Conditions: Myelokathexis Infections Neutropenia Warts Hypogammaglobulinemia
Keywords: Immunodeficiency Neutropenia Mozobil Myelokathexis Warts
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: no

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.

Arms:
arm 1: Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes arm 2: Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes

Interventions: intervention 1: Plerixafor intervention 2: G-CSF
Intervention descriptions: intervention 1: Twice daily low dose injection for 14 months. intervention 2: Twice daily low dose injection for 14 months.

Protocol document:
Prot_SAP_000.pdf: 
Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
 
A Phase III, Double-blind, Randomized, Crossover Study of Plerixafor Versus G-CSF in 
the Treatment of Patients with WHIM Syndrome 
 
 
 
Protocol Number:  
 
14-I-0185 
Version Description:                      Version 6.0 
Version Date:                                 January 9, 2019 
Abbreviated Title:                          Plerixafor vs. G-CSF in WHIMS 
Location of the Study: 
 
NIH Clinical Center  
Total Subjects to be accrued:         30 
Proposed Period:                            6 years 
  
IND: 
 
 
 
118767 
Name of Agent:  
 
plerixafor and G-CSF  
Holder:  
 
 
OCRPRO, DCR, NIAID 
 
 
 
 
 
 
USponsored by 
Office of Clinical Research Policy and Regulatory Operations (OCRPRO) 
Division of Clinical Research (DCR), Office of the Director  
National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
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Page 2 of 74 
 
 
STUDY STAFF ROSTER 
 
Principal Investigator: 
 
David H. McDermott, MD 
Laboratory of Molecular Immunology (LMI)/NIAID 
 
Phone: 301-496-8483 
E-mail: DMCDERMOTT@niaid.nih.gov  
 
Associate Investigators: 
 
Philip M. Murphy, MD 
 
 
 
 
LMI/NIAID 
 
 
 
Phone: 301-496-8616 
 
Harry L. Malech, MD  
 
 
 
 
 
Laboratory of Host Defenses (LHD)/NIAID 
 
 
 
 
 
Phone: 301-480-6916  
 
 
 
 
 
Elizabeth Kang, MD  
 
 
 
 
 
Laboratory of Host Defenses (LHD)/NIAID 
 
 
 
 
 
Phone: 301-402-7567  
 
Research Contact/Study  
Coordinator(s): 
 
 
Daniel Velez, RN 
 
 
 
LMI/NIAID 
 
 
 
Phone: 301-594-1549 
 
 
 
 
 
 
Elena Cho, RN 
 
 
 
 
 
LMI/NIAID 
 
 
 
 
 
Phone: 301-761-7280 
 
Statistician: 
 
 
 
Dean Follmann, PhD 
 
 
 
 
 
Biostatistics Research Branch/DCR/NIAID 
 
 
 
 
 
Phone: 301-451-5128 
 
NIH Pharmacy (NIH):  
 
Michael Kolf  
 
 
 
 
 
NIH Pharmacy/NIH/Clinical Center 
 
 
 
 
 
Phone: 301-496-1031 
 
Sponsor Medical Monitor: 
 
Marc Teitelbaum, MD 
Leidos Biomedical Research, Inc. 
5705 Industry Lane 
Frederick, MD 21704 
Tel: 301-228-4707  
Email: 40TMarc.Teitelbaum@fnlcr.nih.gov40T 
 
Institutional Review Board: 
 
NIAID IRB 
 
 
 
 
 


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Page 3 of 74 
 
 
 
Consultants: 
 
 
 
 
 
 
 
Melissa Meridith, MD 
 
 
 
 
Gynecology, NHGRI 
 
 
 
 
301-402-1816 
 
 
 
 
 
Edward Cowen, MD 
 
 
 
 
 
Dermatology, NCI 
 
 
301-496-4299 
 
 
 
John DiGiovanna, MD  
 
 
Dermatology, NCI 
 
 
301-402-1607 
 
Jeffrey H. Kim, MD 
 
 
 
 
 
ENT, NIDCD 
 
 
301-496-4299 
 
 
 
 
 
Carmen Brewer, PhD 
 
 
 
 
 
Audiology, NIDCD 
 
 
301-496-5294 
 
 
 
 
 
Katherine Calvo, MD 
 
 
 
 
 
Hematologic Pathology, DLM/CC 
 
 
301-594-9578 
 
Pamela Gardner, DDS 
 
 
 
 
 
Dentistry, NIDCR 
 
 
301-443-8010 
 
 
 
 
 
 
 
 
 
 
 
Thomas Fleisher, MD 
 
 
 
 
 
Clinical Immunology, DLM/CC 
 
 
 
 
 
301-496-5568  
 
 
 
 
 
 
Alison McBride, PhD 
 
 
 
 
 
Virology, LVD/NIAID 
 
 
 
 
 
301-496-1370 
 
 
 
 
 
 
Chris Buck, PhD 
 
 
 
 
 
Virology, LCO/NCI 
 
 
 
 
 
301-594-7060 
 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
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Page 4 of 74 
 
 
TABLE OF CONTENTS 
40TSTUDY STAFF ROSTER40T ............................................................................................................. 2 
40TTABLE OF CONTENTS40T .............................................................................................................. 4 
40TLIST OF TABLES40T ....................................................................................................................... 12 
40TLIST OF FIGURES40T ..................................................................................................................... 12 
40TLIST OF ABBREVIATIONS40T ...................................................................................................... 13 
40TPROTOCOL SUMMARY40T ........................................................................................................... 15 
40TPRÉCIS40T ........................................................................................................................................ 17 
40TSTUDY SCHEMA40T ...................................................................................................................... 18 
40T140T 
40TBACKGROUND INFORMATION AND SCIENTIFIC RATIONALE40T .................... 19 
40T1.140T 
40TBackground Information40T .............................................................................................. 19 
40T1.1.140T 
40TCXCR440T ................................................................................................................................. 19 
40T1.1.240T 
40TWHIMS40T ................................................................................................................................ 19 
40T1.240T 
40TDescription of Study Agent: Mozobil™ (plerixafor)40T ................................................... 20 
40T1.2.140T 
40TSummary of Previous Pre-Clinical Studies40T .......................................................................... 21 
40T1.2.240T 
40TSummary of Relevant Clinical Studies40T ................................................................................ 22 
40T1.340T 
40TDescription of Comparator Treatment: G-CSF40T ............................................................ 22 
40T1.3.140T 
40TSummary of Relevant Clinical Studies40T ................................................................................ 22 
40T1.440T 
40TScientific Rationale and Clinical Justification40T ............................................................. 23 
40T1.540T 
40TPreliminary Report of Unexpected Adverse Events in this Study40T ............................... 24 
40T1.5.140T 
40TAn Incident of a New Psoriasis-like Rash40T ........................................................................... 24 
40T1.5.240T 
40TJoint Pain (Arthralgia) and an Incident of Reactive Arthritis40T .............................................. 24 
40T240T 
40TSTUDY OBJECTIVES40T ................................................................................................ 26 
40T2.140T 
40TPrimary Objective40T ........................................................................................................ 26 
40T2.240T 
40TSecondary Objectives40T ................................................................................................... 26 
40T2.340T 
40TExploratory Objectives40T ................................................................................................. 26 
40T340T 
40TSTUDY DESIGN40T ......................................................................................................... 26 
40T3.140T 
40TDescription of the Study Design40T .................................................................................. 26 
40T3.240T 
40TStudy Endpoints40T ........................................................................................................... 27 
40T3.2.140T 
40TPrimary Endpoint40T ................................................................................................................. 27 


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40T3.2.240T 
40TSecondary Endpoints40T ........................................................................................................... 27 
40T3.2.340T 
40TExploratory Endpoint40T ........................................................................................................... 27 
40T440T 
40TSTUDY POPULATION40T .............................................................................................. 27 
40T4.140T 
40TSubject Selection and Recruitment Plan40T ...................................................................... 27 
40T4.240T 
40TInclusion Criteria40T .......................................................................................................... 27 
40T4.340T 
40TExclusion Criteria40T ......................................................................................................... 28 
40T4.440T 
40TJustification for Exclusion of Pregnant or Breast Feeding Women40T ............................. 28 
40T4.540T 
40TJustification for Exclusion of Children <10 Years of Age40T ........................................... 28 
40T540T 
40TSTUDY AGENT AND INTERVENTIONS40T ............................................................... 28 
40T5.140T 
40TDrug Acquisition40T .......................................................................................................... 28 
40T5.1.140T 
40TPlerixafor: Provided by Manufacturer40T ................................................................................. 28 
40T5.1.240T 
40TG-CSF: Obtained Commercially40T .......................................................................................... 29 
40T5.240T 
40TDisposition and Dispensation40T ....................................................................................... 29 
40T5.2.140T 
40TFormulation, Packaging, and Labeling40T ................................................................................ 29 
40T5.2.1.140T 
40TPlerixafor Packaging from Manufacturer40T .................................................................... 29 
40T5.2.1.240T 
40TPlerixafor Repackaging for Study and/or Shipment to Study Participants40T ................. 29 
40T5.2.1.340T 
40TG-CSF Packaging from Manufacturer40T ........................................................................ 29 
40T5.2.1.440T 
40TG-CSF Repackaging for Study and/or Shipment to Study Participants40T ...................... 29 
40T5.2.240T 
40TLabeling of Study Drug40T ....................................................................................................... 29 
40T5.340T 
40TStudy Agent Storage and Stability40T ............................................................................... 29 
40T5.3.140T 
40TStorage at NIH-CC40T ............................................................................................................... 30 
40T5.3.240T 
40TShipment to Participants' Home40T ........................................................................................... 30 
40T5.440T 
40TStudy Agent Preparation and Administration40T .............................................................. 30 
40T5.4.140T 
40TSubject Preparation and Self-Injection40T ................................................................................ 30 
40T5.4.240T 
40TSubject Memory Aid: Injection Site, Injection Volume, Adverse Reactions40T ...................... 30 
40T5.540T 
40TDose-Adjustment and Therapeutic Schedule40T ............................................................... 30 
40T5.640T 
40TStudy Product Accountability Procedures40T ................................................................... 30 
40T5.6.140T 
40TPlerixafor40T.............................................................................................................................. 30 
40T5.6.240T 
40TG-CSF40T .................................................................................................................................. 30 
40T640T 
40TSTUDY SCHEDULE AND ACTIVITIES40T .................................................................. 30 
40T6.140T 
40TRecruitment40T .................................................................................................................. 30 
40T6.240T 
40TScreening40T ...................................................................................................................... 31 
40T6.2.140T 
40TLabs and Procedures40T ............................................................................................................ 31 
40T6.2.240T 
40TAssessment of Overall Health40T .............................................................................................. 31 


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40T6.340T 
40TInitial Evaluation and Baseline Assessment Period40T ..................................................... 31 
40T6.3.140T 
40TMeasurement of Immunological Markers40T ............................................................................ 31 
40T6.3.240T 
40TEvaluations: Dermatology, GYN, Dentistry, ENT, Audiology, and Clinical Photography40T . 31 
40T6.3.340T 
40TAdditional Evaluations if Clinically Indicated (e.g. PFT and CT of Chest and Sinus)40T ........ 31 
40T6.3.440T 
40TBaseline Measure of Bone Density and Spleen Size40T ........................................................... 32 
40T6.3.540T 
40TResearch Blood40T .................................................................................................................... 32 
40T6.3.640T 
40TWart and/or Skin Biopsy (optional)40T ..................................................................................... 32 
40T6.3.740T 
40TBone Marrow Biopsy (optional)40T .......................................................................................... 32 
40T6.3.840T 
40TQuality of Life Assessment of Period Prior to the Study40T ..................................................... 32 
40T6.3.940T 
40TIVIg and Prophylactic Antibiotics40T ....................................................................................... 32 
40T6.3.1040T 
40TDetermining a Minimum Effective Dose for G-CSF40T ....................................................... 32 
40T6.3.1140T 
40TPreparing for Study Drug Shipments and Study Drug Administration at Home40T ............. 33 
40T6.3.1240T 
40TTraining and Practice for Submissions of Completed Subject Memory Aid40T ................... 33 
40T6.3.1340T 
40TSelect a Local Medical Facility for Blood Draws at a Subject’s Home Locale40T .............. 33 
40T6.440T 
40TRandomization and Initiation of the First Study Dose40T ................................................. 33 
40T6.4.140T 
40TWashout Period Prior to theP 
PFirst Study/Comparator Dose (at least 2 days prior to 1Pst
P dose)40T
 
33 
40T6.4.240T 
40TAssessment of Overall Health (within 2 days prior to the 1Pst
P dose)40T ..................................... 33 
40T6.4.340T 
40TConfirm Study Drug Shipment/Injection, Memory Aid, Local Labs, and Reporting 
Infections40T ........................................................................................................................................... 33 
40T6.4.440T 
40TLab Draw Prior to Injection of the 1Pst
P Study/Comparator Dose40T .......................................... 33 
40T6.4.540T 
40TDay of the First Study/Comparator Dose (Day 0)40T ............................................................... 34 
40T6.4.5.140T 
40TPrior to Injection40T.......................................................................................................... 34 
40T6.4.5.240T 
40TAfter Study Drug Injection40T .......................................................................................... 34 
40T6.4.5.340T 
40TProcedures Prior to Leaving NIH-CC40T ......................................................................... 34 
40T6.540T 
40TEquilibration Period for the Treatment (8 weeks)40T ........................................................ 34 
40T6.5.140T 
40TBlood Draws at Subject’s Local Medical Facility Every 2 Weeks40T ...................................... 34 
40T6.5.240T 
40TDose May be Adjusted to Maintain ANC Between 500-1500 cells/μL40T ............................... 34 
40T6.640T 
40TTreatment Period (52 weeks)40T ....................................................................................... 34 
40T6.6.140T 
40TAssessments at NIH-CC Every 4 Months40T ............................................................................ 35 
40T6.6.1.140T 
40TLabs40T ............................................................................................................................. 35 
40T6.6.1.240T 
40TAssessment of Overall Health and Safety40T ................................................................... 35 
40T6.6.1.340T 
40TMeasurement of Immunological Markers40T ................................................................... 35 
40T6.6.1.440T 
40TEvaluations and Consults for Assessment of Infections40T .............................................. 35 
40T6.6.1.540T 
40TResearch Blood40T ........................................................................................................... 35 
40T6.6.1.640T 
40TQuality of Life Assessment40T ......................................................................................... 35 


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40T6.6.1.740T 
40TSkin and Wart Biopsies (optional)40T .............................................................................. 35 
40T6.6.240T 
40TCBC w/diff, ESR, and Chemistries Every 2 Months at Subject’s Local Medical Facility40T .. 35 
40T6.6.340T 
40TVisits to a Subject’s Local Provider for New or Worsening Infections40T ............................... 35 
40T6.6.440T 
40TEnd of Treatment (EOT) Visit for a Study Drug40T ................................................................. 36 
40T6.740T 
40TReverting to a Subject’s Pre-study Treatment40T ............................................................. 36 
40T6.7.140T 
40TWashout Period (2 Days)40T ..................................................................................................... 36 
40T6.7.240T 
40TMonitoring the G-CSF Dose (1-2 Months)40T .......................................................................... 36 
40T6.7.340T 
40TStudy Completion Visit40T ........................................................................................................ 36 
40T6.840T 
40TEarly Completion of Treatment Due to Unwillingness or Inability to Receive Study 
Agent40T ............................................................................................................................. 36 
40T740T 
40TSTUDY PROCEDURES AND EVALUATIONS40T ....................................................... 36 
40T7.140T 
40TAbsolute Neutrophil Count (ANC)40T .............................................................................. 36 
40T7.1.140T 
40TTime of Day Measurement for ANC: Prior to Study Dose40T .................................................. 37 
40T7.1.240T 
40TTarget ANC during 8 week Equilibration Period (500 – 1500 cells/µL)40T ............................. 37 
40T7.1.2.140T 
40TSubjects with a Baseline ANC > 500 cells/µL40T ............................................................ 37 
40T7.1.2.240T 
40TSubjects Unable to Attain ANC >500 cells/μL During Equilibration, Despite Maximal 
Dose40T 
37 
40T7.1.340T 
40TTarget ANC during the 52 week Treatment Period (500 – 7500 cells/µL)40T.......................... 37 
40T7.1.440T 
40TDose Range for Low-Dose Treatment40T ................................................................................. 37 
40T7.240T 
40TAdjusting the Study Dose to Meet ANC Goals40T ........................................................... 38 
40T7.2.140T 
40TInitial Study/Comparator Drug Doses during Equilibration Period40T ..................................... 38 
40T7.2.240T 
40TAdjustment for ANC <500 cells/µL40T .................................................................................... 38 
40T7.2.340T 
40TAdjustment for ANC between 500 – 1500 cells/µL in the Equilibration Period40T ................. 38 
40T7.2.440T 
40TAdjustment for ANC > 1500 cells/µL in the Equilibration Period40T ...................................... 38 
40T7.2.540T 
40TAdjustment for ANC > 7500 cells/µL in the Treatment Period40T ........................................... 38 
40T7.340T 
40TImmune Status: Leukocyte Immunophenotypes40T .......................................................... 38 
40T7.440T 
40TMedication Compliance: Study Drug and Prophylactic Antibiotics40T ............................ 38 
40T7.4.140T 
40TSubject Memory Aid40T ............................................................................................................ 38 
40T7.4.1.140T 
40TIVIg Treatment and Dose40T ............................................................................................ 39 
40T7.4.1.240T 
40TRecord Temperature for Fevers40T ................................................................................... 39 
40T7.4.1.340T 
40TCompliance with Prescribed Prophylactic Antibiotics40T ................................................ 39 
40T7.540T 
40TStudy Drug Side Effects and Toxicity40T ......................................................................... 39 
40T7.5.140T 
40TSubject Memory Aid40T ............................................................................................................ 39 
40T7.5.1.140T 
40TInjection Site Reaction40T ................................................................................................ 39 
40T7.5.1.240T 
40TBone (Skeletal) Pain: back, arms and legs40T .................................................................. 39 
40T7.5.1.340T 
40TOther Pain: shoulder, abdominal etc.40T .......................................................................... 39 


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40T7.5.1.440T 
40THeadache40T ..................................................................................................................... 39 
40T7.5.1.540T 
40TDizziness40T ..................................................................................................................... 40 
40T7.5.1.640T 
40TNausea40T ......................................................................................................................... 40 
40T7.5.1.740T 
40TVomiting40T ..................................................................................................................... 40 
40T7.5.1.840T 
40TDiarrhea40T ....................................................................................................................... 40 
40T7.5.1.940T 
40TSubject Specifies Other Symptoms or Adverse Events.40T .............................................. 40 
40T7.5.240T 
40TCBC, Chemistries, ESR, and Pregnancy for Women of Childbearing Potential40T ................. 40 
40T7.5.340T 
40TSplenic Enlargement40T ............................................................................................................ 41 
40T7.5.3.140T 
40TSpleen Ultrasonography40T .............................................................................................. 41 
40T7.5.3.240T 
40TSpleen Assessment as part of Physical Examination at Research Assessment40T ........... 41 
40T7.5.440T 
40TElectrocardiogram40T ................................................................................................................ 41 
40T7.5.540T 
40TEchocardiogram40T ................................................................................................................... 41 
40T7.5.640T 
40TDual-energy X-ray Absorptiometry (DEXA) Scans40T ............................................................ 41 
40T7.640T 
40TRate and Severity of Infections40T .................................................................................... 41 
40T7.6.140T 
40TSubject Memory Aid: Symptoms of Infections40T ................................................................... 41 
40T7.6.1.140T 
40TIncidence and Severity of Fever40T .................................................................................. 41 
40T7.6.1.240T 
40TNumber of Days with Fever40T ........................................................................................ 41 
40T7.6.1.340T 
40TChange in Severity of Chronic Infection40T ..................................................................... 41 
40T7.6.1.440T 
40TVisits to Local Provider for Medical Exam or Treatment40T ........................................... 41 
40T7.6.1.540T 
40TIncidence and Duration of Antibiotic for Treatment40T ................................................... 41 
40T7.6.240T 
40TClinical Diagnosis and Treatment of Infections40T................................................................... 42 
40T7.6.2.140T 
40TLocal Provider Completes a Diagnosis and Treatment Form (option 1)40T ..................... 42 
40T7.6.2.240T 
40TSubject or Provider forwards Documents Relating to the Infection (option 2)40T ........... 42 
40T7.6.340T 
40TENT and Audiology Evaluation at NIH-CC40T ........................................................................ 42 
40T7.6.440T 
40TDental and Oral Evaluation40T .................................................................................................. 42 
40T7.6.540T 
40TPFT for Subjects with Chronic Respiratory Infections40T ........................................................ 42 
40T7.740T 
40TMonitoring Warts40T ......................................................................................................... 42 
40T7.7.140T 
40TPhotos of Infections and Warts40T ............................................................................................ 42 
40T7.7.240T 
40TRecording the Quantity and Severity of Warts40T .................................................................... 42 
40T7.7.340T 
40TDermatology Evaluation40T ...................................................................................................... 43 
40T7.7.440T 
40TGU/GYN Evaluation40T ............................................................................................................ 43 
40T7.840T 
40TSpecimen Preparation, Handling, and Shipping40T .......................................................... 43 
40T7.940T 
40TQuality of Life (SF36 v2)40T ............................................................................................. 43 
40T7.1040T 
40TRequest for Excess Tissue40T ............................................................................................ 43 
40T840T 
40TPOTENTIAL RISKS AND BENEFITS40T ...................................................................... 43 


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40T8.140T 
40TPotential Risks of plerixafor40T ......................................................................................... 43 
40T8.240T 
40TPotential Risks for G-CSF40T ............................................................................................ 45 
40T8.340T 
40TRisks and Discomforts of Phlebotomy40T ......................................................................... 46 
40T8.440T 
40TRisks and Discomforts of Skin or Wart Biopsies40T ......................................................... 46 
40T8.540T 
40TRisks and Discomforts of Bone Marrow Biopsy40T ......................................................... 46 
40T8.640T 
40TRisks of Stopping G-CSF40T ............................................................................................. 46 
40T8.740T 
40TPotential Benefit40T ........................................................................................................... 46 
40T8.7.140T 
40TReduced Infections40T ............................................................................................................... 47 
40T8.7.240T 
40TImproved Drug Tolerability40T ................................................................................................. 47 
40T8.7.340T 
40TControl of Warts40T .................................................................................................................. 47 
40T8.7.440T 
40TIncreased Leukocyte Response40T ............................................................................................ 47 
40T940T 
40TRESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA40T .... 47 
40T9.140T 
40TIntended Use40T ................................................................................................................. 47 
40T9.240T 
40TStorage and Tracking40T ................................................................................................... 47 
40T9.340T 
40TSharing of Samples and Data40T ....................................................................................... 48 
40T9.440T 
40TReporting Loss or Unanticipated Destruction of Samples40T ........................................... 48 
40T9.540T 
40TDisposition of Samples40T ................................................................................................ 48 
40T9.5.140T 
40TRequest by Study Participant40T ............................................................................................... 48 
40T9.5.240T 
40TAt Completion of Study40T ....................................................................................................... 48 
40T1040T 
40TREMUNERATION PLAN FOR SUBJECTS40T ............................................................. 48 
40T1140T 
40TASSESSMENT OF SAFETY40T ...................................................................................... 48 
40T11.140T 
40TDocumenting, Recording, and Reporting Adverse Events40T .......................................... 48 
40T11.240T 
40TDefinitions40T .................................................................................................................... 48 
40T11.340T 
40TInvestigator Assessment of Adverse Events40T ................................................................ 50 
40T11.3.140T 
40TSeverity40T ............................................................................................................................ 50 
40T11.3.240T 
40TCausality40T .......................................................................................................................... 50 
40T11.440T 
40TInvestigator Reporting Responsibilities to the Sponsor40T ............................................... 51 
40T11.4.140T 
40TAdverse Events40T ................................................................................................................ 51 
40T11.4.240T 
40TSerious Adverse Events40T ................................................................................................... 51 
40T11.4.340T 
40TUnanticipated Problems40T ................................................................................................... 52 
40T11.4.440T 
40TProtocol-Specified Events40T ............................................................................................... 52 
40T11.4.540T 
40TPregnancy40T ........................................................................................................................ 52 
40T11.540T 
40TInvestigator Reporting Responsibilities to the NIAID IRB40T ......................................... 52 
40T11.5.140T 
40TExpedited Reporting40T ........................................................................................................ 52 


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40T11.5.240T 
40TWaiver of Reporting Anticipated Protocol Deviations, Expected UPnonAEs and Deaths40T
 
52 
40T11.5.340T 
40TAnnual Reports40T ................................................................................................................ 52 
40T11.640T 
40TFollow-up of Adverse Events and Serious Adverse Events40T ......................................... 53 
40T11.740T 
40TInvestigator Initiated Trial (IIT) Sponsor Obligations and Reporting Responsibilities40T 53 
40T11.840T 
40THalting Criteria for the Protocol40T .................................................................................. 54 
40T11.8.140T 
40TReporting of Study Halting40T .............................................................................................. 54 
40T11.8.240T 
40TResumption of a Halted Study40T ......................................................................................... 54 
40T11.940T 
40TPausing Criteria for a Subject40T ...................................................................................... 54 
40T11.9.140T 
40TReporting of Pausing for a Subject40T .................................................................................. 54 
40T11.9.240T 
40TResumption of a Paused Study40T ........................................................................................ 54 
40T11.1040T 
40TWithdrawal Criteria for an Individual Subject40T ............................................................. 55 
40T11.1140T 
40TAdditional Enrollment for Withdrawn Subjects40T .......................................................... 55 
40T1240T 
40TSAFETY OVERSIGHT AND MONITORING PLAN40T ............................................... 55 
40T12.140T 
40TSafety Review and Communication Plan40T ..................................................................... 55 
40T12.240T 
40TSponsor Medical Monitor40T ............................................................................................ 55 
40T12.340T 
40TData and Safety Monitoring Board40T .............................................................................. 55 
40T12.440T 
40TProcedures for Emergency Unblinding40T ........................................................................ 55 
40T1340T 
40TCLINICAL MONITORING STRUCTURE40T ................................................................ 56 
40T13.140T 
40TSite Monitoring Plan40T .................................................................................................... 56 
40T1440T 
40TSTATISTICAL CONSIDERATIONS40T ......................................................................... 56 
40T14.140T 
40TStudy Hypotheses40T ......................................................................................................... 56 
40T14.240T 
40TSample Size Justification40T ............................................................................................. 56 
40T14.340T 
40TStudy Population40T .......................................................................................................... 57 
40T14.440T 
40TDescription of Analysis40T ................................................................................................ 57 
40T14.4.140T 
40TEfficacy Analysis – Infection Severity Score (ISS)40T ......................................................... 57 
40T14.4.1.140T 
40TInfection-related Events40T .............................................................................................. 57 
40T14.4.1.240T 
40TSeverity of Fever for an Infection-related Event40T ......................................................... 58 
40T14.4.1.340T 
40TLevel of Antibiotic Treatment for an Infection-related Event40T ..................................... 58 
40T14.4.1.440T 
40TExtent of Hospitalization for an Infection-related Event40T ............................................ 58 
40T14.4.240T 
40TMethod of Analysis40T ......................................................................................................... 58 
40T14.4.340T 
40TInterim Analysis40T .............................................................................................................. 59 
40T14.4.440T 
40TFutility Monitoring40T .......................................................................................................... 59 
40T14.4.540T 
40TSafety Analysis40T ................................................................................................................ 59 


