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JAK Inhibitor Treatment in AGS

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ClinicalTrials.gov Identifier: NCT03921554
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : September 17, 2019
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Adeline Vanderver, MD, Children's Hospital of Philadelphia

Tracking Information
First Submitted Date  ICMJE April 3, 2019
First Posted Date  ICMJE April 19, 2019
Last Update Posted Date September 17, 2019
Actual Study Start Date  ICMJE June 3, 2019
Estimated Primary Completion Date June 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
Measurement of change with AGS scale for Cohort B [ Time Frame: 52 weeks ]
The primary objective is to determine if the administration of baricitinib to patients with AGS results in a change or stability of the AGS scale at baseline for Cohort B at 52 weeks. Results will be matched to historical controls by propensity matching. The AGS scale is a neurologic scale used to evaluate neurologic function of patients under treatment. The scale includes items for head circumference and developmental milestones. A lower score suggests a worse outcome. The range of scores is from 0 (most severe) to 11 (least severe). In addition, longitudinal changes will be evaluated, based on measurements collected at baseline, 1 month, 3 months, and every 3 months post-baseline for up to 288 weeks.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03921554 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
  • Measurement of change with AGS scale for Cohort A and C [ Time Frame: 52 weeks ]
    Secondary objectives will determine if the administration of baricitinib to patients with AGS results in a change or stability of the AGS scale at baseline for Cohort A at 52 weeks, or in the GMFM-88 in Cohort C. Results will be matched to historical controls by propensity matching. The AGS scale is a scale used to evaluate neurologic function of patients under treatment. The scale includes items for head circumference and developmental milestones. A lower score suggests a worse outcome. The range of scores is from 0 (most severe) to 11 (least severe). The Gross Motor Function Measure-88 (GMFM-88) assessment tool include 88 items, each receiving a score from 0 to 3 (0 = does not initiate; 1 = initiates; 2 = partially completes; 3 = completes). Items span the spectrum of gross motor activities in five dimensions: A: Lying and Rolling (17 items), B: Sitting (20 items), C: Crawling and Kneeling (14 items), D: Standing (13 items), E: Walking, Runni
  • Measurement of interferon signaling scores [ Time Frame: 52 weeks ]
    Interferon signature scores (IFN Scores) are based on the mRNA expression of six type I IFN (Interferon)-inducible genes. Scores are derived from blood sampling, which will occur every three months. IFN scores are elevated in the AGS population and not elevated in healthy controls. The scale has not been published yet but it is hypothesized that a lower value in IFN score reflects a better outcome.
  • Gross Motor Function Measure-88 (GMFM-88) [ Time Frame: 52 weeks ]
    This assessment tool include 88 items, each receiving a score from 0 to 3 (0 = does not initiate; 1 = initiates; 2 = partially completes; 3 = completes). Items span the spectrum of gross motor activities in five dimensions: A: Lying and Rolling (17 items), B: Sitting (20 items), C: Crawling and Kneeling (14 items), D: Standing (13 items), E: Walking, Running, Jumping (24 items). Every dimension score is expressed with a percentage. GMFM-88 will be performed every 6 months.
  • Functional measures of neurologic disability [ Time Frame: 52 weeks ]
    The AGS scale is a neurologic scale used to evaluate neurologic function of patients under treatment. The scale includes items for head circumference and developmental milestones. A lower score suggests a worse outcome. The range of scores is from 0 (most severe) to 11 (least severe).
  • Measurement of disease severity assessed by daily diary disease severity scale [ Time Frame: 52 weeks ]
    The diary disease severity scale is a daily survey that caregivers can fill based on the child's clinical condition during the day, and includes items such as uninterrupted sleep, irritability, or skin involvement. This scale has not been published yet but it is hypothesized that a lower value will represent a better outcome.
  • Monitoring of clinically significant clinical laboratory abnormalities: hemoglobin (g/dL) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: hematocrit (%) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: platelets (K/uL) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: aspartate aminotransferase (U/L) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: alanine aminotransferase (U/L) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: gamma glutamyl transferase (U/L) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: alkaline phosphatase (U/L) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: Creatinine kinase (U/L) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: Cholesterol (mg/dL) [ Time Frame: 52 weeks ]
  • Monitoring of clinically significant clinical laboratory abnormalities: low density lipo protein (mg/dL) [ Time Frame: 52 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE JAK Inhibitor Treatment in AGS
Official Title  ICMJE Janus Kinase Inhibitor (Baricitinib) for Aicardi Goutières Syndrome
Brief Summary The primary objective of this study is to assess safety as well as efficacy of baricitinib, a Nanus Kinase (JAK) inhibitor, in patients with Aicardi Goutières Syndrome (AGS), a multisystem heritable disorder of the innate immunity resulting in excessive interferon production
Detailed Description

