| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| WHIM stands for Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome. Hypogammaglobulinemia a condition which impacts your immune function. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective for Randomized Period: To demonstrate the efficacy of mavorixafor in patients with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome as assessed by increasing levels of circulating neutrophils compared with placebo, and relative to a clinically meaningful threshold.
Primary Objective for Open-Label Period. To evaluate the safety and tolerability of mavorixafor in patients with WHIM syndrome.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objective for Randomized Period:
1.To evaluate the safety and tolerability of mavorixafor in patients with WHIM
syndrome.
2.To evaluate the efficacy of mavorixafor in patients with WHIM syndrome as assessed by clinical outcomes (e.g., rate of infections, vaccine titers,
and impression of change in wart burden).
Secondary Objective for Open-Label Period: To evaluate the efficacy of mavorixafor in patients with WHIM syndrome. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for Randomized Period:
1. Be at least 12 years of age.
2. Have signed the current approved informed consent form. Patients under 18 years of age (in
the Netherlands and other applicable regions, patients under 16 years of age) will sign an approved informed assent form and must also have a signed parental/legal guardian consent.
3. Have a genotype-confirmed mutation of CXCR4 consistent with WHIM phenotype.
4. Agree to use a highly effective form of contraception.
5. Be willing and able to comply with this protocol.
6. Have a confirmed ANC ≤400 cells/μL during screening, obtained while patient has no clinical evidence of infection. For ANC count >400 cells/µL due to an ongoing infection, patients may be allowed to rescreen after the infection is determined by the treating physician to be cleared. The Medical Monitor should be notified and approve each rescreen occurrence.
Inclusion criteria for Open-Label Period:
1. Completed the Randomized Period.
2. Granted Early Release from the Randomized Period. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria for Randomized Period:
1. Has known systemic hypersensitivity to the mavorixafor drug substance, its inactive ingredients, or the placebo.
2. Is pregnant or breastfeeding.
3. Has inadequately controlled diabetes (hemoglobin A1C >8.5%).
4. Has a known history of a positive serology or viral load for human immunodeficiency virus or a known history of acquired immune deficiency syndrome.
5. Has, at screening, laboratory tests meeting one or more of the following criteria:
− A positive hepatitis C virus antibody (HCVAb) with confirmation by hepatitis C virus ribonucleic acid polymerase chain reaction reflex testing.
− A positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb).
− NOTE: if a patient tests negative for HBsAg, but positive for HBcAb, the patient would be considered eligible if the patient tests positive for hepatitis B surface antibody (also referred to as anti-HBsAg) on reflex testing.
6. Has, at screening, safety laboratory tests meeting one or more of the following criteria:
− Hemoglobin <8.0 g/dL
− Platelets <75,000 cells/μL
− Estimated glomerular filtration rate based on the Modification of Diet in Renal Disease of ≤29 mL/min/1.73 m2 (Stage 4 or 5 chronic kidney disease).
− Serum aspartate aminotransferase >2.5x the upper limit of normal (ULN)
− Serum alanine aminotransferase >2.5x ULN
− Total bilirubin >1.5x ULN (unless due to Gilbert’s syndrome, in which case total bilirubin ≥3.0x ULN and direct bilirubin >1.5x ULN)
7. Had surgery requiring general anesthesia within the 4 weeks prior to Day 1.
8. Received any of the following treatments:
− Plerixafor within 18 months prior to Day 1.
− Chronic or prophylactic use of antibiotics (systemic or inhaled) within 4 weeks prior to Day 1.
− G-CSF or granulocyte macrophage-colony stimulating factor within 2 weeks of Day 1.
− Ig (including intravenous or subcutaneous) within 5 months of Day 1, unless deemed necessary by the treating physician and after agreement from the Sponsor. Provision is made for a stratum for patients having received any Ig treatment within 5 months of Day 1.
− Systemic glucocorticoid use (>5 mg prednisone equivalent per day) within 2 weeks prior to Day 1.
− Any investigational therapy within 5 half-lives or 2 weeks prior to Day 1, whichever is longer. Prior use of any investigational therapies must be discussed with the Medical Monitor.
9. Is currently taking or has, within 2 weeks prior to Day 1, received any medication that is a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) (ie, amiodarone, carvedilol, dronedarone, quercetin, quinidine, ranolazine, verapamil).
10. Has, at the planned initiation of study drug, a clinically diagnosed active infection (excluding warts), that has the potential to raise the ANC counts.
11. Has had a total splenectomy within 3 years.
12. Has a current diagnosis of myelofibrosis.
13. Has a medical history of hematological malignancies.
14. Has any other medical or personal condition, which in the opinion of the Investigator may potentially compromise the safety or compliance of the patient or may preclude the patient’s successful completion of the clinical study.
15. Has Grade >1 QTc prolongation calculated per Fridericia’s formula.
Exclusion criteria for Open-Label Period:
1.Patients who experience any treatment-limiting toxicity (TLT) during the first 4 weeks of treatment or any critical TLT at any time. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint in Randomized Period: Time (in hours) above ANC threshold of 500 cells/μL over a 24-hour period, assessed 4 times throughout the study (every 3 months).
Primary Endpoint in Open-Label Period: Safety and tolerability of mavorixafor in patients with WHIM syndrome, as assessed by AEs, clinical laboratory evaluations, vital signs, ECG assessments, and physical and ophthalmologic examinations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint analysis will compare the difference between mavorixafor and placebo with respect to the mean time above ANC threshold using MMRM analysis in the ITT Population. Time (in hours) above threshold will be calculated using a linear interpolation, such that the time between intervals where ANC values cross the threshold will be determined based on the slope between the 2 timepoints. |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints for Randomized period are:
1.AUCANC over 24 hours, calculated using the trapezoidal method
2.Infection rate based on infections adjudicated by a blinded, independent adjudication committee.
3. Vaccine titer levels at Week 52 in the Randomized Period in patients vaccinated at Week 13 with Tdap, including pertussis toxin and tetanus.
4.Change from baseline in cutaneous warts, based on dermatologist Clinical Global
Impression of Change (CGI-C).
5. Time to Early Release as confirmed by blinded independent AC.
6. Proportion of neutrophil responders, defined as patients with ANC above the 500 cells/μL threshold at least 50% of the time as well as ANC above threshold for the entire 24-hour period.
7. AUCANC over 24 hours, to be assessed by a within-group comparison to the clinicallymeaningful threshold of ≥500 cells/μL in the mavorixafor treatment group (where the 24-hour threshold AUC is calculated as 500 × 24).
8. Time (in hours) above ALC threshold over a 24-hour period, where the threshold is
defined as 1000 cells/μL
9. AUCALC over 24 hours, calculated using the trapezoidal method
10. Proportion of lymphocyte responders, defined as patients with baseline ALC below the lower limit of normal who achieve on-treatment ALC above the 1000 cells/μL threshold at least 50% of the time as well as ALC above threshold for the entire 24-hour period.
11. Absolute and fold change from baseline for total ALC, AMC, ANC, and WBC.
12. Wart severity based on dermatological assessment, Clinical Global Impression of Severity (CGI-S).
13.Infection characteristics (e.g., type of infection, duration of treatment, severity) as adjudicated by an independent AC.
14. Infection duration, defined as the time from the onset of symptoms to the last day of treatment or symptoms (whichever is last), as adjudicated by an independent AC.
15. Infection-free time
16. Number of days lost from work/school
17. Quality of Life
18. PK of mavorixafor in WHIM patients ≥12 years of age
The secondary efficacy endpoints for Open Label:
1. Vaccine titer levels during the first year of the Open-Label Period, in patients vaccinated with Tdap during the study, including pertussis toxin and tetanus.
2. Vaccine titer levels during the first year of the Open-Label Period for HPV 16 and HPV 18 in patients receiving vaccinations with HPV 9-valent vaccine, recombinant (Gardasil®9) during the study
3. Change from baseline in cutaneous warts, based on dermatologist Clinical Global
Impression of Change
4. Incidence of infection as adjudicated by an independent AC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Key secondary efficacy endpoints represent objectively defined, verifiable clinical outcomes. A hierarchical approach to formal statistical testing will be used, with the hierarchy planned in the order of presentation of secondary endpoints in Section 3.2.1. of the protocol. The ITT Population is the primary population for analysis. The 24-hour AUCANC will be calculated using the trapezoidal method and compared between treatment groups using similar methods as the primary endpoint. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
