The main purpose of the study is to assess immune cell dynamics in Tecfidera-treated MS patients and untreated healthy subjects, and to explore whether differences in immune cell dynamics exist between both populations. The data generated in this…
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Brief title
Condition
- White blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Standard safety:
- nature, frequency, and severity of adverse events;
- concomitant medication.
Immuno-monitoring:
- total leukocyte count and (automated) differential count;
- immunophenotyping for absolute cell counts of the target populations (CD4+
T-cells, naïve and memory CD8+ T-cells, CD19+ B-cells) from whole blood,
including Annexin V expression and PI incorporation (FACS);
- mitochondrial membrane potential for target populations (Mitoscreen according
to GBS SOP T272E, from PBMCs, when sufficient material is available);
- lymphocyte dynamics per isolated target population* (deuterium incorporation
by GCMS, after immunomagnetic purification of target populations from PBMCs):
o production rate;
o disappearance rate.
* also requires assessment of deuterium enrichment in granulocytes and
deuterium enrichment in urine (GCMS)
The specific markers mentioned above are indicative. Other or additional
markers may be selected, as long as no deviation is made from the number and
volume of blood samples reported in the study protocol.
Secondary outcome
Protein or lipid composition and incorporation of deuterium in stratum corneum
proteins or lipids, including ceramides and other lipid classes.
Background summary
Early 2013, Tecfidera (dimethyl fumarate, DMF) was approved by the European
Medicine Agency (EMA) as oral treatment for adult patients with relapsing
remitting multiple sclerosis (RRMS). In clinical studies in RRMS patients,
Tecfidera treatment resulted in a clinically meaningful and statistically
significant reduction disease relapse (Fox et al., 2012; Gold et al., 2012)
Long-term treatment with Tecfidera may result in reductions in lymphocyte
counts (Spencer et al., 2015; Rosenkranz et al., 2015; Khatri et al., 2015;
Berkovich et al., 2015). DMF-induced reduction in lymphocyte counts does not
appear to be disease-related since reductions in lymphocyte counts are also
observed in DMF-treated psoriasis patients (Harries et al., 2005; Wain et al.,
2010). Although some mechanistic insight is available on the immune-modulating
activity of DMF, detailed insight into the specific time course of the drug
effects is lacking. Moreover, neither the exact causes nor the functional
consequences of DMF-induced reductions in lymphocyte counts have been
documented. Therefore, dedicated clinical studies are proposed to gain this
information.
It is not known whether the Tecfidera-induced reductions in blood lymphocyte
counts can be explained by a diminished production, by an enhanced cell death,
or by homing of the immune cells to lymphoid tissues. To obtain mechanistic
insight into the Tecfidera-induced reductions in lymphocyte counts, circulating
lymphocytes can be labelled in vivo with deuterium. This procedure will allow
quantification of the production rate and disappearance rate of the cell
populations of interest. By combining these cell kinetic parameters with
cellular markers for cellular stress (mitochondrial dysfunction) and cell death
and, we aim to investigate whether reduced lymphocyte numbers in
Tecfidera-treated RRMS patients are explained by a reduced production rate, or
a shorter life span due to cell death. In vivo deuterium labeling of human
immune cells has been performed before, both in healthy volunteers and in
patient populations (Vrisekoop et al., 2008; Westera et al., 2015; Hellerstein
et al., 2003). The clinical study described in this protocol aims to assess
immune cell dynamics in Tecfidera-treated MS patients and untreated healthy
subjects, and will explore whether differences in immune cell dynamics exist
between both populations. Based on the data generated in this clinical study, a
subsequent clinical study may be designed exploring the effects of Tecfidera on
lymphocyte counts and dynamics in a more controlled setting.
Apart from the main study objective (exploration of differences in immune cell
dynamics between healthy subjects and Tecfidera-treated MS patients), this
study will also explore the protein or ceramide kinetics in tape stripped skin
from healthy subjects. This tape stripping is non-invasive and not directly
related to Tecfidera effects, and is intended to explore a non-invasive method
for assessment of the epidermal protein or lipid synthesis. Future application
of this methodology could provide insight into the mechanisms and dynamic
processes underlying skin (patho)physiology, and allow objective quantification
of the response to therapeutic agents in clinical trials.
Study objective
The main purpose of the study is to assess immune cell dynamics in
Tecfidera-treated MS patients and untreated healthy subjects, and to explore
whether differences in immune cell dynamics exist between both populations. The
data generated in this clinical study may support the design and specific
methodology of a subsequent clinical study exploring Tecfidera effects on
lymphocyte counts and dynamics in a more controlled setting.
