Clinical trial NCT03995108: Efficacy and Safety Study of Mavorixafor in Participants With Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Mavorixafor in Patients With WHIM Syndrome With Open-Label Extension
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: WHIM Syndrome
Lead sponsor: X4 Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-06-21
Enrollment: 31
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study has a double-blind, Randomized Placebo-Controlled Period and an Open-Label Period. The primary objective of the Randomized Placebo-Controlled Period is to demonstrate the efficacy of mavorixafor in participants with WHIM syndrome as assessed by increasing levels of circulating neutrophils compared with placebo, and relative to a clinically meaningful threshold. The primary objective of the Open-Label Period is to evaluate the safety and tolerability of mavorixafor in participants with WHIM syndrome. Participants are allowed to continue treatment in the Open-Label Period, if regionally applicable, until mavorixafor becomes commercially available, or until the study is terminated by the Sponsor.


Eligibility criteria: Inclusion Criteria for the Randomized Placebo-Controlled Period :

* Have signed the current approved informed consent form. Participants under 18 years of age (in the Netherlands and other applicable regions, participants under 16 years of age) will sign an approved informed assent form and must also have a signed parental/legal guardian consent.
* Have a genotype-confirmed mutation of chemokine (C-X-C motif) receptor 4 (CXCR4) consistent with WHIM phenotype.
* Agree to use a highly effective form of contraception.
* Be willing and able to comply with the protocol.
* Have confirmed ANC ≤400 cells/µL during screening, obtained while participant has no clinical evidence of infection.

Inclusion Criteria for the Open-Label Period:

* Completed the Randomized Period; or
* Granted Early Release from the Randomized Period.

Exclusion Criteria:

* Has known systemic hypersensitivity to the mavorixafor drug substance, its inactive ingredients, or the placebo.
* Is pregnant or breastfeeding.
* Has any medical or personal condition, which in the opinion of the Investigator may potentially compromise the safety or compliance of the participant or may preclude the participant's successful completion of the clinical study.

