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Recruiting Studies | nlrc4
Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency
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| ClinicalTrials.gov Identifier: NCT03113760 |
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Recruitment Status :
Recruiting
First Posted : April 14, 2017
Last Update Posted : April 9, 2018
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Sponsor:
AB2 Bio Ltd.
Information provided by (Responsible Party):
AB2 Bio Ltd.
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Brief Summary:
This is a Phase 3 study to assess the safety and efficacy of Tadekinig alfa in patients with monogenic, interleukin-18 (IL 18) driven autoinflammation due to Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruiting domain (CARD domain) containing 4 (NLRC4) - Macrophage activation syndrome (MAS) mutation (NLRC4-MAS mutation) or X-linked inhibitor of apoptosis (XIAP) deficiency. Because of the likelihood for pathogenic IL-18 in certain monogenic diseases, patients known to harbor deleterious mutations in NLRC4-MAS or XIAP and who have a history of ongoing inflammation will be enrolled if they have ferritin ≥ 500 ng/mL or persistent C reactive protein (CRP) elevation > 2 times the upper limit of normal (ULN) and the patients should have a Modified Autoinflammatory Disease Activity Index (mAIDAI) ≥ 4.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| NLRC4-MAS XIAP Deficiency | Drug: Tadekinig alfa Drug: Placebo | Phase 3 |
The study is designed with a Randomized Double-Blind Placebo-Controlled (RDBPC) 18-week treatment phase, followed by an 8-week Randomized Withdrawal (RW) period for further efficacy and safety evaluation, with no interruption between the two phases of treatment.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 10 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | Multicenter, Randomized, Double-blind, Placebo-controlled Trial With Tadekinig Alfa (r-hIL-18BP) in Patients With IL-18 Driven Monogenic Auto Inflammatory Conditions: NLRC4 Mutation and XIAP Deficiency |
| Actual Study Start Date : | July 21, 2017 |
| Estimated Primary Completion Date : | May 2019 |
| Estimated Study Completion Date : | December 2019 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Tadekinig alfa
Eligible subjects will be randomised to receive either Tadekinig alfa in addition of standard of care during 18 weeks of the Randomised Double Blind Placebo Control (RDBPC) phase, followed by an 8 weeks treatment in the Randomised Withdrawal (RW) phase.
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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: Placebo
Eligible subjects will be randomised to receive the placebo in addition of standard of care, in this double blind study, during 18 weeks of the Randomised Double Blind Placebo Control (RDBPC) phase, followed by an 8 weeks treatment in the Randomised Withdrawal (RW) phase.
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Drug: Placebo
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. |
Primary Outcome Measures :
- Incidence rate of flares [ Time Frame: 18 weeks ]
The primary outcome is the incidence rate of flares (number of flares over the 18-week treatment RDBPC phase) corrected for duration of treatment.
Method of assessment : Biomarkers (CRP / Ferritin) and clinical manifestations of inflammation.
