| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| 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. |
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| 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 participants 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 long-term safety and tolerability of mavorixafor in participants with WHIM syndrome.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objective for Randomized Period:
1. To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome as assessed by increasing levels of circulating lymphocytes compared with placebo and relative to a clinically meaningful threshold.
2. To demonstrate the clinical efficacy of mavorixafor in participants with WHIM syndrome as assessed by a composite endpoint of infections and warts.
3. To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome as assessed by improvement in warts.
4. To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome as assessed by reduction in infections.
Secondary Objective for Open-Label Period: To evaluate the long-term efficacy of mavorixafor in participants with WHIM syndrome. |
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| 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. 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.
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 participant has no clinical evidence of infection. Local laboratory may be used if central laboratory is not available.
a. If the ANC is below the lower limit of detection for the laboratory and the total WBC count is ≤ 400 cells/µL, then the participant is considered eligible for the study.
b. If the ANC is > 400 cells/µL in the context of a recent infection or inflammation prior to screening, it is acceptable to redraw a blood sample and confirm that the ANC meets inclusion criteria (≤ 400 cells/µL) once the infection or inflammatory episode is resolved.
c. If the participant experiences an infection or inflammatory episode between screening and baseline that may impact the ANC, or receives G-CSF between screening and baseline, the baseline visit may be postponed for up to 4 weeks until the ANC has been confirmed to be ≤ 400 cells/µL.
The Medical Monitor should be notified and approve each rescreen occurrence.
Inclusion criteria for Open-Label Period or
1. Completed the Randomized Placebo-Controlled Period.
2. Granted Early Release from the Randomized Placebo-Controlled Period.
3. Blind broken. |
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| 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 a known history of a positive serology or viral load for HIV or a known history of AIDS.
4. Has, at screening, laboratory tests meeting 1 or more of the following criteria:
− A positive hepatitis C virus antibody 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 participant tests negative for HBsAg, but positive for HBcAb, the participant would be considered eligible if the participant tests positive for hepatitis B surface antibody (also referred to as anti-HBsAg) on reflex testing.
5. Has, at screening, safety laboratory tests meeting 1 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)
6. Had surgery requiring general anesthesia within the 4 weeks prior to Day 1.
7. Received any of the following treatments:
− Plerixafor within 6 months prior to Day 1.
− Chronic or prophylactic use of antibiotics (systemic or inhaled) within 4 weeks prior to Day 1.
− Chronic or prophylactic use of G-CSF or granulocyte macrophage-colony stimulating factor within 2 weeks of Day 1.
− Chronic or prophylactic use of 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.
8. Is currently taking or has, within 2 weeks prior to Day 1, received any medication that is prohibited, based on potential for drug-drug interactions.
9. Has, at the planned initiation of study drug, a clinically diagnosed active infection (excluding warts), that has the potential to raise the ANC counts.
10. Has had a total splenectomy within 1 year.
11. Has a current diagnosis of myelofibrosis.
12. Has a medical history of hematological malignancies.
13. Has any other medical or personal condition, that 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.
14. Has corrected QT interval using Fridericia’s formula of > 450ms.
Note: Central results should be used for determination of screening laboratory values when possible. However, local laboratory analysis may be used if central laboratories are not available, or for unscheduled visits, repeated samples, or in place of central laboratory samples that could not be processed or were out of window.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint in Randomized Period: Time above threshold-absolute neutrophil count (TAT-ANC; in hours) of ≥ 500 cells/μL over a 24-hour period, assessed 4 times throughout the study (every 3 months for 12 months) for the Intent-to-Treat (ITT) Population.
Primary Endpoint in Open-Label Period: Safety and tolerability of mavorixafor in participants with WHIM syndrome, as assessed by adverse events (AEs), clinical laboratory evaluations, vital signs, electrocardiogram (ECG) assessments, and physical and ophthalmologic examinations. |
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| 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. |
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| E.5.2 | Secondary end point(s) |
The key secondary endpoints for Randomized period are:
1. Time above threshold-absolute lymphocyte count (TAT-ALC) of ≥ 1000 cells/μL over a 24-hour period assessed 4 times throughout the study (every 3 months for 12 months) in the ITT Population.
