Primary objective* To investigate the plasma pharmacokinetics of the first metabolite of dimethyl fumarate (DMF) - monomethyl fumarate (MMF) - following administration of the delayed- and slow-release FP187-V2B tablet formulation after single dose…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic
Secondary outcome
Bioavailability of a delayed and slow-released DMF formulation;
Safety and tolerability of FP187-V2B
Background summary
Forward Pharma has developed a delayed- and slow-release erosion matrix
formulation, containing only DMF as active ingredient, with the aim of
providing an optimal fumaric acid ester formulation that demonstrates efficacy
while addressing some of the side effects of the delayed immediate-release
formulations. The study is intended to show if there are differences in the
bioavailability, the peak plasma concentration and the related side effect
profile in the fasted state compared to the fed state.
FP187-V2B is a white small biconvex oval tablet with a length of approximately
10 mm, a thickness of approximately 5 mm and a height of approximately 5 mm.
The only active ingredient is 120 mg DMF. DMF is embedded in an erosion matrix
and will be released controlled at the same rate as the matrix is dissolved.
The core tablet is surrounded by a thin enteric coat to prevent the release of
DMF in the stomach but allowing a fast onset of release after the tablet has
reached the upper intestine where the enteric coat dissolves due to the change
in the pH of the environment. Other excipients of the core tablets are:
hydroxypropyl cellulose, lactose monohydrate, colloidal anhydrous silica,
magnesium stearate and for the coating Eudragit® L30 D55, glycerol monohydrate,
triethyl citrate and polysorbate.
Study objective
Primary objective
* To investigate the plasma pharmacokinetics of the first metabolite of
dimethyl fumarate (DMF) - monomethyl fumarate (MMF) - following administration
of the delayed- and slow-release FP187-V2B tablet formulation after single dose
administration under fasted and fed conditions.
Secondary objectives
* To determine the relative bioavailability of MMF from FP187-V2B after single
dose administration under fasted and fed conditions.
* To monitor the safety and tolerability of FP187-V2B based on clinical
investigations, adverse event (AE) reporting and safety laboratory
investigations.
Study design
This study will be conducted as a single center, open-label, Phase I study,
with 2 single dose periods in healthy male and female subjects.
The study will consist of an ambulant screening visit, 2 treatment periods of 3
days each (Day -1 to Day 2), and an ambulant follow-up visit. The subjects will
be hospitalized from the afternoon of Day -1 to the morning of Day 2 of each
period.
Subjects who signed the informed consent form will be screened for eligibility
within 29 to 2 days prior to first study drug administration. Upon
re-confirmation of eligibility (Day -1 of the first treatment period) and
subsequent inclusion into the treatment phase, the subjects will be randomized
to 1 of 2 treatment sequences (see Table 2).
Table 2: Treatment Sequences
Sequence Period 1 Period 2
1 (N=12) A B
2 (N=12) B A
A: 480 mg DMF (4 tablets of 120 mg DMF) as FP187-V2B (fasted)
B: 480 mg DMF (4 tablets of 120 mg DMF) as FP187-V2B (fed)
A single dose of DMF will be administered on Day 1 of each period according to
the randomized treatment sequence. Single dose administrations will be
separated by a washout phase of at least 14 days.
Blood samples for determination of MMF plasma concentrations will be collected
each period until 24 h after single dose administration on Day 1. The subjects
will be discharged from each period after collection of the last
pharmacokinetic sample in the morning of Day 2 if there are no medical
objections.
A follow-up examination will be performed directly after the last drug
administration in the last treatment period.
The trial starts with first subjects signing informed consent and ends with the
last subject undergoing last visit. The total duration of the study is
estimated to be approximately 7 weeks.
Intervention
The study will start with a screening. At the screening a physical examination
will take place and a few other standard medical assessments will be performed
(ECG, vital signs). Furthermore a blood and urine sample will be taken for
laboratory tests and a alcohol breath test and drug screen will be done. During
the stay in the clinic the subject will receive the research medication once on
Day 1. Safety will be monitored and will be assessed throughout the study.
Venous serial blood samples will be collected. The subjects will be asked for
possible side effects on regular basis. A follow-up visit will take place
directly after the last PK sample has been collected.
Study burden and risks
The study drug has been previously administered to humans and was generally
well tolerated. A number of side-effects, possibly linked to administration of
FP187 to healthy volunteers, were reported. These side-effects included
diarrhea, abdominal pain, nausea and flushing (prickling, itching, redness and
sensation of heat starting in the face but can also spread out over more parts
or the whole body).
All these side effects are well known and described for all available
formulations containing DMF, such as Fumaderm® (registered in Germany) or
Psorinovo (available in the Netherlands) for the treatment of psoriasis. It is
also demonstrated over all these years that changes return to normal after the
stop of therapy.
The dose level of 480 mg DMF as a single dose is selected on the basis of
research results in animals and humans. The risk to health at these dose levels
is limited but you may experience one of the above mentioned side-effects or
other symptoms not previously reported. Your health will be closely monitored
during the trial to minimize these risks.
The blood collection procedure is not dangerous, but may cause discomfort or
bruising. Occasionally, fainting, bleeding or an infection at the blood
sampling site can occur.
