Based on the effects of Tα1 on immune cell function, the known disturbances in T lymphocyte numbers and subsets in patients with CVID and the increased prevalence of mood disorders in these patients the following research questions have been…
ID
Source
Brief title
Condition
- Immunodeficiency syndromes
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint of this study will be the increase in absolute and relative
numbers of peripheral blood T regulatory cells, measured after 8 weeks of
treatment and 8 weeks after termination of the clinical study
Secondary outcome
Secondary endpoints include:
EFFICACY
1) Change in depression scores (Hamilton Depression Scale (HAM-D) scores) from
baseline to week 6 and 12 and at 6 weeks after termination of the clinical
study.
2) Change in fatigue scores (Fatigue Severity Scale (FSS)) from baseline to
week 6 and 12 and at 6 weeks after termination of the clinical study.
3) Increase/decrease in numbers of Th1, Th2 and Th17 cells
4) Increase in the balance between naïve and memory T helper cells
5) Alterations in the balance between the Th17/T regulatory cells
6) Decrease in inflammatory gene expression (cluster 1 and 2 gene expression)
in circulating leukocytes
7) Decrease in circulating levels of hCRP, IL-6, CCL2, PTX-3, sCD25, SCF, BDNF
8) Change in health-related quality of life (as measured by the CVID_QoL
Questionnaire)
SAFETY
9) Frequency and type of adverse events
10) Lab tests: mean change and frequency of values outside the normal range
Background summary
Primary antibody deficiency (PAD) : Common Variable Immune Deficiency (CVID)
Primary antibody deficiency (PAD) is an umbrella term encompassing a broad
array of primary immunodeficiency diseases collectively characterized by a
quantitative and/or qualitative impairment of antibody production {Quinti, 2016
#1}. Common variable immune deficiency (CVID) is the most common symptomatic
form of PAD in adults {Geha, 2007 #2}.
CVID shows heterogeneous clinical phenotypes with infections, autoimmune
disorders, granulomatous and inflammatory diseases and cancers {Chapel, 2008
#3;Verma, 2015 #4}. Current treatment options to prevent infections and treat
complications include (prophylactic) antibiotics, immunoglobulin replacement
therapy and immunomodulatory drugs {Bonilla, 2016 #5;Hoernes, 2011
#7;Kuruvilla, 2013 #6}.
Although scarcely studied it has been well recognized that patients with CVID
are at increased risk for development of depression and/or anxiety disorders.
In a cohort of 96 CVID patients it was shown that one-third of CVID patients
were at risk for depression/anxiety {Hajjar, 2017 #9}. In a recent survey among
over 2500 PAD patients in the United States, depression was also overreported
{Hajjar, 2017 #9}. It has been hypothesized that the increased risk of mood
disorders in PAD patients is related to disease-associated morbidity (amongst
others infections, auto-immune disease) and (subsequent) increased loss of days
at work or school and the impact on social life.
However, in recent years it has become more clear that a significant number of
patients with CVID (approximately 20-25%) also show disturbed T lymphocyte
subset distribution and function {Arandi, 2013 #12;Azizi, 2016 #10;Bateman,
2012 #13;Kutukculer, 2016 #11}, which not only explains the increased risk of
(viral) infections and autoimmune complications in these patients but may also
be directly related to the increased risk of mood disorders, as in recent
studies it has been demonstrated that in patients with recurrent mood disorders
inborn T cell defects are present that elicit an aberrant (auto)inflammatory
state of monocytes/macrophages/microglia which in turn results in disturbed
normal frontal brain-hippocampus development and communication leading to
severe mood dysregulations. Partial T cell defects lead to maturation defects
in the CD4+ T helper lineage and in particular to reduced numbers of T
regulatory cells and Th17 cells. It has been hypothesized that the dysregulated
cellular immune responsiveness in lymphocytes could play a role in mood
disorders {Grosse, 2016 #14;Snijders, 2016 #15}. Interestingly, unipolar
depressed patients with severe T cell defects do not respond to treatment with
conventional anti-depressants like selective serotonin-reuptake inhibitors
(SSRIs) and the question arises whether these patients with underlying T cell
defects might benefit from a T-cell enforcing treatment strategy, by promoting
T cell restoration.
