JAK Inhibitor Treatment in AGS

Phase 2

Completed

Conditions: Aicardi Goutieres Syndrome

Interventions: Drug: Baricitinib

Registration Number: NCT03921554

Lead Sponsor: Adeline Vanderver, MD

Brief Summary: 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

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 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

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 eGFR <40 ml/min/1.73 m2 is common in infants <3-6 months.
- The creatinine should be measured using the Isotopic Dilution Mass Spectrometry (IDMS) 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 cluster of differentiation 3/ cluster of differentiation 4 (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
Have 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 American Heart Association (AHA) guidelines, an left ventricle ejection factor (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; 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 echocardiogram results that, in the opinion of the investigator, places them at greater risk if included 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 intravenous immune globulin (IVIg) is permitted.
Have received or be currently treated with Bacillus Calmette-Guerin (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 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 chest x-ray (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 latent tuberculosis infection (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.
- Taking a concomitant medication on the list of exclusion criteria (please consult study team as needed).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Aicardi Goutières Syndrome patients receiving Baricitinib	Baricitinib	Baricitinib will be taken by mouth or via gastrostomy feeding tube or nasogastric tube 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 include 1 mg and 2 mg tablets and will be used without splitting. Dispersion will be permitted to aid in swallowing.

Primary Outcome Measures

Name	Time	Method
Mean and Standard Deviation (SD) of the AGS Scale at 52 Weeks	52 weeks	The primary objective is to determine if the administration of baricitinib to participants with Aicardi-Goutières Syndrome (AGS) results in a change or stability of the AGS scale from baseline to 52 weeks. The AGS scale is a neurologic scale used to evaluate neurologic function of participants 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).

Secondary Outcome Measures

Name	Time	Method
Improvement of the AGS Scale From Screening to Treatment Over Time	All longitudinal values are included. ASG scores were observed from 578 days (on some patients) before treatment to 2383 days after treatment start (on some patients). At visit 215 (with median treatment days = 673), the mean AGS score was 6.2 (SD = 3.5).	The AGS scale is a neurologic scale used to evaluate neurologic function of participants 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). Longitudinal changes are evaluated, based on measurements collected at baseline, 1 month, 3 months, and every 3 months post-baseline for up to 288 weeks. Participants who transferred from the compassionate use study started treatment under the compassionate use study, which was initiated in 2016. AGS scores were assessed retrospectively for study visits completed under the compassionate use study, based on the study visit notes. The Outcome Measure Time Frame for these subjects may therefore be longer than the study duration specified in the Protocol Section of this study record, as the total time of treatment between the two studies they participated in is longer.
Improvement of the GMFM-88 Between Screening and Treatment Over Time	52 weeks	The Gross Motor Function Measure-88 (GMFM-88) assessment tool includes 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. All dimension scores are then averaged to a total GMFM-88 percentage score, which is an estimate of the participant's gross motor function (0 = low motor function; 100 = high motor function). GMFM-88 is performed every 6 months.
Change in Interferon Signaling Gene (ISG) Score Between Screening and Treatment Over Time	All longitudinal values are included. ISG scores were observed from 431 days before treatment to 2383 days after treatment start. At first on treatment visit (median treatment days = 3), the mean ISG score was 14.4 z-score (Standard Deviation = 12.8).	Interferon (IFN) scores are based on the messenger ribonucleic acid (mRNA) expression of six type I IFN signaling genes (ISG) and represent a surrogate marker for autoinflammation in AGS. Scores are derived from blood sampling, which occurs every three months. ISG 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 ISG score reflects a better outcome. Participants who transferred from the compassionate use study started treatment under the compassionate use study, which was initiated in 2016. ISG scores were measured from samples collected under the compassionate use study. The Outcome Measure Time Frame for these subjects may therefore be longer than the study duration specified in the Protocol Section of this study record, as the total time of treatment between the two studies they participated in is longer.
Measurement of Disease Severity Assessed by Daily Diary Disease Severity Scale	All longitudinal values are included. Diary scores were observed from 117 days before treatment to 2476 days after treatment start. At visit 210 (median treatment days = 335), the mean diary average score was 1.2 (SD = 0.4).	The diary disease severity scale is a daily survey that caregivers complete based on the participant's clinical condition during the day and includes items such as uninterrupted sleep, irritability, or skin involvement. Each item is scored from 0 to 4 (0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = more severe symptoms; 4 = severe symptoms). All item scores are then averaged to obtain a total diary score. Participants who transferred from the compassionate use study started treatment under the compassionate use study, which was initiated in 2016. Diaries were already completed and diary scores calculated under the compassionate use study. The Outcome Measure Time Frame for these subjects may therefore be longer than the study duration specified in the Protocol Section of this study record, as the total time of treatment between the two studies they participated in is longer.