Sponsor and the IRB.  
  
35 TRAINING 
Each approved study site will participate in a protocol training program prior to enrollment of 
any subjects in the study.  The program must be attended by the principal investigator at the site, 
and at least one research coordinator, including the coordinator who will have the lead 
responsibility for coordination of the study at the site. 
 
Comprehensive training will be provided by Clinvest to site personnel.  Training topics will 
include protocol, study design, study documents, electronic data capture system, reporting of 
AEs and pregnancy, and any other study related tasks.   
 
36 SAFETY MEASURES 
 
36.1 Adverse Events 
Adverse events (AEs) will be monitored throughout the study. All reported AEs will be 
documented on the appropriate eCRF. 
 
36.2 Physical Examination 
At screening and study exit, the investigator will examine the patient for any detectable 
abnormalities of the following body systems: general appearance; neck (including thyroid); head, 
eyes, ears, nose, and throat; lungs; heart/cardiovascular; abdomen; neurologic; extremities; back; 
musculoskeletal; lymphatic; skin; and other. The neurologic examination should be conducted to 
detect the presence of any significant sensory/motor abnormalities. A digital rectal examination 
is not required. Gynecological examinations are not required. 
 
Weight should be measured at screening, day 1, and end of study visit using the same scale for 
all patients at a given investigator site when possible. 
 
Pregnancy tests for all females of childbearing potential.  Urine pregnancy testing will be 
conducted at screening, on day 1, and at the end of study visit to confirm continued non-pregnant 
status prior to study drug administration or study completion.  
 
36.3 Vital Signs 
Vital signs will be measured at all study visits.  Systolic and diastolic blood pressure and pulse 
rate over 30 seconds should be taken after patients have been at rest (seated) for at least 2 
minutes. Blood pressure should be recorded in mmHg. Pulse rate should be measured in beats 
per minutes.  
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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36.4 ECG  
Twelve-lead ECG will be performed at the study site, per institutional guidelines, at all study 
visits. At each of these visits, 1 ECG reading will be collected and will be reviewed by the 
investigator. The overall interpretation and determination of the clinical relevance of ECG 
findings will be the responsibility of the investigator and will be recorded in the patient’s eCRF. 
 
36.5 Laboratory Assessments 
Laboratory assessment samples are to be obtained at designated visits as detailed in the Schedule 
of Assessments.  
 
36.6 List of Laboratory Analytes 
 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 546254 or other similar 
oligonucleotides 
 
 
 
Table 2.  Laboratory assessments  
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Cholesterol 
• Uric Acid 
• Total bilirubin 
• Direct bilirubin 
(conjugated) 
• Indirect bilirubin 
(unconjugated) 
• ALT 
• AST 
Screening Tests 
• Hepatitis B 
surface antigen 
• Hepatitis C 
antibody 
• HIV antibody 
• Drug/EtOH 
• C1 Esterase 
Inhibitor 
Functional 
Activity 
• Thyroid Panel 
 
Females only 
• FSH  
• Serum βhCG 
• Urine 
Pregnancy 
 
Coagulation 
• aPTT (sec)  
• PT (sec) 
• INR 
 
 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, 
MCHC 
• Platelets 
• White blood cells 
• WBC Differential  
(% and absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
 
Pharmacokinetics 
1. 
ISIS 546254 
levels in plasma 
Inflammatory 
1. Hs-CRP  
 
Urinalysis 
• Color 
• Appearance 
• Specific gravity 
• pH 
• P/C Ratio 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Bilirubin 
• Leukocyte 
esterase 
• Nitrate 
• Microscopic 
examination1 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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• Alkaline 
phosphatase 
• Creatinine kinase 
• GGT 
 
1 Will be performed on abnormal findings unless otherwise specified
 
Hematology, clinical chemistry, urinalysis laboratory, urine drug screen, HIV, HbsAg, and HCV 
serology will be performed at sites local laboratory. Plasma samples for anti-drug-antibody 
screening will also be collected and stored for potential future analysis. Reference ranges will be 
supplied by local laboratory and used by the Investigator to assess the laboratory data for clinical 
significance and pathological changes. 
 
37 FUTURE BIOMEDICAL RESEARCH 
Blood samples will be collected from all patients who consent to participate in the optional 
Future Biomedical Research substudy. If possible, the samples to be used in the substudy will 
be obtained at the same time that the patient is scheduled to have blood drawn for clinical 
laboratory assessments as required at the Screening visit for the main study. All samples 
collected for the substudy will be sent to the designated central laboratory and later shipped 
to a biorepository for storage. Samples collected for the substudy may be stored at the 
biorepository for potential analysis under separate protocols for up to 15 years. Substudy samples 
may be stored for a longer time if a regulatory or governmental authority has active questions 
that are being answered. In this special  circumstance, such substudy samples will be stored until 
these questions have been adequately addressed. 
All patients enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research substudy; however, participation is optional and will require a separate 
informed consent form. A patient who initially consents can withdraw that consent at any 
time and have his or her substudy sample destroyed, including any by-products of the 
sample. 
 
38 SUMMARY OF METHODS OF DATA COLLECTION 
Data required for the evaluation of the primary and some secondary measures will be recorded 
by subjects using a daily e-diary.  The following data will be collected daily with the e-diary: 
• 
Onset and duration of headache  
• 
Severity of headache (mild, moderate, or severe)  
• 
Acute headache medication(s) usage  
• 
Study drug usage 
• 
Associated symptoms 
• 
Unusual symptoms 
 
Questionnaire data required to be directly collected from subject will be obtained at each 
appropriate visit using an electronic device as defined in the protocol.  Questionnaires are to be 
completed by the subject and the answers to the questions on the questionnaires should come 
directly form the subject directly, not from family, friend or the study personnel.   
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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Questionnaire data required to be collected directly from clinicians will be obtained at the 
appropriate visit and recorded in the eCRF per protocol.   
 
39 STATISTICAL ANALYSIS 
Subjects will be randomized 1:1 into the treatment groups.  Randomization will not include any 
type of stratification.   
 
An alpha of .05 will be used for statistical significance. All statistical tests will be two-tailed.   
Descriptive statistics will establish baseline characteristics and adverse event frequency.  Data 
for the safety primary endpoint will be statistically analyzed via Chi-squared analyses and a 2-
tailed Repeated Measures ANOVA for the efficacy primary endpoint.  Data for each of the 
secondary outcome measures will be statistically analyzed via a 2-tailed Repeated Measures 
ANOVA, chi-squared, and/or independent or dependent t-tests as appropriate.  All ANOVAs 
will be followed by univariate post-hoc tests as appropriate. Multiple comparison adjustments 
will be made if needed. 
 
39.1 Modified Intent-to-Treat Population (mITT) 
The modified intent-to-treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug and obtained at least one primary endpoint 
measurement after treating.  The mITT population will be used for efficacy analyses. 
39.2 Safety Population 
The safety population will include all randomized subjects who received at least one dose 
of study drug. 
 
A last observation carried forward (LOCF) method will be utilized to impute missing 
values within a single headache diary.  This type of imputation replaces the missing value 
with the last observation value obtained. If an e-diary day is not recorded, the day will be 
considered a non-headache day.   
 
40 PRIMARY ENDPOINTS 
1. Compare the number of adverse events and laboratory abnormalities through the study 
for subjects treated with ISIS 546254 vs. placebo. 
2. Compare the efficacy of ISIS 546254 in the preventive treatment of chronic migraine, 
measured by mean change in the monthly migraine days comparing baseline to the final 
month of the 4-month treatment period for subjects treated with ISIS 546254 vs. placebo. 
41 SECONDARY ENDPOINTS  
1. Evaluate the efficacy of ISIS 546254 in the preventive treatment of chronic migraine, 
measured by mean change in the monthly headache severity comparing baseline to the 
final month of the 4-month treatment period for subjects treated with ISIS 546254 vs. 
placebo. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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2. Compare the efficacy of ISIS 546254 in the preventive treatment of chronic migraine, 
measured by mean change in the monthly headache days comparing baseline to the final 
month of the 4-month treatment period for subjects treated with ISIS 546254 vs. placebo. 
3. Compare the proportion of patients meeting 50% response criteria, response defined as a 
≥ 50% reduction in the number of headaches from baseline to the final month of the 4-
month treatment period for subjects treated with ISIS 546254 vs. placebo. 
4. Compare the change in frequency in the number of headache days requiring use of 
medication for the treatment of migraine or headache pain (i.e., acute and rescue or 
breakthrough medication use) from baseline to the final month of the 4-month treatment 
period for subjects treated with ISIS 546254 vs. placebo. 
5. Compare change from baseline to the final month of the 4-month treatment period in the 
Migraine Specific Quality of Life (MSQ) Questionnaire for subjects treated with ISIS 
546254 vs. placebo. 
6. Compare the end of treatment month 4 in the physician global impress of change (PGIC) 
for subjects treated with ISIS 546254 vs. placebo. 
7. Compare the end of treatment month 4 in the subjects’ global impression of change 
(SGIC) for subjects treated with ISIS 546254 vs. placebo.  
 
42 COLLECTION AND DERIVATION OF ENDPOINTS 
Data required for the evaluation of endpoints will be recorded for the duration of the study using 
electronic data capture and include subject reported outcomes.  The headache variables will be 
derived from variables collected daily using an electronic headache diary.  On each day, the 
subject will be asked to record their diary data for the previous 24-hour period.    
 
42.1 Primary Efficacy Variable 
1. The variable used to measure mean change in migraine days will be derived from 
subjects self-reported data entered into the e-diary.  It will be based on the number of 
days with migraine headaches, fulfilling ICHD-3 beta criteria, and/or headaches of any 
duration with the use of migraine-specific acute headache medication(s). 
42.2 Secondary Efficacy Variables 
1. The variable used to measure mean change in headache severity will be derived from 
subjects self-reported data entered into the e-diary.  It will be based on the severity 
recorded for each headache.   
2. The variable used to measure mean change in headache days will be derived from 
subjects self-reported data entered into the e-diary. It will be based on the number of days 
recorded as headache. 
3. The variable used to measure the proportion of subjects experiencing a 50% reduction in 
the number of headaches will be derived from subjects self-reported data entered into the 
e-diary. It will be based on the number of days recorded as headache. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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4. The variable used to measure change in frequency of headache days requiring medication 
usage will be derived from subjects self-reported data entered into the e-diary. It will be 
based on the total number of days that any acute, rescue, or breakthrough medication use 
is recorded in the e-diary. 
5. The variable used to measure  change in the MSQ score will be derived from the total 
score on the MSQ subject questionnaire.   
6. The variables used to measure PGIC and SGIC scores will be derived from the total score 
on the PGIC and SGIC subject questionnaires.      
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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43 APPENDIX A 
Proposed Revised International Headache Society Criteria 
for Migraine Without and With Aura 
Headache Classification Committee: J Olesen, et al. The International Classification of 
Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. 
 
1.1 Migraine without aura 
Description: 
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. 
 
Diagnostic criteria: 
A. At least five attacks1 fulfilling criteria B–D 
B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) 
C. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g. walking or 
climbing stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 
 
1.2 Migraine with aura 
Description: 
Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central 
nervous system symptoms that usually develop gradually. 
 
