Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency
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ClinicalTrials.gov Identifier: NCT03113760 |
Recruitment Status :
Recruiting
First Posted : April 14, 2017
Last Update Posted : June 7, 2021
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Condition or disease | Intervention/treatment | Phase |
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NLRC4-MAS XIAP Deficiency | Drug: Tadekinig alfa Other: 0.9% sodium chloride | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 10 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Initial phase of 18 weeks is a single arm, open-label (SAOL) period where Tadekinig alfa is administered in addition to the standard of care treatment used for the control of flares. The SAOL period will be followed by an 8-week randomized withdrawal phase (RW). All patients who completed the study without an ongoing flare at the end of the SAOL phase will be enrollled in the RW phase. In the RW phase patients will be randomized to either Tadekinig alfa or placebo. |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official Title: | Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal Trial With Tadekinig Alfa (r-hIL-18BP) in Patients With IL-18 Driven Monogenic Autoinflammatory Conditions: NLRC4 Mutation and XIAP Deficiency |
Actual Study Start Date : | July 21, 2017 |
Estimated Primary Completion Date : | May 30, 2022 |
Estimated Study Completion Date : | July 30, 2022 |

Arm | Intervention/treatment |
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Experimental: Tadekinig alfa
Patients that have completed the SAOL phase without a flare will receive Tadekinig alfa for addition 8 weeks.
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Drug: Tadekinig alfa
Tadekinig alfa is a soluble glycoprotein of 164 amino acids produced from Chinese Hamster Ovary cell line. Tadekinig alfa is supplied as a colorless to slightly yellow, sterile solution for injection in glass vials containing sodium chloride, and 0.02M sodium phosphate buffer as excipients. It is available in a concentration of 20mg/0.5mL.
Other Names:
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Placebo Comparator: 0.9% sodium chloride
Patients that have completed the SAOL phase without a flare will receive placebo comparator for addition 8 weeks.
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Other: 0.9% sodium chloride
To ensure that the treatment remains blinded for the entire study period, the placebo solutions will be supplied in identical vials and similar labelling as the active drug and will be indistinguishable in terms of their texture, color, and smell. |
- Prevention of flares [ Time Frame: 8 weeks ]
The primary endpoint is time to first occurrence of flare (time to flare) during the 8-week RW phase.
Method of assessment : Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.
- Flare rate [ Time Frame: 8 weeks ]Number of flares experienced per week while each subject is on study treatment during the RW phase
- Response to therapy/treatment failures [ Time Frame: 8 weeks ]Measured by the number of patients that do not respond to the combined treatment of standard of care with the study treatment during the RW phase
- Intensity of flares [ Time Frame: 8 weeks ]Intensity of flares (defined by the level of activity given by the mAIDAI)
- Serum CRP, Serum Ferritin [ Time Frame: 8 weeks ]Laboratory measure ug/mL for CRP, and ng/mL for Ferritin
- Improvement of fevers, improvement of hepato/splenomegaly [ Time Frame: 8 weeks ]Clinical assessments if present at Baseline
- Improvement in serum albumin and liver transaminases, anemia and/or platelet count [ Time Frame: 8 weeks ]Laboratory measures if present at Baseline
- Hospital length of stay [ Time Frame: 8 weeks ]Length of hospitalisation
- Change in Physician Global Assessment (PGA) [ Time Frame: 8 weeks ]Change from RW baseline to Week 26 in the PGA symptom severity score
- Change in mAIDAI score [ Time Frame: 8 weeks ]Change from RW baseline to week 26 (i.e. week 8 of the RW phase) in the mAIDAI total score
- Presence of skin rash - evolution if present at Baseline or appearance during the study [ Time Frame: 8 weeks ]Measured by the local tolerability index
- Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 8 weeks ]Measured by the kcal per day
- Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 8 weeks ]mL per 24hours
- Adverse events will be reported [ Time Frame: 26 weeks (SAOL + RW phases) ]Including AESI (Adverse Events of Special Interest)
- Physical examination findings and vital signs [ Time Frame: 26 weeks (SAOL + RW phases) ]Clinically significant changes from Baseline
- Laboratory assessments [ Time Frame: 26 weeks (SAOL + RW phases) ]Including clinically significant changes from Baseline in hematology with platelet counts, CRP, ESR, ferritin, fibrinogen, D-dimer, liver enzymes. (Followed until resolution)
- Immunogenicity evaluation [ Time Frame: 26 weeks (SAOL + RW phases) ]Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
- Local tolerability at the injection site [ Time Frame: 26 weeks (SAOL + RW phases) ]Evaluated by a standardized assessment

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Ages Eligible for Study: | Child, Adult, Older Adult |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
INCLUSION CRITERIA
- Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation) as confirmed by analysis performed at the central genetics laboratory. If possible, flow cytometry assay will be performed in parallel to confirm diagnosis of XIAP deficiency. (Note: Previous flow cytometry assay results will be permitted for confirmation of XIAP deficiency diagnosis.)
- Patients with XIAP deficiency and a previous bone marrow transplantation are allowed, if they show evidence of primary or secondary graft failure, or failure to achieve phenotypic correction with evidence of XIAP-related disease recurrence or clinically significant mixed chimerism.
- Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4
- Patients receiving stable doses of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti-rheumatic drugs (DMARDs), and/or IL-1 blockade for at least 2 weeks prior to enrollment are allowed into the study. Patients not receiving any of these treatments before start of therapy are also allowed.
- Women of childbearing potential with negative urine pregnancy test (UPT) at all visits (if UPT is positive, a blood test for human chorionic gonadotropin (hCG) to be performed) and who agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods considered highly effective are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence. In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of childbearing potential with infrequent or irregular menstrual cycles. A post-study contraception duration of 4 weeks is recommended taking into account the median half-life of Tadekinig alfa of almost 40h and 5 half-lives representing a duration of 200 hours.
EXCLUSION CRITERIA
- Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency
- Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology)
- Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy
- Presence of life threatening infections
- Oncologic causes of symptoms; current or previous history of malignancy
- Presence of CNS manifestations (i.e. seizures, altered mental status, signs of increased intracranial pressure, chronic papilledema, loss of vision, other sensorineural deficiencies, etc.)
- Patients suffering from biallelic mutations in any of the following genes: PRF1/Perforin, UNC13D/Munc 13-4, STX11/Syntaxin11, STXB2/Munc 18-2, RAB27A/Rab27a (Griscelli syndrome type 2), LYST (Chediak-Higashi syndrome), AP3B1, ADTB3A, HPS2 mutations (Hermansky-Pudlak syndrome 2) and X-linked lymphoproliferative syndrome (XLP)-1 with SH2D1A mutation
- Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods (see definition in Inclusion Criteria above) through 4 weeks after the end of their participation in the study
- Concomitant use of immunosuppression therapies excluded by the protocol. Note: NSAIDs, glucocorticoids, cyclosporine, tacrolimus, and IL-1 inhibitors (anakinra, canakinumab, or rilonacept, or others) are allowed
- Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent
- Hypersensitivity to the active substance or one of the excipients of the investigational product

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03113760
Contact: Eduardo Schiffrin, MD | +41 21 694 00 43 | eduardo.schiffrin@ab2bio.com | |
Contact: Friederike Stein, PhD | +41 21 694 00 40 | friederike.stein@ab2bio.com |
United States, California | |
UCSD _ Department of Pediatrics / Rady Children's Hospital | Recruiting |
La Jolla, California, United States, 92056 | |
Contact: Harold Hoffman, M.D. 858-966-1700 ext 3422 | |
United States, Florida | |
Shands Children's Hospital, University of Florida | Recruiting |
Gainesville, Florida, United States, 32610 | |
Contact: Akaluck Thatayatikom, MD | |
United States, Georgia | |
Children's Healthcare of Atlanta at Egleston | Recruiting |
Atlanta, Georgia, United States, 30322 | |
Contact: Shanmuganathan Chandrakasan, M.D. 404-727-8877 | |
United States, Massachusetts | |
Boston Children's Hospital | Recruiting |
Boston, Massachusetts, United States, 02115 | |
Contact: Fatma Dedeoglu, M.D. 617-355-6117 | |
United States, Ohio | |
Cincinnati Children's Hospital Medical Center | Recruiting |
Cincinnati, Ohio, United States, 45229 | |
Contact: Rebecca Marsh, M.D. 513-803-9063 | |
United States, Pennsylvania | |
Children Hospital of Philadelphia | Recruiting |
Philadelphia, Pennsylvania, United States, 19104 | |
Contact: Ed Behrens, M.D. 267-426-0142 behrens@email.chop.edu | |
United States, Texas | |
Texas Children's Hospital _ Baylor College of Medicine | Recruiting |
Houston, Texas, United States, 77030 | |
Contact: Lisa Forbes-Satter, M.D. 832-824-1319 | |
Canada, Ontario | |
The Hospital for Sick Children | Recruiting |
Toronto, Ontario, Canada, ON M5G 1X8 | |
Contact: Ronald Laxer, M.D. 416-813-5068 | |
Canada, Providence | |
CHU Sainte-Justine | Recruiting |
Montréal, Providence, Canada, QC H3T 1C5 | |
Contact: Fabien Touzot, MD 514-345-4931 | |
Germany | |
Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit | Recruiting |
Freiburg, Baden-Württemberg, Germany, 79106 | |
Contact: Stephan Ehl, MD 0049 761 270-7755 Stephan.ehl@uniklinik-freiburg.de |
Principal Investigator: | Ed M Behrens, MD | Children Hospital of Philadelphia |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | AB2 Bio Ltd. |
ClinicalTrials.gov Identifier: | NCT03113760 |
Other Study ID Numbers: |
NLRC4/XIAP.2016.001 |
First Posted: | April 14, 2017 Key Record Dates |
Last Update Posted: | June 7, 2021 |
Last Verified: | January 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Undecided |
Plan Description: | This information will be provided soon |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Lymphoproliferative Disorders Genetic Diseases, X-Linked Lymphatic Diseases |
Immunoproliferative Disorders Immune System Diseases Genetic Diseases, Inborn |