Primary Objective:* To evaluate the long-term safety of efgartigimod in adult patients with primary immune thrombocytopenia (ITP).Secondary Objectives:First 52-week treatment period only:* To evaluate the long-term efficacy of efgartigimod on…
ID
Source
Brief title
2682/0012
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Frequency and severity of AEs, vital signs, and laboratory assessments.
Secondary outcome
First 52-week treatment period only:
1. Extent of disease control defined as the percentage of weeks in the trial
with platelet counts of *50×10^9/L.
2. Percentage of patients with overall platelet count response defined as
achieving a platelet count of *50×10^9/L on at least 4 occasions at any time
during the 52-week treatment period.
3. Mean change from baseline in platelet count at each visit.
4. For patients rolling-over from the ARGX-113-1801 trial with a platelet count
of <30×10^9/L: time to response is defined as the time to achieve 2 consecutive
platelet counts of *50×10^9/L.
5. The percentage of weeks in the with platelet counts of *30×10^9/L and at
least 20×10^9/L above baseline.
6. In patients with baseline platelet count of <15×10^9/L in the current trial
(ARGX-113-1803), the percentage of weeks in the trial with platelet counts of
*30×10^9/L and at least 20×10^9/L above baseline.
7. In patients with first exposure to efgartigimod: proportion of patients who
achieve a sustained platelet response defined as achieving platelet counts of
at least 50×10^9/L for at least 4 of the 6 visits between week 19 and 24 of the
trial.
8. In patients with first exposure to efgartigimod: proportion of patients in
the overall population achieving platelet counts of at least 50×10^9/L for at
least 6 of the 8 visits between week 17 and 24 of the trial.
9. Rate of receipt of rescue therapy (rescue per patient per month).
10. Reduction in concurrent ITP therapy.
11. Incidence and severity of the WHO-classified bleeding events.
12. Change from baseline in PRO (FACIT-Fatigue, Fact-Th6) and QoL (SF-36) at
planned visits.
13. Pharmacokinetic parameter of efgartigimod: serum concentration observed
predose (Ctrough).
14. Pharmacodynamics markers: total IgG.
First 52-week treatment period and additional 52-week treatment periods:
15. Incidence of anti-drug antibodies (ADA) to efgartigimod.
Background summary
Efgartigimod (ARGX-113) is a modified human immunoglobulin (Ig) G1-derived
crystallized fragment (Fc) of the za allotype that binds with nanomolar
affinity to the human neonatal crystallized fragment receptor (FcRn). Given the
essential role of the FcRn receptor in IgG homeostasis, inhibiting this FcRn
function, as is achieved by efgartigimod, leads to rapid degradation of all
IgGs, including disease-associated autoantibodies of the IgG isotype. This
approach is thought to result in alleviation of signs and symptoms in
IgG-driven autoimmune diseases. Phase 2 trials in immune thrombocytopenia (ITP)
and myasthenia gravis (MG) have indicated that efgartigimod administered by IV
infusion is well tolerated; induces a specific, rapid, and profound PD effect
(i.e. reduction in IgG levels, including autoantibody levels); and is
associated with improvement in clinical signs and symptoms in ITP and MG
patients, separately. Additionally, the safety and tolerability of efgartigimod
is currently being evaluated for the treatment of patients with pemphigus in a
phase 2 trial.
Primary ITP is an acquired autoimmune bleeding disorder characterized by an
isolated low platelet count (<100×10^9/L) in the absence of other causes or
disorders associated with thrombocytopenia. Prevalence of ITP is estimated at
9.5 per 100,000 adults, and incidence rates have been reported at 3.3 adults
per 100,000 years. In adults, the prevalence of ITP increases with age. Adult
ITP can persist for years. Even with best available care, patients rarely
achieve long-term remission, and often require multiple treatment options.
Targeted and selective IgG reduction, as achieved by efgartigimod, has the
potential as an effective new treatment in ITP seen the central role of IgG
autoantibodies in the pathophysiology of ITP. It represents a novel mechanism
of action distinct from that of other existing treatments which are either
broadly immunosuppressive or stimulate thrombopoiesis.
