Comparative Bioavailability of BAFIERTAM™ (Monomethyl Fumarate) and Tecfidera® (Dimethyl Fumarate) in Healthy Subjects
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Test (BLS-11) A single oral dose administration of BLS-11 190 mg (2 × 95 mg monomethyl fumarate delayed-release capsules) at Hour 0 on Day 1 |
Drug: monomethyl fumarate 190 mg
Other Names:
|
| Active Comparator: Reference (Tecfidera) A single oral dose administration of Tecfidera 240 mg (1 × 240 mg dimethyl fumarate delayed-release capsule) at Hour 0 on Day 1 |
Drug: dimethyl fumarate 240 mg
Other Names:
|
Outcome Measures
Primary Outcome Measures
- The Bioequivalent (BE) Comparison of AUC0-inf of Monomethyl Fumarate (MMF) Between Treatments [24 hours]
Pharmacokinetics: Plasma concentrations of MMF will be determined and used to calculate AUC0-inf MMF for each treatment. Venous blood samples were collected immediately prior to dosing (time 0), and then 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.
- The BE Comparison of Cmax of Monomethyl Fumarate (MMF) Between Treatments [24 hours]
Pharmacokinetics: Plasma concentrations of MMF will be determined and used to calculate the Cmax of MMF for each treatment.Venous blood samples were collected immediately prior to dosing, and then 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Continuous non-smoker who had not used nicotine-containing products for at least 3 months prior to the first dose and throughout the study.
-
Body mass index (BMI) ≥ 18.5 and ≤ 29.9 kg/m2 at Screening.
-
Medically healthy as determined by the Investigator or designee with no clinically significant medical history, physical examination, laboratory profiles, vital signs or electrocardiograms (ECGs), as deemed by the Investigator or designee.
-
Females of childbearing potential: not pregnant and either sexually inactive (abstinent) for 14 days prior to the first dose and throughout the study or using one of the following acceptable birth control methods: hormonal oral contraceptives, vaginal ring, transdermal patch, or nonhormone 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 were advised to remain sexually inactive or to keep the same birth control method for at least 7 days following the last dose.
-
Females of non-childbearing potential: had undergone one of the following sterilization procedures at least 6 months prior to the first dose: hysteroscopic sterilization; bilateral tubal ligation or bilateral salpingectomy; hysterectomy; bilateral oophorectomy or were 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.
-
Non-vasectomized male subjects agreed 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 were required for a vasectomized male provided his vasectomy had been performed 4 months or more prior to the first dose of study drug. A male who had been vasectomized less than 4 months prior to the first dose of study drug, followed the same restrictions as a non-vasectomized male.)
-
Males agreed not to donate sperm from the first dose until 90 days after dosing.
-
Understood the study procedures in the Informed Consent Form (ICF), and were willing and able to comply with the protocol.
Exclusion Criteria:
-
Subject was mentally or legally incapacitated or had significant emotional problems at the time of the Screening visit or expected during the conduct of the study.
-
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator or designee.
-
History of any illness that, in the opinion of the Investigator or designee, might have confounded the results of the study or posed an additional risk to the subject by their participation in the study.
-
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose.
-
History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.
-
Female subjects with a positive serum pregnancy test at Screening or Check-in, or who were lactating.
-
Positive urine drug, alcohol, or cotinine results at Screening or Check-in.
-
Positive results at Screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).
-
Seated blood pressure was less than 90/40 mmHg or greater than 140/90 mmHg at Screening.
-
Seated heart rate was lower than 40 beats per minute (bpm) or higher than 99 bpm at Screening.
-
Abnormal 12-lead ECG deemed clinically significant by the Investigator or designee at Screening or prior to the first dose.
-
Unable to refrain from or anticipated 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 was allowed. Hormone replacement therapy was also allowed. Acetaminophen (up to 2 g per 24-hour period) may have been permitted, as necessary during the study.
-
Had 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.
-
Donation of blood or significant blood loss within 30 days prior to the first dose.
-
Plasma donation within 7 days prior to the first dose.
-
Participation in another clinical study within 28 days prior to the first dose. The 28-day window was derived from the date of the last blood collection or dosing, whichever was later, in the previous study to Day 1 of Period 1 of the current study.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Banner Life Sciences LLC
Investigators
- Study Director: Franck Rousseau, MD, Banner Life Sciences LLC
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- BLS-11-104
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | First Randomization Treatment Sequence AB | First Randomization Treatment Sequence BA |
|---|---|---|
| Arm/Group Description | Treatment A: A single oral dose of BLS-11 190 mg (2 x 95 mg) Treatment B: A single oral dose of Tecfidera® 240 mg (1 × 240 mg) | Treatment B: A single oral dose of Tecfidera® 240 mg (1 × 240 mg) Treatment A: A single oral dose of BLS-11 190 mg (2 x 95 mg) |
| Period Title: Overall Study | ||
| STARTED | 25 | 25 |
| COMPLETED | 24 | 25 |
| NOT COMPLETED | 1 | 0 |
Baseline Characteristics
| Arm/Group Title | Randomization Sequence AB | Randomization Sequence BA | Total |
|---|---|---|---|
| Arm/Group Description | Treatment A: A single oral dose of BLS-11 190 mg (2 x 95 mg) MMF Treatment B: A single oral dose of Tecfidera® 240 mg (1 × 240 mg) DMF | Treatment B: A single oral dose of Tecfidera® 240 mg (1 × 240 mg) DMF Treatment A: A single oral dose of BLS-11 190 mg (2 x 95 mg) MMF | Total of all reporting groups |
| Overall Participants | 25 | 25 | 50 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
34.4
(9.85)
|
38.0
(8.22)
|
36.2
(9.17)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
6
24%
|
8
32%
|
14
28%
|
| Male |
19
76%
|
17
68%
|
36
72%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
15
60%
|
12
48%
|
27
54%
|
| Not Hispanic or Latino |
10
40%
|
13
52%
|
23
46%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
6
24%
|
4
16%
|
10
20%
|
| White |
19
76%
|
19
76%
|
38
76%
|
| More than one race |
0
0%
|
2
8%
|
2
4%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
25
100%
|
25
100%
|
50
100%
|
| Weight (kg) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg] |
72.98
(9.450)
|
74.78
(12.512)
|
74.78
(11.011)
|
| Height (cm) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [cm] |
168.6
(7.55)
|
170.3
(10.58)
|
169.5
(9.14)
|
| Body Mass Index (kg/m^2) (kg/m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg/m^2] |
25.625
(2.4142)
|
25.678
(2.9237)
|
25.651
(2.6537)
|
Outcome Measures
| Title | The Bioequivalent (BE) Comparison of AUC0-inf of Monomethyl Fumarate (MMF) Between Treatments |
|---|---|
| Description | Pharmacokinetics: Plasma concentrations of MMF will be determined and used to calculate AUC0-inf MMF for each treatment. Venous blood samples were collected immediately prior to dosing (time 0), and then 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. |
| Time Frame | 24 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| One subject in the Reference (Tecfidera) group was excluded from AUC0-inf calculations because of missing or unreportable values and was excluded from the statistical analyses. |
| Arm/Group Title | Test (BLS-11) | Reference (Tecfidera) |
|---|---|---|
| Arm/Group Description | A single oral dose administration of BLS-11 190 mg (2 × 95 mg monomethyl fumarate delayed-release capsules) at Hour 0 on Day 1 monomethyl fumarate 190 mg | A single oral dose administration of Tecfidera 240 mg (1 × 240 mg dimethyl fumarate delayed-release capsule) at Hour 0 on Day 1 dimethyl fumarate 240 mg |
