Clinical trial NCT04570670
Conditions: Relapsing Remitting Multiple Sclerosis
Sponsor: Banner Life Sciences LLC
Start date: 2017-01-06; Completion date: 2017-02-17
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this study was to assess the bioequivalence of the test product (Bafiertam; BLS-11; monomethyl fumarate) 190 mg versus Tecfidera® (dimethyl fumarate) 240 mg based on the Cmax and Area Under the Curve (AUC) values of monomethyl fumarate (MMF) determined after a single dose under fasting conditions.

Detailed description:
This was a single-dose, open-label, randomized, 2-way crossover study, evaluating the comparative pharmacokinetics of the test product (MMF) versus the reference product (DMF) under fasting conditions. Fifty (50) healthy, adult male and non-pregnant female subjects were enrolled. Screening of subjects occurred within 21 days prior to the first dose. Subjects were randomized to 1 of 2 treatment sequences prior to the first dose.

In each period, subjects received a single oral dose of MMF 190 mg administered as two 95 mg delayed-release capsules (test product) or Tecfidera® 240 mg DMF delayed-release capsule (reference product), followed by blood sampling (including predose samples) up to 24 hours postdose for the determination of plasma concentrations of MMF. There was a washout period of 2 days between the 2 doses.

Safety was monitored throughout the study by repeated clinical and laboratory evaluations.

Arms: arm 1: A single oral dose administration of BLS-11 190 mg (2 × 95 mg monomethyl fumarate delayed-release capsules) at Hour 0 on Day 1 arm 2: A single oral dose administration of Tecfidera 240 mg (1 × 240 mg dimethyl fumarate delayed-release capsule) at Hour 0 on Day 1
Interventions: intervention 1: monomethyl fumarate 190 mg intervention 2: dimethyl fumarate 240 mg
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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Celerion Project No.: CA20782 
Sponsor Project No.: BLS-11-104 
 
 
A Single-Dose, Randomized, Open-Label, 2-Way Crossover, Comparative 
Bioavailability Study of BLS-11 (Monomethyl Fumarate) 190 mg Administered as Two 
95 mg Delayed-Release Capsules and Tecfidera® (Dimethyl Fumarate) 240 mg Delayed- 
Release Capsules in Healthy Male and Female Subjects under Fasting Conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Banner Life Sciences 
and/or Celerion. Any viewing or disclosure of such information that is not authorized in 
writing by Banner Life Sciences and/or Celerion is strictly prohibited. Such information may 
be used solely for the purpose of reviewing or performing this study. 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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1 
PROTOCOL REVISION HISTORY 
 
Date/Name 
Description 
12Dec2016 
by David Goblot 
Final Protocol 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES 
 
A Single-Dose, Randomized, Open-Label, 2-Way Crossover, Comparative 
Bioavailability Study of BLS-11 (Monomethyl Fumarate) 190 mg Administered as Two 
95 mg Delayed-Release Capsules and Tecfidera® (Dimethyl Fumarate) 240 mg Delayed- 
Release Capsules in Healthy Male and Female Subjects under Fasting Conditions 
 
 
SPONSOR: 
Banner Life Sciences 
4125 Premier Drive 
High Point, North Carolina 27265, USA 
 
SPONSOR’S 
REPRESENTATIVE: 
 
 
Franck Rousseau, MD 
Chief Operating Officer 
Banner Life Sciences 
Tel.: +1 336 812-8700 
E-mail: Franck.Rousseau@bannerls.com 
 
 
 
 
 
 
December 12, 2016 
 
 
Signature 
Date 
 
CELERION PRINCIPAL INVESTIGATOR 
AND CLINICAL SITE: 
Jeffrey Zacher, MD 
2420 West Baseline Road 
Tempe, Arizona 85283, USA 
Tel.: +1 602 437-0097 ext. 66038 
Fax: +1 602 437-3386 
E-mail: Jeffrey.Zacher@celerion.com 
 
 
 
 
 
 
Signature 
Date 


BLS-11-104; CA20782; 16.1.1 Protocol and Protocol Amendments 
5 
 
 
BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
   Banner Life Sciences 
 
 
 
2 
PRINCIPAL INVESTIGATOR AND SPONSOR- SIGNATORIES 
 
A Single-Dose, Randomized, Open-Label, 2-Way Crossover, Comparative 
Bioavailability Study ofBLS-11 (Monomethyl Fumarate) 190 mg Administered as Two 
95 mg Delayed-Release Capsules and Tecfidera® (Dimethyl Fumarate) 240 mg Delayed­ 
Release Capsules in Healthy Male and Female Subjects under Fasting Conditions 
 
 
SPONSOR: 
 Banner Life Sciences 
4125 Premier Drive 
High Point, North Carolina 27265, USA 
 
 
SPONSOR'S 
REPRESENTATIVE: 
Franck Rousseau, MD 
Chief Operating Officer 
Banner Life Sciences 
Tel.:+ I 336 812-8700 
E-mail: Franck.Rousseau@bannerls.com 
 
 
 
 
Signature 
Date 
 
CELERION PRINCIPAL INVESTIGATOR 
AND CLINICAL SITE: 
Jeffrey Zacher, MD 
2420 West Baseline Road 
Tempe, Arizona 85283, USA 
Tel.: +1 602 437-0097 ext. 66038 
Fax: +1602437-3386 
E-mail: Jeffrey.Zacher@celerion.com 
 
 
 
 
J -;.,, D,ec.. 2o/ 
I,,, 
Date 
 
 
 
 
 
 
Page 3 
CA20782 (BLS-11-104)_Final Protocol_12Dec2016 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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6 
 
 
 