Please refer to protocol section 1.1 for further details
Study objective
Primary Objective:
* To evaluate the long-term safety of efgartigimod in adult patients with
primary immune thrombocytopenia (ITP).
Secondary Objectives:
First 52-week treatment period only:
* To evaluate the long-term efficacy of efgartigimod on overall platelet count
response.
* To explore the potential for reduction in concurrent ITP therapy.
* To evaluate the effects of efgartigimod treatment on quality-of-life (QoL)
measures and patient-reported outcomes (PRO).
To evaluate the incidence and severity of bleeding events while receiving
treatment with efgartigimod.
To evaluate the use of rescue treatment while receiving treatment with
efgartigimod.
* To assess the pharmacodynamic (PD) effects of efgartigimod.
* To evaluate the pharmacokinetics (PK) of efgartigimod.
First 52-week treatment period and additional 52-week treatment periods:
* To assess the immunogenicity of efgartigimod.
Study design
(This is a summary, for more detailed information please refer to the protocol)
This is a phase 3, multicenter, open-label, long-term extension of the phase 3
randomized, double-blinded, placebo-controlled, parallel-group trial
(ARGX-113-1801; ADVANCE) to evaluate the safety and efficacy of efgartigimod 10
mg/kg intravenous (IV) treatment in adult patients with primary ITP.
The target population is the patients from the ARGX-113-1801 trial Patients
will be offered the opportunity to enroll in this trial if they completed the
24 week trial period in trial ARGX-113-1801.
CHANGE IN EFGARTIGIMOD DOSING FREQUENCY
The assessment of dosing frequency of IV infusions of efgartigimod 10 mg/kg
will continue as in the ARGX-113-1801 trial (i.e. weekly or every other week
[q2w]). If patients were on a fixed dosing frequency in the ARGX-113-1801
trial, a change in dosing frequency is permitted as from visit 1 (baseline).
EARLY DISCONTINUATION
Patients who have an *insufficient response* by visit 12 will exit the trial.
An *insufficient response* is defined as a platelet count of <30×10^9/L in all
of the last 4 visits between visit 9 and visit 12 (both visits inclusive).
Any patient prematurely discontinuing the trial (with the exception of patients
who withrdraw their consent) should perform the assessments listed for the
Early Discontinuation visit 1 week after the last visit performed in the
treatment period as specified in the SoA (Table 1) and complete the 4-week
treatment-free follow-up after the Early Discontinuation visit.
SAMPLE SIZE
The maximum number of patients will be the number of patients who completed the
24-week trial period of the ARGX-113-1801 trial.
CONCURRENT ITP THERAPY
As from the start of the trial, for patients already receiving permitted
concurrent ITP therapy, a decrease in the dose and/or schedule of permitted
concurrent ITP therapy is allowed (permitted concurrent ITP medications include
oral corticosteroids, oral immunosuppressants, dapsone/danazol, fostamatinib,
and/or oral thrombopoietin receptor agonists [TPO-RAs]).
New concurrent ITP therapy cannot be started.
RESCUE THERAPY
Rescue therapy is allowed post-baseline and throughout the trial for patients
with a platelet count of <30×10^9/L and 1 of the following:
- an immediate risk of bleeding or a clinically significant bleeding, or wet
purpura
- requirement for urgent or emergent surgery (elective surgeries must be
postponed until trial completion)
Intervention
IV infusions of efgartigimod 10 mg/kg will continue as in the ARGX-113-1801
trial (i.e. weekly or biweekly). If patients were on a fixed dosing frequency
in the ARGX-113-1801 trial, a change in dosing frequency is permitted as from
visit 1 (baseline).
Study burden and risks
Efgartigimod has been shown to effectively reduce IgG antibodies in several
clinical trials, including healthy volunteers, patients with MG, and with ITP.
