A Randomized, 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, Multiple Myeloma, and Non-Hodgkin Lymphoma
- Trial ID
- 2022-502193-16-00
- Protocol
- GC2202
- Sponsor
- Grifols Therapeutics LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to assess whether weekly administration of **XEMBIFY** plus Standard Medical Treatment (SMT) over a one-year period can reduce the rate of major bacterial infections per subject per year in patients with **hypogammaglobulinemia** associated with B-cell **chronic lymphocytic leukemia** (CLL), compared to a placebo plus SMT group. This is clinically relevant as it aims to address the increased susceptibility to infections in this patient population, potentially improving their quality of life and reducing healthcare burdens.
Secondary objectives include evaluating various aspects of bacterial infections in the study population:
- Time to first onset of major bacterial infections
- Proportion of subjects with major bacterial infections
- Rate of all bacterial infections as determined by the investigator
- Time to first onset of non-major bacterial infections
- Proportion of subjects who experience bacterial infections
- Number of days on antibiotics (oral, parenteral, prophylactic, and therapeutic)
- Rate and duration of hospitalizations due to major bacterial infections
- Rate and duration of hospitalizations due to any infections
- Validated infections documented by positive radiograph, fever, culture, or diagnostic testing for microorganisms
- Rate of all infections of any kind (serious/non-serious) as determined by the investigator
- Time to first onset of any infection
Participants
The clinical trial involves a total of **286 participants** diagnosed with **chronic lymphocytic leukemia** (CLL). The study population includes both male and female subjects aged 18 years and older. Participants were selected based on a confirmed diagnosis of B-cell CLL, with specific criteria including hypogammaglobulinemia with IgG levels below 4 g/L and a RAI staging of intermediate or high. The trial also considers individuals with a documented history of severe or recurrent bacterial infections within the year preceding the screening visit. The population is characterized by a vulnerable group, as indicated by the inclusion of individuals with significant health challenges related to their CLL condition. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants have provided informed consent prior to the commencement of any study-related procedures.
Plans and Procedures
The clinical trial is designed as a **randomized**, multi-center, parallel, double-blinded, placebo-controlled study to evaluate the efficacy, safety, and pharmacokinetics of Xembify plus standard medical treatment compared to placebo plus standard medical treatment. The trial targets patients with **hypogammaglobulinemia** and recurrent or severe infections associated with B-cell chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin lymphoma. The primary objective is to assess whether weekly administration of Xembify over a one-year period reduces the rate of major bacterial infections per subject per year compared to the placebo group. The trial is expected to conclude by June 2026, with recruitment having commenced in August 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of B-cell chronic lymphocytic leukemia, and history of severe bacterial infections. Follow-up visits will occur regularly throughout the 53-week treatment period to monitor safety, efficacy, and pharmacokinetic parameters. The end-of-study visit will finalize data collection and assess the overall outcomes of the trial. The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study protocols.
Key elements of the research methodology include the use of a double-blind design to ensure unbiased results, with both participants and investigators unaware of the treatment assignments. The trial will employ a placebo control to provide a comparative baseline for evaluating the effects of Xembify. Primary endpoints focus on the annual rate of major infections, while secondary endpoints include time to first onset of major bacterial infection, proportion of subjects experiencing infections, and number of hospitalizations due to infections. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the findings.
Treatment
The clinical trial involves the administration of **Xembify**, a **human normal immunoglobulin** solution for injection, with a concentration of 200 mg/ml. This experimental medication is administered subcutaneously. The dosing regimen for Xembify is set at a maximum daily dose of 150 mg/kg, with a total maximum dose of 8400 mg/kg over the course of the study. The treatment period is defined as 53 weeks. Xembify is produced by Instituto Grifols, S.A., and is classified under the ATC code J06BA01, indicating its use as a normal human immunoglobulin for extravascular administration. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.
In addition to the experimental treatment, the study includes the administration of **sodium chloride** as a placebo. Sodium chloride is provided in the form of a solution for injection and is also administered subcutaneously. The placebo is dosed at a maximum of 0.75 ml/kg per day, with a total maximum dose of 43.5 ml/kg over the 53-week treatment period. The use of sodium chloride as a placebo allows for a double-blinded study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This approach is critical for maintaining the integrity of the trial and for accurately assessing the efficacy and safety of Xembify in comparison to the placebo group.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the annual rate of major bacterial infections per subject per year. Major bacterial infections are defined according to the FDA IVIG PID guidance 2008 and include conditions such as bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess.