Primary objectives:
1. Quantification of CD4+, naive and memory CD8+ T-cell and CD19+ B-cell
numbers in Tecfidera-treated MS patients and untreated healthy subjects over
time;
2. Quantification of production and disappearance rates of CD4+, naive and
memory CD8+ T-cells and CD19+ B-cells in Tecfidera-treated MS patients and
untreated healthy subjects;
3. Assessment of markers for cell death and cellular stress, in relation to
cell production and disappearance rates.
Secondary objective:
Quantification of protein or ceramide kinetics in tape stripped skin from
healthy subjects (unrelated to Tefidera effects; independent objective):
exploration of a non-invasive method for assessment of epidermal protein
synthesis, which can also be adapted to measure epidermal lipids. This
methodology could serve as a tool providing insight into the mechanisms and
dynamic processes underlying skin (patho)physiology, and as an objective scale
for quantification of the response to therapeutic agents in clinical trials.
Study design
This is a prospective, single-center, observational study. Eight MS patients
receiving Tecfidera treatment for at least six months will be enrolled. In
addition, eight age- and gender-matched healthy subjects will be included. No
pharmacological intervention will be performed, but all study participants will
receive an investigational product (deuterated water) for the quantification of
production and disappearance rate of circulating immune cells.
In addition, tape stripping will also be performed on the healthy volunteers.
Intervention
All subjects enrolled in this study will be administered deuterated water for 9
weeks. The administration of deuterated water is a methodological intervention,
and as such deuterated water is not regarded as investigational product.
Study burden and risks
Burden: Deuterated water administration, measurements, blood sampling,
compliance with strict lifestyle restrictions and time investment.
Risks: potential side effects of deuterated water and potential complaints
caused by being fasted and blood sample collection.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria, MS patients
- male and female subjects;
- minimal age 18 years at the time of informed consent;
- confirmed relapsing remitting multiple sclerosis (RRMS) patients, with:
- a diagnosis of RRMS according to the revised McDonald criteria;
- a baseline score of 0 to 5.0 on the Expanded Disability Status Scale;
- patients on Tecfidera treatment for at least 6 months;
- ability to participate, and willingness to give written informed consent and to comply with the study restrictions and protocol requirements.;Inclusion criteria, healthy subjects
- healthy male and female subjects;
- minimal age of 18 years at the time of informed consent;
- ability to participate, and willingness to give written informed consent and to comply with the study restrictions and protocol requirements.
Exclusion criteria
Exclusion criteria, MS patients
- positive test result for human immunodeficiency virus antibody (HIV-Ab), hepatitis C antibody (HCV-Ab), and/or hepatitis B surface antigen (HbsAg) at screening;
- evidence of any active or chronic disease or condition, other than MS (based on medical history, a physical examination, vital signs, 12 lead ECG, haematology, blood chemistry and urinalysis) that could, in the opinion of the investigator, interfere with the conduct of the study or the study objectives, or pose an unacceptable risk to the subject;
- a treatment history that includes steroids within one month prior to screening, or any other therapy that in the judgment of the investigator potentially interferes with the study objectives (in case of an insufficient washout period);
- body weight < 50 kg.
- subject is pregnant or breast feeding;
- current substance abuse, including alcohol and drugs;
- positive alcohol test or test for drugs of abuse at screening, with the exception of a positive test due to medicinal cannabis use;
- previous deuterium administration;
- participation in an investigational drug or device study within 3 months prior to screening;
- loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening;
- unwillingness or inability to comply with the study protocol for any other reason.;Exclusion criteria, healthy subjects
- positive test result for human immunodeficiency virus antibody (HIV-Ab), hepatitis C antibody (HCV-Ab), and/or hepatitis B surface antigen (HbsAg) at screening;
- evidence of any active or chronic disease or condition (based on medical history, a physical examination, vital signs, 12 lead ECG, haematology, blood chemistry and urinalysis) that could, in the opinion of the investigator, interfere with the conduct of the study or the study objectives, or pose an unacceptable risk to the subjects;
- a treatment history that includes steroids within 1 months prior to screening, or any other therapy that in the judgment of the investigator potentially interferes with the study objectives (in case of an insufficient washout period);
- body weight < 50 kg;
- subject is pregnant or breast feeding;
- current substance abuse, including alcohol and drugs;
- positive alcohol test or test for drugs of abuse at screening;
- previous deuterium administration;
- participation in an investigational drug or device study within 3 months prior to screening;
- loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening;
- unwillingness or inability to comply with the study protocol for any other reason.
Design
Recruitment
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 |
|---|---|
| CCMO | NL55042.056.15 |