In clinical trials to date, efgartigimod has been well-tolerated in healthy
adult subjects and patients with MG and ITP, separately: the majority of
treatment-emergent AEs (TEAEs) were considered to be mild (grade 1) in
severity. In the completed phase 1 trials ARGX 113 1501, ARGX 113 1702, and
ARGX 113 1901 in healthy volunteers, and in the phase 2 trial ARGX-113-1602 in
patients with MG, no grade *3 TEAEs were reported and no TEAE led to
discontinuation. In patients with ITP, 1 TEAE with grade 4 was reported
(thrombocytopenia), considered unrelated to treatment, and led to treatment
discontinuation.
No clinically significant changes in vital signs and/or electrocardiogram (ECG)
findings have been observed in clinical trials to date.
Safety for use during pregnancy has not been established. Therefore,
efgartigimod should not be administered to pregnant or lactating women.
Reproductive toxicity trials are completed and in reporting phase.
Please refer to protocol section 1.2 for further details.
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Listed location countries
Age
Inclusion criteria
1. Ability to understand the requirements of the trial, to provide written
informed consent (including consent for the use and disclosure of
research-related health information), and to comply with the trial protocol
procedures (including required trial visits).
2. Patients enrolled in the ARGX-113-1801 trial who completed the 24 week trial
period.
3. Women of childbearing potential must have a negative urine pregnancy test at
baseline before trial medication (infusion) can be administered. Women are
considered of childbearing potential unless they are post-menopausal (defined
by continuous amenorrhea) for at least 1 year with a follicle-stimulating
hormone (FSH) of >40 IU/L or are surgically sterilized (i.e. women who had a
hysterectomy, a bilateral salpingectomy, both ovaries surgically removed, or
have a documented permanent female sterilization procedure including tubal
ligation). Follicle-stimulating hormone can be used to confirm post-menopausal
status in amenorrheic patients not on hormonal replacement therapy.
4. Women of childbearing potential should use a highly effective or acceptable
method of contraception during the trial and for 90 days after the last
administration of the IMP. They must be on a stable regimen, for at least 1
month:
* combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation
o oral
o Intravaginal
o Transdermal
* progestogen-only hormonal contraception associated with inhibition of
ovulation:
o Oral
o Injectable
o Implantable
* intrauterine device (IUD)
* intrauterine hormone-releasing system
* bilateral tubal occlusion
* vasectomized partner (provided that the partner is the sole sexual partner of
the trial participant and that aspermia was documented post procedure)
* continuous abstinence from heterosexual sexual contact. Sexual abstinence is
only allowable if it is the preferred and usual lifestyle of the patient.
Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not
acceptable.
* male or female condom with or without spermicide
* cap, diaphragm, or sponge with spermicide
5. Non-sterilized male patients who are sexually active with a female partner
of childbearing potential must use an acceptable method of contraception, ie, a
condom. Male patients practicing true sexual abstinence (when this is in line
with the preferred and usual lifestyle of the participant) can be included.
Sterilized male patients who have had vasectomy with documented aspermia post
procedure can be included. In addition, male patients are not allowed to donate
sperm during this period from signing of informed consent form, throughout the
duration of the trial, and for 90 days after the last administration of IMP.
In addition to the above criteria, for patient who want to continue receiving
efgartigimod during an additional 52-week treatment period (only applicable in
case efgartigimod is not yet commercially available for patients with primary
ITP, or becomes available through another patient program for patients with
primary ITP:
6. Ability to understand the requirements of the additional 52-week treatment
period of the trial, to provide written informed consent (including consent for
the use and disclosure of research-related health information), and to comply
with the trial protocol procedures (including required trial visits).
7. Patient has completed a 52-week treatment period.
Exclusion criteria
1. Introduction or continuation of non-permitted medications during the
ARGX-113-1801 trial (such as anti-CD20 therapy, romiplostim, monoclonal
antibodies, Fc fusion proteins, or live/live-attenuated vaccines).
2. Pregnant or lactating women, and those intending to become pregnant during
the trial or within 90 days after the last dosing.
3. Patients with known medical history of hypersensitivity to any of the
ingredients of efgartigimod.
4. Use of any other investigational drug or participation in any other
investigational 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 | EUCTR2019-002101-21-NL |
| ClinicalTrials.gov | NCT04225156 |
| CCMO | NL71448.100.19 |