Based on the concomitant presence of mood disorders and T lymphocyte subset
disturbances in CVID and based on the current knowledge on T lymphocyte subset
defects, particularly a decrease in regulatory T cells, in mood disorders we
hypothesize that restoration of T lymphocyte subsets in CVID patients could
improve mood disorders. We therefore aim to set up a clinical trial with
thymosin α1 (thymalfasin).
Thymosin α1 (Tα1, thymalfasin)
Tα1 is a 28-amino acid peptide physiologically present in the human body and
originally isolated from the thymus as one of the compounds of a crude thymus
hormone preparation responsible for restoring immune function to thymectomized
mice characterized by T lymphocyte defects. Tα1 shows strong immune modulating
effects. It exerts its immune-modulating activity through the interaction with
Toll-like receptors (TLR), a group of proteins involved in the regulation of
innate immunity, and in particular with TLR9 and TLR2 on dendritic cells (DCs)
and precursor T-cells {Romani, 2007 #24;Romani, 2006 #25}, activating
intracellular signaling pathways such as NF-*B, p38 MAPK, and the
MyD88-dependent pathway {Bistoni, 1982 #26;Peng, 2008 #27;Zhang, 2005 #28}. Tα1
is also able to prevent a pro-inflammatory cytokine storm and possibly
autoimmune events through the activation of indoleamine-2,3-dioxygenase in
plasmacytoid DCs resulting in an increase of regulatory T-cells that ultimately
inhibit the excess of cytokine production {Romani, 2007 #24;Romani, 2006
#25;Xiang, 2014 #29}. Due to the immune stimulating effects of Tα1, the
compound would be expected to show utility for treatment of immune
deficiencies, in particular of T lymphocyte mediated immunodeficiencies.
Although the compound is produced by Sciclone and has been registered in
South-East Asia and China as an enforcement therapy for hepatitis vaccination
and in the treatment of certain cancers, it has only sparsely been used in
immune deficiency syndromes (due to the non-availability in the US and Europe).
A single child with 22q11.2DS was treated with Tα1 {Gupta, 1998 #30}. Blood
cells were taken from this 13-month-old infant before and after 3 months of
treatment with Tα1 and examined for evidence of lymphocyte apoptosis compared
to an age matched healthy control. Prior to treatment with Ta1, the subject
showed increased apoptosis (increased Fas and FasL, decreased Bcl-2 in both CD4
and CD8 cells, increased DNA fragmentation); after treatment with Tα1 the
proportion of lymphocytes undergoing apoptosis decreased. The T lymphocyte
responses (response to mitogen) also improved after treatment, and the subject
showed a marked clinical improvement evidenced by a significant decrease in
infections. No adverse experiences associated with Tα1 were reported in this
patient.
Study objective
Based on the effects of Tα1 on immune cell function, the known disturbances in
T lymphocyte numbers and subsets in patients with CVID and the increased
prevalence of mood disorders in these patients the following research questions
have been postulated:
1) Does Tα1 restore disturbed T lymphocyte (regulatory T cell) populations in
patients with CVID ?
2) Is Tα1 an effective treatment option for mood disorders in CVID patients
with disturbed T lymphocyte populations?
Primary objective
The primary objective of this study is to evaluate in CVID patients with mood
disorders the effect of Tα1 on the increase in absolute and relative number of
T regulatory cells
Secondary objectives
Secondary objectives include:
- Changes in T lymphocyte subset patterns
- Changes in levels of markers of inflammation
- Improvements in depression, fatigue and quality of life scores
- Assessment of adverse events.
Study design
An open-label, single center, 8-week, proof-of-concept trial of thymosin-α1
(thymalfasin) in patients with common variable immune deficiency associated
mood disorders will be conducted.