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40T14.4.640T 
40TSecondary Analysis40T ......................................................................................................... 59 
40T14.4.6.140T 
40TSecondary endpoints40T ................................................................................................... 59 
40T14.4.6.240T 
40TIncidence and Duration of Infection-related Event40T ..................................................... 59 
40T14.4.6.340T 
40TIncidence and Duration of Fever40T ................................................................................. 59 
40T14.4.6.440T 
40TIncidence and Duration of Antibiotic Treatment40T ........................................................ 60 
40T14.4.6.540T 
40TIncidence and Duration of Hospitalization40T .................................................................. 60 
40T14.4.6.640T 
40TSeverity of Chronic Infections40T .................................................................................... 60 
40T14.4.6.740T 
40TUse of Prophylactic Antibiotics40T .................................................................................. 60 
40T14.4.6.840T 
40TControl of Warts40T .......................................................................................................... 60 
40T14.4.6.940T 
40TChange of Leukocyte Blood Counts40T ........................................................................... 60 
40T14.4.6.1040T 
40TQuality of Life and Subject Preference Assessment40T ............................................... 61 
40T14.4.740T 
40TRandomization40T ................................................................................................................. 61 
40T1540T 
40TETHICS/PROTECTION OF HUMAN SUBJECTS40T ................................................... 61 
40T15.140T 
40TInformed Consent Process40T ............................................................................................ 61 
40T15.240T 
40TSubject Confidentiality40T ................................................................................................. 62 
40T1640T 
40TDATA HANDLING AND RECORD KEEPING40T ........................................................ 62 
40T16.140T 
40TData Management Responsibilities40T .............................................................................. 62 
40T16.240T 
40TData Capture Methods40T .................................................................................................. 62 
40T16.340T 
40TTypes of Data40T ............................................................................................................... 62 
40T16.440T 
40TSource Documents and Access to Source Data/Documents40T ........................................ 62 
40T16.540T 
40TStudy Records Retention40T .............................................................................................. 63 
40T1740T 
40TREFERENCES40T ............................................................................................................. 64 
40TAPPENDIX A: SCHEDULE OF PROCEDURES AND EVALUATION40T ................................. 67 
40TAPPENDIX B: FDA APPROVED PACKAGED INSERT: PLERIXAFOR40T ............................. 69 
40TAPPENDIX C: FDA APPROVED PACKAGE INSERT: G-CSF40T ............................................. 70 
40TAPPENDIX D: INFECTION SEVERITY SCORE (ISS)40T ........................................................... 71 
40TAPPENDIX E: DOSING OF PLEXIFOR IN RENAL IMPAIRMENT40T ..................................... 72 
40TAPPENDIX F: SAMPLE SUBJECT MEMORY AID40T ............................................................... 73 
40TAPPENDIX G: EVALUATION OF INFECTION FORM40T ......................................................... 74 
 
 
 


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LIST OF TABLES 
 
40TTable 1:  Sample size required to achieve 90% power under different assumptions for the mean response 
on G-CSF and plerixafor.  Power formula based on a two-sided two sample  t-test with alpha=0.05 using 
the period 1 minus period 2 change in TISS scores as the primary outcome. A standard deviation of 10 for 
the difference is assumed.40T .......................................................................................................................... 56 
 
LIST OF FIGURES 
 
40TFigure 1:  Plerixafor May Reduce Infection Incidence in Patients with WHIM Syndrome.40T ..................... 25 
 
 
 


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LIST OF ABBREVIATIONS 
 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event/Adverse Experience 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
AR 
Adverse Reaction 
ARDS 
Acute Respiratory Distress Syndrome 
 b.i.d. 
 Twice per day (bis in die) 
CFR 
Code of Federal Regulations 
CBC 
Complete Blood Count (with differential) 
CC 
Clinical Center 
CrCl 
Creatinine Clearance (calculated) 
CRF 
Case Report Form 
CRIS 
Clinical Research Information System (for NIH Clinical Center) 
CSO 
Clinical Safety Office 
CXCL12 
CXC chemokine ligand 12, aka SDF-1 
CXCR4 
CXC chemokine receptor 4 
 DEXA 
 Dual-energy X-ray Absorptiometry 
DCR 
Division of Clinical Research 
 DSMB 
 Data and Safety Monitoring Board 
 EBV 
 Epstein-Barr Virus 
ECHO 
Echocardiogram 
 EOT 
 End of Treatment 
EKG 
Electrocardiogram 
ESR 
Erythrocyte Sedimentation Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
 G-CSF 
 Granulocyte Colony-Stimulating Factor 
 GM-CSF 
 Granulocyte Macrophage Colony-Stimulating Factor 
 GRK 
 G Protein-Coupled Receptor Kinase 
GU 
Genitourinary 
GYN 
Gynecology 
HIV 
Human Immunodeficiency Virus 
HPV 
Human Papillomavirus 
HSC 
Hematopoietic Stem Cell 
ICH 
International Conference on Harmonization 
IgA, IgE, IgG, IgM 
Immunoglobulins A, E, G, M 
 IIT 
 Investigator Initiated Trial 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISS 
Infection Severity Score 
 IVIg 
 Intravenous Immunoglobulin 


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LHD 
Laboratory of Host Defenses 
LMI 
Laboratory of Molecular Immunology 
LMF 
Local Medical Facility 
MDS 
Myelodysplastic Syndrome 
MED 
Minimum Effective Dose 
MM 
Multiple Myeloma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
 NIAID 
 National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NIH-HRPP 
National Institutes of Health – Human Research Protection Program 
 NIH-CC 
 National Institutes of Health Clinical Center 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protection 
PFT 
Pulmonary Function Test 
PI 
Principal Investigator 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
 QOL 
 Quality of Life 
RCHSPP 
Regulatory Compliance and Human Subjects Protection Program 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SCN 
Severe Congenital Neutropenia 
SRCP 
Safety Review and Communication Plan 
 SDF-1 
 Stromal Cell-Derived factor-1, aka CXCL12 
SQ 
Subcutaneous (Injection) 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
TISS 
Total Infection Severity Score 
TPN 
Total Parenteral Nutrition 
WBC 
White Blood Cell Count 
WHIMS 
Warts, Hypogammaglobulinemia, Infections, and Myelokathexis 
Syndrome 
UP 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 
 
 


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PROTOCOL SUMMARY 
 
Full Title: 
A Phase III, Double-blind, Randomized, Crossover Study of Plerixafor Versus 
G-CSF in the Treatment of Patients with WHIM Syndrome 
 
Short Title: 
Plerixafor vs. G-CSF in WHIMS 
 
Clinical Phase: 
III 
 
IND Sponsor: 
OCRPRO/DCR/NIAID 
Conducted by: 
Laboratory of Molecular Immunology/NIAID 
 
Principal Investigator:  
David H. McDermott, MD 
 
Sample Size: 
 
N=20 
 
Accrual Ceiling: 
 
n = 30 
 
Study Population: 
 
Subjects (≥10 and ≤75 years of age) with WHIMS  
 
Accrual Period: 
36 months 
Study Design: This is a double-blinded, randomized, crossover study 
comparing the efficacy of the chemokine receptor CXCR4 antagonist 
plerixafor to G-CSF in subjects with a clinical diagnosis of WHIMS and 
mutations in the C-terminus of chemokine receptor CXCR4. Eligible subjects 
who give informed consent are randomized to 1 year of treatment with either 
plerixafor or G-CSF, followed by a crossover to the second drug for 1 year. 
Each treatment arm is preceded by a 2-day washout period followed by an 8-
week equilibration period during which study drug dosing is initiated and 
adjusted to establish an ANC of approximately 500-1500 cells/μL. A subject’s 
ANC is monitored every 2 months during the one-year treatment periods and 
study drug dosage adjusted for ANC ≤500 cells/µL or ≥7500 cells/µL. 
Participants maintain a study Memory Aid in which they record daily 
treatments and any new symptoms. After completing both treatments, subjects 
are offered G-CSF and enter a post-treatment observation period during which 
they continue to submit the study Memory Aid. The study completion visit 
occurs 5-6 months after the last day of the second year of treatment.  
 
Study Duration: 
 
6 years  
 
 
  
Study Agent/Intervention: 
plerixafor (Mozobil™) 
Comparator: 
 
G-CSF (NeupogenPTM
P, filgrastim) 
 
Primary Objective:  
Compare the severity of infection during treatment with each drug 


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Secondary Objectives:  
 
1) 
Compare component measures of infections. 
2) 
Measure the control of warts with plerixafor versus G-CSF. 
3) 
Demonstrate the safety of plerixafor and G-CSF as long-term therapy. 
4) 
Compare the symptoms of chronic infections. 
5) 
Compare quality of life (QOL). 
6) 
Compare drug tolerability and assess subject drug preference. 
7) 
Compare the increase of leukocyte levels from baseline. 
 
Exploratory Objective:   Measure type, location, and cause of infections. 
 
Primary Endpoint: 
The primary endpoint is infection severity, which is measured as a composite 
of multiple weighted parameters according to rules defined in 40TAppendix D40T. 
 
Secondary Endpoints:  
 
1) 
Component measures of infections: incidence and duration of infections, 
fever, antibiotic treatment, and hospitalization. 
2) 
Control of warts as defined by at least a 50% reduction in numbers, areas 
or size of existing warts, or in new warts occurring during treatment. 
3) 
Blood count and immunological parameters. 
4) 
Clinical measures of chronic infection. 
5) 
Treatment side effects. 
6) 
Quality of life scores. 
7) 
Treatment preference. 
  
Exploratory Endpoint:  Identify causative organisms and locations of infections in WHIMS patients.  
 


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PRÉCIS 
 
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.P  
PWHIM 
mutations alter the CXCR4 carboxyl terminus, which enhances and prolongs receptor signaling.(40T140T) 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.(40T240T)  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.(40T3, 440T)  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.(5)  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 G-
CSF 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 40TAppendix A40T. Data will be analyzed as 


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specified in the Statistics section (Section 14) after randomization.  Tolerability and patient drug 
preference will also be assessed.  
 
 
STUDY SCHEMA 
 
 
 
 
 
2d 
8w 
 
52w 
2d 
 
8w 
 
52w 
 
Randomize 
to AB Arm 
 
Wash 
Out 
 
Equilibration  
Treatment A 
 
 
Wash 
Out 
Equilibration 
Treatment B 
Screening & Initial 
Evaluation 
 
 
 
 
 
 
 
 
 
 
Post Treatment 
Study Completion 
Visit (approx. 20w) 
 
Randomize 
to BA Arm 
 
Wash 
Out 
Equilibration 
Treatment B 
 
 
Wash 
Out 
Equilibration 
Treatment A 
 
 
w = week(s) 
d = day(s) 


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1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1 
Background Information 
1.1.1 
CXCR4 
CXCR4 is a member of the chemokine receptor family, which consists of 18 related 7 transmembrane-
domain, G protein-coupled chemoattractant receptors that regulate leukocyte trafficking.(6,40T740T) According 
to studies in gene knockout mice, CXCR4 is essential for life and plays a fundamental role in the 
hematopoietic, cardiovascular, reproductive, and nervous systems during embryonic development.(40T840T) In 
the hematopoietic system, CXCR4 is important for hematopoietic stem cell and neutrophil trafficking 
between blood and bone marrow.  In particular, reduced CXCR4 signaling promotes egress of these cells 
from marrow whereas increased CXCR4 signaling promotes homing to and retention of these cells in 
bone marrow.(40T940T) CXCR4 is also an important HIV co-receptor (with CD4) used by the virus for target 
cell infection, but only for a minority of HIV strains, which are found in patients mainly during the late 
stages of disease.(40T1040T) 
1.1.2 
WHIMS  
Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS) is a rare congenital 
immunodeficiency disorder caused by various mutations that increase CXCR4 signaling.(40T11, 1240T). All 
cases that have been genetically characterized to date involve truncation and missense mutations in the 
intracellular tail of the receptor that are inherited in an autosomal dominant manner.(40T1, 1340T) This domain 
normally mediates negative regulation of the receptor through G protein-coupled receptor kinase (GRK)-
mediated phosphorylation and beta-arrestin-mediated internalization, providing a potential mechanism for 
the increased signaling that is observed.(40T1440T) Consistent with this, truncated WHIMS receptors have been 
reported to undergo reduced ligand-dependent receptor down-regulation.(40T15, 1640T) One WHIMS patient 
has been identified who lacks CXCR4 mutations, however this individual has decreased expression of 
GRK3, which normally mediates CXCR4 desensitization.(40T1740T) Another family has recently been 
identified with 2 affected members with a recessive mutation in CXCR2.  Thus, WHIMS can be thought 
of as a disease caused by excessive CXCR4 function or insufficient CXCR2 function, which validates the 
fundamental role of these receptors in homeostatic leukocyte trafficking in humans. A mouse model in 
which a human WHIMS CXCR4 mutation (S338X) was knocked into one mouse CXCR4 locus 
phenocopies panleukopenia and revealed abnormal immune organ architecture.(40T18, 1940T) It is possible that 
mutations in other immunoregulatory genes may also cause a similar syndrome.  
 
The acronym WHIMS highlights four clinical manifestations of the disease: warts, 
hypogammaglobulinemia, infections, and myelokathexis. Warts are refractory to medical treatment in 
WHIMS and can evolve into fatal skin and anogenital cancer. Hypogammaglobulinemia is moderate and 
variable.  Nevertheless, WHIMS patients have been reported to have poor immunologic memory after 
vaccination, and the resulting low levels of immunoglobulins may predispose them to frequent 
sinopulmonary infections.(40T2040T) Perhaps the earliest and most highly penetrant clinical finding is 
neutropenia, usually severe, which appears to be caused by abnormal retention of mature neutrophils, a 
critical effector cell in innate immunity, in the bone marrow. Most patients also have panleukopenia. This 
picture, which is known as myelokathexis, the ‘M’ in WHIMS, further predisposes the patient to typical 
bacterial skin, soft tissue, and sinopulmonary infections. When the absolute neutrophil count (ANC) is 
reduced below ~500 cells/µL in patients receiving cytoreductive therapy for diseases such as cancer, the 
risk of infection with bacteria and fungi increases: however, the precise relationship between ANC and 
infection risk in WHIMS has not been defined. During infection in WHIMS patients, neutropenia often 
improves and may temporarily normalize, suggesting that the inhibition of marrow release of neutrophils 
can be overcome in the presence of infection. However, the end result of frequent infections in WHIMS 
patients can be serious, with loss of hearing, teeth, and lung function.  Dental disease consists of HPV 
related oral cancers, severe caries, periodontitis, dental abscesses, and premature tooth loss.  Older 


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patients can develop severe bronchiectasis resembling cystic fibrosis, and fatal respiratory failure. Case 
reports of fatal meningitis and Epstein-Barr virus-induced lymphoma in patients with WHIMS provide 
evidence that other immunological problems present in WHIMS patients are clinically significant.(40T21, 
2240T) In addition, an increased prevalence of tetralogy of Fallot has been observed in WHIM patients.(40T2340T) 
 
Current therapeutic recommendations in WHIMS are non-specific, expensive, associated with significant 
side effects, and based on limited direct clinical data. Daily or every other day injection of G-CSF is 
commonly given to increase the ANC, based on a placebo-controlled clinical trial that demonstrated G-
CSF safety and efficacy in reducing the risk of infection in patients with severe congenital neutropenia 
(SCN) of various etiologies.(40T2440T) On the basis of this trial, SCN was approved as an indication for G-CSF 
therapy.  However, only a few patients with WHIMS were included in the trial, so that the actual efficacy 
of G-CSF in modulating clinical endpoints specifically in WHIMS is not known. Monthly infusions of 
intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin are also given to those WHIMS 
patients who have severe hypogammaglobulinemia; however, its efficacy in this setting has not been 
studied.(40T140T) Anecdotal evidence suggests that together these measures may not affect HPV infection in 
WHIMS patients, nor would they be expected to, and do not fully prevent infections (Figure 1).(40T2540T) 
Thus, there is a clear unmet medical need for new treatments in these patients.  For these reasons and 
because of expense and side effect considerations (see below), it is clear that direct studies quantifying the 
clinical efficacy of G-CSF specifically in WHIMS as well as development of more specific treatment 
modalities in WHIMS are needed. 
1.2 
Description of Study Agent: Mozobil™ (plerixafor) 
The Food and Drug Administration (FDA) approved plerixafor (Mozobil™) injection in 2008 for use in 
combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and 
subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple 
myeloma (MM).(40T2640T) Plerixafor was initially developed as an antiretroviral compound for the treatment 
of human immunodeficiency virus (HIV).(40T2740T) It was found to be a specific and reversible inhibitor of the 
chemokine receptor and HIV co-receptor CXCR4, and its plasma concentrations closely correlated with 
the ability to inhibit CXCR4 HIV viral entry into target cells. While initial studies showed that it was a 
safe and effective antiviral drug in animals and humans, CXCR4-using virus is not common in initial HIV 
infection and the drug is not orally bioavailable, limiting its usefulness for treating HIV. However in early 
human studies, it was noted to cause a dramatic and rapid increase in white blood cell count (WBC).  
 
This was consistent with other studies in mice showing that CXCR4 is a strong bone marrow retention 
factor for leukocytes in general and neutrophils and CD34P+ 
Phematopoietic stem cells specifically. This 
prompted successful trials of plerixafor in animals and humans for the purpose of CD34P+ 
Phematopoietic 
stem cell mobilization. This is a procedure in which apheresis of donor blood is done to separate and 
remove CD34P+ 
Pcells, which allows for immune system reconstitution after high dose chemotherapy for 
cancer. Plerixafor is effective either by itself or in combination with granulocyte colony-stimulating factor 
(G-CSF), which is the agent that has traditionally been used for this purpose. In Phase III clinical studies 
that led to its licensure in the US, it was found that there was a dramatic, statistically significant increase 
in the percentage of difficult to mobilize (because of prior chemotherapy) individuals who reached the 
target number of cells collected when plerixafor was used with G-CSF compared to when G-CSF was 
used alone.(40T28, 2940T) 
 
Clinical Pharmacology / Mechanism of Action: Plerixafor is a specific antagonist of the CXCR4 
chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1 (SDF-1 also 
known as CXCL12). Both SDF-1 and CXCR4 are recognized to play a role in the trafficking and homing 
of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell 
CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1 or through the 


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induction of other adhesion molecules. Treatment with plerixafor resulted in leukocytosis and elevations 
in circulating HSC in mice, dogs, and humans. 
 
Pharmacokinetics: Pharmacokinetic studies in normal volunteers and cancer patients have shown that 
plerixafor is rapidly absorbed after subcutaneous (SQ) injection.(40T10, 3040T) Peak plasma concentration is 
observed at 30-60 minutes after a single 0.24 mg dose and the half-life has been estimated at 
approximately 5 hours. The drug is eliminated through the kidneys with 70% excreted unchanged in the 
urine in 24 hours. There are no reported drug-drug interactions, and studies to date have found no 
interactions with the cytochrome P450 system.  In vitro, the drug was negative in tests of mutagenesis. 
However, in vivo, it has been found to be teratogenic in animals and could be excreted in breast milk.  It 
is therefore contraindicated in pregnant women or nursing mothers. The teratogenicity may be a direct 
effect of blocking CXCR4 since animal studies have found the receptor to be critical for several aspects 
of embryogenesis and immune system development.(8,31,32) 
 
Adverse Reactions: The data described herein reflect 2 randomized studies in patients with NHL and 
MM, in which 301 patients treated with plerixafor in combination with G-CSF were compared to 292 
patients who were treated with placebo and G-CSF.(40T28,2940T) Side effects attributed to the drug were 
relatively minor and consisted of mild injection site reactions and gastrointestinal complaints. 
(40TAppendix B40T) In particular, the most common adverse reactions (>10%) reported in patients who 
received plerixafor in conjunction with G-CSF were diarrhea, nausea, fatigue, injection site reactions, 
headache, arthralgia, dizziness, and vomiting. 
 
UGastrointestinal complaintsU: Nausea, vomiting, and diarrhea were frequently reported in cancer patients 
treated with both plerixafor and G-CSF, but also may be attributable to the chemotherapy, the apheresis, 
or the underlying disorder as these have not been a problem in WHIMS patients treated to date. 
 
UInjection site reactionsU: In the randomized studies, 34% of patients with NHL or MM had mild to 
moderate injection site reactions at the site of subcutaneous administration of plerixafor.(28,29) These 
included erythema, hematoma, hemorrhage, induration, inflammation, irritation, pain, paresthesia, 
pruritus, rash, swelling, and urticaria. In contrast, in 2 studies of the drug in WHIMS patients, injection 
site reactions occurred but consisted only of small, self-resolving areas of erythema and pruritus occurring 
mainly at doses of 0.08 mg/kg and above.(40T3, 440T) In the patients treated for 6 months with low doses (0.01-
0.04 mg/kg) no injection site reactions were observed.(5) 
 
UOther adverse events:U Mild to moderate systemic reactions were observed in fewer than 1% of patients in 
cancer studies approximately 30 minutes after plerixafor administration. These events included one or 
more of the following: urticaria, periorbital swelling, dyspnea, hypoxia, vasovagal reactions, orthostatic 
hypotension, and/or syncope. Symptoms generally responded to treatments (e.g., antihistamines, 
corticosteroids, hydration, or supplemental oxygen) or resolved spontaneously (Appendix B), and have 
not been observed in studies of WHIMS patients. 
1.2.1 
Summary of Previous Pre-Clinical Studies 
In vitro studies have demonstrated that plerixafor is specific for CXCR4 and is a reversible inhibitor of 
the natural ligand's (SDF-1, aka CXCL12) ability to bind the receptor. Plerixafor has a very similar ability 
to bind and block the signaling of both wild type and WHIM variants of CXCR4.(40T240T) Long-term 
administration to mice, rats, and monkeys was found to be safe; however, in high doses (10 times > the 
highest human dose) in pregnant rats, the drug was found to be teratogenic causing fetal mortality. Also in 
rats, increased spleen weight was observed after 2 to 4 weeks of daily administration at high doses – 
4 times the highest human dose (Appendix B). 


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1.2.2 
Summary of Relevant Clinical Studies 
Plerixafor in combination with G-CSF has been used in more than 980 patients enrolled in 16 clinical 
studies for the purpose of stem cell mobilization as reported by the manufacturer, Genzyme/Sanofi Corp, 
to the FDA. In one randomized study of 298 patients with NHL where all patients were given 0.24 mg/kg 
of the drug subcutaneously daily for 1 to 7 days (median, 2 days), 59% of those who received the drug 
combination were able to achieve the collection goal of 5 million CD34+ cells/kg versus only 20% who 
received G-CSF alone (p<0.001).(40T2840T) In a second randomized study, 302 patients with multiple myeloma 
were mobilized in the same way and 72% achieved the collection goal of 6 million CD34+ cells/kg versus 
only 34% of those who received G-CSF alone (p<0.001).(40T2940T) In Phase I studies by McDermott, et al and 
Dale, et al., 9 adult WHIMS patients were treated with a dose escalation of plerixafor up to the FDA 
approved dose of 0.24 mg/kg/d and were found to rapidly mobilize all leukocyte subsets to the blood that 
are decreased in the disease.(40T3, 440T)  The lowest dose, 0.02 mg/kg/d, was able to increase the neutrophils to 
greater than 500 cells/µL of blood which is considered the boundary below which an increased risk of 
bacterial and fungal  infection may occur.  One of the 9 had to stop the dose escalation at 0.08 mg/kg 
because of development of an acute exacerbation of chronic bronchitis and possible pneumonia (40T440T), but 
both studies concluded that the drug was safe and effective and that this was proof of principle that 
antagonism of CXCR4 could reverse panleukopenia.  However, these studies left open the question as to 
whether long-term, low dose therapy would be practical, safe, and clinically effective.  We have 
completed a 6-month study of 3 adult WHIMS patients given 0.01-0.02 mg/kg twice/day and found that 
the leukocyte mobilization effects were durable and that the drug was safe for administration up to 6 
months.(5).  
 
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.  
No new warts occurred during treatment and multiple 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 goal of the current study is to answer this question choosing as the 
primary endpoint the severity of infections compared between the plerixafor treatment arm and the 
comparator G-CSF treatment arm using a double-blinded, crossover design.  G-CSF is required as a 
comparator because of its approved use in patients with SCN. 
1.3 
Description of Comparator Treatment: G-CSF 
G-CSF is FDA-licensed and the standard of care for severe chronic neutropenia, and will be used as the 
control or comparator drug in this study.(40T2440T) (see 40TAppendix C40T) G-CSF is a recombinant human protein 
produced in E. coli that is identical in amino acid sequence with the exception of an additional N-terminal 
methionine to a naturally occurring cytokine made by human monocytes, fibroblasts, and endothelial 
cells.  G-CSF acts on specific receptors to regulate the proliferation and differentiation of neutrophil 
progenitors, and augments the bone marrow release and function of mature neutrophils.  It has minimal 
effects on other hematopoietic cell types.  Its effect on bone marrow release of neutrophils is mediated in 
part by interfering with CXCL12 availability at CXCR4. 
1.3.1 
Summary of Relevant Clinical Studies 
In Phase I studies involving 96 subjects with no myeloid malignancies‚ G-CSF administered at doses of 1 
to 70 µg/kg/day resulted in a dose-dependent increase in circulating neutrophil counts.(33-35) Neutrophil 
counts returned to baseline within 4 days after discontinuation of G-CSF therapy. The absolute monocyte 
count was reported to increase in a dose-dependent manner in most subjects receiving G-CSF; however‚ 
the percentage of monocytes in the differential count remained within the normal range. In all studies to 
date‚ absolute counts of eosinophils and basophils were within the normal range following administration 
of G-CSF. Increases in lymphocyte counts following dosing with G-CSF have been reported in some 
healthy individuals and subjects with cancer.  Daily administration of G-CSF has been shown in a 


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randomized Phase III trial to be safe and effective in children and adults with severe chronic neutropenia, 
resulting in sustained increases in the neutrophil count and decreases in infection-related morbidity.(40T2440T) 
In particular‚ daily treatment with G-CSF led to significant beneficial changes in the incidence and 
duration of infection‚ fever‚ antibiotic use‚ and oropharyngeal ulcers in this setting.(24) The lower 
incidence and duration of infections was associated with decreased episodes of hospitalization, diarrhea‚ 
nausea‚ fatigue‚ and sore throat. In that study, the G-CSF dose was adjusted to maintain a median ANC 
between 1500 and 10‚000 cells/mmP3
P. Overall‚ response to G-CSF was observed in 1 to 2 weeks. The 
median ANC after 5 months of G-CSF therapy was 7460/mmP3
P (range, 30/mmP3 
Pto 30‚880/mmP3
P).  
 