Diagnostic criteria: 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
C. At least two of the following four characteristics: 
1. at least one aura symptom spreads gradually over 5 minutes, and/or two or more 
symptoms occur in succession 
2. each individual aura symptom lasts 5-60 minutes 
3. at least one aura symptom is unilateral 
4. the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
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    been excluded. 
44 APPENDIX B 
Proposed Revised International Headache Society Criteria 
for Chronic Migraine 
Headache Classification Committee: J Olesen, et al. The International Classification of 
Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. 
 
1.3 Chronic migraine 
Description: 
Headache occurring on 15 or more days per month for more than 3 months, which has the 
features of migraine headache on at least 8 days per month. 
 
Diagnostic criteria: 
A. Headache (tension-type-like and/or migraine-like) on ≥15 days per month for >3 months 
and fulfilling criteria B and C 
B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 
Migraine without aura and/or criteria B and C for 1.2 Migraine with aura 
C. On ≥8 days per month for >3 months, fulfilling any of the following: 
1. criteria C and D for 1.1 Migraine without aura 
2. criteria B and C for 1.2 Migraine with aura 
3. believed by the patient to be migraine at onset and relieved by a triptan or ergot 
derivative 
D. Not better accounted for by another ICHD-3 diagnosis. 
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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45 APPENDIX C 
Proposed Revised International Headache Society 
Criteria for Medication-Overuse Headache 
Headache Classification Committee: J Olesen, et al. The International Classification of 
Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013, 33:629-808. 
 
8.2 Medication-overuse headache (MOH) 
Description: 
Headache occurring on 15 or more days per month developing as a consequence of regular 
overuse of acute or symptomatic headache medication (on 10 or more, or 15 or more days per 
month, depending on the medication) for more than 3 months. It usually, but not invariably, 
resolves after the overuse is stopped. 
 
General comment: 
In the criteria set out below for the various subtypes, the specified numbers of days of 
medication use considered to constitute overuse are based on expert opinion rather than on 
formal evidence. 
 
Diagnostic criteria: 
A. Headache occurring on >15 days per month in a patient with a pre-existing headache 
disorder 
B. Regular overuse for >3 months of one or more drugs that can be taken for acute and/or 
symptomatic treatment of headache 
C. Not better accounted for by another ICHD-3 diagnosis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
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46 REFERENCES 
 
Baker BF, Monia BP. Novel mechanisms for antisense-mediated regulation of gene expression. 
Biochim Biophys Acta. 1999 Dec 10;1489(1):3-18. 
Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to 
chronic migraine: a longitudinal population-based study. Headache 2008; 48(8):1157–1168. 
Björkqvist J, Jansa A, Renne T. Plasma Kallikrein: the bradykinin-producing enzyme. Thromb 
Haemost 2013; 110: 399-407. 
 
Burstein R and Jakubowski M. Implications of multimechanism therapy: When to treat? 
Neurology 2005; 64(Suppl. 2):S16-S20. 
Buse DC, Manack A, Serrano D, et al. Sociodemographic and comorbidity profiles of chronic 
migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry 2010; 81(4):428–432. 
Ceruti, S, Villa G, Fumagalli M, et al. Calcitonin Gene-Related Peptide-Mediated Enhancement 
of Purigenic Neuron/Glia Communication by the Alogogenic Factor Bradykinin in Mouse 
Trigeminal Ganglia from Wild-Type and R192QCav2.1 Knock-In Mice: Implications for basic 
Mechanisms of Migraine Pain. J Neurosci 2011; 31(10): 3638-3649. 
Chi KN, Eisenhauer E, Fazli L, et al. A phase I pharmacokinetic and pharmacodynamic study of 
OGX-011, a 
2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. 
J Natl Cancer Inst. 2005 Sep 7;97(17):1287-1296. 
Chung J-Y and Kim M. Migraine-like Headache in a Patient with Complement 1 Inhibitor 
Deficient Hereditary Angioedema. J Korean Med Sci 2012; 27: 104-106. 
Crooke ST, Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol 
Toxicol. 1996;36:107-129. 
 