Aicardi Goutières Syndrome (AGS) is a multisystem heritable disorder of the innate immunity resulting in excessive interferon production. Most characteristically, AGS manifests as an early-onset encephalopathy that results in severe intellectual and physical handicap. Interferon is thought to cause injury not only to the brain, but also the skin, liver, lungs, heart and many other organs. Treatment with Janus Kinase (JAK) inhibitors offers the promise of decreasing interferon signaling and limiting the morbidity of this devastating disorder.

The primary objective is to assess safety as well as efficacy of baricitinib, a JAK inhibitor, in patients with Aicardi Goutières Syndrome. Efficacy will be determined primarily by changes in the AGS scale or GMFM-88 depending on baseline motor function of each subject.

The secondary objectives include assessments of safety parameters, and of therapeutic exploratory endpoints including an AGS symptom diary score, a surrogate biomarker, the interferon signaling gene score, and of functional neurologic measures.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Aicardi Goutieres Syndrome
Intervention  ICMJE Drug: Baricitinib
Baricitinib will be taken by mouth as directed by the study doctor. Baricitinib will be dosed by patient age, weight range and estimated glomerular filtration rate (eGFR). Dosing formulations in use in this study will be limited to the 2 mg tablet and will be used without splitting. Dispersion will be permitted to aid in swallowing.
Study Arms  ICMJE Experimental: Aicardi Goutières Syndrome patients receiving Baricitinib
Baricitinib will be taken by mouth as directed by the study doctor. Baricitinib will be dosed by patient age, weight range and estimated glomerular filtration rate (eGFR). Dosing formulations in use in this study will be limited to the 2 mg tablet and will be used without splitting. Dispersion will be permitted to aid in swallowing.
Intervention: Drug: Baricitinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 6, 2019)
100
Original Estimated Enrollment  ICMJE
 (submitted: April 16, 2019)
50
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date June 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Clinical or molecular identification of Aicardi Goutières Syndrome including the following features

    • Cerebrospinal fluid (CSF) or blood markers suggesting elevations of markers of interferon activation including CSF pleocytosis, elevation of interferon, and/or neopterin and tetrahydrobiopterin elevations
    • Evidence of neurologic disease on neuroimaging including intracranial calcifications and or a leukoencephalopathy
    • Clinical features of disease including features such as microcephaly, subacute encephalopathy, myopathy, spastic diplegia, skin involvement, autoimmune hepatitis, hematologic abnormalities
    • OR have documented mutations felt to be pathogenic in an AGS associate gene.
  • ≥6 months of age.
  • ≥8.5 kg in body weight.
  • Lack of features excluding safe use of baricitinib
  • Females after menarche must have a negative urine/serum pregnancy test and must use an acceptable method of contraception if neurologically appropriate, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study. If the Data Safety Monitoring Board (DSMB) determines that the neurologic function of the child is incompatible with the need for contraception, this will not be considered a protocol violation.
  • Parental/guardian permission (informed consent).

Exclusion Criteria:

  • Have received an immunosuppressive biologic agent/monoclonal antibody within 4 half-lives prior to entry, for example, anakinra (4 half- lives=18 hours); etanercept (4 half-lives=18 days); infliximab; or adalimumab (4 half-lives=36 days). Use of intravenous immune globulin (IVIg) is permitted. Exceptions may be considered after discussion with the DSMB.
  • Pregnant or nursing at the time of entry
  • Females of childbearing potential (women >12 or who have had at least one menstrual period regardless of age) who are sexually active and who do not agree to use 2 forms of highly effective methods of birth control (see below) or remain abstinent during the study and for at least 28 days following the last dose of investigational product
  • Sexually active males who do not agree to use 2 forms of highly effective birth control (see below) with female partners of childbearing potential or remain abstinent during the study and for at least 28 days following the last dose of investigational product.
  • Each of the following is considered a single highly effective method of birth control (the patient should choose 2):

    • oral, injectable, or implanted hormonal contraceptives
    • condom with spermicidal foam/gel/film/cream/suppository
    • occlusive cap (diaphragm or cervical/vault caps) with spermicidal
    • foam/gel/film/cream/suppository
    • intrauterine device
    • intrauterine system (for example, progestin releasing coil)
    • vasectomized male (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate)
  • Symptomatic herpes zoster infection within 12 weeks prior to entry or during the screening period
  • Overall health status that in the opinion of the investigator limits the safety of the use of bariticinib
  • Ongoing or incompletely treated severe or systemic infection, excluding cellulitis/osteomyelitis that is felt to be attributable to AGS
  • Have been exposed to a live vaccine within 12 weeks prior to entry or are expected to need/receive a live vaccine (including herpes zoster vaccination) during the course of the study, with the exception of oral rotavirus vaccinations for which the time period is 2 weeks. Young patients who are not yet vaccinated and will be unable to receive live vaccines while they are receiving the program drug (baricitinib) may be included after discussion with the DSMB (see vaccination plan) and a documented conversation of the medical monitor with the parents to ensure parental consent and understanding of the risk/benefit ratio of not receiving scheduled vaccinations.
  • Have an estimated glomerular filtration rate (eGFR) based on the most recent available serum creatinine of <40 mL/min/1.73 m2 if greater than 2 year of age. eGFR will be calculated using the Bedside Schwartz Equation: eGFR (mL/min/1.73 m2) = (0.413 x height) / SCr, with height measured in cm, and serum creatinine (SCr) in units of mg/dL. Subjects with clearance of < 30 mL/min/1.73 m2 of any age will not be enrolled per the FDA label.
  • Have any of the following specific abnormalities on screening laboratory tests:

    • Hemoglobin <10 g/dL (100 g/L) unless the anemia is considered a result of the underlying disease (see below) or age appropriate.
    • Total WBC count <2500 cells/µL unless the low white blood cell (WBC) count is considered a result of the underlying disease (see below).
    • Neutropenia {absolute neutrophil count (ANC)] <1200 cells/µL) unless the low ANC is considered a result of the underlying disease (see below).
    • Thrombocytopenia (platelets <100,000/µL) unless the low platelet count is considered a result of the underlying disease (see below).
    • eGFR <40 mL/min/1.73 m2 unless <24 months in which case discussion with the DSMB to establish if eGFR is age appropriate; subjects with clearance of < 30 mL/min/1.73 m2 of any age will not be enrolled per the FDA label.
  • History of disseminated/complicated herpes zoster (for example, multidermatomal involvement, ophthalmic zoster, central nervous system involvement, postherpetic neuralgia)
  • Evidence of active infection, at the time of entry or during the screening period, that in the opinion of the investigator, would pose an unacceptable risk for participating in the study
  • History of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
  • Have had household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB
  • Have or have had a history of lymphoproliferative disease; or signs or symptoms suggestive of possible lymphoproliferative disease, or active primary or recurrent malignant disease; or been in remission from clinically significant malignancy for <5 years
  • EKG or echocardiogram results that in the consideration of the investigator places them at greater risk for participation in the study
  • Unable or unwilling to make themselves available for the duration of the study and/or are unwilling to follow study restrictions/procedures
  • Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Adeline Vanderver, MD 215-590-1719 vandervera@email.chop.edu
Contact: Laura Adang, MD, PhD adangl@email.chop.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03921554
Other Study ID Numbers  ICMJE 18-015414
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Adeline Vanderver, MD, Children's Hospital of Philadelphia
Study Sponsor  ICMJE Adeline Vanderver, MD
Collaborators  ICMJE Eli Lilly and Company
Investigators  ICMJE
Principal Investigator: Adeline Vanderver, MD Children's Hospital of Philadelphia
PRS Account Children's Hospital of Philadelphia
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP