To Examine the Effect of Horizant (Gabapentin Enacarbil) in Primary Restless Legs Syndrome (RLS) Patients Who Are on Dopaminergic Agents and Exhibiting Augmentation
Phase: NA
Conditions: Restless Legs Syndrome
Sponsor: University of Missouri-Columbia

Horizant in RLS patients exhibiting augmentation:  
 
 
December 8, 2017 
 
 
 
 
CONFIDENTIAL 
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Investigator Initiated Trial (IIT) 
 
 
 
 
 
 
 
PROTOCOL TITLE: To examine the effect of Horizant (Gabapentin Enacarbil) in 
primary Restless legs syndrome (RLS) patients who are on dopaminergic agents and 
exhibiting augmentation. 
 
PROTOCOL NUMBER: XP-IIT-0034 
 
 
ORIGINAL DATE: 10 DECEMBER 2014 
 
AMENDMENT 1: 9 SEPTEMBER 2015 
AMENDMENT 2: 16 OCTOBER 2015 
AMENDMENT 3: 3 DECEMBER 2015 
AMENDMENT 4: 18 MAY 2016 
AMENDMENT 5: 06 JULY 2016 
AMENDMENT 6: 18 NOVEMBER 2016 
AMENDMENT 7: 03 FEBRUARY 2017 
AMENDMENT 8: 08 December 2017 
 
INVESTIGATOR:   PRADEEP SAHOTA, MD 
 
 
AFFILIATION: UNIVERSITY OF MISSOURI-COLUMBIA – SCHOOL OF 
MEDICINE 
 
 

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TABLE OF CONTENTS 
 
1 
CONTACT LIST .................................................................................................................. 4 
1.1 
INVESTIGATOR PERSONNEL ............................................................................................. 4 
1.2 
XENOPORT INC PERSONNEL ............................................................................................. 5 
2 
ACRONYMS AND ABBREVIATIONS ............................................................................. 6 
3 
STUDY FLOW CHART ...................................................................................................... 7 
4....................................................................................................................................................... 7 
4. SUMMARY ............................................................................................................................... 8 
5.1 STUDY RATIONALE: ............................................................................................................. 10 
6.1 STUDY DESIGN: .................................................................................................................... 11 
7. 
STUDY POPULATION: .................................................................................................... 14 
7.1 
NUMBER OF SUBJECTS: 20  (WE BELIEVE THAT WE WILL BE ABLE TO RECRUIT ONLY 20 
ELIGIBLE SUBJECTS DURING THE ONE YEAR ENROLLMENT  PERIOD) ........................................... 14 
7.2 
INCLUSION CRITERIA: .................................................................................................... 14 
7.3 
EXCLUSION CRITERIA: ................................................................................................... 14 
7.4 
MEDICAL HISTORY EXCLUSIONS: AS PER EXCLUSION CRITERIA .................................... 15 
7.5 
TREATMENT HISTORY INCLUSIONS OR EXCLUSIONS: AS PER INCLUSION AND EXCLUSION 
CRITERIA .................................................................................................................................... 15 
7.6 
MISCELLANEOUS : NOT APPLICABLE .............................................................................. 15 
7.7 
SCREENING LOG: WILL BE MAINTAINED ......................................................................... 15 
8. 
STUDY MEDICATION, DESCRIPTION, AND ALLOCATION ................................ 15 
8.1 
HORIZANT STABILITY & STORAGE ................................................................................ 15 
8.6 
TREATMENT SCHEDULE: AS PER STUDY DESIGN. ............................................................ 16 
8.7 
MODIFICATION OF TREATMENT SCHEDULE FOR HORIZANT: .......................................... 16 
8.8 
MODIFICATION OF TREATMENT SCHEDULE FOR OTHER STUDY DRUG : AS PER PROTOCOL.
 
16 
8.9 
DISCONTINUATION OF SUBJECTS FROM INVESTIGATIONAL TREATMENT OR FROM THE 
STUDY 16 
8.10 
DISCONTINUATION OF STUDY DRUG: ............................................................................. 16 
8.11 
TREATMENT COMPLIANCE ............................................................................................. 16 
8.12 
CONCOMITANT THERAPY ............................................................................................... 16 
8.13 
RECORDING CONCOMITANT MEDICATION: MEDICATION RECONCILLIATION WILL BE 
PERFORMED BY STUDY SUPPORT STAFF/PERSONNEL AND CONFIRMED BY INVESTIGATOR DURING 
EACH CLINIC VISIT ...................................................................................................................... 17 
8.14 
EXTENSION STUDY: NOT APPLICABLE ........................................................................... 17 
9. 
SCHEDULE OF EVENTS ................................................................................................. 17 
9.2 
STUDY SITE PERSONNEL AND RESPONSIBILITIES: .......................................................... 17 
10. EFFICACY ASSESSMENTS ............................................................................................. 17 

Horizant in RLS patients exhibiting augmentation:  
 
 
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10.1 
CLINICAL EFFICACY ASSESSMENTS INCLUDE DOCUMENTING ASRS, IRLS, RLS-QOL 
AND MOS-SS EACH VISIT. ......................................................................................................... 17 
10.2 
LABORATORY EFFICACY OR SAFETY ASSESSMENTS ...................................................... 17 
11 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS – DEFINITION & 
REPORTING .............................................................................................................................. 18 
11.1 
DEFINITIONS .................................................................................................................. 18 
11.2 
INVESTIGATOR RESPONSIBILITIES .................................................................................. 20 
11.3 
ADDITIONAL PROCEDURES ............................................................................................ 21 
11.4 
SUBJECT INFORMATION AND CONSENT .......................................................................... 21 
11.5 
SUBJECT DATA PROTECTION .......................................................................................... 21 
12 ETHICAL REQUIREMENTS .......................................................................................... 21 
12.1 
DECLARATION OF HELSINKI ........................................................................................... 21 
12.2 
ETHICS COMMITTEE ....................................................................................................... 21 
13 ADMINISTRATIVE PROCEDURES .............................................................................. 22 
13.1 
INVESTIGATIONAL SITE INITIATION VISIT ...................................................................... 22 
13.2 
INVESTIGATOR FILE ....................................................................................................... 22 
13.3 
MONITORING OF THE STUDY .......................................................................................... 22 
13.4 
QUALITY ASSURANCE .................................................................................................... 22 
13.5 
STUDY FUNDING ............................................................................................................ 22 
14 FURTHER REQUIREMENTS AND GENERAL INFORMATION ............................ 23 
14.1 
EXTERNAL SERVICE ORGANIZATIONS –NOT APPLICABLE .............................................. 23 
14.2 
STUDY COMMITTEES–NOT APPLICABLE ........................................................................ 23 
14.3 
CHANGES TO FINAL STUDY PROTOCOL .......................................................................... 23 
14.4 
RECORD RETENTION ...................................................................................................... 23 
14.5 
REPORTING AND COMMUNICATION OF RESULTS ............................................................ 23 
14.6 
PROTOCOL COMPLETION ................................................................................................ 23 
15 
REFERENCES ............................................................................................................. 25 
15.1 
APPENDIX I: SIGNED AGREEMENT OF THE STUDY PROTOCOL ........................................ 25 
15.2 
APPENDIX II: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ................. 26 
15.3 
APPENDIX IV: MEDWATCH SERIOUS ADVERSE EVENT REPORTING – FORM 3500 ..... 30 
 
 

Horizant in RLS patients exhibiting augmentation:  
 
 
December 8, 2017 
 
 
 
 
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1 
CONTACT LIST 
1.1 
Investigator Personnel 
 
Principal Investigator: Pradeep Sahota, MD 
 
Office: Department of Neurology, University of Missouri (Columbia)-School of Medicine   
 
Phone : 573-882-2742 
 
Fax:    573-884-4249 
 
 
E-Mail: sahotap@missouri.edu 
 
 
 
 
 
Co-Investigator: Manjamalai Sivaraman, MD 
Office: Department of Neurology, University of Missouri (Columbia)-School of Medicine  
Phone: 573-882-8668  
Fax:     573-884-4249  
 
 
 
E-Mail: sivaramanm@missouri.edu  
 
 
 
                                                                
Study Coordinator: Liyan Yin, RN 
 
Office: Department of Neurology, University of Missouri (Columbia)-School of Medicine   
Phone : 573-884-0164   
Fax:      573-884-4249 
E-Mail: Yinliya@health.missouri.edu 
 
 
 
 
Contract Specialist: Harriet Francis 
E-mail: francish@missouri.edu 
Phone number: 573-884-0374 
 
 
 
 
 
 

Horizant in RLS patients exhibiting augmentation:  
 
 
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1.2 
XenoPort Inc personnel 
 
Gwendoline Y. Shang, MD 
XenoPort Inc 
3410 N. Central Expressw 
Santa Clara, CA 95051 
 
 
Medical Science Liaison:   
Panna Patel, Pharm D 
 
 
 
E-Mail : Panna.patel@xenoport.com 
 
 

Horizant in RLS patients exhibiting augmentation:  
 
 
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2 
ACRONYMS AND ABBREVIATIONS 
PI = Principal Investigator 
Subject = Patient = Study Participant 
RLS = Restless Legs Syndrome 
IRLS = International Restless Legs Syndrome-Rating Scale 
ASRS = Augmentation Severity Rating Scale 
RLS-QOL = Restless legs Syndrome–Quality of Life 
MOS-SS = Medical Outcome Study–Sleep Scale 
DA = Dopaminergic Agents 
SSRIs = Selective Serotonin Reuptake Inhibitors 
CBC with differential = Complete Blood Count with differential 
CMP = Comprehensive Metabolic Panel 
FDA = Food and Drug Administration 
 
 
 
 

Horizant in RLS patients exhibiting augmentation:  
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3 
STUDY FLOW CHART 
 
 
Pre-Rx 
‘Screening 
Phase’ 
(duration 
= 15 days) 
Baseline 
Rx 
Phase 1  
Rx 
Phase 2 
  
 
 
 
 
 
 
 
Day 0 
+/-7 
Day 30 
+/-7 
 
Day 90 
+/-14 
 
Day 120 
+/-14 
 
Day 180 
+/-14 
Day  360 
+/-14  
 
Enrolment Period 
1 year 
 
 
 
 
 
 
 
Medical History**  
X 
 
X 
   X 
X 
X 
X 
X 
Concomitant 
Medication(s) 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
ASRS(*) 
X 
X 
X 
X 
X 
X 
X 
 
IRLS(*) 
X 
X 
X 
X 
X 
X 
X 
RLS-QOL(*) 
 
X 
X 
X 
X 
X 
X 
MOS-SS(+*) 
 
X 
X 
X 
X 
X 
X 
CBC and 
differential, CMP 
X 
 
X 
 
 
        
X 
Monitoring & 
Recording of 
Adverse Events  
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Urine pregnancy 
analysis  
X 
 
X 
   X 
X 
X 
X 
X 
Urine sample 
collection (drug 
screen) 
X 
 
 
    
 
 
 
 
Serum pregnancy 
analysis 
Serum Ferritin 
Level 
TBD 
TBD 
TBD 
TBD 
TBD 
TBD 
TBD 
Rx Phase 1 (Day 0-90) = Stable DA + Horizant 
Rx Phase 2 (Day 120-360) = DA taper/Horizant only 

Horizant in RLS patients exhibiting augmentation:  
                                                        December 8, 2017 
 
 
 
 
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+ = Subjects will also be requested to keep a sleep diary.  
* = See attachments.  
** = Medical history includes Interval history between clinic visits. 
4. SUMMARY 
 
Study Title: To examine the effect of Horizant (Gabapentin Enacarbil) in primary 
Restless legs syndrome (RLS) patients who are on dopaminergic agents and exhibiting 
augmentation. 
 
Objectives: 
The Primary objective: is to evaluate the efficacy of Dopamine combined therapy with addition 
of Horizant (600 mg, oral, once daily) for 90 days in the treatment of Augmentation. 
 
The Secondary objectives: is to evaluate the efficacy of Horizant (600 mg, oral, once daily) 
alone with Dopaminergic (DA) taper for up to 270 days in the treatment of Augmentation. 
 
Study Design:  
 
This is an Open label single arm study. The purpose of the study is to demonstrate the 
efficacy of Horizant in patients with RLS who exhibit augmentation while on Dopaminergic 
therapy. Adult patients (age 18-85 years) with diagnosis of primary RLS (diagnosed by study 
investigators) with augmentation on dopaminergic therapy will be screened for participation 
in the study. RLS diagnosis will be made by the study investigators using International RLS 
study group criteria. Patients with augmentation on dopaminergic therapy as defined by NIH 
2007 (refer to attachment) with ASRS of 5 to 15 will be offered to participate in the study. 
Inclusion and exclusion criteria are listed below. The study will be performed after approval 
of the Institutional Review Board of the University of Missouri. 
 
A total of 50 subjects will be entered into the study over a period of 1 year. Written consent 
will be obtained from all patients. After pre-participation evaluation for eligibility, subjects 
will be selected and enrolled in the study and followed for a total of 6 follow up visits (Days 
0, 30, 90, 120, 180, 360). Subjects Enrollment period will last up to 12 months. The total 
duration of study will be 24 months. 
 
Pubmed search (using words Horizant, Augmentation) pulled out several articles (see 
attachments) indicating Horizant is the “only FDA approved Non-Dopaminergic Drug” used 
in the treatment of RLS. Its predictable bioavailability, acceptable safety profile and no case 
reports of augmentation after its use, in the literature makes Horizant the best-suited drug for 
conducting a clinical drug trial focused on examining its potential benefit in RLS patients 
who developed augmentation. 
 
Abrupt withdrawal of DA agent can be potentially dangerous due to DA withdrawal 
symptoms including life-threatening Neuroleptic Malignant Syndrome. Therefore, Rx Phase 
1 and Rx Phase are designed to help improve subject tolerability. 

Horizant in RLS patients exhibiting augmentation:  
                                                        December 8, 2017 
 
 
 
 
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Therefore, during Rx Phase 1, Horizant (600 mg oral once daily at 5 pm) will be added on as 
an adjunct to all subjects’ along with stable dose of their current dopaminergic (DA) agent 
and both medications will be continued for a total period of 90 days from day 0 to day 90. 
 
At the 90th day follow-up visit, with initiation of Rx Phase 2, all subjects will be tapered off 
(by 50% reduction in dose each week) of their current dopaminergic agent while maintaining 
the same dose of Horizant and will be on Horizant monotherapy. All subjects will be 
followed for additional three follow up clinic visits (days 120, 180, 360). 
 
During this period all subjects will be monitored for symptoms of dopamine withdrawal or 
worsening of RLS or emergence of other symptoms which will be managed clinically by 
physicians. All subjects will continue to be on Horizant for the entire duration of this study 
with close follow up.  Of note, if deemed appropriate for reasons related to safety, 
tolerability, and continuation of the study, the PI, at his discretion, may modify the tapering 
schedule of the DA although every attempt will be made to adhere to the protocol specified 
schedule of DA tapering.  
 
During each clinic visit all subjects will undergo careful evaluations (by a physician) that will 
include: medical history such as appearance of any new health problems, any new symptoms/ 
adverse events between clinic visits, concomitant medication(s) history (medication 
reconciliation), physical examination with assessment of vital signs, ASRS, IRLS, RLS-
QOL, and MOS-SS.  
 
All subjects will undergo laboratory testing (CBC with Diff and CMP) during screening, on 
day 30 and day 360 (final clinic visit). In addition, urine sample will be collected at screen 
visit for illegal drug testing. Additional hematology and urine sample analysis for illegal drug 
will be performed as needed at the discretion of the investigators if an adverse event is 
reported by a subject. Serum Ferritin level will be performed as needed at the discretion of 
the investigators. 
 
Urine pregnancy screening is required for all females of childbearing potential at screen and 
each clinical visits, if positive, serum pregnancy test will be performed. Female subjects who 
have undergone surgical sterilization, who are post-menopausal (defined as age >50 and >1 
year of amenorrhea), who have medically documented ovarian failure (defined as age <50 
with serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine βHCG) do not need to undergo 
pregnancy screening. 
 
At study completion, appropriate statistical analysis will be performed to evaluate the 
outcomes. We plan to publish the findings and results of this study. 
 
Study Population:  
Primary RLS patients who developed augmentation on DA therapy and score of 5 to 15 on 
ASRS scale. 
We plan to recruit 50 patients; male and female, age 18-85 years. 

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Recruitment site is University of Missouri-Columbia. We may use advertisement(s) in the 
local media to recruit subjects. 
 
Outcome Parameters/Evaluation:  
The Primary outcome parameter:  
 
1) A reduction in the Augmentation Severity Rating Scale (ASRS)  
2) Improvement in the International Restless Legs Syndrome-Rating Scale (IRLS) 
3) Improvement in the Restless Legs Syndrome-Quality of Life (RLS-QOL) 
4) Improvement in the Medical Outcome Study-Sleep Scale (MOS-SS) 
 
     The Secondary outcome parameters:  
 
1) A reduction in the Augmentation Severity Rating Scale (ASRS)  
2) Improvement in the International Restless Legs Syndrome-Rating Scale (IRLS) 
3) Improvement in the Restless Legs Syndrome-Quality of Life (RLS-QOL) 
4) Improvement in the Medical Outcome Study-Sleep Scale (MOS-SS) 
 
Treatment Group: This is a Single Arm study. All subjects will receive Horizant 600 mg 
once daily. 
  
5. BACKGROUND 
5.1 Study Rationale: 
RLS is common condition that is usually treated with dopaminergic medications. 
Augmentation is the main complication during long-term DA treatment of RLS. It was first 
described in 1996 with overall increase in severity of RLS symptoms typically more severe 
than pre-dopaminergic therapy with earlier occurrence of symptoms and involvement of 
previously uninvolved extremities. It can be a very devastating experience in some patients. 
Augmentation is reported in up to 82% of people taking levodopa (Allen RP, Earley CJ. 
Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205-13) 
 
Features of Augmentation include earlier onset of RLS symptoms, increased severity of 
symptoms, reduced time before symptoms begin when resting, spread of symptoms to 
previously uninvolved body parts, and reduced effectiveness of medications including longer 
time before medication begins to work and less ability to decrease symptoms.  
 
Augmentation severity can be assessed by a validated scale, ASRS, in these patients. 
 
Management of Augmentation has not been studied in clinical trials. Presently, there is no 
approved medication (by FDA) to treat augmentation. In addition, currently, there are no 
specific practice guidelines as to how to treat augmentation. ‘More research is needed to 
identify the optimal approach for treating augmentation once it develops. Sudden withdrawal 
of the offending dopaminergic drug does not appear to be a well-tolerated strategy’ (Kurlan. 
Journal of Parkinsonism & Restless Legs Syndrome Vol 3, 49-52, 2013). 
 

Horizant in RLS patients exhibiting augmentation:  
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Pubmed search (conducted in Jan 2015, with key words “Horizant, Augmentation”)  revealed 
several articles (see attachments) suggesting that Horizant is the only FDA approved Non-
dopaminergic drug used in the treatment of RLS,  with  predictable bioavailability, 
acceptable safety profile and with any reports of augmentation. Therefore, we suggest that 
Horizant may be a best-suited drug to treat augmentation in RLS patients.  Thus, we propose 
to conduct a clinical drug trial to examine Horizant in RLS patients who developed 
augmentation. 
 
Abrupt withdrawal of DA agent can be potentially dangerous due to DA withdrawal 
symptoms including life-threatening Neuroleptic Malignant Syndrome. Therefore, to 
improve subject tolerability and minimize DA withdrawal, we have designed this clinical 
trial into 2 phases: Rx Phase 1 and Rx Phase 2 (described below) 
 
6. Objectives: 
The Primary objective: is to evaluate the efficacy of Dopamine combined therapy with addition  
of Horizant (600mg, oral, once daily) for 90 days in the treatment of Augmentation. 
 
The Secondary objectives: is to evaluate the efficacy of Horizant (600 mg, oral, once daily) alone 
       with Dopaminergic (DA) taper for up to 270 days in the treatment of Augmentation. 
6.1 Study Design:  
This is an Open label Single arm study. The purpose of the study is to demonstrate the 
efficacy of Horizant in patients with RLS who exhibit augmentation while on Dopaminergic 
therapy. Adult patients (age 18-85 years) with diagnosis of primary RLS (diagnosed by study 
investigators) with augmentation on dopaminergic therapy will be screened for participation 
in the study. RLS diagnosis will be made by the study investigators using International RLS 
study group criteria. Patients with augmentation on dopaminergic therapy as defined by NIH 
2007 (refer to attachment) with ASRS of 5 to 15 will be offered to participate in the study. 
Inclusion and exclusion criteria are listed below. The study will be performed after approval 
of the Institutional Review Board of the University of Missouri. 
 
A total of 50 subjects will be entered into the study over a period of 1 year. Written consent 
will be obtained from all patients. After pre-participation evaluation for eligibility, subjects 
will be selected and enrolled in the study and followed for a total of 6 follow up visits (Days 
0, 30, 90, 120, 180, 360). Subjects Enrollment period will last up to 12 months. The total 
duration of study is 36 months. 
 
There is no report of Augmentation due to Horizant use in the literature to this date. 
Therefore, initially Horizant (600 mg oral once daily at 5 pm) will be added on as an adjunct 
to all subjects’ along with stable dose of their current dopaminergic (DA) agent and both 
medications will be continued for a total period of 90 days from day 0 to day 90. 
 
At the 90th day follow-up visit, while maintaining the same dose of Horizant, all subjects 
will be tapered off (by 50% reduction in dose each week) of their current dopaminergic 
agent. Subsequently all subjects will be followed for additional three follow up clinic visits 
(days 120, 180, 360). During this period all subjects will be monitored for symptoms of 
dopamine withdrawal or worsening of RLS or emergence of other symptoms which will be 

Horizant in RLS patients exhibiting augmentation:  
                                                        December 8, 2017 
 
 
 
 
CONFIDENTIAL 
12 
managed clinically by physicians. If deemed appropriate for reasons related to safety, 
tolerability, and continuation of the study, the PI at his discretion may modify the tapering 
schedule of the DA although every attempt will be made to adhere to the protocol specified 
schedule of DA tapering. All subjects will continue to be on Horizant for the entire duration 
of this study with close follow up.  
 
During each clinic visit all subjects will undergo careful evaluations (by a physician) that will 
include: medical history such as appearance of any new health problems, any new symptoms/ 
adverse events between clinic visits, concomitant medication(s) history(medication 
reconciliation), physical examination with assessment of vital signs, ASRS, IRLS, RLS-
QOL, and MOS-SS.  
 
All subjects will undergo laboratory testing (CBC with Diff and CMP) during screening, on 
day 30 and day 360 (final clinic visit). In addition, urine sample will be collected at screen 
visit for illegal drug testing. Additional hematology and urine sample analysis for illegal drug 
will be performed as needed at the discretion of the investigators if an adverse event is 
reported by a subject.  Serum Ferritin level will be performed as needed at the discretion of 
the investigators. 
 
Urine pregnancy screening is required for all females of childbearing potential at screen and 
each clinical visits, if positive, serum pregnancy test will be performed. Female subjects who 
have undergone surgical sterilization, who are post-menopausal (defined as age >50 and >1 
year of amenorrhea), who have medically documented ovarian failure (defined as age <50 
with serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine βHCG) do not need to undergo 
pregnancy screening. 
 
Study Procedure 
If you agree to be in this study, you will sign this form before any study tests are done.  
Talk with your study doctor before starting any new medicine.  This includes medicines you 
buy at the drug store and herbal or dietary supplements (vitamins).  Some drugs, as well as 
alcohol, use can cause serious side effects if taken with the study drug.  
Please ask your study doctor if you have any questions about the medicine(s) you are taking.  
He/she will tell you which medicine you cannot take during the study.   
This study has four periods:  screening, treatment and maintenance and follow-up. 
 
Visit 1:  Screening Period, (prior to treatment with study drug)  
 
Before you begin taking study drug, subject will need to have the following tests to find out 
if you can be in the study.   
• 
Medical history: We will ask about your health and any illnesses and any medicines you 
are taking or have taken within the last 30 days (including over-the-counter medicine, 
vitamins or herbal supplements and how much caffeine you use weekly).  
• 
We will ask you about your current and prior Augmentation treatment, symptoms, your 
usual bedtime and awakening times. 

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• 
You and the staff will complete assessments on how you are feeling and if you have any 
thoughts about harming yourself.   
• 
Physical examination: You will have a full physical examination including neurological 
exam, height and weight. 
• 
Vital signs: You will have your temperature, heart rate, blood pressure, temperature and 
breathing rate collected.   
• 
Urine testing: You will collect a sample of urine for illegal drug screening and pregnancy 
testing.  
• 
Blood testing: We will collect blood samples (2 teaspoons or~10ml) for lab tests 
including hematology. Additional blood sample (~1/4 of teaspoon or 1.25ml) will be 
collected if you are a woman and your urine pregnancy test turn positive.  
• 
Augmentation severity rating scale (ASRS) – 3 item questionnaire to evaluate the 
severity of your augmentation symptom. 
• 
International restless legs syndrome-rating scale (IRLS) - a way to measure severity of 
your symptoms. 
• 
If you are a woman and can have children you must use a medically acceptable method of 
contraception which can include estrogen-progestin oral contraceptive pills, patches, or 
vaginal ring (if one of these methods is chosen it must have been used consistently for 2 
months prior to the first dose of study drug); progestin implant or injection; diaphragm with 
spermicide; male condom plus vaginal spermicide; surgical sterilization; intrauterine device;  
vasectomy of the partner or spouse (>6 months prior to baseline).   
• 
If you are a man, you should not father children while in the study. Your study doctor 
will talk to you about either agreeing to use specific methods of birth control or agreeing to 
abstain from sexual intercourse during the study and for 30 days after study completion.  
• 
We will instruct you on how to discontinue any medications not allowed while you are in 
the study.  Without your regular medications, your medical conditions or symptoms may get 
worse however, we will check with the doctor that prescribed the medication to make sure 
that it is safe for you to stop taking it.  You might not be able to drive or operate machinery. 
If your medical conditions or symptoms do get worse, please call the study doctor at the 
phone number provided in this consent form.   
• 
We will make an appointment for you to return for Visit 2 (baseline visit), within the next 
15 days or less.  
 
Visit 2 (day 0+/-7), visit 3 (day 30+/-7), visit 4 (day 90+/-14), visit 5 (day 120+/-14), visit 6 
(day 180+/-14) and visit 7 (day 360+/-14) will have the following tests and procedures 
except that visit 2, 4, 5 and 6 will not have blood sample collection.  
 
• 
Medical history: We will ask about your health and any illnesses and any changes in 
medicines you are taking or have taken since last visit.  
• 
We will ask you about your current and prior Augmentation treatment, symptoms, your 
usual bedtime and awakening times. 
• 
You and the staff will complete assessments on how you are feeling and if you have any 
thoughts about harming yourself.   
• 
Physical examination: You will have a full physical examination including neurological 
exam, height and weight. 

Horizant in RLS patients exhibiting augmentation:  
                                                        December 8, 2017 
 
 
 
 
CONFIDENTIAL 
14 
• 
Vital signs: You will have your temperature, heart rate, blood pressure, temperature and 
breathing rate collected.   
• 
Blood testing: We will collect blood samples (2 teaspoon or~10ml) for lab tests including 
hematology. Additional blood sample (~1/4 of teaspoon or 1.25ml) will be collected if you 
are a woman and your urine pregnancy test turn positive.  
• 
Urine testing: You will collect a sample of urine for pregnancy testing.  
• 
Augmentation severity rating scale (ASRS) – 3 item questionnaire to evaluate the 
severity of your augmentation symptom. 
• 
International restless legs syndrome-rating scale (IRLS) - a way to measure severity of 
your symptoms. 
• 
Restless legs syndrome-quality of life (RLS-QOL) – a way to measure improvement in 
quality of your life. 
• 
Medical outcome study-sleep scale (MOS-SS) - a way to assess your sleep. 
 
Blood sample collection: a blood sample (2 teaspoon or ~10ml) will be collected for 
complete blood count with differential and comprehensive metabolic panel at screening visit, 
visit 3 (day 30) and visit 7 (Day 360). In addition, it will be performed as needed at the 
discretion of the investigators if an adverse events is reported by a subjects. In other words, if 
a side effect occurs and the investigator feels additional tests will be helpful, then it will be 
done. Additional blood sample (~1/4 of teaspoon or 1.25ml) will also be collected if urine 
pregnancy test turn positive. Serum Ferritin level will be performed as needed at the 
discretion of the investigators. The total amount of blood sample collected will be 6-7 
teaspoon or 30-35ml for the entire study.  
7. STUDY POPULATION: 
7.1  Number of Subjects: 50  (we believe that we will be able to recruit only 50 eligible 
subjects during the one year enrollment  period) 
7.2 Inclusion Criteria: 
 
To be eligible for entry into this study, candidates must meet all of the following 
eligibility criteria before enrollment: 
 
1. Adult patients with diagnosis of RLS for more than one year. 
2. Patients who are on DA therapy for 6 months or longer. 
3. Patients who developed Augmentation (on stable dose of DA) lasting for 3 months or 
longer. 
4. Augmentation severity rating scale of 5 to 15. 
5. Both males and females  
6. Age range = 18-85 year 
7.3 Exclusion Criteria: 
 
Candidates will be excluded from study entry if any of the following exclusion criteria 
exist at the time of screening phase. 
Patients who have history of: 

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o Known Hypersensitivity to Horizant or Gabapentin products 
o Peripheral neuropathy  
o Radiculopathy  
o Peripheral vascular disease  
o Uremia (abnormal BUN or Creatinine on CMP)    
o Anemia 
o Patients who are currently pregnant  
o Patients who currently take opioids, lithium, anti-nausea medications (e.g. 
metoclopramide), dopaminergic antagonists (e.g. Haloperidol), 1st generation 
antihistamines (e.g. diphenhydramine, pseudoephedrine), anti-psychotic 
medications and iron therapy.  
o Subjects with impaired decision making capability. 
7.4 Medical History Exclusions: as per Exclusion criteria  
7.5 Treatment History Inclusions or Exclusions: as per Inclusion and Exclusion 
criteria  
7.6 Miscellaneous : Not applicable 
7.7 Screening Log: will be maintained 
Participating center is required to document all screened candidates initially 
considered for inclusion in this study and to specifically state the reason(s) for 
their exclusion. 
 
8. STUDY MEDICATION, DESCRIPTION, AND ALLOCATION  
Study drug is not to be used beyond the initial expiration date on the drug packaging. 
8.1 Horizant Stability & Storage 
HORIZANT Extended-Release Tablets containing 600 mg of gabapentin enacarbil are 
white to off-white, with occasional black/grey spots, oval-shaped tablets debossed with 
“GS LFG”. They are supplied as follows: 
600 mg: NDC 53451-0101-1: Bottles of 30 
Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F) [see USP 
Controlled Room   
 
 
8.2 Other Study Drug Generic Name (Brand Name®) – Not applicable 
8.3 Randomization Procedure: Not Applicable. 
8.4 Blinding Procedures – Not Applicable 
8.5 Drug Accountability: 
The study site must maintain accurate records demonstrating dates and amount of study 
drug received, to whom they are dispensed (subject-by-subject accounting), and accounts 
of any study drug accidentally or deliberately destroyed.  If drug is provided by 
XenoPort, the investigator must return all unused vials of study drug to XenoPort Inc. 
pursuant to instructions (unless agreed otherwise by XenoPort Inc.). 

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8.6 Treatment Schedule: as per study design. 
8.7 Modification of Treatment Schedule for Horizant: 
 
If deemed necessary for individual subject’s safety, it is at the discretion of 
the treating physician to modify the schedule of dosage of 600 mg according to the 
approved package insert; however, every attempt should be made to maintain the 
scheduled study dosing. 
 
 
 
8.8 Modification of Treatment Schedule for Other Study Drug : as per protocol. 
8.9 Discontinuation of Subjects from Investigational Treatment or from the Study  
Subjects must be withdrawn from the study for the following reasons: 
1.  If a subject develops significant adverse effect(s) after addition of Horizant or subject 
experiences significant DA withdrawal side effects as judge by the investigator. 
2.  If a subject is diagnosed to have a new medical condition while participating in the 
study that would fall into exclusion criteria (6.3) or if management of a newly 
diagnosed acute medical problem requires termination of the study medication. 
3. If a subject becomes pregnant. 
4. If a subject is deceased. 
5. XenoPort Inc. may terminate this study, after consultation with investigators, at any 
time. 
8.10 
Discontinuation of Study Drug: 
The reasons for discontinuation of the study drug must be recorded in the subject’s case 
report form (CRF). 
 
8.11 
Treatment Compliance 
Compliance with study drug will be monitored and recorded by study personnel based on 
information from the treating principal investigator and subjects.  
 
8.12 
Concomitant Therapy 
All subjects will be continued on all their current medications for their medical 
conditions {except medications listed in item 6.3 that can potentially affect the course 
and/or management of RLS}. 
  

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8.13 
Recording Concomitant Medication: Medication reconcilliation will be 
performed by study support staff/personnel and confirmed by investigator 
during each clinic visit 
8.14 
Extension Study: Not Applicable 
9. SCHEDULE OF EVENTS 
9.1 Laboratory Tests: All subjects will undergo laboratory tests (CBC with Diff and CMP) 
during screening phase, on day 30 and day 360 (final clinic visit). In addition, urine 
sample will be collected at screen visit for illegal drug screen. Additional urine illegal 
drug screen and hematology analysis will be performed as needed at the discretion of the 
investigators if an adverse event is reported by a subject.  Serum Ferritin level will be 
performed as needed at the discretion of the investigators. 
 
Urine pregnancy screening is required for all females of childbearing potential at screen 
and each clinical visits, if positive, serum pregnancy test will be performed. Female 
subjects who have undergone surgical sterilization, who are post- menopausal (defined as 
age >50 and >1 year of amenorrhea), who have medically documented ovarian failure 
(defined as age <50 with serum estradiol and follicle-stimulating hormone [FSH] levels 
within the institutional postmenopausal range and a negative serum or urine βHCG) do 
not need to undergo pregnancy screening. 
 
9.2 Study Site Personnel and Responsibilities: 
Where specified, evaluations described in this section must be performed only by the 
personnel indicated.  
9.2.1 
The Independent Assessment Panel or Centralized Reading/Evaluating Group: not 
applicable 
9.3  Visits and Assessments 
During each clinic visit all subjects will undergo careful evaluations (by a physician) that will 
include: medical history such as appearance of any new health problems, any new 
symptoms/adverse events, introduction of new medication(s) between clinic visits, 
concomitant medication(s){medication reconciliation}, physical examination with 
assessment of vital signs, ASRS, IRLS, RLS-QOL, and MOS-SS.  
10. EFFICACY ASSESSMENTS 
10.1 Clinical Efficacy Assessments include documenting ASRS, IRLS, RLS-QOL and MOS-SS 
each visit. 
10.2  Safety and Tilerability Assessments  
The safety and tolerability of Horizant will be determined by the occurrence of and/or 
Changes in: 
• Treatment-emergent adverse events 
• Any clinically significant changes in laboratory tests  

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• Any new complaints or significant changes in physical examination 
 
Patients will be enquired about adverse effects during each visit. 
Labs will be performed as per study design and as needed by investigator’s discretion 
during the study 
 
11 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS – DEFINITION & REPORTING  
 
At the signing of the informed consent form, each subject will be given the names and 
telephone numbers of investigational site personnel for reporting adverse events and 
medical emergencies.  
11.1 Definitions 
11.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An adverse event is any adverse event that is 
experienced by a subject who has received an investigational drug, but that does not 
necessarily have a causal relationship with the investigational drug. 
11.1.2 Serious Adverse Events 
In accordance with 21 Code of Federal Regulations (CFR) Part 312.32 and the 
recommendations of the International Conference on Harmonization (ICH) [Federal 
Register, October 7, 1997, Vol. 62, No. 194, pp 52239-45], any of the following adverse 
events are to be classified as a serious adverse event (SAE): 
 
• An event that results in death. 
• An event that, in the view of the Investigator, places the subject at immediate risk of 
death (a life-threatening event).  This does not include an event that, had it occurred 
in a more severe form, might have caused death. 
• An outcome that results in a congenital anomaly/birth defect diagnosed in a child of a 
subject who participated in this study. 
• An event that requires or prolongs in-patient hospitalization. 
• An event that results in persistent or significant disability/incapacity. 
• Other medically important events that, in the opinion of the Investigator, may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above.  (Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or 
convulsions occurring at home that do not require an in-patient hospitalization.). 
 