 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
 
Sponsor Contact for Serious Adverse Event 
Reporting 
Connie Cosentino, RN 
VP, Clinical Operations 
Banner Life Sciences 
4125 Premier Drive 
High Point, North Carolina 27265, USA 
Tel: +1 336 812-7420 
Mobile: +1 336 330-6664 
Fax: +1 888 818-4197 
E-mail: Connie.Cosentino@bannerls.com 
Protocol Author 
David Goblot, B.Sc., DESS 
Principal Scientist 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.: +1 514 744-8722 
Fax: +1 514 744-8700 
E-mail: David.Goblot@celerion.com 
Certified Clinical Laboratory 
Celerion 
2420 West Baseline Road 
Tempe, Arizona 85283, USA 
Contact: Ed Gritzfeld 
Tel.: +1 602 437-0097 ext. 67172 
Fax: +1 602 437-3386 
Bioanalytical Laboratory 
Nicki Hughes 
BioPharma Services Inc. 
4000 Weston Road 
Toronto, Ontario, M9L 3A2, Canada 
Tel: +1 416-747-8484 
Fax: +1 416 747 9943 
Email: nhughes@biopharmaservices.com 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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Pharmacokinetic and Statistical Analyses 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
and 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.: +1 402 476-2811 
Fax: +1 402 939-0428 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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4 
TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY ............................................................................. 2 
2 PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ......................... 3 
3 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................ 4 
4 TABLE OF CONTENTS ................................................................................................. 6 
5 SYNOPSIS ......................................................................................................................... 9 
6 STUDY EVENTS FLOW CHART ............................................................................... 11 
7 ABBREVIATIONS ......................................................................................................... 13 
8 BACKGROUND AND RATIONALE .......................................................................... 16 
8.1 
Background ............................................................................................................. 16 
8.1.1 
Tecfidera® (Dimethyl Fumarate) .............................................................. 16 
8.1.2 
BLS-11 (Monomethyl Fumarate) ............................................................. 17 
8.2 
Rationale .................................................................................................................. 17 
8.2.1 
Rationale for this Study and Study Design ............................................... 17 
8.2.2 
Rationale for the Dose Selection ............................................................... 18 
8.2.3 
Rationale for Endpoints ............................................................................ 18 
9 STUDY OBJECTIVES AND ENDPOINTS ................................................................. 18 
9.1 
Study Objectives ...................................................................................................... 18 
9.2 
Study Endpoints ...................................................................................................... 18 
10 INVESTIGATIONAL PLAN ........................................................................................ 19 
10.1 Overall Study Design and Plan ............................................................................... 19 
10.1.1 
Confinement, Return Visits, and Follow-Up ............................................ 19 
10.2 Risks and/or Benefits to Subjects ............................................................................ 19 
10.3 Selection of Study Population ................................................................................. 20 
10.3.1 
Inclusion Criteria ...................................................................................... 20 
10.3.2 
Exclusion Criteria ..................................................................................... 21 
10.3.3 
Early Termination of Subjects from the Study ......................................... 22 
10.4 Study Restrictions .................................................................................................... 23 
10.4.1 
Prohibitions and Concomitant Therapy .................................................... 23 
10.4.2 
Meals ......................................................................................................... 23 
10.4.3 
Activity ..................................................................................................... 24 
10.5 Treatments ............................................................................................................... 24 
10.5.1 
Treatments Administered .......................................................................... 24 
10.5.2 
Method of Assigning Subjects to Treatment Groups ................................ 24 


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Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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10.5.3 
Blinding..................................................................................................... 25 
10.5.4 
Treatment Compliance .............................................................................. 25 
11 STUDY PROCEDURES ................................................................................................ 26 
11.1 Screening ................................................................................................................. 26 
11.2 Safety Assessments ................................................................................................. 26 
11.2.1 
Physical Examination................................................................................ 26 
11.2.2 
Vital Signs ................................................................................................. 26 
11.2.3 
ECG Monitoring ....................................................................................... 27 
11.2.4 
Clinical Laboratory Tests .......................................................................... 28 
11.2.5 
Adverse Events ......................................................................................... 29 
11.2.5.1 Adverse Event Definition ......................................................... 29 
11.2.5.2 Monitoring ............................................................................... 29 
11.2.5.3 Reporting .................................................................................. 29 
11.2.5.4 Serious Adverse Event ............................................................. 30 
11.3 Pharmacokinetic Assessments ................................................................................. 30 
11.3.1 
Blood Sampling and Processing ............................................................... 30 
11.3.2 
Analytical Method .................................................................................... 31 
11.4 Blood Volume Drawn for Study Assessments ........................................................ 32 
12 DATA ANALYSIS .......................................................................................................... 33 
12.1 Pharmacokinetic Parameters ................................................................................... 33 
12.2 Statistical Methods .................................................................................................. 34 
12.2.1 
Determination of Sample Size .................................................................. 34 
12.2.2 
Subjects to Analyze ................................................................................... 34 
12.2.3 
Descriptive Statistics ................................................................................. 34 
12.2.4 
Statistical Analysis .................................................................................... 34 
12.3 Safety Evaluation .................................................................................................... 35 
13 STUDY ADMINISTRATION........................................................................................ 36 
13.1 Ethics ....................................................................................................................... 36 
13.1.1 
Institutional Review Board ....................................................................... 36 
13.1.2 
Ethical Conduct of the Study .................................................................... 36 
13.1.3 
Subject Information and Consent ............................................................. 36 
13.2 Termination of the Study ......................................................................................... 36 
13.3 Data Quality Assurance ........................................................................................... 36 
13.4 Direct Access to Source Data/Documents .............................................................. 37 
13.5 Drug Supplies, Packaging and Labeling ................................................................. 37 
13.6 Data Handling and Record Keeping ........................................................................ 37 
13.7 Report Format ......................................................................................................... 37 
13.8 Publication Policy ................................................................................................... 38 


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Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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14 REFERENCES ................................................................................................................ 39 
LIST OF TABLES 
Table 1: 
Blood Volume during the Study .................................................................... 32 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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5 
SYNOPSIS 
 
Compound: 
Monomethyl fumarate (MMF) 
Study Phase and Type: 
Phase 1 – Comparative Bioavailability 
Study Objectives: 
Primary: 
To determine the pharmacokinetic (PK) profiles of MMF after a 
single oral dose of the test product, BLS-11 190 mg 
administered as two 95 mg delayed-release capsules, and the 
reference product, Tecfidera® 240 mg dimethyl fumarate 
(DMF) delayed-release capsule, in healthy male and non- 
pregnant female subjects under fasting conditions. 
To assess if the test and reference products (indicated above) 
are bioequivalent in terms of the Cmax and AUC values of MMF 
after single-dose administration under fasting conditions. 
Secondary: 
To evaluate the safety and tolerability of a single dose of 
BLS-11 190 mg administered as two 95 mg delayed-release 
capsules and a single oral dose of Tecfidera® 240 mg DMF 
delayed-release capsule in healthy male and non-pregnant 
female subjects under fasting conditions. 
Summary of Study 
Design: 
This is a single-dose, randomized, open-label, 2-way crossover 
study evaluating the comparative PK of the test product vs. the 
reference product under fasting conditions. 
In each period, subjects will receive a single oral dose of 
BLS-11 190 mg administered as two 95 mg delayed-release 
capsules (Test product) or Tecfidera® 240 mg DMF 
delayed-release capsule (Reference product), followed by blood 
sampling (including predose sample) up to 24 hours postdose 
for the determination of plasma concentrations of MMF. 
There will be a washout period of at least 2 days between the 
2 doses. 
The clinic will attempt to contact all subjects (including subjects 
who terminate the study early) using their standard procedures 
approximately 7 days after the last study drug administration to 
determine if any adverse events (AEs) have occurred since the 
last study visit. 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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Number of Subjects: 
Fifty (50), healthy, adult male and non-pregnant female subjects 
will be enrolled. 
Space constraints at the clinical research unit (CRU) may 
require subjects to be divided into 2 dosing groups of 
approximately equal size for dosing, as needed. Within each 
dosing group, subjects will be randomized to receive the test 
and reference products in a crossover fashion based on the 
randomization schedule. 
Dosage, Dosage Form, 
Route, and Dose 
Regimen: 
Treatments are described as follows: 
Treatment A: 
a single oral dose administration of Banner Life 
(Test) 
Sciences 190 mg MMF (2 x 95 mg 
delayed-release capsules) on Day 1. 
Treatment B: 
a single oral dose administration of Biogen, Inc. 
(Reference) 
Tecfidera® 240 mg DMF (1 x 240 mg 
delayed-release capsule) on Day 1. 
All study drugs will be administered with approximately 
240 mL of water following an overnight (at least 10 hours) fast. 
Key Assessments: 
Pharmacokinetics: 
The following PK parameters will be calculated for MMF by 
noncompartmental methods, as appropriate or data permitting: 
AUC0-t, AUC0-inf, AUC%extrap, Cmax, tmax, Kel, and t½. 
An analysis of variance (ANOVA) will be performed on the 
natural log (ln)-transformed AUC0-t, AUC0-inf, and Cmax, 
using the appropriate statistical procedure. 
Bioequivalence criteria will be met if the 90% confidence 
intervals (CIs) for the ratios of geometric least-squares means 
(GLSM) of AUC0-inf, and Cmax of MMF of the Test 
(Treatment A) to the Reference (Treatment B) fall within the 
limit of 80.00 and 125.00%. 
The tmax parameter will also be analyzed using an additional 
non-parametric test (Wilcoxon test) for information purpose and 
will not be used to determin product comparability. 
Safety: 
Safety will be monitored through vital sign measurements, 
clinical laboratory tests, and AEs. AEs will be tabulated and 
summary statistics for vital signs and clinical laboratory safety 
tests may be computed and provided, as deemed clinically 
appropriate. 


