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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grifols Therapeutics LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Nov 2023 → ongoing

Decision date (initial)

2023-08-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-502193-16-00

ClinicalTrials.gov

NCT05645107

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

to evaluate whether biweekly administered XEMBIFY + Standard Medical Treatment (SMT) over a one-year period will reduce the rate of major bacterial infections per subject per year in B-cell chronic lymphocytic leukemia (B-cell CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) subjects with hypogammaglobulinemia (HGG) in comparison to the Placebo + SMT group.

Secondary objectives 13

1. To evaluate the time to first onset of major bacterial infections
2. To evaluate the proportion of subjects with major bacterial infections
3. To evaluate rate of all bacterial infections as determined by the Investigator
4. To evaluate the time to first onset of non-major bacterial infections
5. To evaluate the proportion of subjects who experience bacterial infections
6. To evaluate the number of days on antibiotics (including oral, parenteral, oral plus parenteral, prophylactic, and therapeutic) in all subjects
7. To evaluate the rate of hospitalizations due to major bacterial infections in all subjects
8. To evaluate the duration of hospitalizations due to major bacterial infections in all subjects
9. To evaluate the rate of hospitalizations due to any infections in all subjects
10. To evaluate the duration of hospitalizations due to any infections in all subjects
11. To evaluate validated infections documented by positive radiograph, fever (>38°C [>100.4°F] oral or >39°C [>102.2°F] rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or protozoal pathogens (e.g., rapid streptococcal antigen detection test)
12. To evaluate rate of all infections of any kind (serious/nonserious) as determined by the Investigator
13. To evaluate time to first onset of any infection

Conditions and MedDRA coding

Chronic lymphocytic leukemia, Multiple Myeloma and Non-Hodgkin Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Male or Female subjects ≥18 years of age at Screening Visit
2. 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.
3. 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.)
4. 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).
5. Subjects have signed an informed consent form (ICF) prior to initiation of any study procedures.

Exclusion criteria 22

1. Subjects with documented history of hematopoietic stem cell transplant
2. 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
3. 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
4. Subjects with active second malignancies
5. Subjects with known primary immunodeficiency (PI)
6. Subject with a life expectancy less than 1.5 years
7. 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
8. Subjects have had a known serious adverse reaction (AR) to immunoglobulin or any anaphylactic reaction to blood or any blood-derived product
9. 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
10. 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)
11. 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.)
12. 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
13. 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
14. 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
15. This criterion has been removed in protocol version 6.0
16. Subjects who currently have a known hyperviscosity syndrome or hypercoagulable states
17. Subjects who have a known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection
18. 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
19. Subjects have known substance or prescription drug abuse within 12 months before the Screening Visit
20. Subjects have participated in another clinical trial within 30 days prior to Screening Visit (observational studies without investigative treatments [non-interventional] are permitted)
21. Subjects/caregivers are unwilling to comply with any aspect of the protocol for the duration of the study
22. In the opinion of the investigator, subjects may have compliance problems with the protocol and the procedures of the protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annual rate of major infections* (bacterial; infections per year). *Major bacterial infections for the primary endpoint are defined in the appendix “Diagnostic Criteria for Serious Infection Types” from the FDA IVIG PID guidance 2008, which includes bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess

Secondary endpoints 11

1. Time to first onset of major bacterial infection
2. Proportion of subjects who experience major bacterial infections
3. Rate of all bacterial infections (serious/non-serious) as determined by the investigator
4. Time to first onset of non-major bacterial infections
5. Proportion of subjects who experience bacterial infections
6. Number of days on antibiotics (including oral, parenteral, oral plus parenteral, prophylactic, and therapeutic) in all subjects
7. Number of hospitalizations and duration due to any infections
8. Number of hospitalizations and duration due to major bacterial infections
9. The rate of all infections of any kind (serious/nonserious) as determined by the Investigator
10. Validated infections documented by positive radiograph, fever (>38°C [>100.4°F] oral or >39°C [>102.2°F] rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or protozoal pathogens (e.g., rapid streptococcal antigen detection test)
11. Time to first onset of any infection

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grifols Therapeutics LLC

Sponsor organisation

Grifols Therapeutics LLC

Address

8368 Us 70 Bus Highway West

City

Clayton

Postcode

27520-9464

Country

United States

Scientific contact point

Organisation

Grifols Therapeutics LLC

Contact name

BIOPHARMA CLINICAL&PHARMACOVIGILANCE

Public contact point

Organisation

Grifols Therapeutics LLC

Contact name

BIOPHARMA CLINICAL&PHARMACOVIGILANCE

Third parties 2

Locations

5 EU/EEA countries · 44 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 77 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

20 submissions — initial application plus substantial / non-substantial modifications