JAK Inhibitor Treatment in AGS
JAK Inhibitor Treatment in AGS
The primary objective of this study is to assess safety as well as efficacy of baricitinib, a
 Janus Kinase (JAK) inhibitor, in patients with Aicardi Goutières Syndrome (AGS), a
 multisystem heritable disorder of the innate immunity resulting in excessive interferon
 production
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 determine if the administration of baricitinib to patients with
 AGS results in an improvement or stability of the AGS scale at baseline at 52 weeks.

 Secondary objectives will include longitudinal stability of safety measures, improvement of
 interferon signaling scores, improvement of GMFM-88 and functional measures of neurologic
 disability, and improvement of a daily disease severity scale, for the duration of the
 treatment period.
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 associated gene.

 -  Are ≥1 month of age.

 -  Are ≥4.5 kg in body weight.

 -  Females after menarche must have a negative urine/serum pregnancy test and must use an
 acceptable method of contraception, including abstinence, a barrier method (diaphragm
 or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.

 -  Parental/guardian permission (informed consent).

 Exclusion Criteria:

 -  Are pregnant or nursing at the time of entry or unable to use contraception as
 detailed below

 -  Are 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

 -  Are 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)

 -  Overall health status that in the opinion of the investigator limits the safety of the
 use of bariticinib

 -  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 a documented conversation by a physician not affiliated with the study or the
 medical monitor with the parents to ensure parental consent and understanding of the
 risk/benefit ratio of not receiving scheduled vaccinations. These subjects will only
 be included in the study after a physician obtaining consent also describes the
 risk/benefit ratio of not receiving scheduled vaccinations.

 -  Have the following evidence of renal insufficiency:

 -  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.

 -  Children with an eGFR of <40 mL/min/1.73 m2 will not be enrolled, unless <24
 months of age in which case a cut off of <30 ml/min/1.73 m2 will be used due to
 age-based differences in normal eGFR. Normal eGFR of <60 ml/min/1.73 m2 is common
 in children <12 months, and a normal eFGR <40 ml/min/1.73 m2 is common in infants
 <3-6 months.

 -  The creatinine should be measured using the IDMS (Isotopic Dilution Mass
 Spectrometry) technique to monitor the eGFR if available. Other methods are
 allowed but are not preferred. Laboratory testing using other methods will not be
 used to monitor the eGFR.

 -  Have any of the following specific Hematologic abnormalities on screening laboratory
 tests:

 -  Hemoglobin <7 mg/dL (70 g/L). In infants <2 mo of age, 8 mg/dL will be used as a
 threshold

 -  Neutropenia (absolute neutrophil count [ANC] <500 cells/µL)

 -  CD4 <250 cell/µl on lymphocyte subset testing (where Absolute CD4 count=Absolute
 CD3/CD4 count=CD3/CD4 count=CD4 count=Absolute CD3+CD4+ cells)

 -  Thrombocytopenia (platelets <30,000/µL). Patients who are on anticoagulation or
 having a history of life-threatening bleeding should be excluded if platelet
 count is <50,000/µL

 -  Have any of the following infectious risks:

 -  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

 -  Ongoing or incompletely treated severe or systemic infection, excluding
 cellulitis/osteomyelitis that is felt to be attributable to AGS

 -  Have had symptomatic herpes zoster infection within 12 weeks prior to entry or
 during the screening period

 -  Have a history of disseminated/complicated herpes zoster (for example,
 multidermatomal involvement, central nervous system involvement or systemic
 involvement including hepatitis or pneumonitis)

 -  Have a 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

 -  Have liver abnormalities consistent with severe, chronic liver disease

 -  ECG or echocardiogram results that include an arrhythmia unamenable to standard
 treatment, severe pulmonary hypertension, severe heart valvular (greater than mild
 insufficiency or stenosis), or significant left heart failure (Per AHA guidelines, an
 LVEF <50% is considered impaired) or right heart failure (RV function described as
 qualitatively more than mildly diminished systolic function), that in the
 consideration of the investigator places them at greater risk for participation in the
 study

 -  Are unable or unwilling to make themselves available for the duration of the study
 and/or are unwilling to follow study restrictions/procedures

 -  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 is not
 indicated in subjects receiving Natalizumab, Nivolumab, Trastuzumab, Denosumab, and
 Belimumab. Use of IVIg is permitted.

 -  Have received or be currently treated with BCG (Intravesical), Cladribine, Dipyrone,
 Pimecrolimus, and Tacrolimus (Topical).

 -  Are 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.

 -  Have screening laboratory test values outside the reference range for the population
 or investigative site that, in the opinion of the investigator, pose an unacceptable
 risk for the patient's participation in the study and are not attributable to AGS

 -  Have screening thyroid-stimulating hormone and/or thyroxine values outside of the
 laboratory's reference range and are assessed to be clinically significant. If results
 are available from testing within 1 month, then the patient will not have to be
 retested. Patients who are receiving thyroxine as replacement therapy may participate
 in the study provided stable therapy has been administered.

 -  Have screening electrocardiogram (ECG) abnormalities that, in the opinion of the
 investigator, are clinically significant and indicate an unacceptable risk for the
 patient's participation in the study (for example, Bazett's corrected QT interval >450
 msec for males and >470 msec for females).

 -  Have evidence of active or latent TB as documented by a positive purified protein
 derivative (PPD) test (≥5 mm induration between approximately 2 and 3 days after
 application, regardless of vaccination history), medical history, and chest x-ray at
 screening. The patient may also have a QuantiFERON®-TB Gold test. If the test is
 positive or indeterminate, the patient may undergo evaluation including a CXR and PPD
 and assessed for likely risk of active tuberculosis infection. In infants < 12 months
 of age, maternal and paternal testing can be used instead of testing the patient. Risk
 for TB will also be assessed using validated questions from The Red Book: Report of
 the Committee on Infectious Diseases (see below).

 Validated Questions for Determining Risk of LTBI in Children in the United States

 -  Has a family member or contact had tuberculosis disease?

 -  Has a family member had a positive tuberculin skin test result?

 -  Was your child born in a high-risk country (countries other than the United States,
 Canada, Australia, New Zealand, or Western and North European countries)?

 -  Has your child traveled to a high-risk country? How much contact did your child have
 with the resident population?

 -  Have a positive test for hepatitis B defined as (1) positive for hepatitis B
 surface antigen, or (2) positive for anti-hepatitis B core antibody, but negative
 for hepatitis B surface antibody (unless the anti-hepatitis B core antibody is
 thought to be a false positive result). In the latter case, confirmation of the
 presence of hepatitis B virus (HBV) by DNA testing is required. An HBV DNA
 indeterminate result is considered HBV infection. If results are available from
 testing within the previous 3 months, then the patient will not have to be
 retested: If any of the hepatitis B tests have an indeterminate result,
 confirmatory testing will be performed by an alternate method. In infants < 3
 months of age, maternal testing can be used instead of testing the patient.

 -  Have hepatitis C virus (positive for anti-hepatitis C antibody with confirmed
 presence of hepatitis C virus);

 -  Have evidence of HIV infection and/or positive HIV antibodies. If results are
 available from testing within the previous 3 months, then the patient will not
 have to be retested. In infants < 12 months of age, maternal testing can be used
 instead of testing the patient.

 -  Have HIV virus. In infants <12 months of age, maternal testing can be used
 instead of testing the patient.

 -  ECG or echocardiogram results that in the opinion of the investigator places them
 at greater risk if included in the study.

 -  Taking a concomitant medication on the list of exclusion criteria (please consult
 study team as needed).