BLS-11 
Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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6 
STUDY EVENTS FLOW CHART 
 
Events and Assessments a 
Screening b 
Dose Period 1 
Washout c 
Dose Period 2 
FU d 
Day -1 
C-I 
Day 1 
Day 2 
Day -1 
Day 1 
Day 2 
Informed Consent 
X 
Demographic Information 
X 
Complete Medical/Medication History 
X 
Update to Medical/Medication History 
X 
Full Physical Examination 
X 
Brief Physical Examination e 
X 
X 
X n 
Height, BMI 
X 
Weight 
X 
X 
Vital Signs (Sitting HR, BP and T) 
X 
X g 
X h 
X g 
X h, n 
Concomitant Medication Monitoring 
X 
X 
X 
X 
X 
X 
X n 
Clinical Laboratory Evaluations, Fasted i (Hematology, 
Serum Chemistry, and Urinalysis) 
X 
X 
X n 
Serum Pregnancy Test (♀only) 
X 
X 
X n 
Serum FSH (Postmenopausal ♀only) 
X 
Urine Drug / Alcohol / Cotinine Screen 
X 
X 
Serology (HIV, Hepatitis B, Hepatitis C) 
X 
12-Lead Electrocardiogram 
X 
X f 
Study Drug Dosing j 
X 
X 
Begin Confinement 
X k 
End Confinement 
X l 
Blood for Pharmacokinetics 
X m 
X m 
X m 
X m 
Drug Dispensing and Accountability 
X 
X 
AE Monitoring 
X 
X 
X 
X 
X 
X n 
X 


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Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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a: 
For details on Events and Assessments, refer to Section 11. 
b: Within 21 days prior to the first study drug administration. 
c: 
There will be a washout period of at least 2 days between the 2 doses. 
d: The clinic will attempt to contact all subjects (including subjects who terminate the study early) using their standard procedures approximately 7 days after 
the last study drug administration to determine if any AEs has occurred since the last study visit. 
e: 
Symptom-driven physical examination may be performed at other times, at the PI or designee’s discretion. 
f: 
Taken approximately2 hours prior to dosing. 
g: Taken approximately 2 hours predose and at 2 hours postdose of each study drug. 
h: Taken after the 24-hour postdose PK blood sample is obtained. 
i: 
Subjects are reminded to fast for at least 8 hours prior to the blood draw for fasting clinical laboratory evaluation. 
j: 
Study drug will be administered after an overnight fast (for at least 10 hours), followed by another 4 hours of fasting postdose. 
k: Subjects will be admitted to the CRU on Day -1 of Dose Period 1, at the time indicated by the CRU. 
l: 
Subjects will be discharged from the CRU after the last PK sample and the vital signs measurements are obtained at 24 hours postdose in Dose Period 2. 
m: Venous blood samples (10 mL each) will be collected at immediately (within 15 minutes) prior to dosing, and then at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 
6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, and 24 hours postdose. 
n: To be performed at the scheduled time or prior to early termination from the study. 
 
Abbreviations: ♀ = Females, AE = Adverse event, BP = Blood pressure, C-I = Check-in, CRU = Clinical research unit, FSH = Follicle-stimulating hormone, 
FU = Follow-up, HIV = Human immunodeficiency virus, HR = Heart rate, PI = Principal Investigator, PK = Pharmacokinetic, T = Temperature. 


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Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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7 
ABBREVIATIONS 
 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve, from time 0 (dosing time) to the 
last time point (tlast) with measurable drug concentration 
AUC0-inf 
Area under the concentration-time curve, from time 0 (dosing time) 
extrapolated to infinity 
AUC%extrap 
Percent of AUC0-inf extrapolated from last time point with measurable dug 
concentration to infinity 
BE 
Bioequivalence 
BID 
Twice a day 
BMI 
Body mass index 
bpm 
Beats per minute 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cm 
Centimeter 
Cmax 
Maximum observed drug concentration 
CRF 
Case report form 
CRU 
Clinical research unit 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DMF 
Dimethyl fumarate 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
GLSM 
Geometric least-squares means 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 


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Comparative Bioavailability Study Protocol 
Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
Kel 
Apparent terminal first-order decay rate constant 
kg 
Kilogram 
L 
Liter 
ln 
Natural logarithm 
LSM 
Least-squares means 
m2 
Meters squared 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
mL 
Milliliter 
MMF 
Monomethyl fumarate 
mmHg 
Millimeter of mercury 
MS 
Multiple sclerosis 
msec 
Millisecond 
No. 
Number 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
RLD 
Reference Listed Drug 
rpm 
Rotations per minute 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach maximum observed drug concentration 
t½ 
Apparent plasma half-life 
US 
United States 


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Comparative Bioavailability Study Protocol 
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Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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USA 
United States of America 
UV 
Ultraviolet 
vs. 
Versus 
WHO 
World Health Organization 


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Sponsor Project No.: BLS-11-104 
Celerion Project No.: CA20782 
  Banner Life Sciences 
 
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8 
BACKGROUND AND RATIONALE 
 
8.1 
Background 
 
8.1.1 
Tecfidera® (Dimethyl Fumarate) 
Tecfidera® is indicated for the treatment of patients with relapsing forms of multiple sclerosis 
(MS). The mechanism by which DMF exerts its therapeutic effect in MS is unknown. After 
oral administration of Tecfidera®, DMF undergoes rapid presystemic hydrolysis by esterases, 
ubiquitous to the gastrointestinal tract, blood, and tissues, and is converted to its active 
metabolite, MMF, before it reaches the systemic circulation. Dimethyl fumarate is not 
quantifiable in plasma following oral administration of Tecfidera®. 
Further metabolism of MMF occurs through the tricarboxylic acid cycle, with no 
involvement of the cytochrome P450 (CYP) system. Monomethyl fumarate, fumaric and 
citric acids, and glucose are the major metabolites in plasma. 
 
Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of 
the Tecfidera® dose. Renal and fecal elimination are minor routes of elimination, accounting 
for 16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in 
urine. 
 
The terminal half-life (t½) of MMF is approximately 1 hour and no circulating MMF is 
present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with 
multiple doses of Tecfidera®. 
No potential drug interactions with DMF or MMF were identified in in vitro CYP inhibition 
and induction studies, or in P-glycoprotein studies. Single doses of interferon beta-1a or 
glatiramer acetate did not alter the PK of MMF. Aspirin, when administered approximately 
30 minutes before Tecfidera®, did not alter the PK of MMF. 
DMF and the metabolite, MMF, have been shown to activate the nuclear factor 
(erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The 
Nrf2 pathway is involved in the cellular response to oxidative stress. Monomethyl fumarate 
has been identified as a nicotinic acid receptor agonist in vitro. 
 
The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for 
Tecfidera® were flushing, abdominal pain, diarrhea, and nausea. The incidence of flushing 
may be reduced by administration of Tecfidera® with food. Alternatively, administration of 
non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to Tecfidera® dosing 
may reduce the incidence or severity of flushing. 
 
Refer to the approved US product label for detailed background information on Tecfidera®.1 


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8.1.2 
BLS-11 (Monomethyl Fumarate) 
 
As described in Section 8.1.1 above, DMF is rapidly and completely metabolized to MMF, 
an active metabolite. 
 
Two pilot PK studies, Study 1980 and Study 1981, were conducted in which MMF was 
administered directly to human subjects. 
 
These studies evaluated the PK and safety and tolerability of   investigational formulations 
of MMF delayed-release capsules. These studies were conducted to select a formulation and 
dosage strength which is bioequivalent to Tecfidera® 240 mg and to evaluate the tolerability 
of MMF when administered directly to healthy subjects.         of the investigational 
formulations were              and 
In each study, 
Additionally, 2 different 
In both studies the 
relative bioavailability of the MMF formulations were compared to the Tecfidera® 240 mg 
delayed-release oral capsule. 
 
The PK data obtained in the pilot studies informed the development of the formulation and 
dosage strength being investigated in this study. There were no new safety or tolerability 
findings. 
 
Refer to the Investigator’s Brochure (IB) for detailed background information on BLS-11 
(MMF).2 
8.2 
Rationale 
 
8.2.1 
Rationale for this Study and Study Design 
 
This study is designed to meet the objectives outlined in Section 9. 
 
Banner Life Sciences plans to submit a new drug application for BLS-11, which contains 
MMF a new chemical entity that is the active metabolite of an approved drug. 
 
The effectiveness of MMF administered as BLS-11 using a bioequivalence (BE) approach to 
the reference product, Tecfidera® (240 mg DMF delayed-release capsules) will be inferred. 
This study will be 1 of 2 BE studies assessing 2 different test formulations of MMF in 
comparison to the reference formulation under fasting conditions. One (1) of the 2 test 
formulations will then be selected to assess BE under fed/fasting conditions. 
 
Subjects will be randomized to treatment sequences to minimize assignment bias. A 
crossover design is used to control the variability between subjects. The washout period 
between doses is considered sufficient to prevent carryover effects of the treatments. 


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8.2.2 
Rationale for the Dose Selection 
 
The MMF dose, administered as BLS-11, to be examined in this study was selected based on 
the comparative (to Tecfidera®) BE data obtained in the 2 preceding pilot studies. 
8.2.3 
Rationale for Endpoints 
 
The primary objective of this study is to assess the BE of the test product versus the reference 
product based on the Cmax and AUC values of MMF determined after a single dose 
administered under fasting conditions. The active metabolite MMF will be used in the 
comparison since the parent drug, DMF, is rapidly and almost completely metabolized to 
MMF before reaching the systemic circulation and is generally not quantifiable in plasma. 
Statistical analysis will be performed on ln-transformed Cmax and AUC values of MMF 
using ANOVA to determine if BE criteria is met based on the FDA Guidances.3, 4 
9 
STUDY OBJECTIVES AND ENDPOINTS 
9.1 
Study Objectives 
Primary: 
To determine the PK profiles of MMF after a single oral dose of the test product, BLS-11 
190 mg administered as two 95 mg delayed-release capsules, and the reference product, 
Tecfidera® 240 mg DMF delayed-release capsule, in healthy male and non-pregnant female 
subjects under fasting conditions. 
To assess if the test and reference products (indicated above) are bioequivalent in terms of 
the Cmax and AUC values of MMF after single-dose administration under fasting conditions. 
Secondary: 
To evaluate the safety and tolerability of a single dose of BLS-11 190 mg administered as 
two 95 mg delayed-release capsules and a single oral dose of Tecfidera® 240 mg DMF 
delayed-release capsule in healthy male and non-pregnant female subjects under fasting 
conditions. 
9.2 
Study Endpoints 
Pharmacokinetics: 
The primary endpoints for BE assessment will be comparison of AUC0-inf and Cmax of 
MMF between treatments. In addition, AUC0-t will be compared between treatments. 
 
Additional PK parameters AUC% extrap, tmax, Kel, and t½ of MMF will be computed for 
information. 
 
Safety: 
Safety endpoints will include vital signs, clinical laboratory tests, and AEs. 


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Celerion Project No.: CA20782 
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10 INVESTIGATIONAL PLAN 
 
10.1 Overall Study Design and Plan 
 
This is a single-dose, randomized, open-label, 2-way crossover study evaluating the 
comparative PK of the test product vs. the reference product under fasting conditions. 
 
Fifty (50), healthy, adult male and non-pregnant female subjects will be enrolled. Space 
constraints at the CRU may require subjects to be divided into 2 dosing groups of 
approximately equal size for dosing, as needed. 
 
Screening of subjects will occur within 21 days prior to the first dose. 
 
Subjects will be randomized to one of two treatment sequences prior to the first dose. 
 
In each period, subjects will receive a single oral dose of BLS-11 190 mg administered as 
two 95 mg delayed-release capsules (Test product) or Tecfidera® 240 mg DMF 
delayed-release capsule (Reference product), followed by blood sampling (including predose 
sample) up to 24 hours postdose for the determination of plasma concentrations of MMF. 
 
There will be a washout period of at least 2 days between the 2 doses. 
 
Safety will be monitored throughout the study by repeated clinical and laboratory 
evaluations. 
 
Discontinued subjects will not be replaced. 
 
10.1.1 
Confinement, Return Visits, and Follow-Up 
 
Subjects will be housed on Day -1 of Period 1, at the time indicated by the CRU, until after 
the 24-hour blood draw and/or study procedures in Period 2. At all times, a subject may be 
required to remain at the CRU for longer at the discretion of the Principal Investigator (PI) or 
designee. 
 
The clinic will attempt to contact all subjects (including subjects who terminate the study 
early) using their standard procedures approximately 7 days after the last study drug 
administration to determine if any AEs has occurred since the last study visit. 
 
