Plerixafor Versus G-CSF in the Treatment of People With WHIM Syndrome

NCT02231879 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 14018514-I-0185
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is a rare disease. It can cause cancers, infections, and warts. Researchers want to see if a drug called plerixafor can treat WHIMS. Objective: \- To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing infections in people with WHIMS. Eligibility: \- People ages 10-75 with WHIMS who have a CXCR4 gene mutation. Design:

• Participants will be screened with a medical history, physical exam, and blood and urine tests. They may have heart and spleen tests and body scans. They may have samples of skin or warts taken. Researchers may take photographs of warts.
• Participants will start twice daily self-injections of G-CSF. Their doctors will decide the dosage.
• Initial Period (4-12 weeks)
• Participants will:
• continue the injections and their usual antibiotics and/or immunoglobulin
• have blood drawn
• keep a daily health diary
• Participants will visit the clinic for 2 days without injections.
• Adjustment Period 1 (8 weeks):
• Participants will:
• continue twice daily injections from home
• continue the daily health diary
• have blood tests every 2 weeks.
• Treatment Year 1:
• Participants will
• receive either plerixafor or G-CSF injections twice daily
• continue the health diary
• have blood tests every 2 months
• visit the clinic about every 4 months
• At the end of year 1, participants will visit the clinic for an evaluation. They will switch to the other study drug. They will have an 8-week adjustment and 1-year treatment period.
• At the end of year 2, participants will visit the clinic to complete their injections and go back to their previous G-CSF regimen. Participants will continue their daily health diary and have blood tests for 5-6 months.

Conditions

Myelokathexis; Infections; Neutropenia; Warts; Hypogammaglobulinemia

Keywords

Immunodeficiency; Neutropenia; Mozobil; Myelokathexis; Warts

Outcome Measures

Primary Outcomes (2)

• Severity of Infection

  The primary outcome is a Total Infection Severity Score (TISS). Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these scores were summed (weighted based on time at risk) to create a total infection severity score (TISS) in each period for each participant (range 0 to infinity). Drug failures during a period were pre-defined to count as more extreme than any TISS score. The primary analysis outcome is based on the Difference in Total Infection Severity Score (TISS) in Period 1 minus TISS in Period 2 analysis, with drug failures in only one period assigned the highest absolute value for the difference, with the sign defined according to the treatment order (e.g., negative for period 2 drug failures only). Higher values of the difference represent a worse outcome in the first period than in the second period. Thus, each participant's infection severity

  Scores from 12 months treatment on each study drug

• Difference in Total Infection Severity Score

  The primary outcome is a difference: the Total Infection Severity Score (TISS) in Period 1 minus the TISS in Period 2. Higher values represent a worse outcome in the first period than in the second period. Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these individual infection scores were summed (weighted by time at risk) to create a total infection severity score (TISS) in each period. Because there is no pre-determined number of infections, the range is -infinity to +infinity. If a participant has a drug failure in only one period, their difference rank is either the highest rank (if the failure is in Period 1) or the lowest rank (if the failure is in Period 2), failure on both periods gives a difference of 0. 1 subject failed on both treatments, and 3 subjects failed only on plerixafor.

  Scores from 12 months treatment on each study drug

Study Arms (2)

Plerixafor first then G-CSF (PG)

ACTIVE COMPARATOR

Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes

Drug: Plerixafor; Drug: G-CSF

G-CSF first then Plerixafor (GP)

ACTIVE COMPARATOR

Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes

Drug: Plerixafor; Drug: G-CSF

Interventions

Plerixafor DRUG

Twice daily low dose injection for 14 months.

Also known as: Mozobil

G-CSF first then Plerixafor (GP); Plerixafor first then G-CSF (PG)

G-CSF DRUG

Twice daily low dose injection for 14 months.

Also known as: Neupogen

G-CSF first then Plerixafor (GP); Plerixafor first then G-CSF (PG)

Eligibility Criteria

• Age: 10 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects are eligible to enter the study if they meet all of the following criteria:
• Age greater than or equal to 10 and less than or equal to 75 years.
• Heterozygous mutation in the C-tail of CXCR4 in addition to a clinical diagnosis of WHIMS.
• Documented neutropenia with a baseline ANC below 1500 cells/microL of blood.
• History of severe and/or recurrent infections.
• Willingness to interrupt G-CSF medication, 2 days prior to study drug injection.
• Must have a local medical provider for medical management.
• Must be willing to provide blood, plasma, serum, and DNA samples for storage.
• All study subjects must agree not to become pregnant or impregnate a female. Women of childbearing potential must agree to take appropriate steps to avoid becoming pregnant for the duration of the study. Participants in whom pregnancy is biologically possible must use at least 2 study approved methods of contraception, one of which must be a barrier method, and must continue contraception until 5 months after stopping the study drug:
• Male or female condoms with a spermicide,
• Diaphragm or cervical cap with spermicide,
• Intrauterine device,
• Contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved contraceptive,
• Male partner with vasectomy and documented aspermatogenic sterility.
• Willingness to comply with the study medications, visits, and procedures, as deemed necessary by the principal investigator (PI).

You may not qualify if:

• Neutropenia due to maturation defects in the myeloid lineage or a type of neutropenia, which in the investigator s opinion, is unlikely to improve from the medication administered in this study.
• Pregnant or breast-feeding women.
• Known hypersensitivity to plerixafor, G-CSF, or any components of the products.
• Predisposition to or history of life-threatening cardiac arrhythmia.
• Requiring dialysis or having markedly impaired renal function with a Creatinine Clearance (CrCl) \<15 mL/min.
• Condition that in the investigator s opinion places a subject at undue risk by participating in the study.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• McDermott DH, Velez D, Cho E, Cowen EW, DiGiovanna JJ, Pastrana DV, Buck CB, Calvo KR, Gardner PJ, Rosenzweig SD, Stratton P, Merideth MA, Kim HJ, Brewer C, Katz JD, Kuhns DB, Malech HL, Follmann D, Fay MP, Murphy PM. A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome. J Clin Invest. 2023 Oct 2;133(19):e164918. doi: 10.1172/JCI164918.

  PMID: 37561579 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Infections; Neutropenia; Warts; Agammaglobulinemia; Immunologic Deficiency Syndromes

Interventions

plerixafor; Granulocyte Colony-Stimulating Factor; Filgrastim

Condition Hierarchy (Ancestors)

Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Papillomavirus Infections; DNA Virus Infections; Virus Diseases; Skin Diseases, Viral; Tumor Virus Infections; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases; Blood Protein Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Limitations and Caveats

1. Highly variable disease phenotypic expression made crossover design optimal but a placebo arm was not included due to infection risk of severe neutropenia 2. Prophylactic supplemental immunoglobulin and antibiotics were allowed 3. Tolerance of G-CSF was insured prior to randomization but plerixafor was never used before randomization in 17/19 patients, 4. Non-inferiority analysis of primary endpoint was not planned because there were no defined equivalence margins

Results Point of Contact

• Title: Dr. David H. McDermott
• Organization: LMI/NIAID/NIH

dmcdermott@niaid.nih.gov

301-761-6647

Study Officials

• David H McDermott, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2014
• First Posted: September 4, 2014
• Study Start: October 14, 2014
• Primary Completion: October 8, 2020
• Study Completion: February 24, 2021
• Last Updated: April 7, 2023
• Results First Posted: April 7, 2023

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)