A Study to Evaluate the Efficacy and Safety of Efgartigimod PH20 Subcutaneous in Adult Patients With Primary Immune Thrombocytopenia

argenx207 enrolled

Overview

This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group trial to evaluate the efficacy, safety, and effect on QoL/PRO of efgartigimod PH20 SC treatment in adult patients with primary ITP.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

207

Conditions

Primary Immune Thrombocytopenia

Interventions

Efgartigimod PH20 SCBIOLOGICAL

Subcutaneous injection with efgartigimod PH20 SC

Placebo PH20 SCOTHER

Subcutaneous injection with placebo PH20 SC

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: * Ability to understand the requirements of the trial and provide written informed consent, willing and able to comply with the trial protocol procedures * Is at least the local age of consent for clinical studies when signing the ICF. * Confirmed diagnosis of primary ITP made at least 3 months before randomization and based on the American Society of Hematology Criteria, and no known etiology for thrombocytopenia * Diagnosis supported by a response to a prior ITP therapy (other than TPO-RAs), in the opinion of the investigator * Mean platelet count of \<30×10E9/L from at least 3 documented, qualifying counts within the 3 preceding months where at least 2 of the qualifying counts must be taken during the screening period: 1 platelet count collected during the screening period and the predose platelet count on the day of randomization (visit 1). If the third count is not available from the 3 preceding months, this third platelet count can be obtained during the screening period. * A documented history of a platelet count of \<30×10E9/L before screening * At the start of the trial, the participant either takes concurrent ITP treatment(s) and has received at least 1 prior therapy for ITP in the past, or the participant does not take treatment for ITP (see note) but has received at least 2 prior treatments for ITP. Participants receiving permitted concurrent ITP treatment(s) at baseline must have been stable in dose and frequency for at least 4 weeks before randomization. Permitted concurrent ITP medications include corticosteroids, danazol, vinca alkaloids, oral immunosuppressants, dapsone, fostamatinib, and/or oral TPO-RAs. -Agree to use contraceptive measures consistent with local regulations and the protocol Exclusion criteria: * Secondary ITP/thrombocytopenia associated with another condition, eg, lymphoma, chronic lymphocytic leukemia, viral infection, hepatitis, induced or alloimmune thrombocytopenia, thrombocytopenia associated with myeloid dysplasia, or hematopoietic stem cell transplant * Use of anticoagulants (eg, vitamin K antagonists, direct oral anticoagulants) within 4 weeks prior to randomization * Use of any transfusions within 4 weeks prior to randomization * Use of Ig (IV, SC, or intramuscular route) or plasmapheresis (PLEX) within 4 weeks prior to randomization * Use of romiplostim within 4 weeks prior to randomization * Undergone splenectomy less than 4 weeks prior to randomization * Use of an investigational product within 3 months or 5 half-lives (whichever is longer) before the first dose of the IMP * Use of any monoclonal antibody or Fc fusion proteins, other than those previously indicated, within 6 months before the first dose of the IMP (eg, anti-CD20) * At the screening visit, clinically significant laboratory abnormalities as follows: Hemoglobin ≤9 g/dL - OR - International normalized ratio \>1.5 or activated partial thromboplastin time \>1.5×upper limit of normal - OR - total IgG level \<6 g/L * History of malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥3 years before the first administration of IMP. Participants with the following cancer can be included at any time: Adequately treated basal cell or squamous cell skin cancer, Carcinoma in situ of the cervix, Carcinoma in situ of the breast or Incidental histological finding of prostate cancer (TNM stage T1a or T1b) * Uncontrolled hypertension, defined as a repeated elevated blood pressure exceeding 160 mmHg (systolic) and/or 100 mmHg (diastolic) despite appropriate treatments * History of any major thrombotic or embolic event (eg, myocardial infarction, stroke, deep venous thrombosis, or pulmonary embolism) within 5 years prior to randomization * History of coagulopathy or hereditary thrombocytopenia or a family history of thrombocytopenia * Evidence of an active clinically significant bleeding of an organ or internal mucosal bleeding, other than expected in ITP, that warrants emergent treatment or therapeutic procedure based on the investigator's judgment (eg, intracranial hemorrhage, pulmonary hemorrhage, bleeding with ongoing need for packed red blood cell transfusion) * Estimated high risk of a clinically significant bleeding of an organ or internal mucosal bleeding, other than expected in ITP, that warrants emergent treatment or therapeutic procedure according to the investigator's judgment * Clinical evidence of other significant serious diseases, have had a recent major surgery, or who have any other condition in the opinion of the investigator, that could confound the results of the trial or put the participant at undue risk * Positive serum test at screening for an active viral infection with any of the following conditions: Hepatitis B virus (HBV) that is indicative of an acute or chronic infection, unless associated with a negative HBV DNA test, Hepatitis C virus (HCV) based on HCV-antibody assay (unless associated with a negative HCV RNA test), Human immunodeficiency virus (HIV) based on test results that are associated with an acquired immunodeficiency syndrome (AIDS)-defining condition or a CD4 count ≤200 cells/mm3 * Known hypersensitivity reaction to efgartigimod, rHuPH20, or 1 of its excipients * Previously participated in a clinical trial with efgartigimod and have received at least 1 administration of the IMP * Pregnant or lactating or intends to become pregnant during the trial * Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection at screening * Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of ITP or put the participant at undue risk * Clinical evidence of significant unstable or uncontrolled acute or chronic diseases other than ITP (eg, cardiovascular, pulmonary, hematologic, gastrointestinal, endocrine, hepatic, renal, neurological, malignancy, infectious diseases, uncontrolled diabetes) despite appropriate treatments which could put the participant at undue risk * Current or history of (ie, within 12 months of screening) alcohol, drug, or medication abuse * Received a live/live-attenuated vaccine less than 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

Locations (200)

Outcomes

Primary Outcomes

Percentage of Participants With Chronic Immune Thrombocytopenia (ITP) With a Sustained Platelet Count Response Between Weeks 19 and 24

A participant was considered a responder for this endpoint (i.e., had a sustained platelet count response) if the participant had platelet counts of ≥50 × 10\^9/L for ≥4 of the 6 analysis visits between Weeks 19 and 24.

Time frame: Up to 6 weeks (between Weeks 19 and 24)

Secondary Outcomes

Extent of Disease Control Over the 24-Week Treatment Period in the Chronic ITP Population

Extent of disease control was 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.

Time frame: Up to 24 weeks

Percentage of Participants in the Overall Population (Chronic and Persistent ITP) With a Sustained Platelet Count Response Between Weeks 19 and 24

Time frame: Up to 6 weeks (between Weeks 19 and 24)

Percentage of Participants in the Overall Population With Sustained Platelet Count Response Between Weeks 17 and 24

A participant was considered a responder for this endpoint (i.e., had a sustained platelet count response) if the participant had platelet counts of ≥50 × 10\^9/L for ≥6 of the 8 analysis visits between weeks 17 and 24.

Time frame: Up to 8 weeks (between Weeks 17 and 24)

Percentage of Participants in the Overall Population Achieving Overall Platelet Count Response at Any Time During the 24-week Treatment Period

A participant was considered a responder for this endpoint (i.e., had an overall platelet count response) if the participant had platelet counts of ≥50 × 10\^9/L for ≥4 analysis visits at any time during the 24-week treatment period.