Coppola G, Pierelli F, Schoene J. Is the cerebral cortex hyperexcitable or hyperresponsive in 
migraine? Cephalalgia 2007; 27(12): 1427–1439. 
Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ, Group T-M-S. 
Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-
controlled study. Cephalalgia 2007; 27(7):814–823. 
Diener H-C, Dodick DW, Goadsby PJ, et al. Chronic migraine—classification, characteristics 
and treatment. Nat. Rev Neurol 2012; 8: 162–171. 
Engeli R. From Hereditary Angioedema to Migraine. Department of Chemistry and Applied 
BioSciences.  Vol Diploma. Zurich: ETH Zurich, 2004. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 53 of 54 
Fuller-Thomson E, Schrumm M, Brennenstuhl S. Migraine and despair: factors associated with 
depression and suicidal ideation among Canadian migraineurs in a population-based study. 
Depress Res Treat 2013: 401487. 
Gangadha M, Mishra RK, Sriram D, Yogeeswari P. Future Directions in the Treatment of 
Neuropathic Pain: A Review on Various Therapeutic Targets. CNS & Neurologic Disorders – 
Drug Targets 2014; 13: 63-81. 
Hoxha M, Meta D, Kalo T. Hereditary angioedema as a potential cause of cerebral edema. 
Otorhinolaryngologia - Head and Neck Surgery #51, January - February - March 2013, pgs 31-
34. 
Kastelein JJ, Wedel MK, Baker BF, t al. Potent reduction of apolipoprotein B and low-density 
lipoprotein 
cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. 
Circulation. 2006 Oct 17;114(16):1729-1735. 
Linhart O, Obreja O, Kress M. The inflammatory mediators serotonin, prostaglandin E2 and 
bradykinin evoke calcium influx in rat sensory neurons. Neuroscience.  2003; 118:69-74. 
Manack A, Buse DC, Serrano D, et al. Rates, predictors, and consequences of remission from 
chronic migraine to episodic migraine. Neurology 2011; 76(8):711–718. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2'-modified oligonucleotides containing 
2'-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem. 1993 Jul 
5;268(19):14514-14522. 
Paemeleire K, Louis P, Magis D, et al. Diagnosis, pathophysiology and management of chronic 
migraine: a proposal of the Belgian Headache Society Acta Neurol Belg; 27 June 2014 
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of 
endothelium-derived relaxing factor. Nature 1987; 327:524-6. 
Petho G and Reeh PW. Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-
Activating Factor, and Nitric Oxide in Peripheral Nociceptors. Physiol Rev 2012; 90:1699-1775. 
Revenko AS, Gao D, Crosby JR, et al.  Selective depletion of plasma prekallikrein or 
coagulation factor 
XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 2011 Nov 
10;118(19):5302-5311. 
Sharma JN, Al-Banoon A.  The Role of Inflammatory Mediator Bradykinin in Coardiovascular 
and Renal Diseases. Open Access Sci. Rep. 1:142 
 
Silberstein SD, Lipton RB, Dodick DW, et al; for Topiramate Chronic Migraine Study Group. 
Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-
blind, placebo-controlled trial.  Headache 2007; 47(2):170–180. 
Stovner L, Zwart J, Hagen K, et al. Epidemiology of headache in Europe. Eur J Neurol 2006; 13: 
333–345. 

Protocol No.: 15-001IS 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of ISIS 546254 for Preventive Treatment of Chronic Migraine 
Date: 12-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 54 of 54 
Stovner Lj, Hagen K, Jensen R, et al. The global burden of headache: a documentation of 
headache prevalence and disability worldwide. Cephalalgia 2007; 27(3): 193–210. 
Supowit SC, Zhao H, Katki KA, et al. Bradykinin and prostagliandin E1 regulate calcitonin gene-
related peptide expression in cultured rat sensory neurons. Regulatory Peptides 2011; 167:105-
111.