Secondary endpoints include several parameters: the time to first onset of major bacterial infection, the proportion of subjects experiencing major bacterial infections, the rate of all bacterial infections (serious/non-serious) as determined by the investigator, and the time to first onset of non-major bacterial infections. Additional secondary endpoints involve the proportion of subjects experiencing bacterial infections, the number of days on antibiotics, the number and duration of hospitalizations due to any infections, and the number and duration of hospitalizations due to major bacterial infections. The rate of all infections of any kind, validated infections documented by diagnostic testing, and the time to first onset of any infection are also included as secondary endpoints.
These efficacy parameters will be measured and collected throughout the trial duration, with specific timepoints and methods determined by the study protocol. The analysis will involve comparing the outcomes between the group receiving XEMBIFY plus Standard Medical Treatment and the placebo group, both in the context of preventing infections in patients with **hypogammaglobulinemia** associated with B-cell Chronic Lymphocytic Leukemia, Multiple Myeloma, and Non-Hodgkin Lymphoma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or Female subjects ≥18 years of age at Screening Visit
- Subjects with documented and confirmed diagnosis of any of the diseases below: • B-cell CLL according to iwCLL criteria and Rai staging of intermediate (1 and 2) or high (3 and 4); or • MM according to the International Myeloma Working Group criteria (IMWG), RISS stage II or, III; or • Histologically confirmed diagnosis of B-cell NHL, Stage III or above (IV, Progressive/refractory, or recurrent/relapsed stage) according to the Lugano Classification.
- Subjects with HGG with IgG levels <5g/L. (Note: For MM subjects, the IgG level is adjusted by subtracting the M-protein [M-spike] to reflect the true polyclonal IgG concentration.)
- Subjects with documented history of at least one severe infection (bacterial or viral) or recurrent bacterial/viral infections (i.e., ≥ 3 infections) within 12 months before the Screening Visit. Severe infections (bacterial or viral) ≥ Grade 3 (as defined by Common Terminology Criteria for Adverse Events [CTCAE] Grades).
- Subjects have signed an informed consent form (ICF) prior to initiation of any study procedures.
Exclusion Criteria
- Subjects with documented history of hematopoietic stem cell transplant
- Subjects 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
- Subjects with active infections or receiving therapeutic or prophylactic antibiotic treatment at time of Screening Visit. Specific supportive anti-infective prophylactics defined in the CLL NCCN or iwCLL guidelines or recommended in the updated labelling of specific antileukemic medicines used during the participation in the trial is allowed
- Subjects with active second malignancies
- Subjects with known primary immunodeficiency (PI)
- Subject with a life expectancy less than 1.5 years
- Subjects 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
- Subjects have had a known serious adverse reaction (AR) to immunoglobulin or any anaphylactic reaction to blood or any blood-derived product
- Subjects 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
- Subjects 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)
- Females of childbearing potential who are pregnant, have a positive pregnancy test at Screening Visit (serum human chorionic gonadotropin-based assay), are breastfeeding, or unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence*) throughout the study. Note: *True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.)
- Subjects with severe known kidney disease (as defined by estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) as determined by the Principal Investigator
- Subjects 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
- Subjects who 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 (e.g., myocardial infarction, cerebrovascular accident, or transient ischemic attack) or deep venous thrombosis
- This criterion has been removed in protocol version 6.0
- Subjects who currently have a known hyperviscosity syndrome or hypercoagulable states
- Subjects who have a known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection
- Subjects with non-controlled arterial hypertension (systolic blood pressure [SBP] >140 mmHg and/or diastolic blood pressure [DBP] >90 mmHg), and a heart rate (HR) >100 bpm
- Subjects have known substance or prescription drug abuse within 12 months before the Screening Visit
- Subjects have participated in another clinical trial within 30 days prior to Screening Visit (observational studies without investigative treatments [non-interventional] are permitted)
- Subjects/caregivers are unwilling to comply with any aspect of the protocol for the duration of the study
- In the opinion of the investigator, subjects may have compliance problems with the protocol and the procedures of the protocol
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 31 Aug 2023 | 30 |
 Croatia | Recruiting | 31 Aug 2023 | 15 |
 Hungary | Recruiting | 31 Aug 2023 | 16 |
 Poland | Recruiting | 31 Aug 2023 | 20 |
 Romania | Recruiting | 31 Aug 2023 | 13 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SODIUM CHLORIDE | Placebo | — | SUBCUTANEOUS | 0.75 | 53 | SUB12581MIG |
Xembify 200 mg/ml solución inyectable subcutánea | Test | SOLUCIÓN INYECTABLE SUBCUTÁNEA | SUBCUTANEOUS | 150 | 53 | PRD9605574 |