Mild-to-moderate bone pain was reported in approximately 33% of subjects with severe chronic 
neutropenia treated with G-CSF in clinical trials. (see 40TAppendix C40T) This symptom was readily controlled 
with non-narcotic analgesics. Generalized musculoskeletal pain was also noted in a higher frequency of 
subjects treated with G-CSF. Palpable splenomegaly was observed in approximately 30% of subjects. 
Abdominal or flank pain was observed infrequently, and thrombocytopenia (<50‚000/mmP3
P) was noted in 
12% of subjects with palpable spleens. Fewer than 3% of all subjects underwent splenectomy‚ and most 
of these had a pre-study history of splenomegaly. Fewer than 6% of subjects had thrombocytopenia 
during G-CSF therapy‚ most of whom had a pre-existing history of the condition. Thrombocytopenia was 
managed by discontinuing or reducing the dose of G-CSF. An additional 5% of subjects had platelet 
counts between 50‚000/mmP3
P and 100‚000/mmP3
P, with no associated serious hemorrhagic sequelae. 
Epistaxis was noted in 15% of subjects treated with G-CSF‚ which was associated with thrombocytopenia 
in 2% of the subjects. Anemia was reported in approximately 10% of subjects‚ but, in most cases, it 
appeared to be related to frequent diagnostic phlebotomy‚ chronic illness, or concomitant medications. 
Other AEs infrequently observed and possibly related to G-CSF therapy were injection site reaction‚ rash‚ 
hepatomegaly‚ arthralgia‚ osteoporosis‚ cutaneous vasculitis‚ hematuria/proteinuria‚ alopecia‚ and 
exacerbation of some pre-existing skin disorders (e.g.‚ psoriasis). Cytogenetic abnormalities, 
transformation to myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) have been 
observed in subjects treated with G-CSF for severe chronic neutropenia.  
 
As of 31 December 1997, data have become available from a post marketing surveillance study of 531 
subjects with severe chronic neutropenia who had an average follow-up of 4 years. Based on analysis of 
these data, the risk of developing MDS and AML appears to be confined to the subset of subjects with 
congenital neutropenia. A life-table analysis of these data revealed that the cumulative risk of developing 
AML or MDS by the end of the 8Pth
P year of treatment with G-CSF in subjects with congenital neutropenia 
was 16.5%, which represents an annual rate of approximately 2%. Cytogenetic abnormalities, most 
commonly involving chromosome 7, have been reported in subjects treated with G-CSF who had 
previously documented normal cytogenetics. It is unknown whether the development of cytogenetic 
abnormalities, MDS, or AML is related to chronic daily administration of G-CSF or to the natural history 
of congenital neutropenia. It is also unknown if the rate of conversion in subjects who have not received 
G-CSF is different from that of individuals who have received it. Routine monitoring through regular 
complete blood count (CBC) is recommended in all subjects with severe chronic neutropenia.  
1.4 
Scientific Rationale and Clinical Justification 
Published evidence and the package insert of G-CSF suggest that long term, high dose G-CSF therapy 
may be associated with the development of leukemia and myelodysplasia in SCN patients.(40T3640T) Whether 
or not this would occur in WHIMS patients is currently unknown, but is one reason to consider alternative 
therapies.  In addition, patients have been described who due to G-CSF receptor mutations or the 
development of anti-G-CSF antibodies fail to respond to G-CSF with an increased ANC.(40T3740T)  In 
addition, our anecdotal experience is that WHIMS patients experience severe bone pain with the normal 
dosing of G-CSF perhaps due to their increased retention of mature neutrophils in the marrow 


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(myelokathexis). Lastly, G-CSF is not an effective treatment for warts, the signature infection in WHIMS, 
which might be better addressed with mechanism-based therapy such as plerixafor.   
 
Our Phase 1 study has provided preliminary evidence that low dose plerixafor b.i.d. is safe and effective 
over 6 months in mobilizing leukocytes to the blood, reducing infection frequency (Figure 1) and 
reducing wart burden; however, this study was not designed, controlled or powered to establish efficacy 
of plerixafor treatment for the main clinical endpoints in the disease (recurrent infections and warts) or to 
compare its efficacy to G-CSF, the FDA approved therapy for SCN.(5)  
1.5 
Preliminary Report of Unexpected Adverse Events in this Study  
As of May 2017, sixteen subjects have been randomized in this study of which nine have received at least 
some of both study drugs.  
1.5.1 
An Incident of a New Psoriasis-like Rash 
A subject experienced a worsening rash (psoriasis-like) beginning a week after commencing the 1Pst
P study 
drug and the symptoms resolved after switching to the alternate study drug and topical steroid treatment. 
1.5.2 
Joint Pain (Arthralgia) and an Incident of Reactive Arthritis 
Some subjects with a prior history of joint pain (arthralgia or arthritis) prior to enrollment experience a 
recurrence or worsening of their symptoms with G-CSF and/or with the study drug(s).  However, one 
subject who had no prior history of joint pain or G-CSF treatment, experienced pain and swelling in his 
wrist, hands, and knees and had to be discontinued from both study drugs and treated with oral steroids. 
Soon after the pain began, the subject tested positive for urethral chlamydia which causes reactive 
arthritis.  Thus it may be that the subject’s symptoms were exacerbated by the increased circulating 
neutrophil levels caused by both drugs. 
 
 
 


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Figure 1:  Plerixafor May Reduce Infection Incidence in Patients with WHIMS. 
The data for each patient are presented in separate columns. Each infection is represented as a 
dot and plotted by the month it occurred in relation to the start of plerixafor therapy. The time on 
plerixafor is bounded by the red box. Note that data for P2 were unavailable for the 12 month 
period marked by the black box. For P3, the hatched box represents a gap in plerixafor 
administration for the purpose of clinical care.  G-CSF was administered to patients P1 and P2 
both before and after plerixafor treatment, whereas P3 received G-CSF for ~1 month after 
plerixafor. 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Compare the severity of infection during treatment with plerixafor and G-CSF. 
2.2 
Secondary Objectives 
1) Compare component measures of infections. 
2) Measure the control of warts with plerixafor versus G-CSF. 
3) Demonstrate the safety of plerixafor and G-CSF as long-term therapy. 
4) Compare the symptoms of chronic infections. 
5) Compare quality of life (QOL). 
6) Compare drug tolerability and subject drug preference. 
7) Compare the increase of leukocyte levels from baseline. 
2.3 
Exploratory Objectives 
Measure type, location, and cause of infections.  
3 
STUDY DESIGN 
3.1 
Description of the Study Design 
This is a Phase III, double-blinded, randomized, crossover study evaluating plerixafor SQ b.i.d. versus G-
CSF SQ b.i.d. in children and adults 10 to 75 years of age with a clinical diagnosis of WHIMS, with a 
history of recurrent infections and a non-synonymous mutation in the C-tail of CXCR4. Subjects who are 
pregnant or have a history of hematopoietic cancer or life threatening cardiac arrhythmia are excluded.  
 
Interested subjects come to the NIH-CC and sign the study consent, which initiates the Initial Evaluation 
period of the protocol, during which eligibility criteria are evaluated.  Eligible subjects commence this 
approximately 4-12 week period during which unblinded b.i.d. G-CSF treatment is continued or offered, 
if the subject is not already receiving it, and dose is adjusted if necessary to achieve an ANC between 
500-1500 cells/μL of blood. Subjects start completing a daily Memory Aid submitting to the NIH-CC 
once per week. The Memory Aid includes their G-CSF treatment, any new or persistent symptoms, use of 
prophylactic antibiotics, and IVIg treatments. Subjects also report use of any other medications, incidence 
and duration of fever, new infections, incidence & duration of antibiotic treatments, and any 
hospitalizations. Another purpose of this evaluation period is to ensure that subjects are able to comply 
with required study procedures. At completion of the evaluation period, subjects are randomized to begin 
either plerixafor or G-CSF treatment.  Subjects shall hold G-CSF 2 days in advance of commencing study 
medication. The next phase of the study is the Equilibration Period of 8 weeks, during which the blinded 
study drug dose is adjusted for a target ANC of 500-1500 cells/μL with the ANC count measured 
approximately every 2 weeks at a subject’s local medical facility. After this, the study drug dose is 
continued for 52 weeks, during which the dose may be adjusted to maintain the ANC between 
approximately 500-7500 cells/μL.  Also, in this treatment period clinical events are counted and subjects 
visit the NIH-CC approximately every 4 months for a comprehensive assessment of chronic infections, 
warts and immune status. Between NIH-CC visits, subjects visit their local medical facility or local 
provider approximately midway between NIH-CC visits to have blood drawn for CBC/ANC prior to the 
morning dose of study drug and for treatment of new or worsening infections. CBC/ANC is monitored at 
the NIH-CC for safety and the need for additional dose adjustments as determined by the Principal 
Investigator and applied by the unblinded independent pharmacist. Subjects unable to tolerate a study 
drug will be switched to the alternate study agent according to rules specified below in the Statistics 
(section14).  
 


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After completing the 1Pst
P year of treatment, there is a 2-day washout period before a subject crosses over to 
the alternate study drug for the 2Pnd
P year of treatment that is again preceded by an 8-week Equilibration 
period. After completing the 2Pnd
P treatment, there is a 2-day washout period, after which subjects are 
offered the opportunity to restart G-CSF therapy.  There is then a 1-month G-CSF Equilibration and 
subjects continue to maintain their diaries and to visit their local medical facility for blood draws 
approximately every two weeks. A study completion visit at the NIH-CC occurs approximately 5 to 6 
months after the end of the second year of treatment. 
3.2 
Study Endpoints 
3.2.1 
Primary Endpoint 
The primary endpoint is infection severity, which is measured as a composite of multiple weighted 
parameters according to rules defined in 40TAppendix D40T.  
3.2.2 
Secondary Endpoints  
1) Component measures of infections; incidence and duration of infections, fevers, antibiotic treatments, 
and hospitalization. 
2) Control of warts as defined by at least a 50% reduction in numbers, areas or size of existing warts and 
by the number of new warts. 
3) Blood count and immunological parameters. 
4) Clinical measures of chronic infections. 
5) Treatment side effects, 
6) Quality of life scores. 
7) Treatment preference. 
3.2.3 
Exploratory Endpoint 
Identify causative organisms and locations of infections in WHIMS subjects. 
4 
STUDY POPULATION 
4.1 
Subject Selection and Recruitment Plan 
The study is open to patients with WHIMS from 10-75 years of age who may benefit from the study’s 
proposed treatments. WHIMS is a rare genetic disease with approximately 60 patients identified as of 
2014 worldwide in the medical literature. We began seeing WHIMS patients in 2006, and as of May, 
2014 have a cohort of 24 patients, with 50% of these patients accrued in 2012 and 2013. Sixteen of these 
24 patients meet the eligibility criteria for this protocol, which is powered for 20 patients to finish the 
protocol. Additional potential recruits for this study include patients referred by clinical researchers at 
NIH, by academic institutions worldwide, and by local health care providers, as well as patient self-
referrals. A recruitment letter may be sent to relevant health providers to stimulate accrual.  The study 
will also be listed in ClinicalTrials.gov.  We expect to screen 30 patients (accrual ceiling) in order to 
enroll and randomize 20 patients. 
4.2 
 Inclusion Criteria 
Subjects are eligible to enter the study if they meet all of the following criteria: 
1)  Age >10 and <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/μL 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. 


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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).  
4.3 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 (40TAppendix E40T). 
6) Condition that in the investigator’s opinion places a subject at undue risk by participating in the 
study. 
4.4 
Justification for Exclusion of Pregnant or Breast Feeding Women 
Pregnant women are excluded from this study because the effects of plerixafor on the developing human 
fetus are unknown with the potential for teratogenic or abortifacient effects. Lactating women are 
excluded because plerixafor may be excreted in the breast milk and could be potentially harmful to breast-
fed infants. Women of childbearing potential must have a negative pregnancy test prior to receivingP 
Pplerixafor.   
4.5 
Justification for Exclusion of Children <10 Years of Age   
Subjects younger than 10 years of age will be excluded from the study. Although WHIMS is a rare 
congenital immunodeficiency disorder that affects all age groups, plerixafor has known effects on fetal 
development in animal models.(8,32,38)  These are related to early localization of cells during fetal 
development; therefore, we feel that age 10 provides a wide safety window for completion of early 
development and allows us to treat children who may have the most to gain from this treatment in the 
future.  Children as young as 2 months of age have been treated with single high dose (0.24 mg/kg/d) 
plerixafor for stem cell mobilization without serious side effects and chronic G-CSF use is safe in 
children.(40T39,4040T)   
5 
STUDY AGENT AND INTERVENTIONS 
5.1 
Drug Acquisition 
5.1.1 
Plerixafor: Provided by Manufacturer  
Plerixafor is FDA-approved for hematopoietic stem cell mobilization in cancer and is the study drug. It is 
manufactured by Genzyme/Sanofi Corp., Cambridge, MA, USA. The manufacturer supplies the drug, 
which is investigational in this study, at no cost.  


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5.1.2 
G-CSF: Obtained Commercially 
G-CSF is an FDA-approved drug manufactured by Amgen and is the comparator drug in this study 
because it is FDA-approved for the treatment of SCN.  Drug will be sourced commercially and purchased 
per the NIH-CC policy.  
5.2 
Disposition and Dispensation 
The study drug and the comparator drug are dispensed through the NIH-CC’s pharmacy. 
5.2.1 
Formulation, Packaging, and Labeling 
5.2.1.1 
Plerixafor Packaging from Manufacturer  
Plerixafor injection is a sterile, preservative-free, clear, and colorless to pale yellow isotonic solution for 
subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor. Each single-use vial 
is filled to deliver 1.2 mL of the sterile solution containing 24 mg of plerixafor and 5.9 mg of sodium 
chloride in water for injection. Storage at room temperature is recommended at 25°C (77°F) with 
excursions from 15°C-30°C (59°F - 86°F).  
5.2.1.2 
Plerixafor Repackaging for Study and/or Shipment to Study Participants 
Plerixafor vials from the manufacturer will be repackaged by Integrity Bio, Inc into pre-set low-dose 
volumes between 0.01-0.20 mL in sterile syringes for subject self-injection. The syringe provided to the 
subject will contain a dose ranging between 0.01-0.04 mg/kg. The upper limit dose of 0.04 mg/kg in this 
study is low compared to the FDA-approved dose for HSC mobilization (0.24 mg/kg) and was set at this 
level because our treatment goal is to reduce CXCR4 signaling to normal from 2X normal, the typical 
level for WHIMS variants of CXCR4, not to zero.  Syringes will be shipped periodically to the subject 
who will store them at refrigeration temperature until injected. 
5.2.1.3 
G-CSF Packaging from Manufacturer 
G-CSF is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteral administration containing 
filgrastim at a specific activity of 1.0 ± 0.6 x 10 P8
P U/mg (as measured by a cell mitogenesis assay). The 
product is available in single-use vials and prefilled syringes. The single-use vials contain either 300 µg  
or 480 µg  filgrastim at a fill volume of 1.0 mL or 1.6 mL respectively.  Refrigerated storage is 
recommended at 2°C - 8°C (36°F - 46°F), but vials can be left at room temperature for up to 24 hours. 
Drug should not be exposed to direct sunlight. 
5.2.1.4 
G-CSF Repackaging for Study and/or Shipment to Study Participants 
G-CSF vials from the manufacturer will be repackaged by Integrity Bio, Inc into pre-set volumes of 
between 0.01-0.65 mL in sterile syringes for subject self-injection. The syringe and dose provided to a 
subject will range between 0.01-2.0 µg/kg. If randomized to the plerixafor arm, the dose may be 
temporarily reduced during the transition to accommodate potential residual synergistic effects of the 
drugs between the treatment arms. Syringes will be shipped periodically to the subject, who will store 
them at refrigeration temperature until injected. 
5.2.2 
Labeling of Study Drug 
Syringes containing the repackaged plerixafor or G-CSF shall be labeled per NIH Pharmacy policy. An 
investigational use statement (“Caution: New Drug – Limited by Federal [USA] Law to Investigational 
Use”) will also be labeled. 
5.3 
Study Agent Storage and Stability 
Study Drug will be repackaged from the manufacturer package to the study drug configuration prior to 
shipment and stored by the subjects at refrigerator temperature until use. The NIH verified that plerixafor 
is stable when stored in syringes at room or refrigerated temperatures for at least 6 months. Refer to the 
package inserts (40TAppendix B40T & 40TAppendix C40T) and the abstract from the American Association of 


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Pharmaceutical Scientists conference 
(40Thttp://abstracts.aaps.org/Verify/aaps2013/postersubmissions/T2294.pdf40T).  
5.3.1 
Storage at NIH-CC 
Manufacturer-packaged drugs will be stored as indicated by the manufacturer until repackaging into 
syringes. Repackaged drug syringes will be tested for sterility and stability, and stored at refrigerator 
temperature and shipped to the subject home address on a periodic basis with appropriate packaging to 
prevent extremes of temperature. 
5.3.2 
Shipment to Participants' Home 
Subjects receive their study drug approximately once a month or as required. Shipments are prepared by 
the NIH Pharmacy and sent via a rapid courier or provided to subjects on their visits to the NIH-CC.  
5.4 
Study Agent Preparation and Administration 
5.4.1 
Subject Preparation and Self-Injection 
Subjects self-administer the study drug subcutaneously every 12 hours at about the same time each day.  
5.4.2 
Subject Memory Aid: Injection Site, Injection Volume, Adverse Reactions 
Participants are asked to record the quantity injected, the site of injection, and any adverse reaction from 
the injection (see 40TAppendix F40T). Subjects are instructed to seek medical attention and inform study staff or 
the NIH-CC of any adverse events that are life threatening, require immediate medical attention, or limit 
their ability for self-care. 
5.5 
Dose-Adjustment and Therapeutic Schedule 
The study drug dose is adjusted based on the subject’s Absolute Neutrophil Count (ANC) to maintain the 
pre-morning dose ANC count at approximately between 500-1500 cells/μL during the Equilibration 
period. Consideration of concurrent infection or other factors that might increase the ANC will be 
factored into ongoing clinical decisions to adjust the study medication dose.  Blinding will be maintained 
by having the PI or designee make these decisions for both drugs without knowing which drug the subject 
is currently receiving and then having an independent pharmacist who is un-blinded select the drug, dose, 
and shipment based on the subject’s randomization.  
5.6 
Study Product Accountability Procedures 
5.6.1 
Plerixafor 
The PI is responsible for ordering, receipt, and return of plerixafor from/to the manufacturer. NIH-CC’s 
pharmacy is responsible for storing, repackaging, labeling, and shipping plerixafor to the subject.  
5.6.2 
G-CSF 
NIH-CC’s pharmacy is responsible for sourcing and ordering G-CSF from suppliers and for repackaging, 
labeling, and shipping G-CSF to the subject.   
6 
STUDY SCHEDULE AND ACTIVITIES 
A schedule of procedures and evaluation for the study is shown in 40TAppendix A40T. 
6.1 
Recruitment  
Candidates are interviewed to confirm their diagnosis of WHIMS and provided a copy of the study’s 
Informed Consent. A history of recurrent infections and neutropenia, documented CXCR4 mutation, or a 
newly identified mutation made by analyzing specimens obtained from the subject are required to 
determine eligibility.  Subjects interested in the study are scheduled for a screening visit at NIH-CC.  


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6.2 
Screening  
Subjects who have reviewed and signed the informed consent undergo the following procedures. 
6.2.1 
Labs and Procedures 
After reviewing and signing the Informed Consent, subjects undergo the following procedures: 
• Pregnancy test for women of childbearing potential. 
• Viral Screen: HIV, HTLV-1 and 2, Hepatitis B and C. 
• CBC with diff, Chemistries (Acute Care Panel, Creatine Kinase, Hepatic Panel, Mineral Panel, 
Total Protein, Lactate Dehydrogenase, Uric Acid), erythrocyte sedimentation rate (ESR). 
• Prothrombin time (PT), partial thromboplastin time (PTT), Vitamin B-12 & Folate, and Urinalysis. 
• Echocardiogram (within the last 5 years for adult) must be reviewed and approved by the PI. 
• EKG. 
6.2.2 
Assessment of Overall Health 
The following procedures are required to assess the subject’s overall health and safety in the study: 
• Weight. 
• Vital signs (temperature, heart rate, and blood pressure). 
• Medical History including history of infections and warts.  
• Medication History including allergies, concomitant medications, IVIg & G-CSF treatments, and 
prophylactic antibiotics. 
• Contraception counseling as appropriate. 
• Physical Exam. 
• Encourage subjects and their local providers to contact the study coordinator and PI at the onset 
(or suspected onset) of an infection.  
6.3 
Initial Evaluation and Baseline Assessment Period 
It is important to assess and document a subject’s health and ensure they are trained and prepared prior to 
commencing the first study dose. This Initial Evaluation and Baseline Assessment period is targeted to be 
about 2 to 20 weeks or the length of time a subject requires being trained and stable on their low-dose G-
CSF self-injections and able to visit the NIH-CC to commence the first study dose (Section 6.4). 
Procedures for baseline assessment may be completed anytime prior to the first dose, furthermore some 
labs may be drawn and analyzed at the subject’s local medical facility (Section 6.3.12). 
6.3.1 
Measurement of Immunological Markers 
The following procedures are performed to assess the subject’s immunological markers: 
• Quantitative Immunoglobulins 
• Leukocyte Phenotyping 
• Antibody levels for Diphtheria and Tetanus. 
6.3.2 
Evaluations: Dermatology, GYN, Dentistry, ENT, Audiology, and Clinical Photography 
Due to the prevalence of infections and the risk of HPV in patients with WHIMS, dermatologic, 
gynecologic, dental, ENT, and audiology evaluations, and photographs of infections and warts on the 
body surface, will be arranged for subjects prior to commencing their first study treatment, and at the end 
of each their study drug treatments periods. These evaluations are not mandatory; a subject may refuse to 
participate in any of the assessments. These evaluations are not meant to replace care provided by a 
subject’s local provider(s). 
6.3.3 
Additional Evaluations if Clinically Indicated (e.g. PFT and CT of Chest and Sinus) 
Some of our WHIMS patients experience frequent respiratory infections some of which result in 
bronchiectasis and may be debilitating. For these subjects, pulmonary function tests (PFT), sputum 


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cultures, CT or X-ray of the chest and sinus, as well as a pulmonary consult with possible bronchoscopy 
may be arranged to treat and evaluate the status of their infections. These evaluations are not mandatory; a 
subject may refuse to participate in any of the assessments. 
6.3.4 
Baseline Measure of Bone Density and Spleen Size 
• 
Dual-energy x-ray absorptiometry (DEXA) scan. 
• 
Ultrasonography of the spleen. 
6.3.5 
Research Blood 
Research blood will be collected as required and may include the following: ~10 mL of EDTA anti-
coagulated blood (1 purple top), ~10 mL of serum (1 tiger top), and 30-60 mL of heparinized blood (3-6 
green tops).  The blood will be collected for various purposes, including DNA/RNA isolation, EBV-
transformed cell line creation, serum/plasma storage, flow cytometry, cytokine measurements, and drug 
levels. 
6.3.6 
Wart and/or Skin Biopsy (optional)  
Wart and or skin biopsies may be requested for diagnosis and research from subjects but will be optional. 
An experienced provider will perform the procedure. Local anesthetics will be used for the biopsy site; no 
conscious sedation or general anesthesia will be given. The risks of skin/wart biopsy include local pain, 
bleeding, infection, and the potential for scar and keloid formation. Antibiotics and oral analgesics will be 
used to manage pain and infection. The histologic response to plerixafor offers generalizable knowledge 
about the pathophysiology and treatment of this condition. 
6.3.7 
Bone Marrow Biopsy (optional)  
Subjects will have the option of having bone marrow biopsy/aspiration done for research purposes, which 
could be done either as outpatient or inpatient. Local anesthetics will be used for the biopsy site and IV 
conscious sedation may be offered to subjects for comfort; these agents may result in transient local 
discomfort initially and occasionally be associated with allergic reactions. General anesthesia will only be 
given if the participant is admitted for the procedure. The primary risks of bone marrow biopsy include 
local pain, bleeding, and infection. Antibiotics and oral analgesics will be used to manage pain and 
infection if necessary. 
6.3.8 
Quality of Life Assessment of Period Prior to the Study 
Subjects will participate in the quality of life surveys (Section 7.9) with the first survey conducted early in 
the Initial Evaluation and Baseline Assessment period, after a subject has been screened, in order to 
reflect their experience prior to interventions caused by this study.  
6.3.9 
IVIg and Prophylactic Antibiotics 
Subjects on IVIg and prophylactic antibiotics prior to enrollment maintain their treatments, as clinically 
indicated, throughout the study. Though unlikely, it is also possible that subjects may be initiated on these 
treatments during the study if clinically indicated. A subject’s use of IVIg and prophylactic antibiotics 
will be tracked in the subject Memory Aid (Section 6.3.12). 
6.3.10 Determining a Minimum Effective Dose for G-CSF 
In the US, the FDA-approved treatment for SCN is G-CSF and we expect many of the WHIMS subjects 
enrolled in this study to be on daily or every other day treatment with G-CSF prior to enrollment. For this 
study, we need to determine the Minimum Effective Dose (MED) of b.i.d G-CSF injection to achieve an 
ANC of 500-1500 cells/μL. Enrollees, not on b.i.d G-CSF or with an ANC less than the lower limit of the 
target ANC range will have G-CSF initiated or adjusted in this period prior to being randomized.   


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6.3.11 Preparing for Study Drug Shipments and Study Drug Administration at Home 
Subjects will be trained on receiving, storage, preparation, and self-administration of the 
study/comparator drugs. These procedures are reviewed and customized as necessary for each subject at 
their screening visit. To verify the practicability of these procedures, a medication kit containing the 
comparator drug (G-CSF) may be shipped to the subject in this period. 
6.3.12 Training and Practice for Submissions of Completed Subject Memory Aid 
During the initial evaluation and baseline assessment period, subjects have ample time to practice and 
become proficient at completing and submitting their clinical Memory Aid (Sections 7.4-7.6). The 
information collected will assist in monitoring a subject’s response to b.i.d G-CSF (Section 6.3.10) and 
their proficiency at completing the Memory Aid. Subjects will not be randomized to commence study 
treatment unless they demonstrate two successful submissions and express confidence at completing the 
Memory Aid.  
6.3.13 Select a Local Medical Facility for Blood Draws at a Subject’s Home Locale 
Subjects require access to a local medical facility so that we can monitor their response, in between visits 
to the NIH-CC, to home administration of G-CSF or plerixafor. Labs from these facilities will be 
requested during initial evaluation to determine the optimum dose for b.i.d G-CSF (Section 6.3.10), 
during equilibration to adjust their study dose (Section 6.5.1), and during treatment to ensure that their 
response to the study drug dose remains optimum (Section 6.6.2). We will work with each subject to 
ensure that a local medical facility is available for these purposes and all required study procedures are 
paid by the NIH. 
6.4 
Randomization and Initiation of the First Study Dose 
After completing their evaluation and baseline assessment (Section 6.3), subjects are randomized to start 
with either plerixafor or G-CSF for the first year to be followed by the alternate drug for the 2 Pnd
P year. The 
NIH Pharmacy will conduct randomization and neither the subjects nor study staff will be aware of which 
study drug a subject is assigned.  
6.4.1 
Washout Period Prior to the First Study/Comparator Dose (at least 2 days prior to 1st dose) 
All baseline assessments of infection and warts shall be completed prior to a subject receiving their first 
study/comparator drug injection. Subjects withhold their G-CSF or study/comparator drug injection at 
least 2 days prior to the first day of the study/comparator drug injection (Day 0).  
6.4.2 
Assessment of Overall Health (within 2 days prior to the 1st dose)  
A clinical assessment similar to what was conducted at baseline (Section 6.2.2) should be repeated within 
2 days prior to commencing the first study dose. 
6.4.3 
Confirm Study Drug Shipment/Injection, Memory Aid, Local Labs, and Reporting 
Infections 
Review and confirm with the subject the processes established for receiving, storing, or administering the 
study drug, completing and submitting the Memory Aid, and obtaining blood draws at their local medical 
facility. Review and confirm process for reporting infections, diagnosis, and forwarding the information 
from their local provider.  
6.4.4 
Lab Draw Prior to Injection of the 1st Study/Comparator Dose 
• CBC with diff, Chemistries (Acute Care Panel, Creatine Kinase, Hepatic Panel, Mineral Panel, 
Total Protein, Lactate Dehydrogenase, Uric Acid), erythrocyte sedimentation rate (ESR). 
• Quantitative Immunoglobulins  
• Leukocyte Phenotyping 
• Pregnancy test for women of childbearing potential 


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• Research Blood. 
6.4.5 
Day of the First Study/Comparator Dose (Day 0) 
The subject administers the morning dose at NIH-CC while being observed by research personnel to 
confirm that the subject is proficient with self-administered subcutaneous (SQ) injection.  
6.4.5.1 
Prior to Injection 
• Orthostatic measurements (i.e. pulse and blood pressure taken in the supine, sitting, standing, 
position approximately 2 minutes apart) within 1 hour prior to study drug injection. 
• Labs: CBC with diff, chemistries, and ESR (optional if previous labs are within 24h). 
• Research Blood 
6.4.5.2 
After Study Drug Injection 
• Orthostatic measurements 60 min (+/- 20 min) after study drug injection. 
6.4.5.3 
Procedures Prior to Leaving NIH-CC 
• Subjects are supplied with study drug kit and a supply of the study/comparator drug.  
• Counsel subjects with symptomatic or measured orthostasis (decrease in blood pressure > 20 mm 
Hg systolic or increase in pulse >20/min) to exercise additional caution with home dosing. 
• Confirm the schedule and procedure for CBC blood draws at the subject’s local medical facility. 
• Confirm procedures for subject receipt of study/comparator drug, storage, and administration. 
• Confirm procedures for subject submission of reports on newly diagnosed infections and 
treatments by their local provider. Encourage subjects to contact the study coordinator or PI at the 
onset (or suspicion) of an infection. 
• Confirm Subject Memory Aid: completion, schedule, and method of submission to NIH-CC. 
6.5 
Equilibration Period for the Treatment (8 weeks) 
After administering the initial study dose at NIH-CC subjects continue injecting the study/comparator 
medication at home. The first 8 weeks of injection is considered the Equilibration period with ANC 
measured every 2 weeks (+/- 7 days) at the subject’s local medical facility. 
6.5.1 
Blood Draws at Subject’s Local Medical Facility Every 2 Weeks 
Subjects visit their local medical facility every 2 weeks (+/- 7 days) for blood draws prior to the morning 
dose. 
6.5.2 
Dose May be Adjusted to Maintain ANC Between 500-1500 cells/μL 
ANC readings are reviewed at the NIH-CC and the study drug dose may be increased for ANC < 500 
cells/µL and decreased for ANC>1500 cells/µL. However, any decision to adjust must take into 
consideration a subject’s clinical course and status. Dose changes are implemented at the next scheduled 
shipment of study/comparator drug to the subject.  
6.6 
Treatment Period (52 weeks) 
At completion of the Equilibration period, subjects commence a 52 week treatment period with a constant 
dose unless ANC <500 cells/µL, in which case the dose may be increased, or ANC >7500 cells/µL absent 
concomitant infections that may elevate the ANC, in which case the dose will be decreased. Subjects visit 
NIH-CC at the start of treatment and every 4 months (+/- 31 days) of treatment for a comprehensive 
assessment of chronic infections, warts and immune status. Between NIH-CC visits, subjects visit their 
local facility or provider at least once, midway between NIH-CC visits, to have blood drawn for 
CBC/ANC or as needed for treatment of new or worsening infections. The 1Pst
P treatment period ends with 
the End of Treatment (EOT) visit. 


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6.6.1 
Assessments at NIH-CC Every 4 Months 
Subjects visit NIH-CC every 4 months (+/- 31 days) after start of the Treatment Period for a 
comprehensive assessment of their health and safety, pregnancy status if applicable, immunological 
markers, chronic infections, and warts. 
6.6.1.1 
Labs 
• Pregnancy test for women of childbearing potential. 
• CBC with diff, Chemistries (Acute Care Panel, Creatine Kinase, Hepatic Panel, Mineral Panel, 
Total Protein, Lactate Dehydrogenase, Uric Acid), erythrocyte sedimentation rate (ESR). 
6.6.1.2 
Assessment of Overall Health and Safety 
A clinical assessment similar to what was conducted at baseline (Section 6.2.2) should be repeated at each 
4-month visit to the NIH-CC.  
6.6.1.3 
Measurement of Immunological Markers 
The following procedures are performed to assess the subject’s immunological markers: 
• Immune Status (basic): Quantitative Immunoglobulins 
• Leukocyte Phenotyping 
6.6.1.4 
Evaluations and Consults for Assessment of Infections  
Subjects may be scheduled for assessment as determined at the baseline visit or as clinically indicated by 
the PI for worsening of infections and/or warts, as described in Sections 6.3.2 and 6.3.3. 
6.6.1.5 
Research Blood 
As with the baseline assessment visits, research bloods may be collected at each visit to the NIH-CC 
including blood drawn at peak  - e.g. approximately 3 hours after the morning study drug injection.     
6.6.1.6 
Quality of Life Assessment 
Subjects will participate in quality of life surveys (Section 7.9) with the first survey conducted early in the 
Initial Evaluation and Baseline Assessment period and at each 4-month visit to the NIH-CC.  
6.6.1.7 
Skin and Wart Biopsies (optional) 
As with the baseline assessment visits, skin and or wart biopsies may be proposed for research purposes. 
6.6.2 
CBC w/diff, ESR, and Chemistries Every 2 Months at Subject’s Local Medical Facility 
Subjects visit their local medical facility once (at 2 months +/- 31 days) in between their scheduled NIH-
CC visits for monitoring of their ANC and changes in blood counts (e.g. anemia or thrombocytopenia). 
Changes in kidney function and serum electrolytes (chemistry) and ESR (optional) will also be requested 
and the results transmitted to NIH-CC. The blood draw for these tests should be performed prior to the 
morning dose of study drug. 
6.6.3 
Visits to a Subject’s Local Provider for New or Worsening Infections 
Subjects continue visits to their local provider for routine exams and for treatment of new or worsening 
infections. Because the study measures the frequency and severity of infections, it is important that 
subjects submit documentation of infection either through a medical record of their visit or through their 
provider completing a brief form specifying the diagnosis, treatment, and the result of microbial cultures 
( 40TAppendix G40T). Subjects and their local providers are encouraged to contact the study coordinator or PI at 
the onset of infection related events. 


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6.6.4 
End of Treatment (EOT) Visit for a Study Drug 
The last visit to the NIH-CC during the treatment period constitutes the End of Treatment Visit (EOT) 
where a subject ceases injection of the study or comparator drug and the subject’s response to the year’s 
treatment is assessed: 
• All assessments to measure the study drug safety and efficacy are completed. 
• Subject returns all unused study drug to the NIH-CC. 
In addition to the procedures conducted at the 4-month visits during treatment, the following procedures 
are conducted at the EOT visit: 
• 
EKG, 
• 
Dual-energy x-ray absorptiometry (DEXA) scan, 
• 
Ultrasonography of the spleen, 
• 
Vitamin B12 and Folate, 
• 
Antibody levels for Diphtheria and Tetanus. 
6.7 
Reverting to a Subject’s Pre-study Treatment 
After completing both study treatments, subjects revert to their pre-study treatment regimen and are 
offered G-CSF. Subjects continue to submit their diaries and their ANC results to NIH-CC until the Study 
Completion visit. Adjustments to G-CSF dose may be made according to ANC during this phase.  
Subjects of child bearing potential shall continue to maintain at least two forms of contraception.  
6.7.1 
Washout Period (2 Days) 
Subjects reverting back to G-CSF treatment should delay restarting G-CSF for at least two days in order 
to minimize the possibility of drug interaction between plerixafor and G-CSF. 
6.7.2 
Monitoring the G-CSF Dose (1-2 Months) 
To accommodate potential synergistic drug interactions between plerixafor and G-CSF, a subject’s initial 
G-CSF dose will be reduced and their ANC monitored at 2-week intervals (+/- 7 days) for the first month 
and at 2-month (+/- 31 days) intervals thereafter, or as clinically indicated. 
6.7.3 
Study Completion Visit  
The study completion visit occurs approximately 5 to 6 months after the EOT visit of the 2 Pnd
P treatment 
period. The assessments for this visit are described in Section 6.6.1.  
6.8 
Early Completion of Treatment Due to Unwillingness or Inability to Receive Study Agent  
If for any reason a subject is unwilling or unable to continue receiving the study agent during the Dose 
Equilibration or Treatment periods, including reasons such as 1) an inability to maintain a minimum ANC 
level considered safe, defined as ANC greater than or equal to 500 cells/µL, 2) a refusal to continue with 
the study agent, or 3) a Grade 3 or 4 Toxicity to the study agent, a subject would terminate that phase of 
the study and proceed to the next phase. Data handling for patients who fail to complete both arms of the 
study is detailed in the Statistics section (Section 14). 
7 
STUDY PROCEDURES AND EVALUATIONS 
7.1 
Absolute Neutrophil Count (ANC) 
A primary goal in WHIMS treatment is the correction of neutropenia. The Absolute Neutrophil Count 
(ANC) is measured as a component of a Complete Blood Count (CBC) test. Normally between 1500-
7500 cells/µL, most WHIMS patients without G-CSF, Granulocyte Macrophage Colony-Stimulating 
Factor (GM-CSF), or plerixafor treatment will have a Baseline ANC between 0-500 cells/µL.   


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7.1.1 
Time of Day Measurement for ANC: Prior to Study Dose  
The ANC level is measured prior to a study dose. Since plerixafor and G-CSF are administered twice 
daily, the ANC should be measured prior to a dose to measure the minimum ANC level approximately 12 
hours after a study dose.  
7.1.2 
Target ANC during 8 week Equilibration Period (500 – 1500 cells/µL) 
ANC is measured approximately every 2 weeks in this 8-week period and the dose will be adjusted for a 
target ANC approximately between 500-1500 cells/µL that we have found to be achievable with well-
tolerated low-dose plerixafor in our preliminary studies of patients with WHIMS.  
7.1.2.1 
Subjects with a Baseline ANC > 500 cells/µL 
Subjects will be excluded if they do not have neutropenia (Baseline ANC>1500 cells/µL); however, if 
they do have neutropenia, but their baseline ANC average is greater than the target ANC=500 cells/µL, 
then they will be given the minimal dosage of both drugs specified by the study in Section 7.1.4) with 
downwards adjustment possible if they exceed the maximum ANC (7500 cells/µL). Baseline ANC is 
assessed on at least two measurements on separate days, when a subject is not on G-CSF, plerixafor, or 
experiencing an acute infection.  
7.1.2.2 
Subjects Unable to Attain ANC >500 cells/μL During Equilibration, Despite Maximal Dose 
The target ANC of 500 cells/µL is accepted as safe in the medical literature.  Therefore, for participants 
whose baseline ANC is <500 cells/µL, we will administer up to the maximal dose for the study (0.04 
mg/kg b.i.d. for plerixafor or 2 µg/kg b.i.d. for G-CSF), that is needed to increase the ANC to a minimum 
of 500 cells/µL and to maintain it at this level as a minimum.  If in the dose equilibration period a study 
subject fails to attain an ANC of 500 cells/µL on the maximum dose cited above, they would be declared 
a failure on that treatment, stop receiving that treatment, and commence “early” crossover and washout 
process for switching to the 2 Pnd
P Treatment, or if failing to respond during the 2Pnd
P Treatment, a subject 
would terminate all study treatments, revert to their pre-study treatment regimen if appropriate or desired, 
and continue to the Study Completion Visit.  
7.1.3 
Target ANC during the 52 week Treatment Period (500 – 7500 cells/µL) 
After completing the Equilibration period, subjects commence a 52-week treatment period with the goal 
of a constant dose optimized for the subject. During the treatment period, this dose will only be increased 
for ANC <500 cells/µL or decreased for ANC >7500 cells/µL, in 2 consecutive measurements on separate 
days, absent infections that may elevate the ANC.  
7.1.4 
Dose Range for Low-Dose Treatment 
The doses prescribed in this study are significantly lower than the maximum doses that have been used in 
humans for stem cell mobilization. The maximum current approved dosage for plerixafor = 0.24 
mg/kg/day and this is given on up to 4 consecutive days for apheresis (40TAppendix B40T). SCN (most of 
which is due to ELANE mutations) has been treated with G-CSF= 2.3 to 40 µg/kg/day (40TAppendix C40T). 
The dose ranges in this study were selected based on our prior experience with the dosages that are 
effective in patients with WHIMS in reaching the target biomarker window of 500<ANC<1500:  
G-CSF: 
 
0.25 - 2.0 µg/kg twice per day, 
Plerixafor:  
0.01 - 0.04 mg/kg twice per day. 
The dose for plerixafor will be reduced for renal impairment. (40TAppendix E40T)  
We already have experience treating 16 WHIM patients with low dose daily G-CSF for extended 
periods with excellent compliance. In our 6 month Phase 1 study of plerixafor in WHIMS, the drug 
was well-tolerated and compliance was excellent.  Interestingly, we observed that the ANC declined 
more slowly than expected after stopping plerixafor, taking 2-3 weeks to reach the subject’s baseline, 
and that the response to G-CSF once at baseline was greater than expected.(5)  Therefore, subjects 


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assigned G-CSF in the 2Pnd
P year treatment in the present study will be started on a lower dose in the 
Equilibration Period than the optimum dose defined during the evaluation period. The dose will then 
be adjusted if necessary, as guided by the ANC response.  
7.2 
Adjusting the Study Dose to Meet ANC Goals 
A subject’s dose is increased for ANC below 500 cells/µL, and maintained for ANCs up to 1500 cells/µL 
during the 8-week Equilibration period and for ANCs up to 7500 cells/µL during the 52-week treatment 
period. Doses of either drug may be reduced if the steady-state counts exceed the upper ANC thresholds 
in the absence of an acute infection. Two sequential ANC values on different days prior to the morning 
study drug dose will be used at the times indicated in the protocol to make study drug dose adjustments.  
7.2.1 
Initial Study/Comparator Drug Doses during Equilibration Period 
G-CSF - without a known history of treatment with G-CSF:  0.5 µg/kg b.i.d. 
G-CSF - with a history of G-CSF dosing: 
 
 
Specified by PI prior to randomization. 
G-CSF - after recent treatment with plerixafor 
 
Specified by PI prior to randomization. 
Plerixafor:  
 
 
 
 
 
0.01-0.04 mg/kg twice per day. 
7.2.2 
Adjustment for ANC <500 cells/µL 
G-CSF: 
Increase dose to a maximum of 2.0 µg/kg b.i.d. 
Plerixafor: Increase dose to a maximum of 0.04 mg/kg b.i.d. 
7.2.3 
Adjustment for ANC between 500 – 1500 cells/µL in the Equilibration Period 
G-CSF: 
Maintain dose.  
Plerixafor: Maintain dose.  
7.2.4 
Adjustment for ANC > 1500 cells/µL in the Equilibration Period 
G-CSF: 
The G-CSF dose may be reduced after review of a subject’s clinical course. 
Plerixafor: The plerixafor dose may be reduced after review of a subject’s clinical course.  
7.2.5 
Adjustment for ANC > 7500 cells/µL in the Treatment Period 
G-CSF: 
G-CSF dose may be reduced after review of a subject’s clinical course. 
Plerixafor: The plerixafor dose may be reduced after review of a subject’s clinical course. 
7.3 
Immune Status: Leukocyte Immunophenotypes 
Leukocyte numbers available from the CBC (ANC, etc.) will be averaged for each 1-year treatment 
period with either the Study Drug or Comparator Drug and statistical comparison will be performed as 
part of the secondary endpoints.  Lymphocyte flow cytometry results (CD19+, CD4+, CD8+, etc.) will be 
averaged from the 4, 8, and 12 month visits to the NIH-CC for each agent and statistical comparison will 
be performed as part of the secondary endpoints. Changes in leukocyte numbers will also be analyzed by 
length of time on the Study Drug or Comparator Drug.   
7.4 
Medication Compliance: Study Drug and Prophylactic Antibiotics 
7.4.1 
Subject Memory Aid 
It is important to track a subject’s compliance with the study drug, IVIg, and prophylactic antibiotics. 
Compliance is likely to affect a subject’s susceptibility to infection.  Considering the duration of study 
participation, incomplete entries can be expected; therefore, we encourage frequent communications with 
study subjects in an effort to collect all details concerning adverse events, infections, missed doses of 
study agent and other concomitant medications taken.  The references to diary card have been changed to 
memory aid as this is more of a tool the subjects can use in addition to information gathered by the study 
team via frequent communication with subjects such as via phone calls, emails, and phone texts, 
especially whenever a new infection, unusual side effects or a change in medication or dose occurs.   


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7.4.1.1 
IVIg Treatment and Dose 
Subjects record the Date and Dose of the most recent IVIg infused.  
7.4.1.2 
Record Temperature for Fevers 
Subjects record their highest temperature for the day if they have a fever (defined as oral temperature 
>38.3Po
PC. Subjects are encouraged to visit their local provider if they develop a fever. 
7.4.1.3 
Compliance with Prescribed Prophylactic Antibiotics 
Subjects record changes to their use of prophylactic antibiotics. 
7.5 
Study Drug Side Effects and Toxicity 
7.5.1 
Subject Memory Aid 
The most common side effects expected of the study drugs are listed in the Memory Aid (40TAppendix F40T) 
for subjects to rate. Subjects also have the option of specifying additional side effects. The rating scale 
described below is based on CTCAE v4.0. Please note the following definitions for Activities of Daily 
Living (ADL): 
Instrumental ADL: 
Preparing meals, shopping, using telephone and managing money etc.  
Self-care ADL:  
Bathing, dressing, feeding, using toilet, taking medications and not bedridden.  
7.5.1.1 
Injection Site Reaction 
Subjects inject the study drug subcutaneously twice per day and record the Injection Site Reaction defined 
as “intense adverse reaction (usually immunologic) developing at the site of an injection, for the period 
between injections.   
 Not Injected:   
Subject did not inject the drug. 
1 - Tenderness 
Tenderness with or without associated symptoms (warmth, redness, itching). 
2 - Pain 
 
Pain; lipodystrophy; edema (swelling); phlebitis (inflammation of a vein). 
3 - Ulceration 
Ulceration or necrosis; severe tissue damage; operative intervention indicated. 
4 - Life-threatening  Life-threatening consequences; urgent intervention indicated.  
7.5.1.2 
 Bone (Skeletal) Pain: back, arms and legs 
Subjects may complain of pain after treatment, likely due to leukocyte mobilization. Bone pain: marked 
deep aching or throbbing discomfort in the back, arms, and legs. Subjects rate their worst pain for the day. 
1 - Mild 
 
Mild pain. 
2 – Moderate 
Moderate pain; limiting Instrumental ADL. 
3 - Severe  
Severe pain; limiting Self-care ADL. 
7.5.1.3 
Other Pain: shoulder, abdominal etc. 
The study drug may cause enlargement of the spleen, which may result in shoulder or abdominal pain. 
Subjects should record any pain not related to bone pain. 
1 - Mild 
 
Mild pain. 
2 - Moderate 
Moderate pain; limiting Instrumental ADL. 
3 - Severe  
Severe pain; limiting Self-care ADL. 
7.5.1.4 
Headache 
Subjects may complain of headache, a sensation of marked discomfort in various parts of the head. 
Subjects record their worst symptoms for the day. 
1 - Mild  
 
Mild pain. 
2 - Moderate  
Moderate pain; limiting Instrumental ADL. 


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3 – Severe  
Severe pain; limiting Self-care ADL. 
7.5.1.5 
Dizziness 
Subjects may complain of dizziness - disturbing sensation of lightheadedness, unsteadiness, giddiness, 
spinning, or rocking. Subjects record their worst symptoms for the day. 
1 - Mild  
 
Mild unsteadiness or sensation of movement. 
2 - Moderate  
Moderate unsteadiness or sensation of movement; limiting Instrumental ADL. 
3 – Severe 
 
Severe unsteadiness or sensation of movement; limiting Self-care ADL. 
7.5.1.6 
Nausea 
Subjects may experience nausea - a queasy sensation or an urge to vomit - that may be related to the study 
drug. Subjects tabulate their symptoms for that day. 
1 – Mild 
 
Loss of appetite without alteration in eating habits. 
2 – Moderate  
Oral intake decreased w/o significant weight loss, dehydration or malnutrition. 
3 – Severe 
 
Inadequate oral caloric/fluid intake; tube feeding, TPN; hospitalization indicated. 
7.5.1.7 
Vomiting 
Subjects may experience vomiting - a reflexive act of ejecting the contents of the stomach - that may be 
related to the study drug. Subjects tabulate their symptoms for the day. 
1 - 1 to 2 episodes 
1-2 episodes (separated by 5 minutes) in 24 hrs. 
2 – 3 to 5 episodes 
3-5 episodes (separated by 5 minutes) in 24 hrs. 
3 – 6 or more 
≥6 episodes (separated by 5 minutes) in 24 hrs. 
4 – Life-threatening Life threatening consequences, urgent intervention required. 
7.5.1.8 
Diarrhea 
Subjects may experience diarrhea – frequent and watery bowel movement - that may be related to the 
study drug. Subjects tabulate their symptoms for the day. 
1 – Increase <4 stools 
Increase of 1-4 stools per day over baseline. 
2 – Increase 4-6 stools  
Increase of 4-6 stools per day over baseline.  
3 – Increase >=7 stools 
Increase >=7 stools per day; incontinence; hospitalization indicated. 
  
 
 
 
Limiting Self-care ADL. 
4 – Life-threatening   
Life threatening consequences, urgent intervention required. 
7.5.1.9 
Subject Specifies Other Symptoms or Adverse Events. 
Subjects can specify other study drug reactions and rate the severity for that day. 
 
1 – Mild 
 
Mild symptoms; intervention not indicated (required). 
2 – Moderate 
Minimal, local or noninvasive intervention indicated; limiting Instrumental ADL. 
3 – Severe  
Medically significant but not immediately life-threatening. 
Hospitalization indicated, disabling; limiting Self-care ADL. 
4 – Life-threatening Life threatening consequences; urgent intervention required. 
7.5.2 
CBC, Chemistries, ESR, and Pregnancy for Women of Childbearing Potential 
In addition to ANC and the CBC w/diff, we may request additional labs including blood chemistries, and 
ESR. These standard clinical tests will allow us to monitor for changes in blood counts (anemia or 
thrombocytopenia), changes in kidney or liver function, serum electrolytes, and blood glucose. For 
women of childbearing potential, a urine or serum pregnancy test will be conducted. 


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7.5.3 
Splenic Enlargement  
There is a possibility of splenic enlargement with both drugs: very rare cases of splenic rupture have been 
reported in patients following the administration of G-CSF (40TAppendix C40T) and rats given high doses of 
plerixafor were found to have splenic enlargement (40TAppendix B40T). 
7.5.3.1 
Spleen Ultrasonography 
Since WHIMS patients may develop splenomegaly prior to therapy, a spleen ultrasonography will be 
performed prior to the first study dose and at the end of each treatment period. Additional sonograms may 
be performed at subsequent visits if clinically indicated.      
7.5.3.2 
Spleen Assessment as part of Physical Examination at Research Assessment 
Assessment of the spleen will be part of the physical exam at NIH-CC visits every 4 months.  
7.5.4 
Electrocardiogram 
An electrocardiogram (EKG) will be performed during screening to serve as baseline and to rule out 
preexisting cardiac arrhythmia. EKG will be repeated at the EOT visit for each treatment arm. 
7.5.5 
Echocardiogram  
If an echocardiogram (ECHO) has not been performed in the previous 5 years on a subject or the results 
of such a test cannot be obtained, this non-invasive cardiac testing will be performed to look for 
congenital cardiac malformations or cardiac conditions that would predispose a subject to life threatening 
arrhythmia. 
7.5.6 
Dual-energy X-ray Absorptiometry (DEXA) Scans 
To monitor for the loss of bone density, dual-energy x-ray absorptiometry (DEXA) scans will be 
performed prior to the first study dose and at the end of each treatment period.  
7.6 
Rate and Severity of Infections 
7.6.1 
Subject Memory Aid: Symptoms of Infections  
7.6.1.1 
Incidence and Severity of Fever 
Subjects should report symptoms of chills or fevers and take their oral temperature as required. The 
highest temperature measured that day should be recorded. Subjects are encouraged to visit their local 
provider if they develop a fever. 
7.6.1.2 
Number of Days with Fever 
Each day a subject reports an elevated oral temperature at any time during the day above 38.3°C is 
counted as a day with fever.  
7.6.1.3 
 Change in Severity of Chronic Infection 
WHIMS patients often experience ongoing chronic infections with the type, symptom, and severity 
varying amongst the patients. We plan to identify and measure changes in the severity of these infections.  
7.6.1.4 
Visits to Local Provider for Medical Exam or Treatment 
Subjects should record visits at their local facility for medical exams or treatments. 
7.6.1.5 
Incidence and Duration of Antibiotic for Treatment 
Subjects should specify any antibiotic prescribed or taken to treat an infection and record the medication 
activity for that day. The duration of antibiotic use is based on the number of days from the start date to 
the end date of treatment recorded in the Memory Aid. A missed day or missed partial day is included in 
the duration. 