Data from ClinicalTrials.gov

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Investigator Site 0010116

Springdale, Arkansas, United States

Investigator site 0010036

Los Angeles, California, United States

Investigator Site 0010045

Washington D.C., District of Columbia, United States

Investigator Site 0010104

Weston, Florida, United States

Investigator site 0010112

Chicago, Illinois, United States

Investigator site 0010193

Chicago, Illinois, United States

Investigator Site 0010079

Lisle, Illinois, United States

Investigator Site 0010062

Fort Wayne, Indiana, United States

Investigator site 0010042

Iowa City, Iowa, United States

Investigator Site 0010083

Detroit, Michigan, United States

...and 190 more locations

Time frame: Up to 24 weeks

Extent of Disease Control Until Week 12 in the Overall Population

Extent of disease control was defined as the number of cumulative weeks until Week 12 with platelet counts of ≥50×10\^9/L in the overall population.

Time frame: Up to 12 weeks

Percentage of Participants in the Overall Population Achieving Overall Platelet Count Response at Any Time Until Week 12

Time frame: Up to 12 weeks

Mean Change From Baseline in Platelet Count at Each Visit in the Overall Population

Change from Baseline at time point t = value at time point t - Baseline value. Baseline was defined as the last available value prior to first administration of the investigational medicinal product (IMP).

Time frame: Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Safety and Efficacy Follow-up Visit 1 (SEFU1) (up to Week 29), and SEFU2 (up to Week 33)

Time to Platelet Count Response in the Overall Population

Time to platelet count response, defined as the time to have 2 consecutive platelet counts of ≥50 × 10\^9/L via Kaplan-Meier estimates.

Time frame: Up to 24 weeks

Extent of Disease Control Over the 24-Week Treatment Period in the Overall Population

Extent of disease control was defined as the number of cumulative weeks over the planned 24-week treatment period with platelet counts of ≥30×10\^9/L with at least ≥20×10\^9/L above Baseline in the overall population.

Time frame: Up to 24 weeks

Extent of Disease Control Over the 24-Week Treatment Period in the Overall Population for Participants With Baseline Platelet Count of <15×10^9/L

Time frame: Up to 24 weeks

Number of the World Health Organization (WHO)-Classified Bleeding Events (Grade ≥1) in the Overall Population

Assessed using the WHO bleeding scale. The WHO bleeding scale is a five-point scale where Grade 0 = no bleeding; Grade 1 = petechial bleeding; Grade 2 = mild blood loss; Grade 3 = gross blood loss (requires transfusion); and Grade 4 = debilitating blood loss, associated with fatality.

Time frame: Up to 24 weeks

Percentage of Participants With a Platelet Count International Working Group (IWG) Response

IWG complete response was defined as platelet counts of ≥100 × 10\^9/L and the absence of bleeding events (WHO Grading = 0 \[no bleeding\]) for at least 2 separate, consecutive analysis visits at least 7 days apart. IWG response was defined as platelet counts of ≥30 × 10\^9/L and a 2-fold increase of platelet count from Baseline and the absence of bleeding events (WHO grading = 0) for at least 2 separate, consecutive analysis visits that were at least 7 days apart. Initial response was defined as platelet counts of ≥30 × 10\^9/L and a 2-fold increase from the Baseline platelet count at analysis visit 5.

Time frame: Up to 24 weeks

Rate of Receipt of Rescue Therapy (Rescue Per Participant Per Month) in the Overall Population

Rescue therapy was defined as an occurrence where the participant needed treatment with 1 or more rescue treatments. An occurrence was defined as a period of maximum 5 days where 1 or more rescue treatments were administered simultaneously or consecutively to the trial participant. The following rescue treatments were permitted: methylprednisolone, dexamethasone, prednisone, normal immunoglobulins, anti-D (Rho) immunoglobins, or platelet transfusions.

Time frame: Up to 24 weeks

Percentage of Participants for Whom Dose and/or Frequency of Concurrent ITP Therapies Have Increased at Week 12 or Later in the Overall Population

A change in ITP therapy was defined as either an increase in the dose and/or frequency of a concurrent ITP therapy relative to Baseline or the initiation of a new concurrent ITP therapy.