10.2 Risks and/or Benefits to Subjects 
 
The dose of Tecfidera® (DMF) or BLS-11 (MMF) administered in this study is not 
anticipated to induce any potential risk or benefit to subjects participating in this study; the 
single dose of Tecfidera® is administered per the dosing recommendations found in the full 
prescribing information for Tecfidera® (DMF)1 and the single dose of BLS-11 is not greater 
than the dose resulting from the administration of Tecfidera®. 


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Celerion Project No.: CA20782 
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The safety monitoring practices employed by this protocol (i.e., vital signs, clinical 
laboratory tests, and AE questioning) are adequate to protect the subjects’ safety and should 
detect all expected treatment-emergent AEs (TEAEs). 
 
There will be no direct health benefit for study participants from receipt of study drug. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at screening and during the study. 
 
10.3 Selection of Study Population 
 
10.3.1 
Inclusion Criteria 
 
Subjects must fulfill all of the inclusion criteria and none of the exclusion criteria to be 
eligible for participation in the study, unless otherwise specified: 
 
1. Healthy, adult, male or female, 18 - 55 years of age, inclusive, at screening. 
 
2. Continuous non-smoker who has not used nicotine-containing products for at least 
3 months prior to the first dose and throughout the study. 
 
3. Body mass index (BMI) ≥ 18.5 and ≤ 29.9 kg/m2 at screening. 
4. Medically healthy as determined by the investigator or designee with no clinically 
significant medical history, physical examination, laboratory profiles, vital signs or 
ECGs, as deemed by the investigator or designee. 
 
5. For a female of childbearing potential: not pregnant and either be sexually inactive 
(abstinent) for 14 days prior to the first dose and throughout the study or be using one of 
the following acceptable birth control methods: 
 
• hormonal oral contraceptives, vaginal ring, transdermal patch, or non-hormone or 
hormone releasing intrauterine device for at least 3 months prior to the first dose with 
either a physical (e.g. condom, diaphragm, or other) or a chemical (e.g., spermicide) 
barrier method from the time of screening and throughout the study. 
• Depot/implantable hormone (e.g., Depo-Provera®, Implanon®) for at least 3 months 
prior to the first dose and throughout the study. 
 
In addition, female subjects of childbearing potential will be advised to remain sexually 
inactive or to keep the same birth control method for at least 7 days following the last 
dose. 
 
6. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 


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Celerion Project No.: CA20782 
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• hysterectomy; 
• bilateral oophorectomy. 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status 
as per investigator’s or designee’s judgment. 
 
7. A non-vasectomized, male subject must agree to use a condom with spermicide or abstain 
from sexual intercourse during the study until 90 days beyond the last dose of study drug. 
(No restrictions are required for a vasectomized male provided his vasectomy has been 
performed 4 months or more prior to the first dose of study drug. A male who has been 
vasectomized less than 4 months prior to the first dose of study drug must follow the 
same restrictions as a non-vasectomized male). 
 
8. For a male, must agree not to donate sperm from the first dose until 90 days after dosing. 
 
9. Understands the study procedures in the informed consent form (ICF), and be willing and 
able to comply with the protocol. 
 
10.3.2 
Exclusion Criteria 
 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
 
1. Subject is mentally or legally incapacitated or has significant emotional problems at the 
time of the screening visit or expected during the conduct of the study. 
 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the investigator or designee. 
 
3. History of any illness that, in the opinion of the investigator or designee, might confound 
the results of the study or poses an additional risk to the subject by their participation in 
the study. 
 
4. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
dose. 
 
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or 
related compounds. 
 
6. Female subjects with a positive serum pregnancy test at screening or check-in, or who are 
lactating. 
 
7. Positive urine drug, alcohol, or cotinine results at screening or check-in. 
 
8. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg) or hepatitis C virus (HCV). 


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Celerion Project No.: CA20782 
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9. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at 
screening. 
 
10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. 
 
11. Abnormal 12-lead ECG deemed clinically significant by the investigator or designee at 
screening or prior to the first dose. 
 
12. Unable to refrain from or anticipates the use of any drug, including prescription and 
non-prescription medications, or herbal remedies, beginning 14 days prior to the first 
dose and throughout the study. Medication listed as part of acceptable birth control 
methods will be allowed (refer to Section 10.3.1). Hormone replacement therapy will also 
be allowed. Acetaminophen (up to 2 g per 24-hour period) may be permitted, as 
necessary during the study. 
 
13. Has been on a diet incompatible with the on-study diet, in the opinion of the investigator 
or designee, within the 28 days prior to the first dose and throughout the study. 
 
14. Donation of blood or significant blood loss within 30 days prior to the first dose. 
 
15. Plasma donation within 7 days prior to the first dose. 
 
16. Participation in another clinical study within 28 days prior to the first dose. The 28-day 
window will be derived from the date of the last blood collection or dosing, whichever is 
later, in the previous study to Day 1 of Period 1 of the current study. 
 
10.3.3 
Early Termination of Subjects from the Study 
 
Subjects are free to withdraw from the study at any time for any reason. 
 
In addition, subjects may be withdrawn from the study by the investigator or designee for the 
following reasons: 
 
• AEs. 
• Difficulties in blood collection. 
A subject may be withdrawn by the investigator (or designee) or the Sponsor if enrollment 
into the study is inappropriate, the study plan is violated, or for administrative and/or other 
safety reasons. 
If a subject vomits within 5 hours after dosing, i.e., a period equal to two times the median 
tmax of MMF after administration of the reference product, he/she may be withdrawn from 
the study. 
 
The clinical report will include reasons for subject withdrawals as well as details relevant to 
the subject’s withdrawal. 


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Celerion Project No.: CA20782 
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10.4 Study Restrictions 
 
10.4.1 
Prohibitions and Concomitant Therapy 
 
Consumption of foods and beverages containing the following substances will be prohibited 
as indicated: 
 
• Xanthines/Caffeine: 24 hours before each dose and throughout the period of sample 
collection; 
• Alcohol: 48 hours before each dose and throughout the period of PK sample 
collection; 
• Grapefruit/Seville orange: 48 hours before the first dose and throughout the study. 
Concomitant therapies will be prohibited as listed in the exclusion criteria in Section 10.3.2. 
During the study, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the investigator or designee. Acceptable birth control methods as described in 
Section 10.3.1 and hormone replacement therapy will be allowed. 
 
If deviations occur, the investigator or designee will decide on a case-by-case basis whether 
the subject may continue participation in the study based on the time the study drug was 
administered and its pharmacology. 
 
All medications taken by subjects during the study will be recorded. 
 
10.4.2 
Meals 
 
Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour 
after each study drug administration, but will be allowed ad libitum at all other times. Other 
fluids may be given as part of meals and snacks but will be restricted at all other times 
throughout the confinement period. 
 
Subjects will fast overnight for at least 10 hours prior to each study drug administration and 
will continue to fast for 4 hours postdose. 
 
Standard meals will be provided at approximately 4 and 9 hours postdose, and at appropriate 
times thereafter. Snacks will be provided at appropriate times. When confined in the CRU, 
subjects will be required to fast from all food and drink except water between meals and 
snacks. 
 