If a serious adverse event is unresolved when a subject permanently discontinues the study, 
the subject will be followed until the event resolves or the clinical course is stabilized. 
 

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11.1.3 Adverse Event Recording/Reporting 
All adverse events (including pre-dosing and treatment-emergent) should be recorded in 
the subject’s record (or, if applicable, in the adverse event section of the CRF) regardless 
of severity or relationship to investigational drug. 
 
11.1.4 Immediate Reporting of Serious Adverse Events 
 
 
Any SAE required to be reported according to 21 Code of Federal Regulations (CFR) Part 
312.32 and the recommendations of the International Conference on Harmonization (ICH) 
[Federal Register, October 7, 1997, Vol. 62, No. 194, pp 52239-45] that occurs regardless of 
whether or not the subject has undergone any study-related procedures or received 
investigational drug, through the completion of trial, will be reported to the FDA.  The 
investigator will forward a copy of the report to XenoPort in the same time frame that it is 
submitted to the FDA. 
 
The Investigator will notify the local IRB/IEC per local requirements. 
 
11.1.5 Safety Classifications 
The following classifications should be considered when evaluating the relationship of 
adverse events and serious adverse events to investigational drug: 
 
 
 
 
 
Relationship of Event to Investigational Drug 
 
Not related: Any event that does not follow a reasonable temporal sequence from 
administration of investigational drug AND that is likely to have been produced 
by the subject’s clinical state or other modes of therapy administered to the 
subject. 
 
Unlikely: 
Any event that does not follow a reasonable temporal sequence from 
administration of investigational drug OR that is likely to have been produced 
by the subject’s clinical state or other modes of therapy administered to the 
subject. 
 
Likely: 
Any reaction that follows a reasonable temporal sequence from administration 
of investigational drug OR that follows a known response pattern to the 
suspected drug AND that could not be reasonably explained by the known 
characteristics of the subject’s clinical state or other modes of therapy 
administered to the subject. 
 

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Relationship of Event to Investigational Drug 
 
Definitely: 
Any reaction that follows a reasonable temporal sequence from administration 
of investigational drug AND that follows a known response pattern to the 
suspected drug AND that recurs with re-challenge, AND/OR is improved by 
stopping the drug or reducing the dose. 
 
 
Severity of Adverse Events and Serious Adverse Events 
 
The following classifications should be considered when evaluating the severity of adverse events 
and serious adverse events: 
 
 
Severity of Event 
 
Mild: 
Symptoms(s) barely noticeable to subject or does not make subject 
uncomfortable; does not influence performance or functioning; prescription 
drug not ordinarily needed for relief of symptoms(s) but may be given because 
of personality of subject. 
 
Moderate: 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance 
of daily activity is influenced; subject is able to continue in study; treatment for 
symptom(s) may be needed. 
 
Severe: 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on subject’s daily life; severity may cause cessation of 
treatment with investigational drug; treatment for symptom(s) may be given 
and/or subject hospitalized. 
 
11.2Investigator Responsibilities 
The Investigator will: 
• Monitor and record all adverse events 
• Determine the seriousness, causality, and severity of each adverse event 
• Report all serious adverse events to the FDA according to the code of federal regulations 
• Forward a copy of all serious adverse events reports sent to the FDA and XenoPort Inc. 
in the same time frame 
• Actively and persistently pursue follow-up of serious adverse events  
• Forward a copy of the follow-up information to XenoPort Inc. 
  

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11.3Additional Procedures 
11.3.1 Procedures for Handling Pregnancy 
Further treatment with Horizant (Gabapentin enacarbil) should be discontinued in subjects 
who become pregnant during the course of the study.   
11.4Subject Information and Consent 
Prior to any testing under this protocol, including screening tests and evaluations, all subjects 
will sign an informed consent form that complies with the requirements of both 21 CFR Part 
50 and HIPAA before entering the study.  Or, a consent form that complies with the 
requirements of 21 CFR Part 50 and a separate HIPAA compliant authorization form for the 
use of and disclosure of the subject’s protected health information (PHI) will be obtained 
from the subject in accordance with local practice and regulations. 
 
The background of the proposed study and the benefits and risks of the procedures and study 
will be explained to the subject.  A copy of the informed consent document signed and dated 
by the subject will be given to the subject.  Confirmation of a subject’s informed consent will 
also be documented in the subject’s medical records prior to any testing under this protocol, 
including screening tests and evaluations. 
11.5Subject Data Protection 
The subject will not be identified by name in any study reports, and these reports will be used 
for research purposes only.  Every effort will be made to keep the subject’s personal medical 
data confidential. 
 
12 ETHICAL REQUIREMENTS 
The sponsor and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and in the applicable ICH and GCP guidelines, and must also 
conduct the study according to local regulations. 
12.1 Declaration of Helsinki 
 
The Investigator must follow the recommendations contained in the Declaration of Helsinki, 
amended at the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000, with 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 
2002.  See Appendix II in Section 15.2. 
 
12.2 Ethics Committee 
The Investigator must obtain written EC/REB approval of the protocol, ICF, and other 
required study documents prior to starting the study. In addition, XenoPort must approve the 
investigational site’s ICF submitted to the site’s EC/REB. 
 

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13 ADMINISTRATIVE PROCEDURES 
13.1 Investigational Site Initiation Visit 
An investigational site initiation visit will be conducted by a representative from the sponsor 
prior to enrollment of any study subjects. The study site will be considered active for 
enrollment following a satisfactory initiation visit.  
 
13.2 Investigator File  
The Investigator should maintain an Investigator File. This file should be used for filing all 
study-related documents. The Investigator will be responsible for keeping the Investigator 
File updated and ensuring that all required documents are filed during and after the study. 
The Investigator File may be inspected during monitoring visits and will remain with the 
Investigator after the study. 
 
13.3 Monitoring of the Study  
During the course of the study, the XenoPort-designated Monitor will visit the Investigator(s) 
at regular intervals by prior arrangement. The monitoring visits will be conducted to ensure 
protocol adherence, appropriate subject enrollment, quality of data, and continued adequacy 
of the investigational site and its facilities. 
 
13.4 Quality Assurance 
During and/or after completion of the study, quality assurance officers named by the Sponsor 
or the regulatory authorities may wish to perform on-site audits. The Investigator will be 
expected to cooperate with any audit and to provide assistance and documentation (including 
source data) as requested. 
 
13.5Study Funding 
XenoPort will financially support the work of the Investigator as it pertains to the conduct of 
this study.  All financial details are provided in a separate contract between the Investigator 
and XenoPort. 
 

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14 FURTHER REQUIREMENTS AND GENERAL INFORMATION 
14.1External Service Organizations –Not applicable 
14.1.1 Data Coordinating Center –Not applicable  
14.1.2 Central Laboratories for Laboratory Evaluations–Not applicable   
14.2Study Committees–Not applicable 
14.2.1 Independent Assessment Panel–Not applicable 
14.2.2 Publication Policy 
 
XenoPort Inc. reserves the right to a 30-day courtesy review of all publication materials, such 
as abstracts, posters, or manuscripts, related to the study prior to submission of such 
publication(s).  Investigators should refer to their Clinical Trial Agreement for additional 
details regarding the disclosure of study results. 
14.3Changes to Final Study Protocol 
 
All protocol amendments must be submitted to the IRB/EC.  Protocol modifications that 
impact subject safety, the scope of the investigation, or the scientific quality of the study 
must be approved by the IRB/EC and submitted to the appropriate regulatory authorities (if 
applicable) before implementation of such modifications to the conduct of the study.  In the 
event of a protocol modification, the subject consent form also may require modifications. 
 
It is the responsibility of the PI to submit all revisions to the protocol and consent form 
to XenoPort before submitting to their IRB. 
14.4Record Retention 
 
Appropriate, local, and/or institution-specific guidelines regarding retention of records must 
be followed. 
14.5Reporting and Communication of Results 
 
All reporting and communication of study results should be consistent with accepted 
publications, such as abstracts, posters, or manuscripts.   
14.6Protocol Completion 
 
The IRB/EC must be notified of completion or termination of the protocol.  Within 3 months 
of protocol completion or termination, the investigator must provide a final clinical summary 
report to the IRB/EC.  The principal investigator must maintain an accurate and complete 
record of all submissions made to the IRB/EC, including a list of all reports and documents 
submitted.  Health Authorities of participating countries may be notified about the study end 

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and/or study results within defined corresponding timelines. A copy of these reports should 
be sent to XenoPort Inc.  Adverse events, which are reported to regulatory authorities, must 
be submitted promptly to the IRB/EC. 
 
 
 14.7 STUDY TITLE: Use of and Study of Horizant in patients with Restless Leg Syndrome 
(RLS) on dopaminergic agonist/s exhibiting augmentation  
 
 
   PRINCIPAL INVESTIGATOR: Name:  Pradeep Sahota MD 
 
 
 
 
Institution/Organization:  Neurology; University of Missouri – School of Medicine 
 
 

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15 REFERENCES 
15.1Appendix I: Signed Agreement of the Study Protocol 
 
I have read the foregoing protocol entitled ‘Use of Horizant in primary Restless legs 
syndrome (RLS) patients on dopamine agonist exhibiting augmentation’ and agree to 
conduct the study as detailed herein and to inform all who assist me in the conduct of this 
study of their responsibilities and obligations. 
 
 
 
To be signed upon final approval 
 
           
 
Principal Investigator's Signature 
 
 
 
Date 
 
 
 
Pradeep Sahota, MD 
 
Principal Investigator's Name (Print) 
 
 
 
Neurology Dept., University of Missouri (Columbia)–School of Medicine  
 
Investigational Site (Print) 
 
 
 
 
University of Missouri – Columbia – School of Medicine 
 
XenoPort personnel’s Name and Title (Print) 
 
 
 
 
 
XenoPort personnel’s Signature

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15.2 
Appendix II: World Medical Association Declaration of Helsinki 
 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly  
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
 
 
A. INTRODUCTION 
 
1. The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
 
2. It is the duty of the physician to promote and safeguard the health of the people. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
 
3. The Declaration of Geneva of the World Medical Association binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient.” 
 
4. Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
 
5. In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
 
6. The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility and 
quality.  
 
7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
procedures involve risks and burdens.  
 
8. Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 

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themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care.  
 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to reduce or 
eliminate any of the protections for human subjects set forth in this Declaration. 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
 
11. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and on adequate laboratory and, where appropriate, animal experimentation. 
 
12. Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
 
13. The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any other 
kind of undue influence.  This independent committee should be in conformity with the laws and 
regulations of the country in which the research experiment is performed.  The committee has the 
right to monitor ongoing trials.  The researcher has the obligation to provide monitoring 
information to the committee, especially any serious adverse events.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
 
14. The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration. 
 
15. Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a medically qualified person and never rest on the 
subject of the research, even though the subject has given consent. 
 
16. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject 
or to others.  This does not preclude the participation of healthy volunteers in medical research.  
The design of all studies should be publicly available. 
 
17. Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
 

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18. Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
 
19. Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
 
20. The subjects must be volunteers and informed participants in the research project. 
 
21. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's 
information and to minimize the impact of the study on the subject's physical and mental integrity 
and on the personality of the subject. 
 
22. In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
 
23. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who is 
not engaged in the investigation and who is completely independent of this relationship. 
 
24. For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from the 
legally authorized representative in accordance with applicable law.  These groups should not be 
included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to the 
consent of the legally authorized representative. 
 
26. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
 
27.  Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports of 
experimentation not in accordance with the principles laid down in this Declaration should not be 
accepted for publication. 

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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL 
CARE 
 
28. The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical 
research is combined with medical care, additional standards apply to protect the patients who are 
research subjects. 
 
29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists.  
 
30. At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
 
31. The physician should fully inform the patient which aspects of the care are related to the research.  
The refusal of a patient to participate in a study must never interfere with the patient-physician 
relationship. 
 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not 
exist or have been ineffective, the physician, with informed consent from the patient, must be free to 
use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgment 
it offers hope of saving life, re-establishing health or alleviating suffering.  Where possible, these 
measures should be made the object of research, designed to evaluate their safety and efficacy. In all 
cases, new information should be recorded and, where appropriate, published.  The other relevant 
guidelines of this Declaration should be followed.  

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15.3 
Appendix IV: MEDWATCH Serious Adverse Event Reporting – Form 3500 
 

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References/Attachments:  Please refer to attached pdf files.