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7.6.2 
Clinical Diagnosis and Treatment of Infections 
While enrolled in the study, subjects continue visits to their local medical provider for clinical care, as per 
their routine prior to enrollment. The diagnosis and treatment results of their infection should be 
submitted to NIH-CC using either or both of the following methods: 
7.6.2.1 
Local Provider Completes a Diagnosis and Treatment Form (option 1) 
The local provider completes the Diagnosis and Treatment form: 
• 
Date of Visit,  
• 
Chief Complaint, Onset of Symptoms, 
• 
Diagnosis, New/Chronic/Recurrent/Exacerbation,  
• 
Infection: Site, Type (viral, fungal, bacterial, etc..), Suspect Causative Organism,  
• 
Treatment Prescribed, and  
• 
Results of related Laboratory Tests or Cultures, 
• 
Outcome of Infections (Resolved, Resolved with residual Symptoms, Ongoing), 
• 
Provider will be encouraged to contact study staff. 
Localized infection sites that are contiguous will be considered as 1 single infection. A sample form that 
can be used by the study coordinator, PI, or local care provider is shown in 40TAppendix G40T.  
7.6.2.2 
Subject or Provider forwards Documents Relating to the Infection (option 2) 
Subject obtains or requests a copy of their medical records related to the infection to be sent to NIH-CC.  
7.6.3 
ENT and Audiology Evaluation at NIH-CC 
Subjects with a history of ear or sinus infections are scheduled for Audiology and ENT at baseline and 
completion of each study drug treatment. Additional consults may be scheduled as medically necessary. 
7.6.4 
Dental and Oral Evaluation 
Subjects are scheduled for assessment of dental caries, periodontal disease, and HPV at baseline and 
completion of each study drug treatment. Additional consults may be scheduled as medically necessary. 
7.6.5 
PFT for Subjects with Chronic Respiratory Infections 
WHIMS patients frequently suffer from repeated pulmonary infections that result in bronchiectasis and 
chronic bronchitis.  Subjects may undergo pulmonary function tests during screening and at the end of 
each treatment period. In addition, subjects with a history of respiratory infections may be scheduled for a 
pulmonary consult at screening to optimize their therapy. Additional consults can be scheduled if needed 
for new or worsening infections/lung function 
7.7 
Monitoring Warts 
7.7.1 
Photos of Infections and Warts 
For subjects with warts who consent to clinical photography, a comprehensive photo set encompassing an 
overview of the external surface of the body will be taken at baseline and at the end of each treatment 
period, including detailed photographs of the hands and feet, which are typical sites for warts in WHIM 
patients.  Detailed photos may be taken of particular warts and other types of skin infections, including 
infections in the anogenital areas if applicable. The photos will serve as the measure of the number and 
severity of infection. To ensure consistent measurements, a similar set of photos will be taken at 
subsequent visits to the NIH-CC. 
7.7.2 
Recording the Quantity and Severity of Warts 
A case report form will be utilized to document the type, appearance, and location of the warts, 
photographs of the warts, treatments of existing warts, appearance of new warts, and representative 
warts/wart areas of interest will be quantified and tracked at each visit to the study center. 


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7.7.3 
Dermatology Evaluation 
Subjects will be evaluated by dermatology at baseline and at the completion of each study drug. 
Additional consults may be scheduled if requested by dermatology or for new or worsening cutaneous 
infections. 
7.7.4 
GU/GYN Evaluation  
Subjects will be scheduled for a genitourinary or gynecology exam at baseline and at the completion of 
each study drug. Additional exams can be scheduled if requested by GU/GYN or for new or worsening 
infections.  
7.8 
Specimen Preparation, Handling, and Shipping 
As the transmission of human immunodeficiency virus (HIV) and other blood-borne pathogens can occur 
through contact with contaminated needles, blood, and blood products, appropriate precautions will be 
employed by all personnel involved in the drawing of blood and the shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and Prevention 
and the NIH.  
7.9 
Quality of Life (SF36 v2) 
Subjects will complete a validated Quality of Life questionnaire (SF-36, version 2) at Baseline and at the 
4, 8, 12 month visits to NIH-CC during the treatment period. At completion of the second treatment 
period, subjects will be asked whether they prefer the first drug they received or the second.  
7.10 Request for Excess Tissue 
Tissue removed for medical indications at the NIH or elsewhere that is not required for a subject’s 
medical care and would otherwise be discarded, with the subject’s permission, may be requested to be 
sent to the NIH for pathologic or research purposes. 
8 
POTENTIAL RISKS AND BENEFITS 
8.1 
Potential Risks of plerixafor 
The dose for plerixafor in this study is 0.01-0.04 mg/kg SQ twice per day is 3 to 12 times less than the 
FDA-approved and commonly prescribed dose of 0.24 mg/kg per day when used in combination with G-
CSF for hematopoietic stem cell mobilization. The most common adverse reactions (ARs; ≥10%) 
associated with plerixafor at 0.24 mg/kg/day in combination with G-CSF administered subcutaneously to 
subjects with cancer at doses that were over 3-12 fold higher than the dose that will be used in the current 
study include diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and 
vomiting.  
 
UInjection site reactionsU: A temporary urticaria-like, pruritic, raised and erythematous lesion can occur at 
the injection site and is common with higher doses than will be used in this study. These reactions 
typically resolve within minutes with no treatment. Prolonged reactions if problematic will be treated with 
standard medical therapies such as topical corticosteroids, oral antihistamines, etc. 
 
Musculoskeletal Pain:  Musculoskeletal pain may affect bones, muscles, ligaments, tendons, or nerves 
and may include one or a combination of the following types of pain:  Bone Pain (deep dull pain from the 
back, legs, and arms), Joint Pain or Arthralgia (pain and/or swelling in the joints), Back Pain, and or Pain 
in the Extremities.  
  
Gastrointestinal side effects: Various side effects related to gastrointestinal function have been reported 
after doses of 0.24 mg/kg including abdominal pain, diarrhea, constipation, nausea, and vomiting, all at 


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higher rates than in subjects given placebo. In general, these have not resulted in the need to stop the 
medication. 
 
Excessively high white counts (leukocytosis): Because of the mechanism of action of this medication, it is 
expected that white blood cell counts will rise. However, normal volunteers have not risen above 25,000 
cells/µL of blood after 1 day of treatment at 0.24 mg/kg/day. The subjects likely to be enrolled in this 
study generally have low circulating WBC and are unlikely to develop leukocytosis.  As an additional 
safety measure, we are starting participants at a low dose of study medication and can lower it if indicated 
by a high ANC count (>7500 cells/µL). 
 
Thrombocytopenia and bleeding: Lower platelet counts (thrombocytopenia) have been reported with 
administration of both study/comparator drugs, but no serious bleeding events have been reported for 
plerixafor to date.  
 
Splenic enlargement: An increase in spleen size has been shown to occur in rats treated with plerixafor at 
proportionately higher doses than will be used here. Although this has not been reported as causing any 
severe problems in humans, we will monitor for clinical signs of problems by asking subjects about left 
shoulder or left upper quadrant abdominal pain at NIH-CC visits. If these occur, the subject will be 
evaluated by medically appropriate imaging and the study drug may be stopped at the discretion of the PI. 
In addition, spleen size will be monitored by ultrasound as specified in 40TAppendix A40T. 
 
Cardiac Arrhythmia: In one human study, 2 HIV-infected patients developed a non-life threatening 
cardiac arrhythmia consisting of frequent premature ventricular contractions.(40T1040T) Individuals who are at 
high risk for life threatening arrhythmia based on EKG or cardiac problems detected on ECHO or who 
have a past history of life threatening cardiac arrhythmia will be excluded from this study. 
 
Paresthesia: In one human study, some HIV-infected patients developed some transient perioral or 
peripheral numbness that resolved with discontinuation of the drug. The patients affected were treated 
with doses considerably higher than will be used in this study and the problem may have been related to 
other medications, which HIV-infected patients commonly use, or HIV itself.  
 
Exacerbation of Chronic Bronchitis/Pneumonia: One of three WHIM subjects treated with plerixafor in 
our previous 6 month Phase 1 trial developed an acute exacerbation of chronic bronchitis and a 
pneumonia during treatment.(5)  However, this is already common in untreated WHIMS patients, so 
cannot be considered a risk of plerixafor.  WHIM patients often develop bronchiectasis as they age as a 
result of repeated lung infections. This may lead to poor clearance of sputum and chronic bronchitis with 
frequent exacerbations and chronic colonization of the sputum with bacterial and fungal pathogens typical 
for cystic fibrosis patients, (i.e., Pseudomonas, Stenotrophomonas, and Aspergillus). Increased circulating 
neutrophils from either plerixafor or G-CSF could contribute to thickened sputum, which may worsen this 
chronic problem.  If subjects have chronic respiratory symptoms, sputum culture for these bacteria as well 
as tuberculosis and atypical mycobacteria will be obtained at the screening visit.  Subjects who suffer 
from this disease complication may receive pulmonary consultation and have their pulmonary treatment 
regimen optimized prior to randomization and study drug initiation. This pulmonary regimen may include 
drug treatments such as inhaled or nebulized beta adrenergic agonists, anticholinergic medications, 
hypertonic saline, prophylactic antibiotics, or DNase enzymes, and physical stimulation of the cough 
reflex with breathing devices or treatments to improve sputum clearance. 
 
Varicella Zoster Infection: During chronic plerixafor therapy we observed reactivation of herpes zoster in 
one of three subjects.(5)  The subject was treated with oral acyclovir and the infection resolved 
completely within days.   


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8.2 
Potential Risks for G-CSF 
Allergic-type Reactions:  Allergic-type reactions occurring on initial or subsequent treatment have been 
reported in <1 in 4000 of subjects treated with G-CSF. These have generally been characterized by 
systemic symptoms involving at least two body systems‚ most often skin (rash‚ urticaria‚ facial edema)‚ 
respiratory (wheezing‚ dyspnea)‚ and cardiovascular (hypotension‚ tachycardia). Some reactions occurred 
on initial exposure. Reactions tended to occur within the first 30 minutes after administration and 
appeared to occur more frequently in subjects receiving intravenous G-CSF. Rapid resolution of 
symptoms occurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚ and/or 
epinephrine. Symptoms recurred in more than half the subjects who were rechallenged. 
 
Splenic Rupture: Splenic rupture, including exceedingly rare fatal cases, has been reported following the 
administration of G-CSF. Individuals receiving G-CSF who report typical left upper abdominal and/or 
shoulder pain will be evaluated for an enlarged spleen or splenic rupture. In addition, spleen size will be 
monitored by ultrasound as specified in 40TAppendix A40T. 
 
Musculoskeletal Pain:  Musculoskeletal pain may affect bones, muscles, ligaments, tendons, or nerves 
and may include one or a combination of the following types of pain:  Bone Pain (deep dull pain from the 
back, legs, and arms), Joint Pain or Arthralgia (pain and/or swelling in the joints), Back Pain, and or Pain 
in the Extremities.  
 
 
Acute respiratory distress syndrome (ARDS): ARDS has been reported in patients receiving G-CSF, and 
is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Subjects 
receiving G-CSF who develop fever, lung infiltrates, or respiratory distress should be evaluated for the 
possibility of ARDS. In the event that ARDS occurs, G-CSF should be withheld until resolution of ARDS 
or discontinued. Subjects will receive appropriate medical management for this condition. 
 
Alveolar Hemorrhage: alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis 
requiring hospitalization has been reported in healthy donors undergoing peripheral blood progenitor cell 
mobilization. Hemoptysis resolved with discontinuation of G-CSF.  
 
Growth Factor for Tumor: G-CSF is a growth factor that primarily stimulates neutrophils. However‚ the 
possibility that G-CSF can act as a growth factor for any tumor type cannot be excluded.  
 
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The incidence 
of antibody development in subjects receiving G-CSF has not been adequately determined. While 
available data suggest that a small proportion of subjects developed binding antibodies to G-CSF, the 
nature and specificity of these antibodies has not been adequately studied. Cytopenias resulting from an 
antibody response to exogenous growth factors have been reported on rare occasions in subjects treated 
with other recombinant growth factors. There is a theoretical possibility that an antibody directed against 
G-CSF may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia; however, 
this has not been reported in clinical studies or in post-marketing experience. Subjects who develop 
hypersensitivity to G-CSF may have allergic or hypersensitivity reactions to other E coli-derived proteins. 
 
Cutaneous Vasculitis: Cutaneous vasculitis has been reported in subjects treated with G-CSF. In most 
cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved subjects 
with severe chronic neutropenia receiving long-term G-CSF therapy. Symptoms of vasculitis generally 
developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many 
subjects were able to continue G-CSF at a reduced dose. 
 


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Aortitis - inflammation of the aorta:  Aortitis has been reported in patients who received G-CSF. 
Symptoms may include fever, abdominal pain, feeling tired, and back pain.   
The following AEs have been identified during post-approval monitoring of G-CSF: splenomegaly, 
splenic rupture, ARDS, alveolar hemorrhage and hemoptysis, sickle cell crisis, cutaneous vasculitis, 
aortitis, Sweet’s syndrome (acute febrile neutrophilic dermatosis), decreased bone density and 
osteoporosis in pediatric severe chronic neutropenia subjects receiving chronic treatment with G-CSF.  
8.3 
Risks and Discomforts of Phlebotomy 
53TSubjects will undergo repeat blood sampling on several occasions during the initial phase of the study 
and during the treatment period. For research blood purposes, each venipuncture will be for 3 mL to 120 
mL of blood in adults. 53TPhlebotomy for blood tests may cause pain, lightheadedness/fainting, or lead to 
the formation of a small subcutaneous hematoma caused by blood leaking from a punctured blood vessel. 
The hematoma causes only minor discomfort; it is not dangerous and requires no treatment other than 
reassurance to the subject. There is also a small risk of infection at the site of the needle puncture, which 
can be readily treated with antibiotic therapy. At the time of enrollment, each subject will be asked about 
their participation in other research studies to ensure that the amount of blood drawn does not exceed the 
limits allowed for adult subjects by the NIH Clinical Center (Medical Administrative Series Policy #: 
M95-9: Guidelines for Limits of Blood Drawn for Research Purposes in the Clinical Center. Available at: 
http://cc-internal.cc.nih.gov/policies/PDF/M95-9.pdf 
8.4 
Risks and Discomforts of Skin or Wart Biopsies 
Wart or skin biopsies may be requested for diagnosis and research from subjects but will be optional. An 
experienced clinician will perform the procedure. Unless the procedure is being performed in conjunction 
with a clinically indicated surgery, only local anesthetics will be used to prepare the biopsy site. The risks 
of wart biopsy include local pain, bleeding, infection, and the potential for scar and keloid formation. 
Antibiotics and oral analgesics will be used to manage pain and infection. The differences in the immune 
response during plerixafor and G-CSF treatment offers generalizable knowledge about the 
pathophysiology and treatment of this condition and knowledge of infecting types of HPV and the 
presence of other co-infecting viruses may have clinical implications for the subject (i.e., risk of cancer 
development is increased with “high risk” HPV types). 
8.5 
Risks and Discomforts of Bone Marrow Biopsy 
Subjects have the option of having bone marrow biopsy done for research purposes, which could be 
performed as an outpatient procedure. Local anesthetics will be used to prepare the biopsy site and IV 
conscious sedation may be offered to subjects for comfort; these agents may result in transient local 
discomfort initially and occasionally be associated with allergic reactions. General anesthesia will only be 
given if the participant is admitted for the procedure. The primary risks of bone marrow biopsy include 
local pain, bleeding, and infection. Antibiotics and oral analgesics will be used to manage pain and 
infection. 
8.6 
Risks of Stopping G-CSF 
Subjects receiving G-CSF at the time of randomization will have the agent stopped for two days prior to 
receiving the first dose of study drug.  This short washout period is to avoid the possibility of synergy 
between G-CSF and plerixafor.  The risk of infection during the two day washout period is unlikely to be 
significantly increased.  Moreover, the subjects will be closely monitored at the NIH-CC as outpatients 
during this period.   
8.7 
Potential Benefit 
G-CSF is an FDA-approved treatment for neutropenia and has been shown to reduce infection in 
congenital neutropenia.(40T2440T) (40TAppendix C40T) Plerixafor is a specific antagonist of CXCR4 and provides a 
novel molecularly targeted potential therapy for WHIMS. Recent Phase I dose-escalation studies of 


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plerixafor in a total of 9 subjects demonstrated that the drug mobilizes not only neutrophils but also all 
other leukocyte subsets that are decreased in the blood of WHIMS patients.(40T3, 440T) Furthermore, low-dose 
therapy with plerixafor alone for 6 months in 3 subjects resulted in a reduction of infections, no new warts 
and possible improvement of existing warts, and no safety concerns.(5) This collective experience 
appeared to be an improvement compared to pre and post study treatments of the same subjects with G-
CSF. 
8.7.1 
Reduced Infections 
G-CSF has been shown to be effective in alleviating neutropenia and reducing infection in patients with 
chronic neutropenia (40T2440T) and there is some limited anecdotal and retrospectively controlled evidence that 
plerixafor may also have clinical benefits.  The aim of this study is to define which drug is superior in 
WHIMS patients. The crossover design ensures that all subjects are able to receive both treatments: 
subjects without prior treatment with either agent may experience improved outcomes from either 
treatment, while subjects previously on G-CSF may obtain benefits with plerixafor. 
8.7.2 
Improved Drug Tolerability 
In our clinical experience treating WHIMS patients with G-CSF and plerixafor, we have identified low 
dose ranges able to maintain the ANC within the target range for the present study of 500-1500 
cells/microliter, which is considered in the literature as ‘safe’.  At these doses, we have observed no 
toxicity attributed to either plerixafor or G-CSF and both appear to be well-tolerated.   
8.7.3 
Control of Warts 
Limited evidence suggests that during chronic treatment with plerixafor in WHIMS patients, warts are 
improved in appearance and size and seem not to recur which is different from the patient’s prior 
experience on/off G-CSF therapy.  This may indicate a beneficial effect of plerixafor treatment in HPV 
disease.(5)  This study is designed to further investigate and validate this preliminary result. 
8.7.4 
Increased Leukocyte Response 
Preliminary published evidence suggests that plerixafor is capable of increasing all leukocytes measured 
that are diminished in the circulation of WHIMS patients (neutrophils, CD4+/CD8+ lymphocytes, B cells, 
and monocytes) in contrast to G-CSF, which increased mainly neutrophils.(3-5)  It is currently unknown 
whether the increased circulating leukocytes convey the expected benefits in terms of reducing infection 
or improving the immune system function and this study is designed to further investigate and validate 
this. 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
9.1 
Intended Use 
Sample collection, handling, storage, and shipment will follow NIH-CC policies and procedures. We will 
make a summary of radiology and laboratory results available to subjects and their local physicians. 
Samples and data collected under this protocol may be used to study the causes of primary 
immunodeficiency, the consequences thereof, and its treatment. Genetic testing to determine the cause of 
the underlying disorder will be performed utilizing another appropriate protocol and will not be 
performed as part of this protocol.  
9.2 
Storage and Tracking 
Access to stored samples will be limited using either a locked room or a locked freezer. Samples and data 
will be stored using codes assigned by the investigators. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. Samples and data acquired will be 
tracked using software designed for this purpose. 


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9.3 
Sharing of Samples and Data 
Other investigators at the NIH or outside may wish to study these samples and/or data. In that case, IRB 
approval must be sought prior to any sharing of samples and/or data. Any clinical information shared 
about the sample would similarly require prior IRB approval. 
9.4 
Reporting Loss or Unanticipated Destruction of Samples 
Any loss or unanticipated destruction of samples or data (for example, due to freezer malfunction) that is 
a Serious Protocol Deviation or compromises the scientific integrity of the data collected for the study, 
will be reported to the National Institute of Allergy and Infectious Diseases (NIAID) IRB. 
9.5 
Disposition of Samples 
9.5.1 
Request by Study Participant 
Subjects may decide at any point not to have their samples stored. The PI will destroy or assure the 
destruction of all known remaining samples and report what was done to both the subject and to the IRB. 
This decision will not affect the subject’s participation in other protocols at NIH. 
9.5.2 
At Completion of Study 
At the completion of the protocol (termination), samples will either be destroyed, or after IRB approval, 
transferred to another existing protocol. 
10 REMUNERATION PLAN FOR SUBJECTS 
Study subjects and their families will not receive any per visit reimbursement for the clinical trial. 
However for optional procedures performed for research purposes only, $120.00 will be paid for each 
wart and/or skin biopsy, and $200 paid for each bone marrow biopsy. 
11 ASSESSMENT OF SAFETY 
11.1 Documenting, Recording, and Reporting Adverse Events  
At each contact with the subject, information regarding AEs will be elicited by appropriate questioning 
and examinations and they will be:  
• 
Immediately documented in the subject’s medical record/source document. 
• 
Recorded in Clinical Research Information Management System, and 
• 
Reported as outlined below (e.g., IND sponsor, IRB, FDA). 
11.2 Definitions  
Adverse Event (AE)  
An AE is any untoward or unfavorable medical occurrence in a human subject, including any abnormal 
sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, temporally associated 
with the subject’s participating in the research, whether or not considered related to the research.  
 
Adverse Reaction (AR) or Adverse Drug Reaction (ADR)  
An AE that is caused by an investigational agent (drug or biologic). 
 
Suspected Adverse Reaction (SAR)  
An AE for which there is a reasonable possibility that the investigational agent caused the AE. 
‘Reasonable possibility’ means that there is evidence to suggest a causal relationship between the drug 
and the AE. A SAR implies a lesser degree of certainty about the causality than an AR, which implies a 
high degree of certainty. 
 
Serious Adverse Event (SAE) 


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A serious AE (SAE) is an AE or any untoward medical occurrence that at any time results in 1 or more of 
the following outcomes: 
• Death 
• Life threatening event (immediate threat to life) event  
• An inpatient hospitalization or prolongation of an existing hospitalization,  
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, 
• A congenital anomaly or birth defect, 
• A medically important event*  
 
*Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious, such as important medical events that may not be immediately life threatening or 
result in death or hospitalization, but they may jeopardize the subject or may require intervention to 
prevent 1 of the other outcomes listed above.  
 
Unexpected Adverse Event  
An AE is unexpected if it is not listed in the Investigator’s Brochure or Package Insert (for marketed 
products) or is not listed at the specificity or severity that has been observed.  It is the responsibility of the 
IND Sponsor to make this determination. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
A SUSAR is a Suspected Adverse Reaction that is both Serious and Unexpected.   
 
Unanticipated Problem (UP)  
An UP is any event, incident, experience, or outcome that is 
1. Unexpected in terms of nature, severity, or frequency in relation to: 
• 
The research risks that are described in the IRB-approved research protocol and informed consent 
document, investigator’s brochure, or other study documents; and 
• 
The characteristics of the subject population being studied; and 
2. Possibly, probably, or definitely related to participation in the research; and 
3. Places subjects or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. Per the IND sponsor, an AE with a serious 
outcome will be considered increased risk. 
 
Unanticipated Problem That Is Not an Adverse Event (UPnonAE) 
Unanticipated problem that is not an Adverse Event (UPnonAE): An unanticipated problem that does not 
fit the definition of an adverse event, but which may, in the opinion of the investigator, involve risk to the 
subject, affect others in the research study, or significantly impact the integrity of research data.  Such 
events would be considered a non-serious UP. For example, we will report occurrences of breaches of 
confidentiality, accidental destruction of study records, or unaccounted-for study drug. 
 
Protocol Deviation 
Any change, divergence, or departure from the IRB approved study procedures in a research protocol. 
Protocol deviations are designated as serious or non-serious and further characterized as 
 
1. Those that occur because a member of the research team deviates from the protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 


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Serious Protocol Deviation: A deviation that meets the definition of a Serious Adverse Event or 
compromises the safety, welfare or rights of subjects or others. 
 
Non –compliance:  The failure to comply with applicable NIH HRPP policies, IRB requirements, or 
regulatory requirements for the protection of human subjects. Non-compliance is further characterized as 
1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that, is neither serious nor continuing. 
11.3 Investigator Assessment of Adverse Events 
If a diagnosis is clinically evident (or subsequently determined), the diagnosis rather than the individual 
signs and symptoms or lab abnormalities will be recorded as the AE. All AEs occurring after enrollment 
through the final study visit will be documented and recorded, and those not related to disease progression 
will be reported as described below in Section 11.4 and Section 11.5.   
 
A laboratory abnormality should be reported as an AE if it requires an intervention. Interventions include, 
but are not limited to, discontinuation of treatment, dose reduction/delay, additional assessments, or 
concomitant treatment. In addition, any medically important laboratory abnormality may be reported as 
an AE at the discretion of the investigator. This could include a laboratory result for which there is no 
intervention but the abnormal value suggests disease or organ toxicity. 
 
The investigator will evaluate all AEs with respect to the seriousness (criteria listed above), severity 
(intensity or grade), and causality (relationship to the study agent and relationship to research) according 
to the following guidelines.  
11.3.1 Severity 
The investigator will grade the severity of each AE according to the “Common Terminology Criteria for 
Adverse Events (CTCAE)” (v 4.0): 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
 
Severity grading for clinical events not found in the toxicity table will be graded according to the 
following grading scale: 
1. Grade 1 (Mild): Events causing no or minimal interference with usual social and functional 
activities. 
2. Grade 2 (Moderate): Events causing greater than minimal interference with usual social and 
functional activities. 
3. Grade 3 (Severe): Events causing inability to perform usual social and functional activities. 
4. Grade 4 (Potentially Life-Threatening):P 
PEvents causing inability to perform basic self-care 
functions OR medical or operative intervention is indicated to prevent permanent impairment, 
persistent disability, or death.  Note:  A severity assessment of “potentially life-threatening” event 
is not necessarily the same as a life-threatening event, when used as an "SAE" criterion. The latter 
means that the event is an immediate threat to life as opposed to a potential threat to life. 
5. Grade 5 (Death).  
11.3.2 Causality    
Causality (likelihood that the event is/is not related to the study agent) will be assessed considering the 
factors listed under the following categories:  


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Definitely Related  
• 
Reasonable temporal relationship. 
• 
Follows a known response pattern. 
• 
Clear evidence to suggest a causal relationship. 
• 
There is no alternative etiology. 
 
Probably Related 
• 
Reasonable temporal relationship. 
• 
Follows a suspected response pattern (based on similar agents). 
• 
No evidence of a more likely alternative etiology. 
 
Possibly Related 
• 
Reasonable temporal relationship. 
• 
Little evidence for a more likely alternative etiology. 
 
Unlikely Related 
• 
Does not have a reasonable temporal relationship.  
OR 
• 
Good evidence for a more likely alternative etiology. 
 
Not Related 
• 
Does not have a temporal relationship.         
OR 
• 
Definitely due to an alternative etiology. 
 
Note: Other factors (e.g., dechallenge, rechallenge) should also be considered for each causality category, 
when appropriate. Causality assessment is based on available information at the time of the assessment of 
the AE. The investigator may revise the causality assessment as additional information becomes 
available. 
11.4 Investigator Reporting Responsibilities to the Sponsor  
11.4.1 Adverse Events 
Line listings, frequency tables, and other summary AE data will be submitted to the IND sponsor when 
needed for periodic safety reviews, review of IND annual reports, review of IND safety reports, and 
preparation of final study reports. 
11.4.2 Serious Adverse Events 
All SAEs (regardless of relationship and whether or not they are also UPs) must be reported on the Safety 
Expedited Report Form (SERF) and sent to the Sponsor Clinical Safety Office (CSO) by fax or e-mail 
attachment. Deaths and immediately life threatening SAEs must be reported to the CSO within 1 business 
day after the site becomes aware of the event. All other SAEs must be reported within 3 business days of 
site awareness. 
 
SPONSOR CLINICAL SAFETY OFFICE CONTACT INFORMATION:  
OCRPRO Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
Phone: 301-846-5301 


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Fax: 301-846-6224 
E-mail: rchspsafety@mail.nih.gov  
11.4.3 Unanticipated Problems 
Unanticipated Problems that are also adverse events must be reported to the CSO and sent by fax or e-
mail attachment no later than 7 calendar days of site awareness of the event. UPs that are not AEs are not 
reported to the Sponsor CSO.  
Report all UPs that are also adverse events to the CSO on the NIH Problem Report Form. 
11.4.4 Protocol-Specified Events 
There are no protocol-specified events. 
11.4.5 Pregnancy 
Pregnancy itself is not an AE. However, complications from pregnancy are AEs and may be SAEs. 
Pertinent obstetrical information for all pregnancies will be reported to the CSO via fax or e-mail within 3 
business days from the site’s awareness of the pregnancy.   
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous, or elective termination of the pregnancy) 
will be reported to the CSO within 5 business days of the site’s awareness of the outcome on a protocol-
specified form. In the event of pregnancy, the subject will be followed to term for safety monitoring. In 
the event of pregnancy: 
• 
Treatment for the subject will be un-blinded; 
• 
If subject is being treated with plerixafor, the study drug will be discontinued; 
• 
If subject is being treated with G-CSF, the study comparator drug may be withheld for the 1Pst
P 
trimester; 
• 
Subject will be advised to notify their obstetrician; 
• 
Pregnancy will be reported to the Data Safety Monitoring Board (DSMB). 
11.5 Investigator Reporting Responsibilities to the NIAID IRB  
11.5.1 Expedited Reporting 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, and serious or continuing 
non-compliance will be reported within 7 calendar days of investigator awareness. Serious Adverse 
Events that are possibly, probably, or definitely related to the research will be reported to the NIAID IRB 
within 7 calendar days of investigator’s awareness, regardless of expectedness. 
11.5.2 Waiver of Reporting Anticipated Protocol Deviations, Expected UPnonAEs and Deaths   
Anticipated deviations in the conduct of the protocol will not be reported to the IRB unless they occur at a 
rate greater than anticipated by the study team. Expected adverse events will not be reported to the IRB 
unless they occur at a rate greater than that known to occur in WHIMS. If the rate of these events exceeds 
the rate expected by the study team, the events will be classified and reported as though they are 
unanticipated problems. Deaths related to the natural history of WHIMS will be reported at the time of 
continuing review. 
11.5.3 Annual Reports  
 
The following items will be reported to the NIAID IRB in summary at the time of continuing review: 
• 
Serious and non-serious unanticipated problems  
• 
Expected SAEs that are possibly, probably, or definitely related to the research; 
• 
SAEs that are not related to the research;  
• 
All adverse events, except expected AEs and deaths granted a waiver of reporting.  
• 
Serious and Non-Serious Protocol deviations  


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• 
Serious, continuing, and minor non-compliance 
• 
Any trends or events that in the opinion of the investigator should be reported. 
11.6 Follow-up of Adverse Events and Serious Adverse Events 
AEs that occur following enrollment of the subject (by signing the informed consent) are followed until 
the final outcome is known or until the end of the study. AEs that have not resolved by the end of the 
study will be recorded as “ongoing”, and will be followed until the final outcome is known. If it is not 
possible to obtain a final outcome for an SAE, the investigator will record the reason a final outcome 
could not be obtained. SAEs that occur after the end of the study that are reported to and are assessed by 
the investigator to be possibly, probably, or definitely related must be reported to the CSO, as described 
above. 
11.7 Investigator Initiated Trial (IIT) Sponsor Obligations and Reporting Responsibilities 
Serious and unexpected suspected adverse reactions as defined in FDA 21 Code of Federal Regulations 
(CFR) 312.32 and determined by the IND sponsor will be reported to the FDA as IND safety reports. The 
IND sponsor will also submit an IND Annual Report of the progress of the investigation to the FDA, as 
defined in 21 CFR 312.33.  AEs that are also UPs will be summarized by the IND sponsor and distributed 
to investigators. 
 
For this Investigator Initiated Trial (IIT): 
• 
The IIT sponsor (OCRPRO) warrants that the study will be performed in compliance with all 
applicable local and international laws and regulations, including without limitation ICH E6 
guidelines for Good Clinical Practices.  
• 
The IIT sponsor shall be responsible for the respect of all obligations required by applicable local 
and international laws and regulations.  
• 
The sponsor shall be responsible for ensuring submission of required expedited and periodic 
reports to the FDA and the NIAID IRB. The IIT sponsor is responsible for providing any “Dear 
Investigator Letter” (DIL) for new safety finding received from Sanofi group entity to the 
investigators and Ethics Committee.  
• 
The sponsor must report the following information in English to the Sanofi group entity 
Pharmacovigilance contact: 
1. Routine transmission of: All Serious Adverse Events (SAEs). These events must be 
transmitted within 1 working day of the sponsor’s awareness or identification of the event.  
     Results of any relevant complementary exams performed to obtain the final diagnosis of any 
SAE (e.g., hospital discharge summary, autopsy, consultation) will be made available to 
Sanofi group entity upon request. 
2. Other events or periodic reports (e.g. Development Safety Update Report (DSUR)), 
submitted to the FDA must be transmitted at the time of submission. 
3. Other significant safety issues or findings in a study pertaining to safety of product must be 
transmitted within 3 working days. 
4. The study report of any IIT must contain a section describing safety review and conclusion. 
5. The reference safety information to be used by the IIT sponsor for evaluation of expectedness 
of adverse events shall be the current approved product label available in the country. 
 
 
SANOFI GROUP ENTITY PHARMACOVIGILANCE CONTACT 
 
Fax/email of SAE Reports to Sanofi: 


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IST/ISS Investigators will notify Sanofi via fax or email, attention Sanofi Pharmacovigilance (PV): 
  
Fax:  908-203-7783 (US)    
E-mail:USPVmailbox@sanofi.com 
11.8 Halting Criteria for the Protocol  
Halting the study requires immediate discontinuation of the study agent administered to subjects and 
suspension of enrollment in this study until a decision is made whether or not to continue the study agent 
administration. 
 
The halting criteria include:  
1. Two or more subjects experience the same or similar SAEs that are unexpected and are possibly, 
probably, or definitely related to the study agent, or 
2. Any safety issue that the site investigators determine should halt the study.  
 
The IRB, IND sponsor, or the FDA may halt the study at any time following review of any safety 
concerns. The DSMB may recommend a study halt. 
11.8.1 Reporting of Study Halting 
If a halting requirement is met, a description of the event(s) or safety issue must be reported by the PI 
within 1 business day to the sponsor CSO by fax or e-mail. The PI must inform the IRB that a halting 
requirement has been met. 
11.8.2 Resumption of a Halted Study 
The IND sponsor, in collaboration with the PI and the DSMB, will determine if it is safe to resume the 
study. The IND sponsor will notify the PI of this decision. The conditions for resumption of the study will 
be defined in this notification. The PI will notify the IRB of the decision to resume the study. 
11.9 Pausing Criteria for a Subject  
The decision to suspend administration of a study agent for a single subject requires discontinuation of 
study agents administrated to the study subject until a decision is made whether or not to continue the 
administration of the study agent.   
 
The pausing criteria for a single subject in this study include:  
1. A subject experiences an SAE or a grade 3 or greater AE that is unexpected (as determined by the IND 
Sponsor) and is possibly, probably, or definitely related to the study agent; or 
2. Development of any exclusion criteria may be cause for discontinuation; or 
3. Any safety issue that the investigator determines should pause administration of the study agent to a 
single subject. The IND sponsor, in collaboration with the PI, may also pause for an individual subject 
if a safety concern is identified during routine aggregate data analysis. 
11.9.1 Reporting of Pausing for a Subject  
If a pausing requirement is met, a description of the AEs or safety issue must be reported by the site 
investigator via fax or email within 1 business day to the sponsor CSO, PI, the IRB and the DSMB. 
11.9.2 Resumption of a Paused Study 
The IND sponsor in collaboration with the PI and DSMB will determine if it is safe to resume 
administration of the study agents to the subject/group. The IND sponsor will notify the site investigators 
of this decision. The site investigators will notify their local IRB(s) of the decision to resume 
administration of the study agents prior to resumption.  


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11.10 Withdrawal Criteria for an Individual Subject  
An individual subject will be withdrawn from the study for any of the following:  
1. A subject’s decision (investigator should attempt to determine the reason for the subject’s 
decision). 
2. Any clinical AE, laboratory abnormality, or other medical condition or situation such that 
continued participation in the study would not be in the best interest of the subject.  Subjects will 
be followed for the duration of the study for indicated safety assessments. 
3. Non-compliance with study procedures to the extent that it is potentially harmful to the subject or 
to the integrity of the study data. 
4. A change in the subject’s baseline condition after enrollment so that the subject no longer meets 
the inclusion/exclusion criteria.   
11.11 Additional Enrollment for Withdrawn Subjects 
Subjects who are not evaluable as described in the Statistics (Section 14) may be replaced with other 
eligible subjects. 
12 SAFETY OVERSIGHT AND MONITORING PLAN  
12.1 Safety Review and Communication Plan 
A Safety Review and Communication Plan (SRCP) has been developed for the protocol. The SRCP is an 
internal communications document between the PI and the IND sponsor CSO, which delineates the safety 
oversight responsibilities of the PI, the CSO, and other stakeholders. The SRCP also includes the overall 
plan for conducting periodic safety surveillance assessments. 
12.2 Sponsor Medical Monitor 
A sponsor medical monitor representing the IND sponsor (OCRPRO), has been appointed for the safety 
oversight in this clinical study. The sponsor medical monitor will be responsible for performing safety 
assessments as outlined in a Safety Review and Communications Plan.  
12.3 Data and Safety Monitoring Board  
The NIAID intramural DSMB will review the IRB-approved protocol, informed consent documents, data 
and safety monitoring plan and any stopping guidelines of the study prior to initiation and twice a year. 
The board may convene additional reviews as necessary.  The board will review the study data to evaluate 
the safety, efficacy, study conduct and progress, and scientific validity and integrity of the trial. All SAEs, 
UPs, and IND safety reports will be reported by the PI to the DSMB at the same time they are submitted 
to the IRB or IND sponsor. As part of this responsibility, the DSMB members must be satisfied that the 
timeliness, completeness, and accuracy of the data submitted to them for review are sufficient for 
evaluation of the safety and welfare of the study subjects. The DSMB may also convene as needed, if 
stopping criteria are met, or other safety issues arise that the PI and/or NIAID clinical director or designee 
would like the DSMB to address. The PI will notify the DSMB of any cases of intentional or 
unintentional unblinding as soon as possible. The PI will notify the board at the time pausing or halting 
criteria are met and obtain a recommendation concerning continuation, modification, or termination of the 
study. The PI will submit the written DSMB recommendations and summary reports to the NIAID IRB.  
12.4 Procedures for Emergency Unblinding 
In the event of a pregnancy occurring during treatment or Grade 4 or 5 toxicity in a participant their drug 
treatment will be unblinded and the subject and their local physician will be told of their status.  
Whenever possible the PI and investigators will not be made aware of their treatment status.  If this is 
unavoidable, the IRB, DSMB, and CSO will be notified. 


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13 CLINICAL MONITORING STRUCTURE 
13.1 Site Monitoring Plan 
As per International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 5.18, clinical 
protocols are required to be adequately monitored by the study sponsor. This study monitoring will be 
conducted according to the NIAID Intramural Clinical Monitoring Guidelines. Monitors under contract to 
the NIAID/OCRPRO will visit the clinical research site to monitor all aspects of the study in accordance 
with appropriate regulations and the approved protocol. The objectives of a monitoring visit will be: 1) to 
verify the existence of signed informed consent documents for each monitored subject; 2) to verify the 
prompt and accurate recording of all monitored data points and prompt reporting of all SAEs; 3) to 
compare abstracted information with individual subjects’ records and source documents (subjects’ charts, 
laboratory analyses and test results, physicians’ progress notes, nurses’ notes, and any other relevant 
original subject information); and 4) to ensure the investigators compliance with the protocol, and 
completeness and accuracy of the study records. The monitors also will inspect the clinical site regulatory 
files to ensure that regulatory requirements (Office for Human Research Protections [OHRP]) and 
applicable guidelines (ICH-GCP) are being followed. During the monitoring visits, the investigator 
(and/or designee) and other study personnel will be available to discuss the study progress and monitoring 
visit. 
  
The investigator (and/or designee) will make study documents (e.g., consent forms, and pertinent hospital 
or clinical records) readily available for inspection by the local IRB, site monitors, and NIAID staff for 
confirmation of the study data. A specific protocol-monitoring plan will be discussed with the PI and 
study staff prior to enrollment. The plan will outline the frequency of monitoring visits based on factors 
such as study enrollment, data collection status, and regulatory obligations. 
 
A monitoring visit will occur after the first five participants have been treated for 6 months in order to 
ensure completeness of reports sent by outside labs and to verify the presence of  Memory Aid forms. 
14  STATISTICAL CONSIDERATIONS 
14.1 Study Hypotheses 
The primary hypothesis is that the Total Infection Severity Score (TISS) will be significantly reduced 
while on plerixafor compared to GCSF. The TISS score is the sum of the Infection Severity Scores 
(40TAppendix D40T) for all infections during each period (1 year of treatment). Secondary endpoints include 
infection related parameters, wart response, immunological parameters, and measures of chronic 
infections, side effects, quality of life, and treatment preference. 
14.2 Sample Size Justification 
The primary endpoint is the change in the total infection severity score during period 1 minus the total 
infection severity score during period 2. Retrospective data on 11 subjects treated with G-CSF for one 
year provided a mean TISS score of 21 with a standard deviation of 10.  We conservatively assume that 
there will be a reduction of 50% between the TISS score during the plerixafor period and the TISS score 
during the G-CSF period. Table 1 provides some power calculations based on a two group t-test using an 
alpha = 0.05 two-sided test and setting power at 90%.  The groups are defined by their randomization 
sequence Gp (meaning G-CSF first then plerixafor) or pG (for plerixafor treatment first, followed by G-
GSF).    
Table 1:  Sample size required to achieve 90% power under different assumptions for the mean 
response on G-CSF and plerixafor.  Power formula based on a two-sided two sample t-test with 
alpha=0.05 using the period 1 minus period 2 change in TISS scores as the primary outcome. A 
standard deviation of 10 for the difference is assumed. 


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Mean TISS 
while on G-CSF 
Mean 
TISS 
while on 
plerixafor 
Percent 
Reduction in 
TISS 
Mean Change 
for 
Gp group 
Mean 
Change 
for pG 
group 
Mean 
Difference 
in changes 
between 
groups 
Total 
Sampl
e Size 
21 
10 
52.4% 
11 
-11 
22 
12 
21 
11 
47.6% 
10 
-10 
20 
14 
21 
12 
42.9% 
9 
-9 
18 
16 
21 
13 
38.1% 
8 
-8 
16 
20 
21 
14 
33.3% 
7 
-7 
14 
24 
 
From Table 1, we see that with 16-20 subjects we can detect 38%-43% reductions in TISS while on 
plerixafor.   Such reductions would be clinically meaningful and we will thus aim to enroll 20 subjects.  
While the Wilcoxon two sample rank sum test will be used in the analysis to provide some robustness 
against aberrant TISS scores, the power based on a t-test is a good approximation to the power for a 
Wilcoxon test. We use the two sample Wilcoxon test instead of the one sample paired difference 
Wilcoxon test to provide robustness to the possibility of secular trends in the TISS score over the two 
periods.   
14.3 Study Population 
Our study population will be genetically proven WHIM patients (known compatible heterozygous 
CXCR4 mutation) age 10-75 who have a history of recurrent infections and are neutropenic (ANC<1500 
at baseline).  These individuals would be likely to benefit from either the study drug or the comparator 
agent.  Subjects will be recruited for participation among those being followed at NIH (24 as of May 
2014), followed elsewhere in the US or other countries, newly diagnosed by dermatologists, 
immunologists, gynecologists, urologists, or primary care physicians or self-referred.  
As with US subjects, subjects recruited from other countries will receive their routine care and obtain 
blood counts from their local providers and visit the NIH-CC per study schedule. 
14.4 Description of Analysis 
14.4.1 Efficacy Analysis – Infection Severity Score (ISS) 
Data from a subject’s study Memory Aid such as visits to a subject’s local medical provider, anti-
infective prescriptions, fevers (oral temperature >38.3Po
PC), hospitalization, and diagnoses of infection 
from the subject’s medical provider, are collected, reviewed and scored at the study center by the PI 
according to specific pre-defined weighting rules (40TAppendix D40T) designated the ISS. 
14.4.1.1  Infection-related Events 
An Infection-related Event is defined by any of the following: 
1) Diagnosis of Infection by a Clinician: Subjects are encouraged to visit their local medical 
provider if they experience symptoms of a new or worsening infection such as fevers, chills, 
aches, pain, worsened cough, swelling, redness, etc. Subjects record visits to their local medical 
provider in their Memory Aid and provide documentation of the diagnosis and treatment to the 
NIH-CC. If a provider clinically diagnoses an infection (i.e. otitis, sinusitis, dental infection, 
bronchitis, pneumonia, abscess), this is recorded and counted as an Infection-related Event.  
2) Presumed Diagnosis of Infection by a Clinician: The precise cause of an infection cannot always 
be determined. A differential diagnosis of possible infections and/or biomarker indications of an 
infection will be counted as an infection.  
3) Resolution of Infection Symptoms after Treatment with Antibiotics: Subjects with chronic or 
recurrent infections may have a standing prescription for antibiotics without need to visit their 
local medical providers prior to initiating treatment. Because subjects record their symptoms of 


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infection and any antibiotic taken for treatment in their Memory Aid (40TAppendix F40T), resolution of 
likely symptoms of infection (for example fever, pain, or worsened cough) coincident with 
commencing an antibiotic regimen will be counted as an Infection-related Event even if not 
diagnosed clinically. 
14.4.1.2 Severity of Fever for an Infection-related Event 
The highest temperature recorded during an episode of infection is scored as described in Appendix D. 
Fevers that are of indeterminate origin (i.e. not clearly associated with an Infection) are counted as a 
fever, but are not included in the ISS. 
14.4.1.3 Level of Antibiotic Treatment for an Infection-related Event 
The highest level of prescribed antibiotic treatment (topical, oral, or parenteral) for an Infection is scored 
and described in the Infection Severity Score in 40TAppendix D40T.  
14.4.1.4 Extent of Hospitalization for an Infection-related Event 
The highest level of care is scored as described in the Infection Severity Score in Appendix D.  
14.4.2 Method of Analysis 
For the primary analysis of our data we will use a two-sample Wilcoxon test under a ranking scheme 
where we form a score for each person  
 
 
S = (TISS during period 1 – TISS during period 2), 
 
where TISS is the Total Infection Severity Score, which is the sum of all ISSs during a period. For 
example, if a subject had 3 infections on plerixafor with ISSs of 4, 1, 3 and 2 infections on GCSF with 
ISSs of 5,1, the score would be (4+1+3) – (5+1) = 8-6=2.    
 
It is possible that not all subjects will have complete follow-up for both periods.  We next describe how to 
handle such subjects. Drug failures are subjects who must discontinue their assigned drug because 1) drug 
is intolerable and the subject refuses to take the study drug, 2) the ANC is reliably less than 500 cells/µL 
or 3) an adverse event precludes further study drug administration.  Drug failures in treatment period 1 
cross over to the opposite arm; drug failures in treatment period 2 receive best available therapy.  A drug 
failure should get the worst rank. Let S* be the largest of the absolute value of the scores for all subjects 
with complete data.  To operationalize giving the worst rank, we will give drug failures during the first 
period a score of S*+1. If a drug failure occurs during the second period, they receive a score of -(S*+1).  
Subjects who are drug failures in each period receive a score of 0.    
 
Apart from drug failures, some subjects may drop out of the study for reasons different than the above 
three. For subjects who drop out in period 2 after at least 3 months of follow-up an adjusted score will be 
formed. 
S = TISS in period 1 -  (TISS in period 2)/f 
 
where f is the fraction of intended follow-up attained in period 2 (note that f>=3/12). Based on these 
scores, we will calculate a permutation p-value using the two-sample Wilcoxon rank test. Subjects who 
drop out in period 1 or before 3 months of period 2 will be excluded from the primary analysis.  
 
If missing data and drug failures are substantial, different sensitivity analyses will be conducted. These 
could include discarding all such subjects or developing a model to help allow imputation of missing data, 
or performing a model based analysis.  
 
All tests will be two-sided with a type I error rate of 0.05. 


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14.4.3 Interim Analysis 
After 10 subjects have data for the primary analysis, an interim analysis will be performed. If the two-
sample Wilcoxon test of TISS scores achieves a one-sided permutation p-value of 0.05 or less indicating 
better TISS scores on G-CSF versus plerixafor, serious consideration should be given to stopping the 
study for futility.  
 
A subject has data for the primary analysis if  
1) They have completed 1 year of plerixafor treatment and 1 year of G-CSF treatment 
2) Are a drug failure on either plerixafor or G-CSF (or both) 
3) They drop out in period 2 after 3 months of follow-up. 
 
No interim analysis for efficacy is planned; it is difficult for a rank-based procedure to achieve a small p-
value after 10 subjects, and we anticipate the study will be entirely or nearly entirely enrolled by the time 
10 subjects have complete data for the primary endpoint.   
14.4.4 Futility Monitoring 
The study will be monitored for operational futility.  If fewer than 10 subjects have been enrolled  
after 2 years (counting time from the first enrollment), or if it is clear earlier that fewer than 10 subjects 
will be enrolled after 2 years, the study will be closed to further recruitment, and subjects already enrolled 
may choose to continue on the study or revert to best available medical therapy. If after 3 years the 
recruitment has plateaued at some level less than 20, the DSMB should consider closing the study to 
further recruitment while continuing the study of the enrolled subjects until all have data for the primary 
analysis.    
14.4.5 Safety Analysis 
The following tables of AEs will be completed after unblinding the study: 
• 
A listing of all SAEs including the treatment arm to which the subject was assigned. 
• 
Frequency tables of AEs by treatment arm, severity, and reported relationship to treatment.  
14.4.6 Secondary Analysis 
14.4.6.1 Secondary endpoints  
 
Secondary endpoints (incidence of fevers and number of febrile days, incidence of hospitalization and 
number of hospital days, incidence of antibiotic treatment and number of antibiotic days, number of 
infections and number of days with infections, number of new visible warts, and the change in severity 
for existing warts) will follow the same type of analysis as described above with the TISS being replaced 
by number of fevers, number of febrile days, etc. All tests will be two-sided with a type I error rate of 
0.05.  
14.4.6.2 Incidence and Duration of Infection-related Event 
An infection-related Event will be counted as an incidence of infection. The duration of infection is the 
number of days the symptoms of infection are present. 
14.4.6.3 Incidence and Duration of Fever 
Febrile days are defined as days in which the subject’s oral temperature  ≥ 38.3°C, at any point during the 
day (or 24 hour period). Contiguous days of fever will be counted as an incidence of fever. For 
subsequent fevers to be considered a new/additional incidence of fever, an interval of at least 48 hours 
without fever related symptoms such as elevated temperature, chills, aches, and fatigue must separate 
each event of a fever.  


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14.4.6.4 Incidence and Duration of Antibiotic Treatment 
A prescribed treatment with a new antibiotic (oral, IV, or topical) is counted as an incidence of antibiotic 
treatment.  The duration of antibiotic treatment is the number of days a subject is under treatment with an 
antibiotic other than a prophylactic antibiotic; missing an occasional dose does not invalidate the count 
for that day. For example if a subject is asked to take a 10 day course of antibiotics for otitis this will 
count as one episode of otitis and 10 days of antibiotic therapy regardless of whether the subject actually 
takes all 10 days or misses a day.  Additional antibiotic treatments during or after the initial treatment are 
counted as additional incidences of antibiotic treatment. 
14.4.6.5 Incidence and Duration of Hospitalization 
An incidence of hospitalization is an admission to a hospital for treatment of an infection or presumed 
infection. Hospital days are defined as any day that a subject is in a hospital for treatment due to a 
diagnosis (or presumed diagnosis) of infection. The duration of an infection related event is the number of 
days the symptoms of infection persists. 
14.4.6.6 Severity of Chronic Infections 
Subjects with chronic and/or frequently recurring infections record the severity of their symptoms in their 
Memory Aid. At the Initial Evaluation period prior to randomization and treatment, a baseline of their 
symptoms is documented and incorporated into their Memory Aid. During treatment, any significant 
change in baseline such as worsening infection that affects their function or require symptomatic 
treatment (e.g., over the counter medication) are recorded, as well as any significantly improved 
symptoms that improves their function or reduces their need for symptomatic treatment (e.g., over the 
counter medication) are computed as used as a measure of their severity of infection. 
14.4.6.7 Use of Prophylactic Antibiotics  
At the Initial Evaluation period prior to randomization and treatment, a subject’s use of prophylactic 
antibiotics is documented and incorporated into their Memory Aid. Subjects record their compliance with 
these prophylactics in their Memory Aid. Changes in prescription or to a subject’s use of the prophylactic 
are recorded. Although this information is not a direct measure of a subject’s severity of infection, it is 
collected to provide background information that may explain confounding or extrinsic factors that may 
affect a subject’s rate and severity of infection.  Subjects who are prescribed prophylactic antibiotics will 
be encouraged to continue them throughout the study so as to minimize any confounding. 
14.4.6.8 Control of Warts 
Existing warts will be documented at baseline visits prior to treatment with either the study drug or the 
comparator agent via clinical photographs, if the subject consents. Every 4 months during the treatment 
period clinical photography will be repeated in areas with new or existing warts. Our main endpoint will 
be the number of new visible warts occurring during each 52-week treatment period. We will also analyze 
the size changes of existing untreated warts and the regrowth of treated/removed warts as secondary 
endpoints. A two-sample Wilcoxon paired difference test will be used for analysis. 
14.4.6.9 Change of Leukocyte Blood Counts 
Leukocyte numbers available from the CBC (ANC, etc.) will be averaged throughout each 1-year 
treatment period with either the Study Drug or Comparator Drug and statistical comparison will be 
performed as part of the secondary endpoints.  Lymphocyte flow cytometry results (CD19+, CD4+, 
CD8+, etc.) will be averaged from the 4, 8, and 12 month visits to the NIH-CC for each agent.  In 
addition both of these averages will be compared to the subject baseline defined as the average of any 
measurements of G-CSF and plerixafor within 6 months of starting the study at NIH-CC. A two-sample 
Wilcoxon paired difference test will be used for analysis. Changes in leukocyte numbers will also be 
analyzed by length of time on the Study Drug or Comparator Drug.   


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14.4.6.10    Quality of Life and Subject Preference Assessment 
The subjects will complete a validated Quality of Life (QOL) questionnaire (SF-36 version 2) during the 
4, 8, and 12 month visits in the Treatment period at the NIH-CC, and the responses will be averaged and 
compared. Changes in QOL scores will also be analyzed by length of time on the Study Drug or 
Comparator Drug.  At completion of the second treatment period, subjects will be asked whether they 
prefer the first drug they received or the second. A two-sample Wilcoxon paired difference test will be 
used for analysis. 
14.4.7 Randomization 
Randomization will be blocked so that after every 4 subjects, 2 will have been assigned initial treatment 
with G-CSF and 2 will have been assigned initial treatment with plerixafor. 
15 ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 Informed Consent Process 
Informed consent is a process where information is presented to enable persons to decide voluntarily 
whether or not to participate as a research subject. It is an ongoing conversation between the human 
research subject and the researchers, which begins before consent is given and continues until the end of 
the subject's involvement in the research. Discussions about the research will provide essential 
information about the study and will include the purpose, duration, experimental procedures, alternatives, 
and risks and benefits. Subjects will be given the opportunity to ask questions and have them answered.  
 
Subjects will sign the informed consent documents prior to undergoing any research procedures. Subjects 
may withdraw consent at any time throughout the course of the study. A copy of the informed consent 
documents will be given to the subjects for their records. The researcher will document the signing of the 
consent forms in the subject’s medical record. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline to 
participate in the study.  
 
The acquisition of main study informed consent will be documented in the participant’s medical records, 
as required by 21 CFR 312.62. The informed consent form will be signed and personally dated by the 
participant and the person who conducted the consenting process. The original signed informed consent 
form will be retained in the subjects’ medical chart and a copy of it will be provided to them.  
 
Consent from Non-English Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, the participant will be 
provided with the CC Short Written Consent Form for Non-English Speaking Research Participants in the 
participant’s native language and a verbal explanation of the purpose, procedures and risks of the study as 
described MAS Policy M77-2, NIH HRPP SOP 12 and 45 CFR 46.117(b)(2). The IRB-approved English 
consent form will serve as basis for the verbal explanation of the study. The investigator will obtain an 
interpreter unless the investigator is fluent in the prospective participant’s language. Preferably, the 
interpreter will be someone who is independent of the participant (i.e., not a family member). Interpreters 
provided by the CC will be used whenever possible. The interpreters will translate the IRB-approved 
English consent form verbatim and facilitate discussion between the participant and investigator. 
 
The IRB-approved English consent form will be signed by the investigator obtaining consent and a 
witness to the oral presentation. The CC Short Written Consent Form will be signed by the participant 
and a witness who observed the presentation of information. The interpreter may sign the consent 
document as the witness and, in this case, will note “Interpreter” under the signature line. A copy of both 
signed forms will be provided to the participant to take home. 
 


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The investigator obtaining consent will document the consent process in the participant’s medical record, 
including the name of the interpreter. Further, all instances of use of the CC Short Written Consent Form 
will be reported to the IRB at the time of annual review. If the CC Short Written Consent Form is used 
three times or more for the same language, this will be reported to the IRB immediately. 
15.2 Subject Confidentiality 
The investigator will ensure that the subjects’ anonymity is maintained. Subjects will not be identified in 
any publicly released reports of this study. All records will be kept confidential to the extent provided by 
federal, state, and local law. The study monitors and other authorized representatives of the sponsor may 
inspect all documents and records required to be maintained by the investigator, including, but not limited 
to, medical records. The investigator will inform the subjects that the above-named representatives will 
review their study-related records without violating their confidentiality. To maintain subject 
confidentiality, all laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified only by a coded number to maintain subjects’ confidentiality. All records will be kept 
locked and all computer entry and networking programs will be done with coded numbers only. Clinical 
information will not be released without written permission of the subject, except as necessary for 
monitoring by IRB, FDA, NIAID, OHRP, or the sponsor’s designee. 
16 DATA HANDLING AND RECORD KEEPING 
16.1 Data Management Responsibilities 
The investigator is responsible for assuring that the data collected is complete, accurate, and recorded in a 
timely manner. Source documentation (the point of initial recording of information) should support the 
data collected in the electronic data system, and must be signed and dated by the person recording and/or 
reviewing the data. All the data should be reviewed by the investigator and signed in ink or electronically.  
16.2 Data Capture Methods 
Study data will be collected at the study site and maintained in an electronic data system. These forms or 
systems are to be completed on an ongoing basis during the study. Only authorized individuals shall 
perform data entry into the electronic data system. Corrections to the electronic data system shall be 
tracked electronically (password protected or through an audit trail) with the time, date, name of the 
individual making the correction, and details of the change being made. 
16.3 Types of Data 
Source documents include, but are not limited to, the subject’s medical records, laboratory reports, EKG 
tracings, x-rays, radiologist’s reports, subject’s diaries, biopsy reports, ultrasound photographs, progress 
notes, pharmacy records, and any other similar reports or records of procedures performed during the 
subject’s participation in the study 
16.4 Source Documents and Access to Source Data/Documents 
Study data will be collected and maintained in NIH-CC electronic records, and the subject’s study binder. 
The PI is responsible for assuring that the data collected are complete, accurate, and recorded in a timely 
manner. Source documentation (the point of initial recording of a piece of data) should support the data 
collected, and must be signed and dated by the person recording and/or reviewing the data. Source 
documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical trial. Source documents include, but 
are not limited to, the subject’s medical records, laboratory reports, progress notes, pharmacy records and 
any other similar reports or records of procedures performed during the subject’s participation in the 
study. Data from the data system will be collected directly from the subjects during study visits or will be 
abstracted from the subjects’ medical records. Each subject’s medical record must record his/her 


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participation in the clinical trial and study agent (with doses) and any other medical interventions or 
treatments administered, as well as any adverse reactions experienced during the trial.    
 
To maintain the subjects’ confidentiality, access to the data will be limited. Authorized representatives 
from NIAID and regulatory agencies will be permitted to examine clinical records for the purposes of 
quality assurance review, audits, and evaluation of the study safety and progress. 
16.5 Study Records Retention 
The investigator is responsible for retaining all essential documents listed in the ICH GCP guideline. 
Essential documentation for all the study subjects is to be maintained by the investigators in a secure 
storage facility for a minimum of 3 years according to NIAID policies. The FDA requires study records to 
be retained for up to 2 years after marketing approval or disapproval (21 CFR 312.62), or until at least 
2 years have elapsed since the formal discontinuation of clinical development of the investigational agent 
for a specific indication. These records are also to be maintained in compliance with IRB, state, and 
federal medical records retention requirements, whichever is longest. All stored records are to be kept 
confidential to the extent required by federal, state, and local law.  
 
Should the investigator wish to assign the study records to another party and/or move them to another 
location, the investigator must provide written notification of such intent to OCRPRO/NIAID, with the 
name of the person who will accept responsibility for the transferred records and/or their new location. 
Prior to the destruction or relocation of research records, NIAID must be notified in writing and written 
permission from OCRPRO/NIAID is required. 
 
 


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Ma, Q., Jones, D., Borghesani, P.R., Segal, R.A., Nagasawa, T., Kishimoto, T., Bronson, R.T., 
and Springer, T.A. 1998. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar 
neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A 95:9448-9453. 
33. 
Gabrilove, J.L., Jakubowski, A., Fain, K., Grous, J., Scher, H., Sternberg, C., Yagoda, A., 
Clarkson, B., Bonilla, M.A., Oettgen, H.F., and et al. 1988. Phase I study of granulocyte colony-
stimulating factor in patients with transitional cell carcinoma of the urothelium. J Clin Invest 
82:1454-1461. 
34. 
Morstyn, G., Campbell, L., Souza, L.M., Alton, N.K., Keech, J., Green, M., Sheridan, W., 
Metcalf, D., and Fox, R. 1988. Effect of granulocyte colony stimulating factor on neutropenia 
induced by cytotoxic chemotherapy. Lancet 1:667-672. 
35. 
Bronchud, M.H., Scarffe, J.H., Thatcher, N., Crowther, D., Souza, L.M., Alton, N.K., Testa, 
N.G., and Dexter, T.M. 1987. Phase I/II study of recombinant human granulocyte colony-
stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer. Br J 
Cancer 56:809-813. 
36. 
Rosenberg, P.S., Zeidler, C., Bolyard, A.A., Alter, B.P., Bonilla, M.A., Boxer, L.A., Dror, Y., 
Kinsey, S., Link, D.C., Newburger, P.E., Shimamura, A., Welte, K., and Dale, D.C. 2010. Stable 
long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF 
therapy. Br J Haematol 150:196-199. 
37. 
Connelly, J.A., Choi, S.W., and Levine, J.E. 2012. Hematopoietic stem cell transplantation for 
severe congenital neutropenia. Curr Opin Hematol 19:44-51. 
38. 
Nagasawa, T., Nakajima, T., Tachibana, K., Iizasa, H., Bleul, C.C., Yoshie, O., Matsushima, K., 
Yoshida, N., Springer, T.A., and Kishimoto, T. 1996. Molecular cloning and characterization of a 
murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine 
homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc Natl Acad Sci U S 
A 93:14726-14729. 
39. 
Vettenranta, K., Mottonen, M., and Riikonen, P. 2012. The use of plerixafor in harvesting 
autologous stem cells in the pediatric setting. Pediatr Blood Cancer 59:197-198. 
40. 
Aabideen, K., Anoop, P., Ethell, M.E., and Potter, M.N. 2011. The feasibility of plerixafor as a 
second-line stem cell mobilizing agent in children. J Pediatr Hematol Oncol 33:65-67. 
 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
 
APPENDIX A: SCHEDULE OF PROCEDURES AND EVALUATION 
 
 
 
 
 
 
Evaluations 
 
Screening, Initial 
Evaluation Period and 
Baseline Assessments 
(Screening & Baseline) 
 
1Pst
P Equilibration Period 
(Day Prior, Day 0, & Local Labs)  
 
 
1Pst
P Year Treatment Period (52 
weeks) 
 
2Pnd
P Equilibration 
& 2Pnd
P Year 
TreatmentPa 
 
 
Reversion to 
Pre-study Treatment 
Screening 
V1 
W –(2 to 
20) 
Baseline 
V2 
Prior to 
Injection 
V3 
D -1/0 
1Pst
P Dose 
V3 
D 0 
Local 
LabsPa 
L 1, 2, 3 
W 2, 4, 6 
(± 7d) 
Evaluation 
V 4, 5, 6 
M 0, 4, 8 
(± 31d) 
Local 
LabsPa 
L 4, 5, 6 
M 2, 6, 10 
(± 31d) 
EOT 
V7 
M 12 
(± 
31d) 
2Pnd
P Study DrugPb 
V 8-12 
L 7-12 
M13 to 26 
(± 31d) 
 
Local LabsPa 
L 13-15 
W 2, 4 
(± 7d) 
M 28 
(± 31d) 
Study 
Completio
n 
V13 
M 30 
(± 61d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
X 
 
X 
X (x5) 
 
 
X 
Vital Signs: Temp, Pulse, Blood Pressure 
X 
 
X 
XPc 
 
X 
 
X 
X (x6) 
 
 
X 
Pregnancy testing as applicable and 
contraception counseling as appropriate. 
X 
 
X 
 
 
X 
 
X 
X (x5) 
 
 
X 
CBC with Differential 
X 
L 
X 
 
L 
X 
L 
X 
X (x5) 
L (x6) 
 
L 
X 
ESR and ChemistryPd 
X 
L 
X 
X 
L 
X 
L 
X 
X (x6) 
 
L 
X 
Vitamin B12, Folate   
X 
 
 
 
 
 
 
X 
X 
 
 
PT/PTT, Urinalysis, Viral PanelPe
P    
 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Echocardiogram (within 5 years) 
 
X 
 
 
 
 
 
 
 
 
 
 
History, Medications, Allergies, 
contraceptive counseling, and Physical 
Exam   
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X (x4) 
 
 
X 
Review/adjust subject’s IVIg, 
prophylactic antibiotic and G-CSF dose 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
_____________________________________________________________________________________________ 
 
 
Page 68 of 74 
 
 
 
Ultrasonogram of the spleen, DEXA Scan 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Quantitative Immunoglobulin and 
Leukocyte Phenotyping. Research blood 
as required. 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X (x5) 
 
 
X 
Antibody levels  
(Includes Tetanus, Diphtheria) 
 
X 
 
 
 
 
 
X 
X 
 
 
Photographs of cutaneous Warts 
(Photo of genital Warts is optional) 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X (x4) 
 
 
X 
Standard Consults: Dermatology, Dental, 
GYN, ENT and Audiology 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Additional Procedures/Consults if 
clinically indicated: PFT, chest-CT, 
sinus-CT, etc. 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
QOL (SF-36v2) Questionnaire 
 
X 
 
 
 
X 
 
X 
X (x4) 
 
 
Training/Review: Memory Aid, local 
labs, drug shipment, storage, and 
administration   
 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
G-CSF or plerixafor stopped at least 2 
days prior the 1Pst
P day of injection 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Optional: wart, skin, & bone marrow 
biopsies  
 
 
O 
 
 
 
 
O 
 
 
 
O 
 
O 
 
 
O 
Submission and review of subject 
Memory Aid 
 
X 
X (x4) 
X (x26) 
X (x30) 
 
X (x10) 
 
AE monitoring 
 
X 
X (x4) 
X (x26) 
X (x30) 
 
X (x10) 
 
V=visit; D=study Day; d= days; W=Study Week (from start of 1Pst
P injection); M= Study Month; O=Optional; L= may be performed at subject’s Local facility; G-CSF=granulocyte colony stimulating factor;  
CBC=complete blood count; ESR; PT/PTT=prothrombin time/partial thromboplastin time; EKG=electrocardiogram; ENT=ear, nose, and throat; QOL=Quality of Life; AEs=adverse events.  
Pa
PLocal Labs: Subjects may obtain their laboratory tests locally and the results sent to the NIH. If practical, provisions will be made for labs to be drawn at a Quest facility, at no cost, and accessible to the subject. ESR 
test is optional for local lab draws. 
Pb
P Column represents the summation and aggregate of the activities for the Equilibration and Treatment Period of the second (alternate) study drug.  
Pc
PIn addition to vital signs, orthostatic pulse and blood pressure should be measured prior to injection and 60 +/- 20m post injection. 
Pd
PChemistry: NIH -Acute Care Panel, Hepatic Panel, Mineral Panel, Serum Protein, Lactate Dehydrogenase, Serum Uric Acid, & Creatine Kinase, and ESR. For home monitoring (local labs), BUN and creatinine are 
required.  Additional chemistries labs may be requested, and ESR if available may be requested.  
Pe
PThis includes HIV, hepatitis B/C. HTLV type 1 and II. 
Pf
PSubjects will be instructed on how to record body temperature, fever, symptoms of infection, and anti-infective treatments/prophylaxis on a daily basis, and how to self-administer the study drugs.


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
 
APPENDIX B: FDA APPROVED PACKAGED INSERT: PLERIXAFOR 
 
Plerixafor (Mozobil™) is an FDA approved product.  The approved package insert is considered a 
comprehensive source of safety data. The current version of the package insert is available on the 
Mozobil™ website (http://products.sanofi.us/Mozobil/mozobil.html).  


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
 
APPENDIX C: FDA APPROVED PACKAGE INSERT: G-CSF 
 
G-CSF, NeupogenPTM 
P(filgrastim) is an FDA-approved drug. The approved package insert is considered a 
comprehensive source of safety data. The current version of the package insert is available on the 
NeupogenPTM
P website (40Thttp://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf40T). 
 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
_____________________________________________________________________________________________ 
 
 
Page 71 of 74 
 
 
APPENDIX D: INFECTION SEVERITY SCORE (ISS) 
 
Type of Infection 
Fever 
Anti-Infective 
Hospitalization 
Total 
  
0:  No chills/fever 
0:  No Treatment 
0:  No Hospitalization 
 
1:  Non-sterile site 
1:  38.3 -39º C 
1:  Topical 
1:  Emergency Room 
 
2:  Sterile site 
2:  > 39º C 
2:  Oral 
2:  Hospitalized 
 
  
  
3:  Parenteral 
3:  ICU 
 
 
 
 
 
 
1 to 2 
0 to 2 
0 to 3 
0 to 3 
1 to 10 
 
 
These parameters will be used to develop a score for each infection.  Non-sterile site infections are those 
which occur in areas of the body routinely exposed to and colonized by microorganisms such as the oral 
cavity, bronchioles and upper respiratory tract, nasopharynx, vagina, GI tract, and skin; while, sterile sites 
would include the lower respiratory tract, blood, muscle, bone, joints, urinary bladder, and other typically 
sterile locations.  Fever will refer to the maximum oral temperature recorded during the infection.  Anti-
infective treatment is scored based on the highest level of treatment i.e. intravenous antibiotic that is 
changed to oral would score a 3.  Similarly hospitalization will refer to the highest level of care received 
at any point during the infection.  Scores for each parameter will be added and thus the score for any 
given incidence of infection can range from 1-10.   
 
 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
_____________________________________________________________________________________________ 
 
 
Page 72 of 74 
 
 
APPENDIX E: DOSING OF PLEXIFOR IN RENAL IMPAIRMENT 
 
In subjects with moderate and severe renal impairment (estimated creatinine clearance [CrCl] ≤50 
mL/min), each dose of plerixafor (MozobilPTM
P ) will be reduced by one-third. Because of the renal 
excretion of the drug, this reduction in subjects with moderate and severe renal impairment is expected to 
result in similar drug levels compared with subjects with normal renal function. 
 
 
The following (Cockroft-Gault) formula may be used to estimate Creatinine Clearance (CrCl):  
 
Males: 
    
Creatinine clearance (mL/min) = 17Tweight (kg) X (140 – age in years)17T 
                                                        
72 X serum creatinine (mg/dL) 
    
 
Females: 
    
Creatinine clearance (mL/min) = 0.85 X value calculated for males 
 
Since there is insufficient information to make dosage recommendations in subjects on hemodialysis, 
subjects on dialysis or who have a CrCl <15 ml/min are excluded from this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
 
APPENDIX F: SAMPLE SUBJECT MEMORY AID 
Study Contact Information: Email and Phone # 
Date 
MM/DD/YY 
Complete each question by circling ONE Answer from each row. 
Infection Related Treatments 
 
  
 
 
 
Drug 1 
Route 
Frequency 
Yes 
  
No 
  
Drug 2 
Route 
Frequency 
Yes 
  
No 
Additional Antibiotics: 
Route: 
Frequency: 
No 
  
Yes 
Study Drug and Side Effects 
Morning Injection 
Batch ID 
 Site of Injection 
  
No 
  
  
Evening Injection 
Batch ID 
Site of Injection 
  
No 
  
  
Morning Injection Site Reaction 
None 
  
Tenderness 
Pain 
Ulceration 
Evening Injection Site Reaction 
None 
  
Tenderness 
Pain 
Ulceration 
Bone/Skeletal Pain (arms, legs, back) 
None 
  
Mild 
Affects Function 
Affects Self-care 
Pain (abdomen, shoulder etc.) 
None 
  
Mild 
Affects Function 
Affects Self-care 
Headache 
None 
  
Mild 
Affects Function 
Affects Self-care 
Dizziness 
None 
  
Unsteadiness 
Affects Function 
Affects Self-care 
Nausea 
None 
  
Loss of Appetite 
Reduced Oral Intake 
Tube Feeding 
Vomiting 
None 
  
1 to 2 
3 to 5 
6 or more 
Diarrhea 
None 
  
Increase 1-4 stools 
Increase 4-6 stools 
7 or more 
Additional Side Effect: 
No 
  
Mild 
Affects Function 
Affects Self-care 
Additional Side Effect: 
No 
  
Mild 
Affects Function 
Affects Self-care 
Fevers and Infections (please inform study staff) 
  
Record your highest temp for the day 
Enter Temp 
Missed School/Work due to side effect of study drug  
No 
  
Partial Day 
Full Day 
  
Missed School/Work because of Infection 
No 
  
Partial Day 
Full Day 
  
Visits to the Doctor 
Visit to Doctor for Infection or Side Effects 
No 
  
Visit to Doctor 
Emergency Room 
Hospital 
Treatment: 
Route: 
Frequency: 
Taken 
  
Not Taken 
Treatment: 
Route: 
Frequency: 
Taken 
  
Not Taken 
Please inform study staff of any events that are disabling or require immediate medical attention. 
Notes: 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Legend: 
Bolded Entries 
Prefilled by NIH 
  
  
  
Subject selects 1 Item per row 
Italicized entries 
Optional entries by subject 


Plerixafor vs. G-CSF in WHIMS – Version 6.0 
January 9, 2019 
 
 
APPENDIX G: EVALUATION OF INFECTION FORM 
 
Directions: Please circle relevant items and fill in underlined sections.  Use a different form for each 
infection unless contiguous and related.   
 
1) Date of Office or ER Visit, Hospitalization:_________________________ 
 
2) Chief Complaint:_____________________________________________________ 
 
3) Date of Onset of Symptoms:_________________________________________ 
 
4) Diagnosis (New / Chronic / Recurrent / Exacerbation):  Otitis, Sinusitis, Dental Infection, Pharyngitis, 
Other oral infection, Bronchitis, Pneumonia, Cellulitis, Cutaneous abscess, Osteomyelitis, Endocarditis, 
Meningitis, Joint Infection, Gastroenteritis, urinary tract infection, unknown 
Other or further information:  ______________________________________ 
 
5) Site of Infection:____________________________________ 
 
6) Likely Cause of Infection: Viral, Bacterial, Fungal, Parasite, Unknown,  
 
Other: ________________________________________       
 
7) Treatment Prescribed: __________________________________________________________ 
 
8) Route of Treatment: Topical, Oral, intravenous 
 
9) Length of Treatment Prescribed (days):_______________________________________ 
 
Relevant Laboratory Results: 
 
10) Culture/Test Result: _____________________________________ pending or not performed.  
 
11) Outcome of Infection:  Pending, Unknown, Resolved, Resolved with residual symptoms, Ongoing,  
 
Other:_____________________________  
 
12) Additional Information (optional): ____________________________________________ 
 

ICF_001.pdf: 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Institute of Allergy and Infectious Diseases 
 
 
STUDY NUMBER: 
14-I-0185 
PRINCIPAL INVESTIGATOR: David H. McDermott, MD 
 
 
STUDY TITLE: 
A Phase III, Double-blind, Randomized, Crossover Study of Plerixafor Versus G-CSF in the 
Treatment of Patients with WHIM Syndrome 
 
 
Continuing Review Approved by the IRB on 05/21/18 
Amendment Approved by the IRB on 02/06/19 (H) 
 
 
 
Date Posted to Web: 02/27/19 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not 
lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking 
part in at least one study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH 
doctors or research staff before you agree to the study. 
 
Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
THE CONSENT PROCESS 
 
You or your child are invited to take part in a study to find out whether a medication named plerixafor is safe and 
effective in patients with WHIMS, which stands for warts, hypogammaglobulinemia, infections, and myelokathexis 
syndrome. In this study, we will compare plerixafor to granulocyte colony-stimulating factor (G-CSF), the currently 
recommended treatment for inherited neutropenia, for the prevention of infections in children and adults with WHIMS. 
The following informed consent document gives background information on the disorder, explains the research goals of 
the study we are proposing, the reasons for trying plerixafor, and the specific methods we will use to give you the 
medication. Once you know about the study and the tests that will be done, you will be asked to sign this form to join 
this study.
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 2 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
YOUR UNDERLYING DISEASE 
You have been diagnosed with a rare inherited condition called WHIMS caused, by various mutations (genetic changes) 
that increase the activity of a gene called CXCR4. CXCR4 plays an important role in your immune system development as 
well as how the blood stem cells work in your bone marrow. Blood stem cells are cells that can form all parts of your 
blood including red and white blood cells. Neutrophils make up the majority of your white blood cells (WBCs) and are 
particularly important in fighting off infections. When neutrophil counts drop below normal (a condition known as 
neutropenia), the body is less able to fight off infection. Excessive function of the CXCR4 gene causes mature neutrophils 
to be retained within the bone marrow rather than being released to the blood, and is one of the causes of severe 
inherited neutropenia (low white blood counts). Patients with WHIMS are at risk for severe warts that can become 
cancerous and also for skin, soft tissue, ear, mouth, sinus, and lung bacterial infections. The result of these infections 
can be very serious causing permanent disability and death. 
Current treatments for WHIMS are based on limited clinical experience, and there are no controlled clinical studies just for 
this disease. The available treatments consist of daily or every other day injection of a white blood cell growth stimulating 
medication called granulocyte colony-stimulating factor (G-CSF), and monthly infusion of intravenous immunoglobulin 
(IVIG) or weekly injection with subcutaneous immunoglobulin. These therapies are expensive, non-specific, have 
significant side effects and toxicities, and do not fully correct all problems, especially warts and human papillomavirus 
(HPV) related cancers. 
Two recently published studies done at the National Institutes of Health (NIH) and University of Washington have shown 
that plerixafor could safely restore the blood counts to normal in 9 WHIM patients for a 1-2 week period.  A second study 
at the NIH has shown that this can be done for 6 months using twice daily low dose therapy in 3 patients. Therefore, 
plerixafor may offer a well-tolerated new treatment for WHIMS. 
 
PURPOSE OF THE STUDY 
The purpose of this study is to compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for the prevention 
of infections in children and adults with WHIMS. The Food and Drug Administration (FDA) has already approved G-CSF for 
the treatment of severe neutropenia, and the use of plerixafor in combination with G-CSF to further increase the number 
of blood stem cells in the blood. However, the FDA has not approved plerixafor for specific treatment of WHIMS. 
Plerixafor will be used in this study with permission from the FDA for experimental use. That means we don’t know if 
plerixafor is safe in people with WHIMS, or if it will work to treat WHIMS.  
What is G-CSF? 
Granulocyte-colony stimulating factor (G-CSF) is FDA-approved for treating inherited neutropenia (low neutrophil count). 
G-CSF is commonly given daily or every other day to increase the neutrophil counts in the blood. The NIH Clinical Center 
Pharmacy will purchase the G-CSF from Amgen.  
What is plerixafor? 
Plerixafor is an FDA-approved drug designed for occasional use in combination with G-CSF to increase the number of 
stem cells that can be collected prior to bone marrow transplantation. Plerixafor blocks the CXCR4 receptor that in WHIMS 
patients is overactive and normalizes its function thereby allowing the movement of mature neutrophils out of the bone 
marrow and into the blood. Plerixafor is not currently approved for long-term use, or the treatment of WHIMS or patients 
with neutropenia. Genzyme/Sanofi Corp is the manufacturer of plerixafor and will provide the drug for this study. 
 
SUBJECT POPULATION 
Twenty subjects (10 to 75 years of age) will be enrolled in the study. To be in the study, you must have a mutation in the 
CXCR4 gene, agree to use contraception if capable of having children, and have a local physician for your medical care.  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 3 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
STUDY DESIGN 
Participants are selected at random (by chance, as in a coin toss) to first receive either plerixafor or G-CSF injections 
twice a day for a period of one year. Participants and study staff directly involved with the participants are not told which 
drug is being provided therefore, both are “blinded” to the treatment. After the first year of treatment with one of the 
drugs, participants are switched to the other drug in the second year of treatment. Your study participation time is 
approximately 3 years and requires approximately 11 visits as an outpatient to the NIH Clinical Center and approximately 
16 visits to a local medical facility for blood draws to measure your blood counts. 
 
Screening Visit: Before starting the study, you will be asked to visit the NIH Clinical Center for about 2-3 days. The 
study doctor will ask you about your health and your medical history, examine you, and measure your height, weight and 
vital signs. You will be asked about any medications you have been taking. You may be required to have an ultrasound 
(imaging test using sound waves) of your spleen, heart tracing (electrocardiogram [ECG]) and echocardiogram 
(ultrasound test of the heart), CT Scan (computed tomography) of your sinus, chest, abdomen, and pelvis, and other 
medical procedures as may be deemed necessary by the study doctor. Blood and urine samples to measure your immune 
function and chemical balance, including tests for hepatitis B and C virus, and human immunodeficiency virus (HIV) that 
causes acquired immunodeficiency syndrome (AIDS) will be obtained. If you are a woman of childbearing potential, your 
blood or urine will also be tested to see if you are pregnant. These procedures are required to evaluate your eligibility and 
assess if it is safe for you to participate in the study. 
The study doctor will assess the activity of your current disease by asking questions about the symptoms of your disease 
(like skin conditions) and medications you are taking for them. We may request an optional small skin or wart tissue 
sample and take photographs of any warts on your skin and oral, nasal and genital tissue with your permission. 
Depending on your medical history or the location and extent of your infections, you may be referred to and evaluated by 
various specialists at the NIH Clinical Center including skin doctors (dermatologist), female reproductive doctor 
(gynecologist), male reproductive doctor (urologist), hearing tests (audiologist), ENT (ear, nose, and throat doctors), oral 
specialists (dentist or oral surgeon), and blood doctors (hematologist or immunologist). 
If you are now being treated with G-CSF, the dose will be adjusted and the frequency increased to twice per day. If you 
are not being treated with G-CSF, you will be trained and start with twice daily self-injection of G-CSF at a dose specified 
by the study doctor.  
Initial Evaluation (approximately 2-20 weeks): After successfully completing the screening visit, you will begin an 
Initial Evaluation period of about 2-20 weeks from your home. You will continue the G-CSF injections as prescribed by the 
study doctor as well as your preventative regimens with antibiotics and/or immunoglobulin as applicable. You will visit 
your local medical facility for a blood draw to measure your blood counts at least once in this period, and more often if 
there is a change in G-CSF dose. If you experience any new or significant worsening of infections, you will be required to 
visit your local medical provider for diagnosis and treatment, and provide the medical records and results of your visit to 
the study doctor. You will be trained to complete a detailed health  Memory Aid every day and submit the completed form 
to your study doctor every week. The Memory Aid will be submitted by secure email or by a mutually agreed method. 
Randomization to Treatment Arms and Washout Period (2 days): After successfully completing the Initial 
Evaluation period, you will be assigned by random selection to start treatment with either plerixafor or G-CSF. Neither you 
nor the research staff will know which drug you have been assigned to take first. You will visit the NIH Clinical Center for 
approximately 2 days as an outpatient with your G-CSF injections withheld, prior to commencing the study treatment.  
Equilibration Period (8 weeks): After starting your treatment, you will continue your twice a day injections from 
home, complete your daily health Memory Aid and submit the Memory Aid to your study doctor every week, go to your 
local medical facility for blood tests every 2 weeks or as requested by the study doctor, and go to your local medical 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 4 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
provider for any new or significant worsening of your infections and provide the results of the visit to your study doctor. 
This is a period of adjustment for the treatment drug to take full effect and an opportunity to adjust your treatment dose.  
Treatment Period (52 weeks): After your 8-week period of adjustment at home, you will visit the NIH Clinical Center 
for evaluation as you begin the Treatment period. You will continue your routine as in the Equilibration period, visit the 
NIH Clinical Center approximately every 4 months, and visit your local medical facility for blood tests at the approximate 
midpoint period (about 2 months) between your visits to the NIH.  
Switching to the Alternate Treatment Arm (Washout, Equilibration, and Treatment Periods – 60 weeks):  
At the end of your first year of treatment, you will visit the NIH for an evaluation and complete your first study year 
injections at least 2 days prior to commencing the 2nd study drug treatment. As with the first year, you will undergo an 8-
week Equilibration and 52-week Treatment period with the 2nd study drug. It is also possible that you may be switched to 
the alternate treatment arm prior to fully completing the first treatment arm if you are not able to tolerate or respond to 
the first treatment.   
Reverting to Your Pre-Study Treatment (Post-Treatment Period 4 months):  
At the end of your second year of treatment, you will visit the NIH Clinical Center to complete your final study injections 
and revert to your pre-study G-CSF regimen. You will continue completing your daily health diary and submit it to your 
study doctor every week or as requested, and visit your local medical provider for any new infections and provide the 
results of your visit to your study doctor. You will visit your local medical facility for blood tests approximately every 2 
weeks in the first month or as instructed by the study doctor, and at approximately 2 months until your End of Study visit 
to the NIH Clinical Center. If you are capable of conceiving or having children, you must continue birth control through 
this period.  
When this study is completed, you will be returned to the care of your local physician. It is important to stress that 
participation in this protocol does not constitute a promise of long-term medical care here at the NIH Clinical Center. You 
may decide not to take part in this study or you may choose at any point to stop receiving the study drug and withdraw 
from the study; in either case you will be returned to the care of your local physician. 
 
STUDY PROCEDURES 
Physical exam with medical and medication history: You will be evaluated by the study staff and will undergo a 
physical exam. You will be asked about how you are feeling, if you’ve had any recent illness, and about the medications 
you are taking now and have taken in the past, including non-prescription drugs. Your height and weight will also be 
measured at some of the visits.  
Vital signs: Your height, weight, blood pressure, heart rate, respiratory rate, and temperature will be recorded.  
EKG: This procedure records the normal electrical activity of your heart. Electrodes, which are soft, sticky patches 
attached to wires, will be placed on the skin of your chest, arms, and legs. The procedure doesn’t cause any harm, 
however the sticky patches used for the procedure may cause minor discomfort when removed, especially if they’re 
placed in a region of the chest with hair. 
Echocardiogram: This procedure will be done only if you haven’t had it done in the past 5 years. The echocardiogram 
takes pictures of your heart using sound waves, which are displayed on a monitor, to measure the size of the heart 
muscle and to see how well it works. It’s like a sonogram that pregnant women get to see how the baby is growing. It 
doesn’t hurt, but you will need to remain quiet and follow directions.  
CT Scan Sinus, Chest, Abdomen, and Pelvis: These x-rays are performed if medically necessary to assist in the 
evaluation of your illness. The dose of radiation from the x-rays and CT scans will be kept as low as possible. Unless the 
person is pregnant, this level of radiation is generally considered safe. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 5 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
DEXA Scan: Dual-energy X-ray Absorptiometry (DEXA) is a low-dose x-ray procedure to measure the loss of bone 
density; this test is commonly used to test for osteoporosis. Unless the person is pregnant, this level of radiation is 
generally considered safe. 
Spleen ultrasonogram: The sonogram takes pictures of your spleen using sound waves, which are displayed on a 
monitor; it’s like a sonogram that pregnant women get to see how the baby is growing. It doesn’t hurt, but you will need 
to remain quiet and follow directions.  
Pulmonary Function Test (PFT): The pulmonary function test is performed to assess your lung function by measuring 
the volume of air moving in and out. You will be requested to blow air forcefully into a machine. You might experience 
some dizziness or headache from the exertion when undergoing the test and experience some coughing or shortness of 
breath after the tests. 
Audiology Tests: If you have a history of hearing loss and ear infections, an audiologist will evaluate your hearing 
function. You will sit in a sound proof room and asked to raise your arms to various tones that are generated as part of 
the test.  
Ear, Nose, and Throat (ENT) Consultation: If you have concerns or have had recent or recurring infections in your 
sinus, ears, nose, or throat, an ENT consultation will be arranged to evaluate the status or risk of infection. The ENT 
specialist may use various tools to illuminate and examine your ears, nose, and throat. 
Gynecology or Urological Consultation: A gynecologist (for female patients) or urologist (for male patients) will 
evaluate your genitals for warts and HPV infection. The examination will take place in a private room and surface 
scrapings or a small piece of tissue may be taken for additional evaluation.  
Dermatology Consultation: A dermatologist will evaluate your skin for warts and HPV infections. The examination will 
take place in a private room and skin scrapings or a small piece of skin may be taken for additional evaluation. 
Dental Consultation: A dentist will evaluate your teeth, gums, and mouth for infections and the presence of HPV 
lesions. Oral swabs of your oral cavity as well as x-rays may be taken as part of the evaluation.  
Clinical Photography of Skin Lesions or Warts: We will take pictures of your warts and skin lesions including a 
comprehensive set of the external surface of your body and detailed photographs of the hands and feet, which often are 
sites of infections. Pictures will be taken prior to the first study treatment and after each one-year treatment period. 
Additional photos may be taken of particular warts and other types of skin infections, including infections of the buttocks 
and genitals if applicable. These pictures will help us determine if the treatments improved the appearance of your warts 
or if new warts have appeared in other parts of your body. The photographs will be coded and will not have your name 
on them. If such pictures are used for publication, you will not be identified in any way.  
Urine collection: A sample will be collected for routine analysis to check if your kidneys are working well.  
Pregnancy test: If you are a woman of childbearing age, your blood or urine will be tested to see if you are pregnant.  
Blood draw: Blood will be drawn from a vein in your arm to measure your blood cell counts, to monitor your liver and 
kidney function, and to evaluate markers of your disease. The total volume of blood collected during the study will not 
exceed the guidelines for blood collected for research in adult and children subjects at the NIH Clinical Center. While in 
the study, please inform study staff if you are participating in other studies or have blood drawn for any other reason. 
The risks associated with drawing blood from a vein in your arm include pain, bruising, lightheadedness, fainting, and 
rarely, infection at the site. Some of the blood draws will be done at your local laboratory or physician’s office. The study 
doctor will let you know the exact time of when the blood draws should be done prior to your morning injection, and 
arrange for the results to be sent to your study doctor. 
HIV and Other Viral Testing: As part of this study, we will test you for infection with the human immunodeficiency 
virus (HIV), the virus that causes AIDS; for hepatitis A, B, and C which cause liver disease; and for HTLV-1/-2, which 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 6 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
cause diseases similar to multiple sclerosis and hairy cell leukemia. If you are positive for any of these viral infections, we 
will tell you what the results mean, how to find care, how to avoid infecting others, how we report newly diagnosed HIV 
infection, and the importance of informing your partners at possible risk because of these infections. 
Wart Biopsy: Wart biopsies may be requested for diagnosis or research; biopsies conducted only for research purposes 
are optional. If you agree to a wart biopsy, an experienced practitioner will perform the procedure. Only local anesthetics 
will be used to prepare the biopsy site; no conscious sedation or general anesthesia will be given. The risks of wart biopsy 
include local pain, bleeding, infection, and potential scar and keloid formation (wide scar). Antibiotics and oral analgesics 
(numbing medicine) will be used to manage pain and infection. 
Bone Marrow Biopsy: Bone marrow biopsies may be requested for diagnostic or research purposes; biopsies conducted 
only for research purposes are optional. If you agree to a bone marrow biopsy, an experienced practitioner will perform 
the procedure and use appropriate measures to reduce any discomfort during the procedure. The risks of bone biopsy 
include local pain, bleeding, and infection. Topical antiseptic and oral or injected pain medicines (numbing medicine) will 
be used to manage pain and infection after the procedure. 
Request for Excess Tissue: If you have had tissue removed for medical indications at the NIH or elsewhere that is not 
required for your medical care and would otherwise be discarded, with your permission, we may request it to be sent to 
us for pathology and other research studies. 
Quality of Life Questionnaire (health survey): During your visits to the NIH, you will be requested to complete a 
questionnaire about your overall health and well being. The survey is commonly used in many studies and has 36 short 
multiple-choice questions and should take about 20 minutes to complete.  
Memory Aid card/reporting new infections/treatments: You will be instructed on how to complete your Memory 
Aid card every day to record the following: location of each injection, side effects you’re experiencing, changes in the 
medications you’re taking, changes in the symptoms you’re having, the date and duration of any fevers or new antibiotic 
treatments, the diagnosis of any new infections, or any hospitalizations. You will have to submit your Memory Aid entries 
every week to your study doctor. You will be instructed on how to submit your Memory Aid entries.  
 
RISK ASSOCIATED WITH RADIATION EXPOSURE 
This research study involves exposure to radiation from Dual-energy X-ray Absorptiometry (DEXA) scans, an x-ray 
procedure to measure the loss of bone density. You will receive three scans with an exposure of 0.000030 rem 
each: prior to start of treatment and at the end of each one-year treatment. The total radiation you will receive 
from the three DEXA scans in this study is 0.000090 rem. This radiation exposure is not required for your medical 
care and is for research purposes only. The average person in the United States receives a radiation exposure of 
0.3 rem per year from natural sources, such as the sun, outer space, and the earth's air and soil. If you would like 
more information about radiation, please ask the investigator for a copy of the pamphlet, An Introduction to 
Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this study is harmful, 
there is indirect evidence it may not be completely safe. There may be a very slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either from other research studies or 
from medical tests or care, so we can make sure that you will not receive too much radiation. Radiation exposure 
includes x-rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine 
scans in which radioactive materials were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. If you are breast-feeding and the 
protocol involves injection of radioactive material you will not be permitted to participate.  It is best to avoid 
radiation exposure to unborn or nursing infants since they are more sensitive to radiation than adults.  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 7 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
RISKS ASSOCIATED WITH THIS STUDY (PLERIXAFOR OR G-CSF) 
In this study, 9 subjects have received both study drugs (plerixafor and G-CSF) as of May 2017.  A subject experienced a 
new severe rash (psoriasis-like) beginning a week after commencing the 1st study drug, which resolved after switching to 
the alternate study drug and topical steroid treatment.  Another subject, who has never received G-CSF prior to the 
study, experienced pain and swelling in his hands and knees on each of the study drugs and was discontinued from both 
study agents. The subject was diagnosed with Arthralgia and Reactive Arthritis and his symptoms resolved with oral 
steroid treatment.   
RISKS ASSOCIATED WITH PLERIXAFOR 
Risks associated with long-term use of plerixafor: The FDA has approved plerixafor for single or short-term use in 
mobilizing stem cells (blood cells in the bone marrow are released to circulate in the blood). However, the FDA has not 
approved plerixafor for daily treatment or use over long periods. The risks of prolonged treatment with plerixafor are not 
known. In this study, you will receive plerixafor twice a day for about 14 months, but at a daily dose that is much lower 
(approximately 3-12 times lower) than has been approved for single or short-term use in stem cell mobilization.  
Risks associated with plerixafor injection: Plerixafor is usually injected at a dose of 0.24 mg/kg once or for several 
daily injections. For this study, plerixafor will be injected at a dose of 0.01-0.04 mg/kg twice a day, which is an injected 
amount that is much lower than is typically used. Nevertheless, the most common side effects as listed in the product 
label that can be associated with plerixafor at doses much higher than the dose you will receive in this study are listed 
below – please inform the study doctor if you experience any of these reactions: 
Injection site reactions: When you are given a dose of plerixafor, this will be injected under your skin and may cause 
slight pain, redness, bruising, or itching where the study drug is injected. Most of these resolve within minutes and 
require no treatment. We will treat any prolonged reactions (if problematic) with standard medical therapies. 
Bone Pain: Bone pain is often experienced as a deep dull pain that cannot always be easily localized. Bone pain can often 
be readily controlled through over the counter medication such as Advil or Tylenol.  
Joint Pain or Arthralgia/Arthritis: Pain in the joints without swelling (arthralgia) has been reported frequently when 
plerixafor is given in conjunction with G-CSF.  Initial treatment is with over the counter medication such as Advil or 
Tylenol.  Arthritis is a joint pain with swelling and stiffness. If you have any joint problems, you should report it to your 
study doctor. Additional diagnosis and treatment might be needed. 
Gastrointestinal side effects: Various side effects related to gastrointestinal (gut) function have been reported after doses 
of 0.24 mg/kg including abdominal pain, diarrhea, constipation, nausea, flatulence (gassiness), and vomiting. In general, 
these have not resulted in the need to stop the medication. 
Thrombocytopenia and bleeding: Lower platelet counts (thrombocytopenia) have been reported with use of plerixafor. We 
will check this with periodic blood counts and the drug will be stopped if dangerously low levels are encountered. 
Splenic enlargement (large spleen size): An increase in spleen size has been shown to occur in rats treated with plerixafor 
at proportionately much higher doses than used here. Although this has not been reported as causing any severe 
problems in humans, we will monitor for clinical signs of problems by asking you about left shoulder or abdominal pain 
under your left rib cage. If these symptoms occur, call your doctor immediately and inform your study doctor. 
Risk of allergic reactions: Mild to moderate reactions such as itchiness, swelling around the eye, difficulty in breathing, 
or low oxygen in the blood during has been observed during or within 30 minutes of plerixafor injection. Stop the 
injection right away and call your doctor or seek emergency care right away. 
Risk of fainting or low blood pressure: Low blood pressure and fainting has been observed within 2 hours of plerixafor 
injection. If you experience low blood pressure with injections, appropriate precautions should be taken. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 8 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Fetal harm in pregnant women: The fetal risks associated with plerixafor are not known, but animal data has shown 
some risk. Because of this, all study patients must agree not to become pregnant or impregnate a female. Females of 
childbearing potential must have a negative pregnancy test before beginning the study agent. You and your partners 
must use 2 methods of birth control and continue contraception until the end of the study. 
Breast-feeding: Because there is an unknown but potential risk to infants who are being breast-fed from a mother who 
has been treated with plerixafor, participants must agree not to breastfeed during the study. 
 
RISKS ASSOCIATED WITH G-CSF 
Risks associated with long-term use of G-CSF: The FDA has approved G-CSF for the treatment of inherited 
neutropenia (low neutrophil count). However, patients on long-term treatment of G-CSF over several years may have a 
cumulative risk (risk that increases with amount and length of use) of genetic mutations which may lead to 
Myelodysplastic Syndrome (MDS) a form of pre-leukemia, and Acute Myeloid Leukemia (AML). Leukemia is a form of 
cancer in your blood caused by uncontrolled growth of white blood cells and is fatal if not treated with chemotherapy 
and/or bone marrow transplant. The manufacturer’s product label reports a cumulative risk of 16.5% after 8 years of G-
CSF treatment for patients with inherited neutropenia. Although the results from the manufacturer are not specifically 
limited to patients with WHIMS and patients with WHIMS are thought to be at less risk of this complication, and the dose 
used in this protocol is less than typically used for other studies, the risk of leukemia in long term G-CSF treatment may 
be a concern. 
Risks associated with G-CSF injection: G-CSF is usually injected at a dose of 2.3 to 40 μg/kg/day. For this study, G-
CSF will be injected at a dose of 0.5-2.0 μg/kg twice a day, which is an injected amount that is much lower than is 
typically used. Nevertheless, the most common side effects as listed in the product label that can be associated with G-
CSF at doses much higher than the dose you will receive in this study are listed below – please inform the study doctor if 
you experience any of these reactions: 
Injection site reactions: When you are given a dose of G-CSF, this will be injected under your skin and may cause slight 
pain, redness, bruising, or itching where the study drug is injected. Most of these resolve within minutes and require no 
treatment. We will treat any prolonged reactions (if problematic) with standard medical therapies. 
Bone Pain: Bone pain is often experienced as a deep dull pain that cannot always be easily localized. Bone pain can often 
be readily controlled through over the counter medication such as Advil or Tylenol.  
Joint Pain or Arthralgia/Arthritis: Pain in the joints without swelling (arthralgia) has been reported frequently with G-CSF.  
Initial treatment is with over the counter medication such as Advil or Tylenol Arthritis is a joint pain with swelling and 
stiffness. If you have any joint problems, you should report it to your study doctor. Additional diagnosis and treatment 
might be needed. 
Thrombocytopenia and bleeding: Lower platelet counts (thrombocytopenia) have been reported with use of G-CSF. We 
will check this with periodic blood counts and the drug will be stopped if dangerously low levels are encountered. 
Splenic rupture: Splenic rupture, including exceedingly rare fatal cases, has been reported following the administration of 
G-CSF. However, these are at doses typically much higher than used in this study, We will monitor for clinical signs of 
problems by asking you about left shoulder or abdominal pain under your left rib cage. If these symptoms occur, call your 
doctor immediately and inform your study doctor.  
Risk of serious allergic reactions: Allergic-type reactions have been reported in <1 in 4000 of subjects treated with G-
CSF.  These reactions can cause rash and itchiness over the whole body, shortness of breath, wheezing, dizziness, 
swelling around the mouth or eye, fast pulse, and sweating may occur during or within 30 minutes of G-CSF injection. 
Stop the injection right away and call your doctor or seek emergency care right away. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 9 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Immunogenicity: As with all therapeutic proteins, there is a potential for causing allergies and antibodies to develop 
against the drug. Low blood cell counts resulting from an antibody response to proteins have been reported on rare 
occasions in subjects treated with other similar drugs so there is a chance that your body might develop an immune 
reaction to the G-CSF drug that could either block the drug’s effect or cross react with your body’s natural G-CSF.  
Aortitis - inflammation of the aorta:  Inflammation of the aorta (the large blood vessel which transports blood from the 
heart to the body) has been reported in patients who received G-CSF. Symptoms may include fever, abdominal pain, 
feeling tired, and back pain. Call your healthcare provider if you experience these symptoms. 
Fetal harm in pregnant women: The fetal risks associated with G-CSF are not known, but animal data has shown 
some risk. As a condition for participating in this study, participants must agree not to become pregnant or impregnate a 
female. Females of childbearing potential must have a negative pregnancy test before beginning the study agent. You 
and your partners must use 2 methods of birth control until the end of the study. 
Breast-feeding: It is not known if G-CSF is excreted in human milk. Due to the potential risk to infants who are being 
breast-fed from a mother who has been treated with G-CSF, participants must agree not to breastfeed during the study.  
 
BENEFITS ASSOCIATED WITH THE STUDY 
If you take part in this study, the treatment drugs are expected to increase your neutrophil counts, but their 
effectiveness in reducing your risk of infection are not known, and that is what this study is designed to answer. This 
study is not designed to provide you with any direct benefit in terms of relieving your neutropenia in the long term.   
 
ALTERNATIVES TO PARTICIPATING IN THIS STUDY 
You may choose to not participate in this study and obtain care from your usual health care providers. 
 
STOPPING STUDY PARTICIPATION 
You can stop participating in this study at any time. Tell a member of the study staff if you no longer want to participate. 
This decision will not affect your ability to receive care at the NIH Clinical Center or your participation in other studies. 
Blood and tissue samples and data collected prior to this request will be stored for the duration of the study, unless you 
specifically request the removal of all your samples from the study. 
 
EARLY REMOVAL FROM THE STUDY 
You may be removed from this study without your consent for the following reasons: 
• 
You develop a health problem, an abnormal lab test, or any medical disease that, in the opinion of the study doctor, 
puts you at increased risk of harm or is not in your best interest. 
• 
The study is stopped or cancelled. 
• 
You become pregnant. 
• 
You don’t keep your appointments or refuse to undergo study procedures as required. 
 
COMPENSATION 
You will not be paid for your participation in this study. However, if you agree to biopsies performed for research, we will 
compensate you $120 for a skin/wart biopsy and $200 for a bone marrow biopsy - or the equivalent in gift cards for 
participants under age 18. 
 
COSTS ASSOCIATED WITH THE STUDY 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 14-I-0185 
 
CONTINUATION:  page 10 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
There will be no charge to you or your health insurance company for any tests, procedures or medications that are 
directly related to this study. This includes blood tests required by the study and drawn at your local medical facility. Cost 
of other medical care provided outside the NIH during this period will not be covered.   
 
NEW FINDINGS 
Any new findings discovered during this study that are considered relevant to your health will be fully discussed with you. 
 
UNANTICIPATED MEDICAL INFORMATION 
During the course of this study, it is possible (although not likely) that we will obtain unanticipated information about 
your health. If this information is considered to be relevant to your health care, we will provide it to you or, if you prefer, 
to your referring physician. 
 
 
STORED SAMPLES/DATA AND FUTURE RESEARCH 
If you agree to participate in this study, you also agree to let us store your blood samples, biopsies, and data for future 
research. The stored samples/data may help us learn more about WHIMS. The samples/data will be labeled with a code 
that only the study staff can link to you. Any information that can be traced back to you will be kept as private as 
possible. If you change your mind and decide you don’t want us to store your samples, please contact us. We will do our 
best to comply with your request but cannot guarantee that we will always be able to destroy all your samples.  
Your coded samples/data might be sent to other study doctors for their research. Other information, such as your sex, 
age, health history, or ethnicity might also be shared. Your samples will not be sold, and you will not be paid for any 
products that result from this research. Future research that uses your samples/data may not help you, but it may help us 
learn more about WHIMS and other health problems. In general, the research tests performed in this study are not like 
routine medical tests, and they may not relate directly to your medical care. 
 
 
CONFLICT OF INTEREST 
The NIH reviews its staff researchers at least yearly for conflicts of interest. You may ask your study staff for additional 
information or a copy of the Protocol Review. 
CLINICALTRIALS.GOV 
 A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required by US Law. This web 
site will not include information that can identify you. At most, the web site will include a summary of the results 
from the clinical trial. You can search this web site at any time. 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
14-I-0185 
CONTINUATION:  page 11 of 11 pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings, the 
people who take part are not named and identified. In most cases, the NIH will not release any information about your 
research involvement without your written permission. However, if you sign a release of information form, for example, for 
an insurance company, the NIH will give the insurance company information from your medical record. This information 
might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries. The Clinical Center will provide short-term medical care for any injury 
resulting from your participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments. The amount of payment to research volunteers is guided by the National Institutes of Health policies. In 
general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Dr. David McDermott, Building 10, Room 
11N107, Telephone (301) 496-8483. 
 
You may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM MAY 21, 2018 THROUGH MAY 20, 2019.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name