| Measure Participants | 49 | 48 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
2984
(25.9)
|
3116
(23.9)
|
| Title | The BE Comparison of Cmax of Monomethyl Fumarate (MMF) Between Treatments |
|---|---|
| Description | Pharmacokinetics: Plasma concentrations of MMF will be determined and used to calculate the Cmax of MMF for each treatment.Venous blood samples were collected immediately prior to dosing, and then 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. |
| Time Frame | 24 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Test (BLS-11) | Reference (Tecfidera) |
|---|---|---|
| Arm/Group Description | A single oral dose administration of BLS-11 190 mg (2 × 95 mg monomethyl fumarate delayed-release capsules) at Hour 0 on Day 1 monomethyl fumarate 190 mg | A single oral dose administration of Tecfidera 240 mg (1 × 240 mg dimethyl fumarate delayed-release capsule) at Hour 0 on Day 1 dimethyl fumarate 240 mg |
| Measure Participants | 49 | 49 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
1760
(34.8)
|
1680
(33.8)
|
Adverse Events
| Time Frame | 7 days | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Test (BLS-11) | Reference (Tecfidera) | ||
| Arm/Group Description | A single oral dose administration of BLS-11 190 mg (2 × 95 mg monomethyl fumarate delayed-release capsules) at Hour 0 on Day 1 monomethyl fumarate 190 mg | A single oral dose administration of Tecfidera 240 mg (1 × 240 mg dimethyl fumarate delayed-release capsule) at Hour 0 on Day 1 dimethyl fumarate 240 mg | ||
All Cause Mortality |
||||
| Test (BLS-11) | Reference (Tecfidera) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/50 (0%) | 0/49 (0%) | ||
Serious Adverse Events |
||||
| Test (BLS-11) | Reference (Tecfidera) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/50 (0%) | 0/49 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Test (BLS-11) | Reference (Tecfidera) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 31/50 (62%) | 29/49 (59.2%) | ||
| Cardiac disorders | ||||
| Palpitations | 1/50 (2%) | 0/49 (0%) | ||
| Gastrointestinal disorders | ||||
| Abdominal distension | 0/50 (0%) | 1/49 (2%) | ||
| Abdominal pain | 1/50 (2%) | 0/49 (0%) | ||
| Abdominal pain upper | 0/50 (0%) | 1/49 (2%) | ||
| Diarrhea | 0/50 (0%) | 2/49 (4.1%) | ||
| Nausea | 0/50 (0%) | 1/49 (2%) | ||
| General disorders | ||||
| Chills | 1/50 (2%) | 0/49 (0%) | ||
| Feeling Hot | 1/50 (2%) | 0/49 (0%) | ||
| Vessel puncture site erythema | 0/50 (0%) | 1/49 (2%) | ||
| Vessel puncture site pain | 0/50 (0%) | 1/49 (2%) | ||
| Vessel puncture site swelling | 0/50 (0%) | 1/49 (2%) | ||
| Nervous system disorders | ||||
| Dizziness | 1/50 (2%) | 0/49 (0%) | ||
| Hypoaesthesia | 1/50 (2%) | 0/49 (0%) | ||
| Psychiatric disorders | ||||
| Anxiety | 1/50 (2%) | 0/49 (0%) | ||
| Euphoric mood | 1/50 (2%) | 0/49 (0%) | ||
| Reproductive system and breast disorders | ||||
| Metrorrhagia | 1/50 (2%) | 0/49 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Nasal congestion | 0/50 (0%) | 2/49 (4.1%) | ||
| Rhinorrhoea | 1/50 (2%) | 0/49 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Pruritus generalised | 1/50 (2%) | 0/49 (0%) | ||
| Skin fissures | 1/50 (2%) | 1/49 (2%) | ||
| Vascular disorders | ||||
| Flushing | 30/50 (60%) | 25/49 (51%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Thomas Lategan, PhD |
|---|---|
| Organization | Banner Life Sciences LLC |
| Phone | 3368990959 |
| thomas.lategan@bannerls.com |
- BLS-11-104