Primary Objective:- To evaluate the efficacy of efgartigimod compared to placebo in achieving a sustained platelet count response in patients with chronic primary immune thrombocytopenia (ITP), with a sustained platelet count response defined as…
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Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of patients with chronic ITP with a sustained platelet count
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.
Secondary outcome
Key Secondary Efficacy Endpoints Subject to Alpha Control:
- Extent of disease control defined as the number of cumulative weeks over the
planned 24 week treatment period with platelet counts of *50×10^9/L in the
chronic ITP population.
- Proportion of patients in the overall population (chronic and persistent ITP)
with a sustained platelet count 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.
- Incidence and severity of the WHO-classified bleeding events in the overall
population.
- 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.
Other Secondary Endpoints Not Subject to Alpha Control:
- Percentage of patients with overall platelet response defined as achieving a
platelet count of *50×10^9/L on at least 4 occasions at any time during the
24-week treatment period.
- Extent of disease control defined as the number of cumulative weeks until
week 12, with platelet counts of *50×10^9/L.
- Percentage of patients with overall platelet response defined as achieving a
platelet count of *50×10^9/L on at least 4 occasions at any time until week 12.
- Mean change from baseline in platelet count at each visit.
- Time to response defined as the time to achieve 2 consecutive platelet counts
of *50×10^9/L.
- Rate of receipt of rescue therapy (rescue per patient per month).
- Proportion of patients for whom dose and/or frequency of concurrent ITP
therapies have increased at week 12 or later
- The number of cumulative weeks over the planned 24-week treatment period with
platelet counts of *30×10^9/L and at least 20×10^9/L above baseline.
- In patients with baseline platelet count of <15×10^9/L, the number of
cumulative weeks over the planned 24 week treatment period with platelet counts
of *30×10^9/L and at least 20×10^9/L above baseline.
- Change from baseline in PRO (FACIT-Fatigue, Fact-Th6) and QoL (SF-36) at
planned visits.
- Incidence of anti-drug antibodies (ADA) to efgartigimod.
- Pharmacokinetic parameters of efgartigimod: maximum observed serum
concentration (Cmax) and serum concentration observed predose (Ctrough).
- Pharmacodynamics markers: total IgG, IgG isotypes (IgG1, IgG2, IgG3, IgG4),
antiplatelet antibody levels.
Safety Evaluation
- Evaluate the incidence and severity of AEs, AE(S)Is, and serious AEs (SAEs).
- Evaluate vital signs, electrocardiogram (ECG), and laboratory assessments.
Exploratory Endpoint
- Platelet functionality and immature platelet fraction.
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
(ie. 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 per
100,000 adults/year. 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 efficacy of efgartigimod compared to placebo in achieving a
sustained platelet count response in patients with chronic primary immune
thrombocytopenia (ITP), with a sustained platelet count response defined as
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.
Secondary Objectives:
- To evaluate the efficacy of efgartigimod compared to placebo in overall
platelet count response.
- To evaluate the safety and tolerability of efgartigimod administered
intravenously (IV) weekly or q2w.
- To evaluate the incidence and severity of bleeding events while receiving
treatment with efgartigimod compared to placebo.
- To evaluate the use of rescue treatment and changes in concurrent ITP therapy
while receiving treatment with efgartigimod compared to placebo.
- To evaluate the effects of efgartigimod treatment on quality-of-life (QoL)
measures and patient-reported outcomes (PRO) compared to placebo.
- To assess the immunogenicity of efgartigimod.
- To assess the pharmacokinetics (PK) of efgartigimod.
- To assess the pharmacodynamic (PD) effects of efgartigimod.
Exploratory Objective:
- To explore the effects of efgartigimod on pathogenic actions caused by
autoantibodies.
Study design
This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled,
parallel-group, up to 31-week trial to evaluate the efficacy, safety, and
impact on QoL of efgartigimod 10 mg/kg IV treatment in adult patients with
primary ITP.
The target population are adult patients with persistent or chronic primary
ITP, having an average platelet count of <30×10^9/L, and at the start of the
trial being on concurrent ITP treatment(s) and having received at least 1 prior
therapy for ITP in the past, or not being on treatment for ITP but having
received at least 2 prior treatments for ITP. If patients are receiving
concurrent ITP therapies at baseline, these therapies should have been
maintained at a stable dose and dosing frequency for 4 weeks prior to
randomization. As of week 12, the start or an increase in the dose and/or
schedule of permitted concurrent ITP therapy is allowed for patients who have
an *insufficient response* (ie. no platelet count of *30×10^9/L in any of the
visits during the last 4 weeks). These patients will be considered as *non-
responders* for the primary endpoint analysis.
After confirmation of eligibility, the patients enter a 24-week treatment
period and will be randomized to receive efgartigimod 10 mg/kg IV or placebo,
weekly from visits 1 to 4 and then from visits 5 to 16 either weekly or q2w,
adjusted according to their platelet counts. From visits 17 to 24, patients
will be fixed on the dosing schedule they were receiving at visit 16 or at the
last visit at which IMP was administered (ie. either weekly or biweekly).
Patients completing the 24 week randomized trial period will perform the
End-of-Treatment visit and can enter the open-label extension trial
(ARGX-113-1803) to receive efgartigimod 10 mg/kg IV. The platelet counts from
the ARGX-113-1801 trial will be taken into account to assess the dosing
frequency in ARGX-113-1803.
Patients who complete the 24-week trial period but who do not enter the
open-label extension trial ARGX-113-1803, or patients who discontinue the trial
early, with the exception of patients who withdraw their consent, will be
followed for 4 weeks for ongoing safety and efficacy monitoring.
For patients who discontinue the trial early, all the assessments listed for
the Early Discontinuation visit as specified in the schedule of assessments,
will be performed.
Intervention
Weekly or q2w treatment with efgartigimod (ARGX-113) at doses of 10 mg/kg body
weight at infusion visits. The maximum total dose per infusion for IMP is 1,200
mg for patients with body weight *120 kg measured at infusion visits.
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 the phase 2 trial ARGX-113-1603 in patients with ITP, 1
TEAE with grade 4 was reported (thrombocytopenia), considered unrelated to
treatment, and led to treatment discontinuation.
No deaths have occurred in any efgartigimod trial. There is no evidence of an
increased risk of infection.
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. Please
refer to the current Investigator*s Brochure for more information regarding the
preclinical and clinical trials, and the potential risks and benefits of
efgartigimod. In summary, the favorable balance between risks and anticipated
efficacy/benefits supports the use of efgartigimod in clinical development.
Please refer to protocol section 1.2 for further details.
Industriepark Zwijnaarde 7
Zwijnaarde 9052
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Industriepark Zwijnaarde 7
Zwijnaarde 9052
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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. Male or female patient aged *18 years.
3. Confirmed ITP diagnosis, at least 3 months before randomization and
according to the ASH Criteria, and no known other etiology for thrombocytopenia.
4. Diagnosis supported by a response to a prior ITP therapy (other than TPO
RAs), in the opinion of the investigator.
5. Mean platelet count of <30×10^9/L from 2 qualifying counts, 1 platelet count
collected during the screening period and the pre-dose platelet count on the
day of randomization (visit 1).
6. At the start of the trial, the patient is either on concurrent ITP
treatment(s) and has received at least 1 prior therapy for ITP in the past, or
the patient is not on treatment for ITP but has received at least 2 prior
treatments for ITP. Patients receiving permitted concurrent ITP treatment(s) at
baseline, must have been stable in dose and frequency for at least 4 weeks
prior to randomization.
Permitted concurrent ITP medications include oral corticosteroids, oral
immunosuppressants, dapsone/danazol, fostamatinib and/or oral TPO-RAs.
Patients not receiving concurrent ITP therapy are also eligible for the trial
if they have not received prior ITP therapy for at least 4 weeks prior to
baseline, and 6 months in case of prior ITP therapy with an anti-CD20 therapy
(e.g. rituximab).
7. Women of childbearing potential must have a negative serum pregnancy test at
the screening visit and a negative urine pregnancy test at baseline before
study 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 an FSH of >40 IU/L or are surgically
sterilized (ie 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 on hormonal
replacement therapy.
8. 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 documented aspermia 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
9. 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 a 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 ICF, throughout the duration of the
trial, and for 90 days after the last administration of IMP.
Exclusion criteria
1. ITP/thrombocytopenia associated with another condition, e.g. lymphoma,
chronic lymphocytic leukemia, viral infection, hepatitis, induced or alloimmune
thrombocytopenia, or thrombocytopenia associated with myeloid dysplasia.
2. Use of anticoagulants (e.g. vitamin K antagonists, direct oral
anticoagulants) within 4 weeks prior to randomization.
3. Use of any transfusions within 4 weeks prior to randomization.
4. Use of Ig, (IV, subcutaneous or intramuscular route), or plasmapheresis
(PLEX), 4 weeks prior to randomization.
5. Use of anti-CD20 therapy (eg. rituximab) within 6 months prior to
randomization.
6. Use of romiplostim within 4 weeks prior to randomization.
7. Undergone splenectomy less than 4 weeks prior to randomization.
8. Use of any other investigational drug within 3 months or 5 half-lives of the
drug (whichever is longer) prior to randomization.
9. Use of monoclonal antibodies or crystallized fragment (Fc) fusion proteins,
other than those previously indicated, within 3 months prior to randomization.
10. At the screening visit, clinically significant laboratory abnormalities as
below:
a. Hemoglobin *9 g/dL.
- OR -
b. International normalized ratio >1.5 or activated partial thromboplastin time
>1.5×ULN.
- OR -
c. Total IgG level <6 g/L.
11. Patients who have a history of malignancy, including malignant thymoma, or
myeloproliferative or lymphoproliferative disorders, unless deemed cured by
adequate treatment with no evidence of recurrence for *3 years before
screening. Patients with completely excised non-melanoma skin cancer (such as
basal cell carcinoma or squamous cell carcinoma) or cervical carcinoma in situ
would be permitted at any time.
12. Uncontrolled hypertension, defined as a repeated elevated blood pressure
exceeding 160 mmHg (systolic) and/or 100 mmHg (diastolic) despite appropriate
treatments.
13. History of any major thrombotic or embolic event (eg. Myocardial
infarction, stroke, pulmonary embolism, deep venous thrombosis) within 12
months prior to randomization.
14. History of coagulopathy or hereditary thrombocytopenia or a family history
of thrombocytopenia.
15. History of a recent or planned major surgery (that involves major organs
e.g. brain, heart, lung, liver, bladder, or gastrointestinal tract) within 4
weeks of randomization.
16. Patients with known serum-positivity or who test positive for an active
viral infection at screening with: Hepatitis B Virus (HBV) (except patients who
are anti-HBs Ab positive because of HBV vaccination), Hepatitis C Virus, HIV.
17. Clinical evidence of significant unstable or uncontrolled acute or chronic
diseases other than ITP (e.g. cardiovascular, pulmonary, hematologic,
gastrointestinal, endocrine, hepatic, renal, neurological, malignancy,
infectious diseases, uncontrolled diabetes) despite appropriate treatments
which could put the patient at undue risk.
18. Patients with known medical history of hypersensitivity to any of the
ingredients of the IMP.
19. Patients who previously participated in a clinical trial with efgartigimod
and have received at least 1 administration of the IMP.
20. Pregnant or lactating females.
21. Employees of the investigator or trial center, with direct involvement in
the proposed trial or other trials under the direction of that investigator or
trial center, as well as family of the employees or the investigator.
22. Patients who received a live/live-attenuated vaccine within 4 weeks before
screening. The receipt of any inactivated, sub-unit, polysaccharide, or
conjugate vaccine at any time before screening is not considered an exclusion
criterion.
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 | EUCTR2019-002100-41-NL |
| ClinicalTrials.gov | NCT04188379 |
| CCMO | NL70782.100.19 |