2. Composite Clinical Efficacy Endpoint for mavorixafor based on total infection score and total wart change score in the ITT Population.
3. Total wart change score for mavorixafor based on central blinded, independent review of 3 target skin regions in the ITT Population.
4. Total infection score for mavorixafor based on number and severity of infections adjudicated by a blinded, independent Adjudication Committee (AC) in the ITT Population.
Some of other secondary endpoints are:
1. Time to Early Release as confirmed by blinded independent AC in the ITT Population.
2. TAT-ALC of ≥ 1000 cells/μL in participants with lymphopenia at baseline.
3. Composite endpoint based on total infection score and total wart change score for participants with warts at baseline or participants with non-Ig use.
4. Total infection score based on infections adjudicated by a blinded, independent AC for participants with non-Ig use.
5. Total wart change score (Clinical Global Impression of Change [CGI-C]) based on blinded central review of 3 target skin regions for participants with warts at baseline.
6. Total wart change score (CGI-C) based on local dermatologist review of all regions for participants with warts at baseline.
7. Patient Global Impression of Change (PGI-C) from baseline.
8. Patient Global Impression of Severity (PGI-S) during treatment.
9. Vaccine titer levels at Week 52 in the Randomized Placebo-Controlled Period in all participants vaccinated at Week 13 with tetanus, diphtheria, and pertussis vaccine (Tdap), including pertussis toxin and tetanus.
10. Vaccine titer levels at Week 52 in the Randomized Placebo-Controlled Period for human papillomavirus (HPV) 16 and HPV 18 in all participants receiving vaccinations with HPV 9-valent vaccine, recombinant (Gardasil®9) during the study.
11. Change from baseline in wart severity based on local dermatological assessment (all regions) and central dermatological assessment (3 target skin regions) as determined by the Clinical Global Impression of Severity (CGI-S) for participants with warts at baseline and the ITT Population.
12. Infection characteristics (eg, type of infection, duration of treatment, severity) by treatment group as adjudicated by an independent AC.
13. Infection-free time by treatment group.
14. Number of days lost from work/school by treatment group.
15. Quality of life by treatment group as measured by the 36-Item Short Form Survey and EQ-5D-5L, Life Quality Index, for all participants.
16. Quality of life by treatment group as measured by The Dermatology Life Quality Index.
17. Quality of life by treatment group in adolescent participants as measured by the Pediatric Quality of Life Inventory.
18. Change from baseline in anogenital (AG) warts, based on dermatologist CGI-C and AG wart severity assessment, in participants with AG evaluation.
19. Frequency of events requiring rescue treatment due to infection.
20. Incidence, frequency, and duration of hospitalizations due to infections.
21. Incidence of newly developed warts.
22. Area under the curve for absolute neutrophil count (AUCANC) over 24 hours, calculated using the trapezoidal method.
23. Proportion of neutrophil responders, defined as participants with ANC ≥ 500 cells/μL threshold at least 50% of the time, as well as ANC above threshold for the entire 24-hour period.
24. AUCANC over 24 hours, to be assessed by a within-group comparison with the clinically meaningful threshold of ≥ 500 cells/μL in the mavorixafor treatment group (where the 24-hour threshold area under curve is calculated as 500 × 24).
The secondary efficacy endpoints for Open Label:
1. Proportion of neutrophil responders, defined as participants with ANC ≥ 500 cells/μL threshold.
2. Proportion of lymphocyte responders, defined as participants with baseline ALC below the lower limit of normal who achieve on-treatment ALC ≥ 1000 cells/µL threshold.
3. Absolute and fold change from baseline for total ALC, AMC, ANC, and WBC count.
4. Vaccine titer levels during the Open-Label Period, in all participants vaccinated with Tdap during the study, including pertussis toxin and tetanus.
5. Vaccine titer levels during 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
6. Change from baseline in cutaneous warts, based on central review of CGI-C and CGI-S.
7. Change from baseline in cutaneous warts, based on local dermatologist review of CGI-C and CGI-S.
8. Change over time in PGI S and PGI C.
9. Total infection score as adjudicated by an independent AC |
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| 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. 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. |
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| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Israel |
| Korea, Republic of |
| United States |
| Russian Federation |
| Austria |
| Denmark |
| France |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
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| 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
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| 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 |
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