The trial will be conducted as accurate as possible following the flow chart.
Circumstances can change, for instance by reaction of the body or by new
available information.
Deutscher Platz 5a Deutscher Platz 5a
Leipzig 04103
DE
Deutscher Platz 5a Deutscher Platz 5a
Leipzig 04103
DE
Listed location countries
Age
Inclusion criteria
1. Subject is informed and given ample time and opportunity to think about his participation and has given his/her informed consent in writing.
2. Subject is male or female, Caucasian, and in the age range between 18 and 55 years (inclusive).
3. Females of childbearing potential must be either surgically sterile (hysterectomy or tubal ligation) or use a highly effective (failure rate <1%) medically accepted contraceptive method during the investigational periods as well as 90 days after trial is finished such as:
- Systemic contraceptive (oral, implant, injection),
- Intrauterine device inserted for at least one month prior to trial entrance
- Sexual abstinence or vasectomized partner
4. Male subjects must agree to use a condom with spermicide or abstain from sexual intercourse throughout the trial (including washout intervals between treatment periods) until 90 days after the last dose of trial drug in the last treatment period.
OR
Have been surgically sterilized prior to inclusion.
AND
Agree not to donate sperm during participation in the trial and up to 90 days after follow-up visit.
5. Subject has a body weight of at least 50 kg and a body mass index in the range of 18.5 and 30.0 kg/m2 (inclusive) at screening.
6. Subject is non-smoker or smokes up to 10 cigarettes per day (or equivalent).
7. Subject shows negative alcohol breath test and drug urine test.
8. Subject is in good general health in the opinion of the Investigator, as determined by medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature), 12-lead electrocardiogram (ECG), and clinical laboratory parameters (hematology, clinical chemistry, and urinalysis). Minor deviations of laboratory values from the normal range may be accepted, if judged by the Investigator to have no clinical relevance.
9. Standard liver function tests including ALT, AST, *-GT should not exceed the upper limit of normal for the local laboratory at Screening and Day -1 of Period 1. Minor deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance.
10. Be willing and able to consume the entire high-calorie, high-fat breakfast meal in the designated timeframe required in the designated study period.
11. Subject is willing and able to comply with all conditions and requirements of the study.
12. Subjects who participated in a previous study investigating FP187 are allowed to participate in this study.
Exclusion criteria
1. Subject shows clinically significant abnormalities in physical examination, vital signs, 12-lead ECG, or clinical laboratory parameters (especially for leukocytes and differential count, liver enzymes, and serum creatinine) according to the Investigator*s judgment.
2. Has leukopenia (leukocyte count <3.5 x 109/L) or eosinophilia (count > 0.75 x 109/L) or lymphocytopenia (count <1.02 x 109/L) at screening and Day -1 of Period 1.
3. Has a creatinine value outside the normal range (female: <90 µmol/L; male: <110 µmol/L) and an estimated creatinine clearance (Cockcroft-Gault) <90 mL/min at screening and Day -1 of Period 1.
4. Subject with, or a history of clinically significant neurologic, gastrointestinal, renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, hematological, or other major disorders.
5. Subject who has a supine blood pressure at screening, after resting for at least 5 min: systolic blood pressure >139 or <90 mmHg, or diastolic blood pressure >89 or <55 mmHg.
6. Subject who has a supine pulse rate at screening, after resting for at least 5 min, outside the range of <50 or >90 beats/min.
7. Subject who donated blood (* 500 ml) or plasma (* 100 ml) or had a comparable blood loss (approximately 500 mL) during the last 3 months prior to start of this study and subject who donated more than 1.5 L of blood during the last 10 months prior to start of this study.
8. Subject with a known history of drug allergies or with a known allergy to any medicine chemically related to the study medication.
9. Subject who has had a clinically significant illness within 4 weeks prior to screening.
10. Subject with a history of chronic alcohol (regular intake of more than 35 g ethanol per day) or drug abuse within the last 6 months prior to first administration or evidence of such abuse as indicated by the laboratory profile conducted during the screening examination.
11. Subject who is demonstrating excess in xanthine consumption (more than 6 cups of coffee or equivalent per day).
12. Subject who has received prescription drugs or over-the-counter medication within 2 weeks prior to the first administration (with the exception of up to 1000 mg paracetamol per day).
13. Subject who received any investigational medication within 1 month prior to the first administration or has taken part in 4 (or more) other clinical trials within 10 months prior to the first administration.
14. Subject who received any treatment agents known to alter the major organs or systems within 1 month prior to the first administration (e.g., barbiturates, phenothiazines, cimetidine, etc.).
15. Subject shows positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus (HIV) I/II antibodies and antigen tests.
16. Male subjects and female subjects of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate, i.e., less than 1% per year, when used consistently and correctly (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner) [5]. Female subjects will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation, or post-menopausal for at least 2 years.
17. Female subject who has a positive pregnancy test, is pregnant or lactating, or plans to become pregnant during the course of the study.
18. Male subject who plans to father a child during the course of the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002040-17-NL |
| CCMO | NL57797.056.16 |