Each meal and/or snacks served at the CRU will be standardized and will be similar in 
caloric content and composition and will be taken at approximately the same time in each 
period/day. 


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Celerion Project No.: CA20782 
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10.4.3 
Activity 
 
Subjects will remain ambulatory or seated upright for the first 4 hours following study drug 
administration, except when they are supine or semi-reclined for study procedures. 
 
However, should AEs occur at any time, subjects may be placed in an appropriate position or 
will be permitted to lie down on their right side. 
 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion 
of the study. 
 
10.5 Treatments 
 
10.5.1 
Treatments Administered 
 
The test product (for Treatment A) will be supplied as 95 mg MMF delayed-release capsules 
(Banner Life Sciences). 
 
The reference product (for Treatment B) will be supplied as Tecfidera® 240 mg DMF 
delayed-release capsules (Biogen, Inc.). 
 
All study drugs will be administered with approximately 240 mL of water following an 
overnight (at least 10 hours) fast. 
 
Subjects will be instructed not to crush, split, or chew the study drugs. 
Treatments A and B are described as follows: 
Treatment A (Test): 
a single oral dose administration of 190 mg MMF (2 x 95 mg 
delayed-release capsules) at Hour 0 on Day 1. 
 
Treatment B (Reference): a single oral dose administration of Tecfidera® 240 mg DMF 
(1 x 240 mg delayed-release capsule) at Hour 0 on Day 1. 
 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period, as per the randomization scheme. 
 
The exact clock time of dosing will be recorded. 
 
10.5.2 
Method of Assigning Subjects to Treatment Groups 
 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned 
a unique randomization identification number prior to the first dose, different from the 
screening number, and will receive the corresponding product, per a randomization scheme 
generated at Celerion. 


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Celerion Project No.: CA20782 
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Subjects will receive each treatment on one occasion. The sequences to be used in the 
randomization will be AB and BA. 
 
Space constraints at the CRU may require subjects to be divided into 2 dosing groups of 
approximately equal size for dosing, as needed. Within each dosing group, subjects will be 
randomized to receive the test and reference products in a crossover fashion based on a 
randomization schedule. 
 
Discontinued subjects will not be replaced. 
 
10.5.3 
Blinding 
 
This is an open-label study. 
 
10.5.4 
Treatment Compliance 
 
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the subjects 
have swallowed the study drug in whole without chewing. Once a subject has finished the 
dosing water, the qualified designee will use a flashlight and a tongue depressor to check the 
subject’s mouth. Subjects’ hands will also be verified to ensure that the study drug was 
ingested. 


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Celerion Project No.: CA20782 
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11 STUDY PROCEDURES 
 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. 
Additional evaluations/testing may be deemed necessary by the PI or designee and/or the 
Sponsor for reasons related to subject safety. 
 
For this study, the blood collection for PK assessment of MMF is the critical parameter event 
and blood samples need to be collected as close to the exact time point as possible. However, 
time deviation from scheduled sampling time will not be considered as protocol deviation, as 
long as the actual clock time of each sample collection is documented in the CRF. All other 
procedures should be completed as close to the prescribed/scheduled time as possible, but 
can be performed prior or after the prescribed/scheduled time. The actual date and clock time 
for all procedures are to be documented in the CRFs. 
 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
 
11.1 Screening 
 
Within 21 days prior to the first dose, medical history and demographic data, including name, 
sex, age, race, ethnicity, body weight (kg), height (cm), BMI (kg/m2) and history of tobacco 
use will be reported. Each subject will have a physical examination, vital sign measurements 
(heart rate, blood pressure, and temperature), 12-lead ECG, and the laboratory tests of 
hematological, hepatic and renal function and additional tests as noted in Section 11.2.4. 
 
11.2 Safety Assessments 
 
11.2.1 
Physical Examination 
 
A full physical examination (PE) will be performed at screening as per Study Events Flow 
Chart (Section 6). Brief PE will be performed on Day -1 of each dose period and 
symptom-driven PE may be performed at other times, if deemed necessary by the PI or 
designee. 
 
11.2.2 
Vital Signs 
 
Single measurements of body temperature, blood pressure and heart rate, will be measured as 
outlined in the Study Events Flow Chart (Section 6). Additional vital signs may be taken at 
any other times, if deemed necessary. 
 
Vital signs measurements will be performed with subjects in a seated position, except when 
they are supine or semi-reclined because of study procedures and/or AEs (e.g. nausea, 
dizziness) or if deemed necessary by the PI or designee. 


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Blood pressure and heart rate will be measured approximately 2 hours prior to Day 1 dosing 
of each period for the predose time point. When scheduled postdose, vital signs will be 
performed within approximately 10 minutes of the scheduled time point. 
 
11.2.3 
ECG Monitoring 
 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Additional ECGs may be taken at any other times, if deemed necessary by the PI 
or designee. 
 
ECGs will be performed with subjects in a supine position. All ECG tracings will be 
reviewed by the PI or designee. 
 
ECGs will be measured approximately 2 hours prior to Day 1 dosing of Period 1. 


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11.2.4 
Clinical Laboratory Tests 
 
All tests listed below will be performed as per Study Events Flow Chart (Section 6). In 
addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI or designee. 
 
Hematology 
Serum Chemistry* 
• 
Hemoglobin 
• 
Hematocrit 
• 
Total and differential leukocyte 
count 
• 
Red blood cell count 
• 
Platelet count 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Alanine aminotransferase 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Glucose (fasting) 
• 
Creatinine** 
 
Urinalysis 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein*** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood*** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase*** 
• 
HIV test 
• 
HBsAg 
• 
HCV 
• 
Urine drug screen 
 Opiates 
 Opioids 
 Amphetamines 
 Barbiturates 
 Benzodiazepines 
 Cocaine 
 Cannabinoids 
• 
Urine alcohol screen 
• 
Serum pregnancy test 
(for females only) 
• 
FSH (for postmenopausal females only) 
• 
Urine cotinine 
 
* 
Subjects are reminded to fast for at least 8 hours prior to the blood draw for fasting clinical 
laboratory evaluation. 
 
** At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula. 
 
*** If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination (for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will 
be performed. 


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11.2.5 
Adverse Events 
 
11.2.5.1 
Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
A suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
 
11.2.5.2 
Monitoring 
Subjects will be monitored throughout confinement for adverse reactions to the study 
formulations and/or procedures. Prior to release, subjects will be asked how they are feeling. 
At the beginning of the second period subjects will be queried with an open-ended question 
such as: ‘How have you been feeling since your last visit?’ 
 
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test 
value(s) will be evaluated by the PI or designee and treated and/or followed up until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the PI or designee. 
 
Treatment of serious adverse events (SAEs) will be performed by a physician, either at 
Celerion or at a nearby hospital emergency room. Where appropriate, medical test(s) and/or 
examination(s), will be performed to document resolution of event(s). Outcome may be 
classified as resolved, improved, unchanged, worse, fatal, or unknown (lost to follow-up). 
 
11.2.5.3 
Reporting 
All AEs that occurred during this clinical study will be recorded. The PI or designee will 
review each event and assess its relationship to drug treatment (likely, probably, possibly, 
unlikely or unrelated). Each sign or symptom reported will be graded on a 3-point severity 
scale (mild, moderate, or severe), and the date of onset, time of onset, and outcome of each 
event will be noted. 
 
The following definitions will be used for rating the severity of AEs: 
Mild 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate 
The AE interferes with daily activity, but the subject is still able to function. 
Medical intervention may be considered. 
Severe 
The AE is incapacitating and requires medical intervention. 


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11.2.5.4 
Serious Adverse Event 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs will 
be reported to the Sponsor via fax or e-mail within one working day of becoming aware of 
the event, whether or not the serious events are deemed drug-related. All serious event 
reporting will adhere to 21 CFR 312.32 for Investigational New Drugs (IND) and to the 
Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and 
BA/BE, dated December 2012. The institutional review board (IRB) will be notified of the 
Alert Reports as per FDA regulations. 
 
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above 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. 
 
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI 
(or designee) or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the IB or is 
not listed at the specificity or severity that has been observed; or is not consistent with the 
risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
 
If a SAE occurs to a subject on this study, contact the Sponsor personnel listed in Section 3. 
 
11.3 Pharmacokinetic Assessments 
 
11.3.1 
Blood Sampling and Processing 
 
For all subjects, blood samples for the determination of MMF will be collected in prechilled 
blood collection tubes containing sodium fluoride/potassium oxalate as the stabilizer and 
anticoagulant, respectively at scheduled time points as delineated in the Study Events Flow 
Chart (Section 6) by direct venipuncture using a disposable sterile needle at each time of 
collection. 
 
Blood collection tubes will be placed in an ice bath at least 5 minutes prior to blood 
collection. Immediately upon blood collection, the collection tubes will be gently inverted 


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8-10 times to allow mixing with the anticoagulant and the stabilizer, and will be cooled in an 
ice bath and centrifuged (approximately at 2056 x gravity for 7 minutes) under refrigeration 
at a temperature of approximately 4°C as soon as possible and no later than 60 minutes upon 
collection. Plasma samples will be divided into 4 aliquots and stored in suitably labeled 
polypropylene tubes which are prechilled and contain pre-aliquoted an appropriate volume 
(100 μL per 1 mL of plasma) of the 10% (v/v) phosphoric acid solution in each tube as a 
stabilizer. The storage tubes will be labeled, at a minimum, with Sponsor company, protocol 
number, subject number, sample matrix, study period, study day, scheduled sample time and 
tube number (eg., #1, #2, #3, #4). Tubes will be stored in an upright position in a 
non-self-defrosting freezer with the temperature maintained at approximately -70°C or lower 
until shipment to the designated bioanalytical laboratory where samples will be stored at 
approximately -70°C or lower. Samples should be placed into the freezer within 90 minutes 
of blood collection. 
 
At the end of the study, the first aliquot (Aliquot #1) of each plasma sample will be shipped 
together to the Sponsor’s designated bioanalytical laboratory; while the second aliquot 
(Aliquot #2) will be sent after receipt in good condition of the previous shipment. The other 
aliquots of each sample will be retained at the CRU until further instruction for shipment. 
 
Additional instruction for blood sampling, collection, processing, and sample shipment will 
be provided separately. 
 
11.3.2 
Analytical Method 
 
Samples will be analyzed for plasma MMF using validated bioanalytical methods. Samples 
from subjects to be assayed are specified in Section 12.2.2. 


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11.4 Blood Volume Drawn for Study Assessments 
Table 1: Blood Volume during the Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
 
** If additional safety or PK analysis is necessary or if larger collection tubes are required to obtain sufficient 
plasma/serum for analysis, additional blood may be obtained (up to a maximum of 90 mL). 
Sample Type 
Number of 
Time Points 
Approximate 
Volume per Time 
Point * (mL) 
Approximate Sample 
Volume Over Course of 
Study (mL) 
Screening laboratory safety tests (including 
hematology, serum chemistry, and serology), 
FSH (for postmenopausal female subjects 
only) and serum pregnancy (for female 
subjects only). 
1 
12.5 
12.5 
On-study hematology and serum chemistry 
(this includes serum pregnancy for female 
subjects only when scheduled at the same 
time) 
2 
12.5 
25 
Blood for MMF 
44 
10 
440 
Total Blood Volume (mL)→ 
477.5 ** 


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12 DATA ANALYSIS 
 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
 
12.1 Pharmacokinetic Parameters 
 
PK analysis of plasma concentration vs. time data of MMF will be performed using 
noncompartmental methods with the following parameters calculated as appropriate or data 
permitting: 
 
AUC0-t: 
The area under the concentration-time curve, from time 0 (dosing 
time) to the last time point (tlast) with measureable drug 
concentration, as calculated by the linear trapezoidal method. 
AUC0-inf: 
The area under the concentration-time curve from time 0 (dosing 
time) extrapolated to infinity. AUC0-inf is calculated as the sum 
of AUC0-t plus the ratio of the last measurable drug 
concentration to the apparent terminal first-order decay rate 
constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated from the last time point with 
measurable drug concentration to infinity calculated as 
(1 - AUC0-t/AUC0-inf)*100. 
Cmax: 
Maximum observed drug concentration. 
tmax: 
Time to reach Cmax. If the maximum value occurs at more than 
one time point, tmax is defined as the first time point with this 
value. 
Kel: 
Apparent terminal first-order decay rate constant calculated from 
a semi-log plot of the plasma concentration-time curve. The 
parameter will be calculated by linear least-squares regression 
analysis using at least 3 appropriate time points in the terminal 
log-linear phase. 
t½: 
Apparent plasma half-life which will be calculated as 0.693/Kel. 
 
No value for Kel, AUC0-inf, AUC%extrap, or t½ will be reported for cases that do not 
exhibit an apparent terminal log-linear phase in the concentration-time profile. No PK 
parameters will be calculated for subjects with 3 or fewer consecutive time points with 
detectable concentrations throughout the collection period. 


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12.2 Statistical Methods 
 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by 
Celerion and agreed upon with the Sponsor. This document may modify the plans outlined in 
the protocol; however, any major modifications of the primary endpoints definition and/or its 
analysis will also be reflected in a SAP amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and will be presented 
in the SAP and clinical study report. 
 
12.2.1 
Determination of Sample Size 
 
The sample size was calculated 5 using a power of at least 95% and an alpha error of 5%. The 
power was defined as the probability of having a 90% CI to a Test/Reference ratio within the 
acceptance criteria of 80.00 - 125.00%. A true ratio between 95 - 105% was assumed and an 
intra-subject CV of 24% was used. A total of 50 subjects will be dosed. This includes 6 
additional subjects to account for possible dropouts or non-evaluable data. 
 
12.2.2 
Subjects to Analyze 
 
PK Population: Plasma samples from all subjects will be assayed even if the subjects do not 
complete the study. All subjects who comply sufficiently with the protocol and display an 
evaluable PK profile (e.g., exposure to treatment, availability and validity of measurements, 
and absence of major protocol violations) will be included in the PK analyses to determine 
PK parameters of MMF. Subjects who vomited within 5 hours after drug dosing may be 
excluded from the PK analyses. 
 
Statistical Population: Statistical analysis will be performed on all subjects contributing to 
PK parameters of MFF (Cmax, AUC0-inf, and AUC0-t). However, BE assessment will be 
primarily based on PK parameter data from subjects who complete the study or have 
sufficient data for a pairwise comparison, i.e., from both treatments. 
 
Safety Population: All subjects who received at least one dose of the study drug will be 
included in the safety evaluations. 
 
12.2.3 
Descriptive Statistics 
 
Values will be calculated for the plasma concentrations and the PK parameters listed in 
Section 12.1 using appropriate summary statistics to be fully outlined in the SAP. 
 
12.2.4 
Statistical Analysis 
 
An ANOVA will be performed on the ln-transformed AUC0-t, AUC0-inf, and Cmax using 
SAS® Proc Mixed. The ANOVA model will include sequence, treatment, and period as fixed 
effects, and subject nested within sequence as a random effect. Each ANOVA will include 
calculation of least-squares means (LSM) of the ln-transformed parameter as well as the 
LSM difference between treatments. 


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Ratios of geometric LSM (GLSM) will be calculated using the exponentiation of the 
difference between treatment LSM from the analyses on the ln-transformed AUC0-t, 
AUC0-inf, and Cmax. These ratios will be expressed as a percentage, test relative to the 
reference (Treatment A vs. Treatment B). 
 
Consistent with the two one-sided test, 6 90% CIs for the GLSM ratios will be derived by 
exponentiation of the CIs obtained for the LSM difference between treatments resulting from 
the analyses on the ln-transformed AUC0-t, AUC0-inf, and Cmax. The CIs will be expressed 
as a percentage, test relative to the reference (Treatment A vs. Treatment B). 
 
Bioequivalence criteria will be met if the 90% CIs for the ratios of GLSMs of Cmax and 
AUC0-inf of MMF of the Test (Treatment A) to the Reference (Treatment B) fall within the 
limit of 80.00 and 125.00%. 
 
Time to maximal drug concentration, tmax, will also be analyzed without transformation 
using a non-parametric method (Wilcoxon test). This analysis will only be performed for 
information purpose, not for BE assessment. 
 
Additional details of statistical analysis methods will be included in the SAP. 
 
12.3 Safety Evaluation 
 
All safety data will be populated in the individual CRFs. All safety data will be listed by 
subjects. 
 
Dosing dates and times will be listed by subject. 
 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion and summarized by treatment for the number of 
subjects reporting the TEAE and the number of TEAEs reported. A by-subject AE data 
listing including verbatim term, coded term, treatment, severity, and relationship to treatment 
will be provided. 
 
Safety data including vital signs assessments and clinical laboratory evaluations will be 
summarized by treatment and point of time of collection. 
 
Descriptive statistics using appropriate summary statistics will be calculated for quantitative 
safety data as well as for the difference to baseline, when appropriate. In addition, a shift 
table describing out of normal range shifts will be provided for clinical laboratory results. 
 
Concomitant medications will be listed by subject and coded using the most current version 
of WHO drug dictionary available at Celerion. Medical history will be listed by subject. 


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13 STUDY ADMINISTRATION 
 
13.1 Ethics 
 
13.1.1 
Institutional Review Board 
 
This protocol will be reviewed by the Chesapeake Research Review, Inc. IRB, and the study 
will not start until the IRB has approved the protocol or a modification thereof. The IRB is 
constituted and operates in accordance with the principles and requirements described in the 
US Code of Federal Regulations (21 CFR Part 56). The IRB is compliant to International 
Conference on Harmonisation (ICH) guidelines, and may be reached at: 
 
Chesapeake IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, Maryland 21046, USA 
Tel.: +1 410 884-2900 
 
13.1.2 
Ethical Conduct of the Study 
 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration 
of Helsinki, GCP, and the ICH harmonized tripartite guideline regarding 
GCP (E6 Consolidated Guidance, April 1996). 
 
13.1.3 
Subject Information and Consent 
 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and 
date an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
 
Subjects will be given a copy of their signed ICF. 
 
13.2 Termination of the Study 
 
Celerion reserves the right to terminate the study in the interest of subject welfare. 
 
13.3 Data Quality Assurance 
 
Standard operating procedures are available for all activities performed at Celerion relevant 
to the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, GCP and Good Laboratory Practice requirements as well 
as applicable regulatory requirements and local laws, rules and regulations relating to the 
conduct of the clinical study. 


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The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using SAS® 
or comparable statistical program to check for missing data, data inconsistencies, data ranges, 
etc. Corrections are made prior to database lock. 
 
13.4 Direct Access to Source Data/Documents 
 
Celerion will ensure that the Sponsor, IRB and inspection by domestic and foreign regulatory 
authorities will have direct access to all study-related sites, source data/documents, and 
reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event that 
other study-related monitoring should be done by other parties, they will be required to sign a 
confidentiality agreement prior to any monitoring and auditing. 
 
13.5 Drug Supplies, Packaging and Labeling 
 
The Sponsor will supply sufficient quantities of the study formulations to allow completion 
of this study. The lot numbers and expiration dates (where available) of the study drugs 
supplied will be recorded in the final report. 
 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be retained by Celerion, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies remain, this 
fact will be documented in the pharmacy product accountability records. 
 
13.6 Data Handling and Record Keeping 
 
Celerion standard CRFs will be supplied. CRFs are printed off directly from the database. 
Each CRF is reviewed and signed by the PI. 
 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Celerion until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the Sponsor to 
inform the PI/Institution as to when these documents no longer need to be retained. 
 
13.7 
Report Format 
Per the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 
Expert Working Group), a full final report will be written per the ICH E3 Guideline 
(Structure and Content of Clinical Study Reports). 


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13.8 Publication Policy 
 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 


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14 REFERENCES 
 
1 Tecfidera® (240 mg dimethyl fumarate) delayed-release capsules, full prescribing 
information (electronic monograph) published on the FDA website (document revised: 
Feb/2015). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/ 
204063s014lbl.pdf, accessed on: 17Oct2016. 
 
2 Monomethyl fumarate (200 mg and 95 mg delayed-release capsules). Investigator’s 
Brochure. Banner Life Sciences. 2016. 
 
3 Food and Drug Administration: Center for Drug Evaluation and Research (CDER). 
Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally 
Administered Drug Products - General Considerations (March 2003). Available at: 
http://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail- 
BioEquiv.pdf, accessed on:  17Oct2016. 
4 Food and Drug Administration: Center for Drug Evaluation and Research (CDER). 
Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or 
INDs - General 
Considerations 
(Draft 
March 
2014). 
Available 
at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM389370.pdf, accessed on:  17Oct2016. 
5 Hauschke D, Steinijans VW, Diletti E. and Burke M. Sample size determination for 
bioequivalence assessment using a multiplicative model. J Pharmacokinet Biopharm 
1992;20(5):557-561. 
6 
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm 1987;15: 657-680.