Time frame: Up to 13 weeks (between Weeks 12 and 24)

Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue) at Week 24 in the Overall Population

The FACIT-fatigue scale is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during his/her usual daily activities over the past week. The level of fatigue was measured by recording item responses on a 5-point Likert scale ranging from 0 "not at all" to 4 "very much". All items were summed to create a single fatigue score with a range from 0 to 52, where a higher FACIT-F score indicated more severe symptoms. A negative change score from Baseline indicated improvement in quality of life (QoL).

Time frame: Baseline and Week 24

Change From Baseline in Functional Assessment of Cancer Therapy Questionnaire-Th6 (Fact-Th6) at Week 24 in the Overall Population

The FACT-Th6 uses a 5-level Likert scale (0=not at all to 4=very much), with participants rating their degree of concern in the past 7 days. The 6 selected items pertain to ability to do usual activities, worry about problems with bleeding or bruising, worry about the possibility of serious bleeding, avoidance of physical or social activity because of concern with bleeding or bruising and frustration due to the inability to carry out usual activities. All items were summed to create a single score with a range from 0 to 24, where a higher score indicated less severe symptoms. A positive change score from Baseline indicated improvement in QoL.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24

Change From Baseline in Short Form-36 (SF-36) at Week 24 in the Overall Population

The SF-36 is a 36-item scale constructed to survey health-related QoL on 8 domains: limitations in physical activities due to health problems; limitations in social activities due to physical or emotional problems; limitations in usual role activities due to physical health problems; bodily pain; general mental health (psychological distress and well-being); limitations in usual role activities due to emotional problems; vitality (energy and fatigue); and general health perceptions. The scores from the 8 domains were evaluated independently and aggregated into 2 norm-based summary component measures of physical and mental health. The summary component scores could range from 0 to 100, where a higher score indicated improvement in QoL. A positive change score from Baseline indicated improvement in QoL.

Time frame: Baseline and Week 24

Incidence and Prevalence of Antibodies to Efgartigimod and/or rHuPH20 in the Overall Population

Anti-drug antibody (ADA) incidence was defined as the percentage of participants with treatment-induced or treatment boosted ADA (denominator: number of evaluable participants). ADA prevalence was defined as the percentage of participants with treatment-unaffected ADA, treatment-induced ADA or treatment-boosted ADA (denominator: number of evaluable participants).

Time frame: Up to 35 weeks

Titers of Antibodies to Efgartigimod and/or rHuPH20 in the Overall Population

A titer was determined in the samples with a positive assay response.

Time frame: Weeks 3, 7, 11, 15, 19, 23, 24, SEFU1 (up to Week 29), and SEFU2 (up to Week 33)

Incidence and Prevalence of Neutralizing Antibodies (NAb) to Efgartigimod and/or rHuPH20 in the Overall Population

Samples were tested for the presence of NAb against efgartigimod and/or rHuPH20 and titers for NAb against rHuPH20. NAb incidence is defined as the total percentage of participants with participant classification "baseline negative-postbaseline positive" and "baseline positive-postbaseline positive". NAb prevalence is defined as the total percentage of participants with participant classification "baseline negative-postbaseline positive," "baseline positive-postbaseline positive," or "baseline positive-postbaseline negative".

Time frame: Up to 35 weeks

Serum Efgartigimod Trough Concentration (Ctrough) in the Overall Population

All pharmacokinetic (PK) samples were collected predose, on the day of IMP administration.

Time frame: Predose on Weeks 1, 2, 3, 17, 19, 21, 23, and 24

Percentage Change From Baseline in Total IgG in the Overall Population

Samples were collected predose, on the day of IMP administration.

Time frame: Baseline and Weeks 1, 2, 3, 17, 19, 21, 23, and 24

Number of Participants With Antiplatelet Antibodies in the Overall Population

The antiplatelet antibody was positive if optical density value \>0.129.

Time frame: Weeks 7, 15, 23, and 24