search
Back to results

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

Primary Purpose

Myelokathexis, Infections, Neutropenia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Plerixafor
G-CSF
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelokathexis focused on measuring Immunodeficiency, Neutropenia, Mozobil, Myelokathexis, Warts

Eligibility Criteria

10 Years - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • INCLUSION CRITERIA:

Subjects are eligible to enter the study if they meet all of the following criteria:

  1. Age greater than or equal to 10 and less than or equal to 75 years.
  2. Heterozygous mutation in the C-tail of CXCR4 in addition to a clinical diagnosis of WHIMS.
  3. Documented neutropenia with a baseline ANC below 1500 cells/microL of blood.
  4. History of severe and/or recurrent infections.
  5. Willingness to interrupt G-CSF medication, 2 days prior to study drug injection.
  6. Must have a local medical provider for medical management.
  7. Must be willing to provide blood, plasma, serum, and DNA samples for storage.
  8. 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.
  9. Willingness to comply with the study medications, visits, and procedures, as deemed necessary by the principal investigator (PI).

EXCLUSION CRITERIA:

If any of the following exclusion criteria are met, a subject will not be enrolled in this study:

  1. 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.
  2. Pregnant or breast-feeding women.
  3. Known hypersensitivity to plerixafor, G-CSF, or any components of the products.
  4. Predisposition to or history of life-threatening cardiac arrhythmia.
  5. Requiring dialysis or having markedly impaired renal function with a Creatinine Clearance (CrCl) <15 mL/min.
  6. Condition that in the investigator s opinion places a subject at undue risk by participating in the study.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Plerixafor first then G-CSF (PG)

G-CSF first then Plerixafor (GP)

Arm Description

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

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

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

Full Information

First Posted
September 3, 2014
Last Updated
April 6, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
search

1. Study Identification

Unique Protocol Identification Number
NCT02231879
Brief Title
Plerixafor Versus G-CSF in the Treatment of People With WHIM Syndrome
Official Title
A Phase III Double-Blind Randomized Crossover Study of Plerixafor Versus G-CSF in the Treatment of Patients With WHIM Syndrome.
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
October 14, 2014 (Actual)
Primary Completion Date
October 8, 2020 (Actual)
Study Completion Date
February 24, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.
Detailed Description
Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency disorder caused by gain-of-function mutations in the gene for the chemokine receptor CXCR4. Normally, CXCR4 is expressed on most leukocyte subsets and functions in part to promote hematopoietic stem cell (HSC) and neutrophil homing to and retention in bone marrow. WHIM mutations alter the CXCR4 carboxyl terminus, which enhances and prolongs receptor signaling. As a result, egress of normally produced and functional neutrophils from the bone marrow to the blood is impaired causing neutropenia, a bone marrow pathologic finding referred to as myelokathexis. A similar mechanism may also affect other leukocyte subsets since WHIM patients usually are panleukopenic. Consequently, WHIM patients are predisposed to frequent acute bacterial infections, especially in the sinopulmonary tract, that may cause chronic morbidity, respiratory insufficiency and in some cases premature death. WHIM patients also have marked difficulty clearing infections with Human Papillomavirus (HPV), resulting in persistent cutaneous and anogenital warts that in several reported cases have evolved into cancer. Several deaths have also occurred due to cancer associated with Epstein -Barr virus (EBV) infection. Therapies currently used for WHIMS are non-specific and expensive, and include Granulocyte Colony-Stimulating Factor (G-CSF) (the drug currently approved by the Food and Drug Administration (FDA) to treat severe congenital neutropenia), intravenous immunoglobulin (IVIg), and prophylactic antibiotics. None of these measures has been formally evaluated for efficacy in WHIM syndrome (WHIMS); however, in our clinical experience based on the treatment of 24 WHIM patients seen at the National Institutes of Health (NIH) since 2006, recurrent bacterial infections continue to occur, despite the fact that the absolute neutrophil count (ANC) can be readily maintained above 500 cells/microliter by G-CSF and IgG levels can be restored to the normal range by IVIg. Thus, there continues to be a major unmet medical need for effective therapy in WHIMS despite the availability and application of best therapy for neutropenia and hypogammaglobulinemia in these patients. Plerixafor (Mozobil ) is a specific small molecule antagonist of CXCR4, licensed by the FDA for HSC mobilization for transplantation in cancer, and is therefore a logical candidate for molecularly targeted treatment of WHIMS. The goal of treatment would be to reduce CXCR4 signaling to normal, not to zero, thus, absent any off-target effects, targeted chronic treatment with this agent may be safe. In this regard, 2 recent short term Phase I dose-escalation studies of plerixafor, one from our group, in a total of 9 patients demonstrated that the drug could safely mobilize not only neutrophils, but also all other leukocyte subsets that are decreased in the blood of WHIM patients. A follow-up Phase I study, conducted by our group, in 3 patients given plerixafor 0.02-0.04 mg/kg/d for 6 months demonstrated that these hematopoietic effects were durable. Moreover, the frequency of infection was reduced on plerixafor as compared to retrospective data mined for the three years before starting therapy and prospective data collected for one year after ending therapy, even though 2 of the patients were taking GCSF during the comparison time periods. No new warts occurred during treatment and several existing warts improved or resolved. Although these results are encouraging, the small number of patients studied, limited duration of drug treatment, and retrospective mining of control data leave open to question whether plerixafor is truly efficacious for clinical outcomes in WHIMS. The randomized, double blinded, crossover trial described here is designed to answer this question by establishing the long-term safety and clinical efficacy (primary endpoint: infection severity; multiple secondary endpoints including wart control) of plerixafor as compared to G-CSF in the treatment of WHIMS patients 10-75 years of age. G-CSF as a comparator is required because of its approved use in patients with severe congenital neutropenia (SCN). Brief outline of study we intend to randomize 20 patients and treat them in a double-blinded manner for 1 year with G-CSF and 1 year with plerixafor using a crossover design to allow direct comparison of infection severity during treatment with both agents, at doses determined by the patient s individual neutrophil response. A schedule of events has been provided in Appendix A. Data will be analyzed as specified in the Statistics section (Section 14) after randomization. Tolerability and patient drug preference will also be assessed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelokathexis, Infections, Neutropenia, Warts, Hypogammaglobulinemia
Keywords
Immunodeficiency, Neutropenia, Mozobil, Myelokathexis, Warts

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Plerixafor first then G-CSF (PG)
Arm Type
Active Comparator
Arm Description
Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes
Arm Title
G-CSF first then Plerixafor (GP)
Arm Type
Active Comparator
Arm Description
Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes
Intervention Type
Drug
Intervention Name(s)
Plerixafor
Other Intervention Name(s)
Mozobil
Intervention Description
Twice daily low dose injection for 14 months.
Intervention Type
Drug
Intervention Name(s)
G-CSF
Other Intervention Name(s)
Neupogen
Intervention Description
Twice daily low dose injection for 14 months.
Primary Outcome Measure Information:
Title
Severity of Infection
Description
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
Time Frame
Scores from 12 months treatment on each study drug
Title
Difference in Total Infection Severity Score
Description
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.
Time Frame
Scores from 12 months treatment on each study drug

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: 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). EXCLUSION CRITERIA: If any of the following exclusion criteria are met, a subject will not be enrolled in this study: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David H McDermott, M.D.
Organizational Affiliation
National Institute of Allergy and Infectious Diseases (NIAID)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-I-0185.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

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

We'll reach out to this number within 24 hrs