Patients will be treated according to the following schemes:
Thymosin-α1 (Zadaxin) 1.6 mg subcutaneously once daily for 1 week followed by
subcutaneous administration twice a week for 7 weeks
Intervention
In this 8-week open-label study, patients will be treated for 8 weeks with
Zadaxin, by subcutaneous injections, starting with once daily injections for
one week followed by 2 injections per week for 7 weeks,1.6 mg
Study burden and risks
Study participants will be screened for eligibility at the outpatient clinics
of their hospital.
Baseline visit and visits 8 and 16 weeks after initiation of study treatment
will include blood drawings (43 ml per visit) and questionnaires.
The study drug is registered for use in several countries worldwide and side
effects/adverse effects in previous studies were found to be limited.
Also in clinical practice, adverse effects are limited.
Benefits for the patients would be the potential clinical improvement in mood
disorders, by introducing this immunomodulatory, targeted therapy.
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
Written informed consent must be obtained before any assessment is performed.
Suffering from the following condition
Common variable immunodeficiency (CVID), with an established diagnosis
according to the diagnostic criteria from the European Society for
Immunodeficiences (ESID) 2014, in accordance with the International Union of
Immunological Societies (IUIS).
Presence of a depressive mood disorder as determined by the Hamilton Rating
Scale for Depression (HAM-D) (above 12).
Age between 18 and 75.
In case of concomitant use of classical (tricyclic) or non-tricyclic
antidepressants (SSRI, SNRI, MAOI, other), with or without mood stabilizer: a
stable dosing regimen for a duration of at least 12 weeks prior to inclusion in
the clinical study
Exclusion criteria
- Active, concomitant autoimmune disease manifestations
- Renal insufficieny definied by a creatinine clearance of less than 30 ml/min
(CKD-EPI or MDRD formula)
- Hepatic impairment, i.e. unexplained persistent liver function abnormalities
- Laboratory parameters at the pre-treatment visit showing any of the following
abnormal results: transaminases > 2x the upper limit of normal (ULN) and/or
bilirubin > 2x ULN
- Severe cardiac (LVEF < 45%) and/or pulmonary disease (FVC <50%)
- History of heart failure, symptomatic coronary artery disease, significant
ventricular
- tachyarrhythmia, stent placement, coronary artery bypass surgery, and/or
myocardial infarction
- Use of other investigational drugs, within 5 half-lives of enrollment or
within 30 days, whichever is longer
- History of hypersensitivity to any of the study treatments or excipients or
to drugs of similar chemical classes.
- Pregnant or nursing (lactating) women, where pregnancy is defined as the
state of a female after conception and until the termination of gestation.
- Women of child-bearing potential, defined as all women physiologically
capable of
becoming pregnant, unless they are using highly effective methods of
contraception
during dosing and for 2 days after last dose of study medication. Highly
effective
contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle
of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal,
postovulation methods) and withdrawal are not acceptable methods of
contraception.
- Female sterilization (have had surgical bilateral oophorectomy with or
without hysterectomy) or total hysterectomy or tubal ligation at least 6 weeks
before taking study treatment. In case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level
assessment.
- Male sterilization (at least 6 months prior to screening). For female
patients on the study, the vasectomized male partner should be the sole partner
for that patient.
- Use of oral, injected or implanted hormonal methods of contraception or
placement of an intrauterine device (IUD) or intrauterine system (IUS) or other
forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone contraception.,
In case of use of oral contraception women should have been stable on the same
pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not in of child bearing potential if
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy or tubal ligation at least six weeks ago. In the case of
oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level
assessment she is considered not of child bearing potential., - History of
malignancy within the last 5 years, except for resected basal or squamous cell
carcinoma of the skin, treated cervical dysplasia, or treated in situ cervical
cancer.
- Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule. , - Any condition or treatment, which in the opinion of the
investigator, places the subject at unacceptable risk as a patient in the
trial.
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 | EUCTR2021-003327-15-NL |
| CCMO | NL78339.078.21 |