A Study to Evaluate Efficacy, Safety, and Pharmacokinetics of XEMBIFY® Plus Standard Medical Treatment (SMT) Compared to Placebo Plus SMT to Prevent Infections in Participants With Hypogammaglobulinemia and Recurrent or Severe Infections Associated With B-cell Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The primary purpose of the study is to evaluate whether weekly administered XEMBIFY® plus Standard Medical Treatment (SMT) over a one-year period will reduce the rate of major bacterial infections per participant per year in participants with hypogammaglobulinemia (HGG) associated with B-cell chronic lymphocytic leukemia (CLL) in comparison to the Placebo plus SMT group.

Official Title
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A Multi-Center, Parallel, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate Efficacy, Safety, and Pharmacokinetics of XEMBIFY® Plus Standard Medical Treatment Compared to Placebo Plus Standard Medical Treatment to Prevent Infections in Patients With Hypogammaglobulinemia and Recurrent or Severe Infections Associated With B-cell Chronic Lymphocytic Leukemia

Conditions
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Hypogammaglobulinemia, Bacterial Infections, B-cell Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Xembify
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants ≥18 years of age at screening Participants with documented and confirmed diagnosis of B-cell CLL according to International Workshop on CLL (iwCLL) criteria. Participants with hypogammaglobulinemia with immunoglobulin G (IgG) levels <4 grams per liter (g/L) Participants with RAI staging of intermediate (1 and 2) or high (3 and 4) as documented in the participant's medical history. Participants with documented history of at least one severe bacterial infection or recurrent bacterial infections (that is., ≥ 3 infections) within 12 months before the screening visit. Severe bacterial infections ≥ Grade 3 (as defined by Common Terminology Criteria for Adverse Events [CTCAE] Grades). Exclusion Criteria: Participants with documented history of hematopoietic stem cell transplant. Participants currently receiving immunoglobulin replacement therapy (IgRT) or have received IgG replacement treatment (i.e., prior immune globulin replacement therapy) within 6 months before the screening visit. Participants with active infections or receiving therapeutic or prophylactic antibiotic treatment at time of screening visit. Specific supportive anti-infective prophylactic defined in the CLL National Comprehensive Cancer Network (NCCN) or iwCLL guidelines or recommended in the updated labelling of specific antileukemic medicines used during the participation in the trial is allowed. Participants with active second malignancies. Participants with known primary immunodeficiency (PI). Participants with a life expectancy less than 1.5 years. Participants with clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place the subject at undue medical risk. Participants have had a known serious adverse reaction (AR) to immunoglobulin or any anaphylactic reaction to blood or any blood-derived product. Participants have a history of blistering skin disease, bleeding disorder, diffuse rash, recurrent skin infections, or other disorders where SC therapy would be contraindicated during the study based upon the Investigator's discretion. Participants have known Selective Immunoglobulin A (IgA) Deficiency (with or without antibodies to IgA) (Note: exclusion is for the specific diagnostic entity. It does not exclude other forms of humoral primary immunodeficiency which have decreased IgA in addition to decreased IgG requiring IgG replacement). Participants with severe known kidney disease [as defined by estimated glomerular filtration rate [eGFR] less than (<) 30 milliliter (mL)/min/1.73 square meter (m2)] as determined by the Principal Investigator. Participants that have liver enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gammaglutamyl transferase [GGT], or lactate dehydrogenase [LDH]) greater than 3 times the upper limit of normal (ULN) at the Screening Visit as defined by the testing laboratory. Participants have a history (either 1 episode within the year prior to the Screening Visit or 2 previous episodes over a lifetime) of or current diagnosis of thromboembolism (example, myocardial infarction, cerebrovascular accident, or transient ischemic attack) or deep venous thrombosis. Participants are currently receiving anti-coagulation therapy which would make SC administration inadvisable (vitamin K antagonists, nonvitamin K antagonist oral anticoagulants [example, dabigatran etexilate targeting Factor IIa, rivaroxaban, edoxaban, and apixaban targeting Factor Xa], and parenteral anticoagulants [example, fondaparinux]). Participants currently have a known hyperviscosity syndrome or hypercoagulable states. Participants have a known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection. Participants with non-controlled arterial hypertension (systolic blood pressure [SBP] more than (>)140 millimeters of mercury (mmHg) and/or diastolic blood pressure [DBP] >90 mmHg), and/or a heart rate (HR) >100 bpm. Participants with known substance or prescription drug abuse within 12 months before the Screening Visit. Participants have participated in another clinical trial within 30 days prior to screening (observational studies without investigative treatments [non-interventional] are permitted).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XEMBIFY + Standard Medical Treatment (SMT)<br>Participants will receive a loading dose of 150 milligrams per kilograms per day (mg/kg/day) (Week 1, Days 1 to 5) subcutaneously (SC) for 5 consecutive daily doses followed by weekly infusions of 150 mg/kg starting Week 2 (Day 8) through Week 53 (end of Treatment Phase). The SMT will include the antileukemic treatments and the other supportive treatments that the participants will need during their participation. | Drug: Xembify<br>* SC infusion pump<br>* Other names: Immune Globulin Subcutaneous (Human), 20% (IGSC 20%);|
| Placebo Comparator: Placebo + SMT<br>Participants will receive sterile 0.9 percent Sodium Chloride Injection, United States Pharmacopeia (USP) or equivalent starting at Week 1 (Days 1 to 5) SC for 5 consecutive daily doses followed by weekly infusions starting at Week 2 (Day 8) through Week 53. The SMT will include the antileukemic treatments and the other supportive treatments that the participants will need during their participation. | Drug: Placebo<br>* SC infusion pump<br>* Other names: 0.9% Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Rate of Major Bacterial Infections per Year |  | Up to Week 53 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Onset of Major Bacterial Infection |  | Up to Week 53 | 
| Percentage of Participants who Experience Major Bacterial Infections |  | Up to Week 53 | 
| Rate of all Bacterial Infections Determined by the Investigator |  | Up to Week 53 | 
| Time to First Onset of Non-Major Bacterial Infections |  | Up to Week 53 | 
| Percentage of Participants who Experience Bacterial Infections |  | Up to Week 53 | 
| Number of Days on Which Participants Were on Antibiotics |  | Up to Week 53 | 
| Number of Hospitalizations due to any Infections |  | Up to Week 53 | 
| Duration of Hospitalizations due to any Infections |  | Up to Week 53 | 
| Number of Hospitalizations due to Major Bacterial Infections |  | Up to Week 53 | 
| Duration of Hospitalizations due to Major Bacterial Infections |  | Up to Week 53 | 
| Rate of all Infections as Determined by the Investigator |  | Up to Week 53 | 
| Number of Participants with Validated Infections |  | Up to Week 53 | 
| Time to First Onset of any Infection |  | Up to Week 53 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XEMBIFY, CLL, SMT, Hypogammaglobulinemia (HGG)