Secondary Outcome Measures :
- Time to flare [ Time Frame: 26 weeks ]measured by the time spent from the resolution of the initial flare to the reactivation of the disease
- Intensity of flares [ Time Frame: 26 weeks ]Defined by the level of activity given by biomarkers and clinical manifestations
- Treatment failures [ Time Frame: 26 weeks ]Measured by the number of patients that do not respond to the combined treatment of standard of care with the study treatment
- Serum CRP, Serum Ferritin [ Time Frame: 26 weeks ]Laboratory measure ug/mL for CRP, and ng/mL for Ferritin
- Improvement of fevers, improvement of hepato/splenomegaly [ Time Frame: 26 weeks ]Clinical assessments if present at Baseline
- Improvement in serum albumin and liver transaminases, anemia and/or platelet count [ Time Frame: 26 weeks ]Laboratory measures if present at Baseline
- Hospital length of stay [ Time Frame: 26 weeks ]Length of hospitalisation
- Physician Global Assessment [ Time Frame: 26 weeks ]Measured through a scale 0 to 10
- Presence of skin rash - evolution if present at Baseline or appearance during the study [ Time Frame: 26 weeks ]Measured by the local tolerability index
- Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 26 weeks ]Measured by the kcal per day
- Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline [ Time Frame: 26 weeks ]mL per 24hours
- Adverse events will be reported [ Time Frame: 26 weeks ]Including AESI (Adverse Events of Special Interest)
- Physical examination findings and vital signs [ Time Frame: 26 weeks ]Clinically significant changes from Baseline
- Laboratory assessments [ Time Frame: 26 weeks ]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 ]Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
- Local tolerability at the injection site [ Time Frame: 26 weeks ]Evaluated by a standardized assessment
Information from the National Library of Medicine
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| Ages Eligible for Study: | up to 17 Years (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
INCLUSION CRITERIA
- Patients ≤ 17 years of age
- Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation)
- 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
EXCLUSION CRITERIA
- Patients > 17 years of age
- 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
- Patients suffering from familial hemophagocytic lymphohistiocytosis (f HLH)
- Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods
- Concomitant use of immunosuppression therapies excluded by the protocol.
- Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent
Information from the National Library of Medicine
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
Contacts
| Contact: Eduardo Schiffrin, MD | +41 21 694 00 43 | eduardo.schiffrin@ab2bio.com | |
| Contact: Lalla Myriam Mercier-Lamrani, MBA | +41 21 694 00 47 | myriam.mercier@ab2bio.com |
Locations
| United States, Alabama | |
| Children's of Alabama (CoA) | Not yet recruiting |
| Birmingham, Alabama, United States, 35233 | |
| Contact: Randy Cron, Dr. 205-996-7584 | |
| United States, California | |
| UCSD _ Department of Pediatrics / Rady Children's Hospital | Recruiting |
| La Jolla, California, United States, 92056 | |
| Contact: Harold Hoffman, Dr. | |
| United States, Massachusetts | |
| Boston Children's Hospital | Not yet recruiting |
| Boston, Massachusetts, United States, 02115 | |
| Contact: Fatma Dedeoglu, Dr. 617-355-6117 | |
| United States, Ohio | |
| Cincinnati Children's Hospital Medical Center | Recruiting |
| Cincinnati, Ohio, United States, 45229 | |
| Contact: Rebecca Marsh, Dr. 513-803-9063 | |
| United States, Pennsylvania | |
| Children Hospital of Philadelphia | Recruiting |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Contact: Ed Behrens, Dr. | |
| Children's Hospital of Pittsburgh of UPMC | Recruiting |
| Pittsburgh, Pennsylvania, United States, 15224 | |
| Contact: Scott Canna, Dr. 412-692-9934 | |
| United States, Texas | |
| Texas Children's Hospital _ Baylor College of Medicine | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Lisa Forbes, Dr. 832-824-1319 | |
| Canada | |
| CHU Sainte-Justine | Recruiting |
| Montréal, Canada | |
| Contact: Julie Barsalou, MD 514-345-4931 | |
Sponsors and Collaborators
AB2 Bio Ltd.
Investigators
| Principal Investigator: | Eduard Behrens, MD | Children Hospital of Philadelphia |
Additional Information:
| Responsible Party: | AB2 Bio Ltd. |
| ClinicalTrials.gov Identifier: | NCT03113760 History of Changes |
| Other Study ID Numbers: |
NLRC4/XIAP.2016.001 |
| First Posted: | April 14, 2017 Key Record Dates |
| Last Update Posted: | April 9, 2018 |
| Last Verified: | April 2018 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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 | |
Additional relevant MeSH terms:
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Lymphoproliferative Disorders Genetic Diseases, X-Linked Lymphatic Diseases |
Immunoproliferative Disorders Immune System Diseases Genetic Diseases, Inborn |