Primary outcomes:
measure: Randomized Placebo-Controlled Period: Time (in Hours) Above Threshold-Absolute Neutrophil Count (TAT-ANC in hours) of ≥ 500 Cells/Microliter (µL) over a 24-hour period
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 min (each ± 5 min) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 min) post-dose at Baseline, Weeks 13, 26, 39, and 52
measure: Open-Label Period: Percentage of Participants With Adverse Events (AEs)
timeFrame: From Day 1 (end of randomized period) up to end of study (30 days post-treatment in open-label period [Week 56 of open-label period])
Secondary outcomes:
measure: Randomized Placebo-Controlled Period: Time (in Hours) Above Threshold-Absolute Lymphocyte Count (TAT-ALC) of ≥ 1000 Cells/µL over a 24-hour period
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52
measure: Randomized Placebo-Controlled Period: Composite Clinical Efficacy for Mavorixafor based on total infection score and total wart change score
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Change From Baseline in Total Warts Score at Week 52
timeFrame: Baseline, Week 52
measure: Randomized Placebo-Controlled Period: Total Infection Score for Mavorixafor
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Time to Early Release
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: TAT-ALC of ≥ 1000 Cells/µL in Participants With Lymphopenia
timeFrame: Baseline
measure: Randomized Placebo-Controlled Period: Total Infection Score for Participants With Non-Immunoglobulin (non-Ig) Use (Percentage of Participants With Infections)
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Change in Total Wart Score at Baseline, Based on Clinical Global Impression of Change (CGI-C)
timeFrame: Baseline
measure: Randomized Placebo-Controlled Period: Composite Clinical Efficacy (Total Infection Score and Total Wart Change Score) for Participants With Non-Ig Use
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Change in Total Wart Score at Baseline (CGI-C), Based on Local Dermatologist Review
timeFrame: Baseline
measure: Randomized Placebo-Controlled Period: Participant Global Impression of Change (PGI-C)
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Participant Global Impression of Severity (PGI-S)
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Vaccine Titer Levels at Week 52 in Participants Vaccinated at Week 13, With Tetanus, Diphtheria, and Pertussis (Tdap) Including Pertussis Toxin, and Tetanus
timeFrame: Week 52
measure: Randomized Placebo-Controlled Period: Vaccine Titer Levels at Week 52 for Human Papillomavirus (HPV) 16 and HPV 18 in Participants Receiving Vaccinations With HPV 9-Valent Vaccine, Recombinant (Gardasil®9)
timeFrame: Week 52
measure: Randomized Placebo-Controlled Period: Change From Baseline in Clinical Global Impression of Severity (CGI-S), Based on Local Dermatologist Review
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Number of Participants with Infections
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Infection-Free Time
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Number of Days Lost From Work/School
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Quality of Life as Measured by 36-Item Short Form Survey Score
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Quality of Life as Measured by EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Score
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Quality of Life as Measured by Life Quality Index (LQI) Score
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Quality of Life as Measured by Dermatology LQI Score
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Quality of Life as Measured by Pediatric Quality of Life Inventory (PedsQL) Score
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Change From Baseline in Anogenital (AG) Warts Based on Dermatologist CGI-C Assessment
timeFrame: Baseline to Week 52
measure: Randomized Placebo-Controlled Period: Change From Baseline in Anogenital (AG) Warts Based on AG Wart Severity Assessment
timeFrame: Baseline to Week 52
measure: Randomized Placebo-Controlled Period: Number of Events Requiring Rescue Treatment Due to Infection
timeFrame: Baseline to Week 52
measure: Randomized Placebo-Controlled Period: Number of Participants With Incidence and Duration of Hospitalizations Due to Infection
timeFrame: Baseline to Week 52
measure: Randomized Placebo-Controlled Period: Number of Participants With Incidence of Newly Developed Warts
timeFrame: Baseline to Week 52
measure: Randomized Placebo-Controlled Period: Area Under the Curve for ANC (AUCANC) Using Trapezoidal Method
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52
measure: Randomized Placebo-Controlled Period: Percentage of Neutrophil Responders
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Mavorixafor Treatment Group: AUCANC
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52
measure: Randomized Placebo-Controlled Period: Area Under the Curve for ALC (AUCALC)
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52
measure: Randomized Placebo-Controlled Period: Percentage of Lymphocyte Responders
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Change From Baseline in Total ALC, Absolute Monocyte Count (AMC), ANC, and White Blood Cell (WBC) at Week 52
timeFrame: Baseline, Week 52
measure: Absolute and Fold Change From Baseline in Absolute T, B and Natural Killer Lymphocyte at Week 52
timeFrame: Baseline, Week 52
measure: Randomized Placebo-Controlled Period: Number of Participants With AEs
timeFrame: Baseline up to Week 52
measure: Randomized Placebo-Controlled Period: Pharmacokinetics (PK), Maximum Observed Plasma Concentration (Cmax) of Mavorixafor
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline
measure: Randomized Placebo-Controlled Period: PK, Time to Reach Cmax (Tmax) of Mavorixafor
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 min (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline
measure: Randomized Placebo-Controlled Period: PK, Half-Life of (T1/2) of Mavorixafor
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline
measure: Randomized Placebo-Controlled Period: PK, Area Under the Curve (AUC) of Mavorixafor
timeFrame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline
measure: Open-Label Period: Percentage of Neutrophil Responders
timeFrame: Baseline up to Week 52 of open-label period
measure: Open-Label Period: Percentage of Lymphocyte Responders
timeFrame: Baseline up to Week 52 of open-label period
measure: Open-Label Period: Absolute and Fold Change From Baseline in Total ALC, AMC, ANC, and WBC at Week 52
timeFrame: Baseline up to Week 52 of open-label period
measure: Open-Label Period: Vaccine Titer Levels During the First Year of Open-Label Period, in Participants Vaccinated With Tdap During the Study Including Pertusis Toxin and Tetanus
timeFrame: Year 1 of open-label period
measure: Open-Label Period: Vaccine Titer Levels During the First Year of the Open-Label Period for HPV 16 and HPV 18 in Participants Receiving Vaccinations With HPV 9-Valent Vaccine, Recombinant (Gardasil®9) During the Study
timeFrame: Year 1 of open-label period
measure: Open-Label Period: Change From Baseline in Cutaneous Warts at Week 52, Based on Central Review of CGI-C
timeFrame: Baseline, Week 52 of open-label period
measure: Open-Label Period: Change From Baseline in Cutaneous Warts, Based on Central Review of CGI-S
timeFrame: Baseline, Week 52 of open-label period
measure: Open-Label Period: Change From Baseline in Cutaneous Warts, Based on Local Dermatologist CGI-C
timeFrame: Baseline, Week 52 of open-label period
measure: Open-Label Period: Change From Baseline in Cutaneous Warts, Based on Local Dermatologist CGI-S
timeFrame: Baseline, Week 52 of open-label period
measure: Open-Label Period: Change Over Time in PGI-C
timeFrame: Baseline up to Week 52 of open-label period
measure: Open-Label Period: Change Over Time in PGI-S
timeFrame: Baseline up to Week 52 of open-label period
measure: Open-Label Period: Total Infection Score (Percentage of Participants With Infections)
timeFrame: Baseline up to Week 52 of open-label period
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California San Diego Health/Rady Children's Hospital
state: California
city: Thousand Oaks
country: United States
facility: California Dermatology Institute
state: California
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University Medical Center
state: Maryland
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Auchenflower
country: Australia
facility: Wesley Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Children's Health Queensland Hospital
state: Queensland
city: Wien
country: Austria
facility: Medical University of Vienna - Medizinische Universität Wien
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Lyon
country: France
facility: CHU de Lyon, Institut d'Hematologie et d'Oncologie Pediatrique
state: Rhne
city: Paris Cedex 12
country: France
facility: CHU Paris Est, Hôpital d'Enfants Armand-Trousseau
city: Paris
country: France
facility: Hopital Necker-Enfants Malades
city: Debrecen
country: Hungary
facility: University of Debrecen, Affiliated Department of Infectology
state: Hajdu-Bihar
city: Afula
country: Israel
facility: HaEmek Medical Center
city: Brescia
country: Italy
facility: Università degli Studi di Brescia, Scienze Cliniche e Sperimentali
state: Piazza Del Mercato
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital, Children's Hospital
city: Amsterdam
country: Netherlands
facility: Emma Children's Hospital Academic Medical Center (AMC)
city: Moscow
country: Russian Federation
facility: Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
city: Saint Pertersburg
country: Russian Federation
facility: Academician I.P. Pavlov First Saint Petersburg State Medical University
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu Barcelona
state: Esplugues De Llobregat
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocío
state: Sevilla
city: Sarıcam
country: Turkey
facility: Cukurova University Faculty of Medicine
state: Adana
Study officials:
affiliation: X4 Pharmaceuticals
name: Chief Medical Officer
role: STUDY_DIRECTOR
References: